International Journal of Molecular Sciences

17 pages, 906 KiB

Open AccessReview

Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension

by Natalia Muñoz-Durango^1,†, Cristóbal A. Fuentes^2,†, Andrés E. Castillo², Luis Martín González-Gómez², Andrea Vecchiola², Carlos E. Fardella^2,* and Alexis M. Kalergis^1,2,*

¹ Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8330025 Santiago, Chile

² Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile

^† These authors contributed equally in this manuscript.

Int. J. Mol. Sci. 2016, 17(7), 797; https://doi.org/10.3390/ijms17070797 - 23 Jun 2016

Cited by 218 | Viewed by 36789

Abstract

Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control [...] Read more.

Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control of blood pressure, but they are also associated with the genesis of arterial hypertension, thus constituting a need for pharmacological interventions. Chronic high pressure generates mechanical damage along the vascular system, heart, and kidneys, which are the principal organs affected in this condition. In addition to mechanical stress, hypertension-induced oxidative stress, chronic inflammation, and the activation of reparative mechanisms lead to end-organ damage, mainly due to fibrosis. Clinical trials have demonstrated that renin-angiotensin-aldosterone system intervention in hypertensive patients lowers morbidity/mortality and inflammatory marker levels as compared to placebo patients, evidencing that this system controls more than blood pressure. This review emphasizes the detrimental effects that a renin-angiotensin-aldosterone system (RAAS) imbalance has on health considerations above and beyond high blood pressure, such as fibrotic end-organ damage. Full article

(This article belongs to the Special Issue Molecular Research on Hypertension)

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16 pages, 3827 KiB

Open AccessArticle

One Pot Selective Arylation of 2-Bromo-5-Chloro Thiophene; Molecular Structure Investigation via Density Functional Theory (DFT), X-ray Analysis, and Their Biological Activities

by Nasir Rasool^1,*, Aqsa Kanwal¹, Tehmina Rasheed¹, Quratulain Ain¹, Tariq Mahmood², Khurshid Ayub², Muhammad Zubair¹, Khalid Mohammed Khan³, Muhammad Nadeem Arshad^4,5, Abdullah M. Asiri^4,5, Muhammad Zia-Ul-Haq⁶ and Hawa Z. E. Jaafar^7,*

¹ Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan

² Department of Chemistry, COMSATS Institute of Information Technology, University Road, Tobe Camp, Abbottabad 22060, Pakistan

³ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan

⁴ Departments of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

⁵ Center of Excellence for Advanced Materials Research (CEAMR), Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

⁶ The Patent Office, Karachi 75270, Pakistan

⁷ Department of Crop Science, Faculty of Agriculture, 43400 UPM Serdang, Selangor, Malaysia

Int. J. Mol. Sci. 2016, 17(7), 912; https://doi.org/10.3390/ijms17070912 - 28 Jun 2016

Cited by 20 | Viewed by 5571

Abstract

Synthesis of 2,5-bisarylthiophenes was accomplished by sequential Suzuki cross coupling reaction of 2-bromo-5-chloro thiophenes. Density functional theory (DFT) studies were carried out at the B3LYP/6-31G(d, p) level of theory to compare the geometric parameters of 2,5-bisarylthiophenes with those from X-ray diffraction results. The [...] Read more.

Synthesis of 2,5-bisarylthiophenes was accomplished by sequential Suzuki cross coupling reaction of 2-bromo-5-chloro thiophenes. Density functional theory (DFT) studies were carried out at the B3LYP/6-31G(d, p) level of theory to compare the geometric parameters of 2,5-bisarylthiophenes with those from X-ray diffraction results. The synthesized compounds are screened for in vitro bacteria scavenging abilities. At the concentration of 50 and 100 μg/mL, compounds 2b, 2c, 2d, 3c, and 3f with IC₅₀-values of 51.4, 52.10, 58.0, 56.2, and 56.5 μg/mL respectively, were found most potent against E. coli. Among all the synthesized compounds 2a, 2d, 3c, and 3e with the least values of IC₅₀ 77, 76.26, 79.13 μg/mL respectively showed significant antioxidant activities. Almost all of the compounds showed good antibacterial activity against Escherichia coli, whereas 2-chloro-5-(4-methoxyphenyl) thiophene (2b) was found most active among all synthesized compound with an IC₅₀ value of 51.4 μg/mL. All of the synthesized compounds were screened for nitric oxide scavenging activity as well. Frontier molecular orbitals (FMOs) and molecular electrostatic potentials of the target compounds were also studied theoretically to account for their relative reactivity Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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10 pages, 1245 KiB

Open AccessArticle

MicroRNA-21a-5p Functions on the Regulation of Melanogenesis by Targeting Sox5 in Mouse Skin Melanocytes

by Pengchao Wang¹, Yuanyuan Zhao², Ruiwen Fan¹, Tianzhi Chen¹ and Changsheng Dong^1,*

¹ College of Animal Science and Technology, Shanxi Agricultural University, Taigu 030801, Shanxi, China

² Wujiang River Institute of Agriculture & Forestry Economics, Tongren University, Tongren 554300, Guizhou, China

Int. J. Mol. Sci. 2016, 17(7), 959; https://doi.org/10.3390/ijms17070959 - 24 Jun 2016

Cited by 43 | Viewed by 6331

Abstract

MicroRNAs (miRNAs) play an important role in regulating almost all biological processes. miRNAs bind to the 3′ untranslated region (UTR) of mRNAs by sequence matching. In a previous study, we demonstrated that miR-21 was differently expressed in alpaca skin with different hair color. [...] Read more.

MicroRNAs (miRNAs) play an important role in regulating almost all biological processes. miRNAs bind to the 3′ untranslated region (UTR) of mRNAs by sequence matching. In a previous study, we demonstrated that miR-21 was differently expressed in alpaca skin with different hair color. However, the molecular and cellular mechanisms for miR-21 to regulate the coat color are not yet completely understood. In this study, we transfected miR-21a-5p into mouse melanocytes and demonstrated its function on melanogenesis of miR-21a-5p by targeting Sox5, which inhibits melanogenesis in mouse melanocytes. The results suggested that miR-21a-5p targeted Sox5 gene based on the binding site in 3′ UTR of Sox5 and overexpression of miR-21a-5p significantly down-regulated Sox5 mRNA and protein expression. Meanwhile, mRNA and protein expression of microphthalmia transcription factor (MITF) and Tyrosinase (TYR) were up-regulated, which subsequently make the melanin production in melanocytes increased. The results suggest that miR-21a-5p regulates melanogenesis via MITF by targeting Sox5. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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12 pages, 3454 KiB

Open AccessArticle

Subinhibitory Concentrations of Allicin Decrease Uropathogenic Escherichia coli (UPEC) Biofilm Formation, Adhesion Ability, and Swimming Motility

by Xiaolong Yang, Kaihui Sha, Guangya Xu, Hanwen Tian, Xiaoying Wang, Shanze Chen, Yi Wang, Jingyu Li, Junli Chen^* and Ning Huang^*

Research Unit of Infection and Immunity, Department of Pathophysiology, West China School of Preclinical & Forensic Medicine, Sichuan University, Chengdu 610000, Sichuan, China

Int. J. Mol. Sci. 2016, 17(7), 979; https://doi.org/10.3390/ijms17070979 - 29 Jun 2016

Cited by 35 | Viewed by 7999

Abstract

Uropathogenic Escherichia coli (UPEC) biofilm formation enables the organism to avoid the host immune system, resist antibiotics, and provide a reservoir for persistent infection. Once the biofilm is established, eradication of the infection becomes difficult. Therefore, strategies against UPEC biofilm are urgently required. [...] Read more.

Uropathogenic Escherichia coli (UPEC) biofilm formation enables the organism to avoid the host immune system, resist antibiotics, and provide a reservoir for persistent infection. Once the biofilm is established, eradication of the infection becomes difficult. Therefore, strategies against UPEC biofilm are urgently required. In this study, we investigated the effect of allicin, isolated from garlic essential oil, on UPEC CFT073 and J96 biofilm formation and dispersal, along with its effect on UPEC adhesion ability and swimming motility. Sub-inhibitory concentrations (sub-MICs) of allicin decreased UPEC biofilm formation and affected its architecture. Allicin was also capable of dispersing biofilm. Furthermore, allicin decreased the bacterial adhesion ability and swimming motility, which are important for biofilm formation. Real-time quantitative polymerase chain reaction (RT-qPCR) revealed that allicin decreased the expression of UPEC type 1 fimbriae adhesin gene fimH. Docking studies suggested that allicin was located within the binding pocket of heptyl α-d-mannopyrannoside in FimH and formed hydrogen bonds with Phe1 and Asn135. In addition, allicin decreased the expression of the two-component regulatory systems (TCSs) cognate response regulator gene uvrY and increased the expression of the RNA binding global regulatory protein gene csrA of UPEC CFT073, which is associated with UPEC biofilm. The findings suggest that sub-MICs of allicin are capable of affecting UPEC biofilm formation and dispersal, and decreasing UPEC adhesion ability and swimming motility. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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18 pages, 3217 KiB

Open AccessArticle

Phase Transitions of Isotropic to Anisotropic Biocompatible Lipid-Based Drug Delivery Systems Overcoming Insoluble Benznidazole Loading

by Letícia Streck¹, Víctor H. V. Sarmento²

, Paula R. L. Machado³, Kleber J. S. Farias³, Matheus F. Fernandes-Pedrosa¹ and Arnóbio Antônio Da Silva-Júnior^1,*

¹ Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte, UFRN, Gal. Gustavo Cordeiro de Farias, Petrópolis, 59.072-570 Natal, RN, Brazil

² Department of Chemistry, Federal University of Sergipe, UFS, Alberto Carvalho Campus, Av. Vereador Olímpio Grande, 49.500-000 Itabaiana, SE, Brazil

³ Immunology Laboratory, Department of Clinical Analysis and Toxicology, Federal University of Rio Grande do Norte, UFRN, Gal. Gustavo Cordeiro de Farias, Petrópolis, 59.072-570 Natal, RN, Brazil

Int. J. Mol. Sci. 2016, 17(7), 981; https://doi.org/10.3390/ijms17070981 - 30 Jun 2016

Cited by 18 | Viewed by 5533

Abstract

Previous studies reported low benznidazole (BNZ) loading in conventional emulsions due to the weak interaction of the drug with the most common oils used to produce foods or pharmaceuticals. In this study, we focused on how the type of surfactant, surfactant-to-oil ratio w [...] Read more.

Previous studies reported low benznidazole (BNZ) loading in conventional emulsions due to the weak interaction of the drug with the most common oils used to produce foods or pharmaceuticals. In this study, we focused on how the type of surfactant, surfactant-to-oil ratio w/w (SOR) and oil-to-water ratio w/w (OWR) change the phase behavior of different lipid-based drug delivery systems (LBDDS) produced by emulsion phase inversion. The surfactant mixture composed of soy phosphatidylcholine and sodium oleate (1:7, w/w, hydrophilic lipophilic balance = 16) stabilized medium chain triglyceride in water. Ten formulations with the clear aspect or less turbid dispersions (five with the SOR ranging from 0.5 to 2.5 and five with the OWR from 0.06 to 0.4) were selected from the phase behavior diagram to assess structural features and drug-loading capacity. The rise in the SOR induced the formation of distinct lipid-based drug delivery systems (nanoemulsions and liquid crystal lamellar type) that were identified using rheological measurements and cross-polarized light microscopy images. Clear dispersions of small and narrow droplet-sized liquid-like nanoemulsions, Newtonian flow-type, were produced at SOR from 0.5 to 1.5 and OWR from 0.12 to 0.4, while clear liquid or gel-like liquid crystals were produced at SOR from 1.5 to 2.5. The BNZ loading was improved according to the composition and type of LBDDS produced, suggesting possible drug location among surfactant layers. The cell viability assays proved the biocompatibility for all of the prepared nanoemulsions at SOR less than 1.5 and liquid crystals at SOR less than 2.5, demonstrating their promising features for the oral or parenteral colloidal delivery systems containing benznidazole for Chagas disease treatment. Full article

(This article belongs to the Section Materials Science)

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12 pages, 3977 KiB

Open AccessArticle

Novel Hybrid Peptide Cecropin A (1–8)-LL37 (17–30) with Potential Antibacterial Activity

by Xu-Biao Wei, Ru-Juan Wu, Da-Yong Si, Xiu-Dong Liao, Lu-Lu Zhang and Ri-Jun Zhang^*

Laboratory of Feed Biotechnology, State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China

Int. J. Mol. Sci. 2016, 17(7), 983; https://doi.org/10.3390/ijms17070983 - 29 Jun 2016

Cited by 42 | Viewed by 6087

Abstract

Hybridizing different antimicrobial peptides (AMPs) is a particularly successful approach to obtain novel AMPs with increased antimicrobial activity but minimized cytotoxicity. The hybrid peptide cecropin A (1–8)-LL37 (17–30) (C-L) combining the hydrophobic N-terminal fragment of cecropin A (C) with the core antimicrobial fragment [...] Read more.

Hybridizing different antimicrobial peptides (AMPs) is a particularly successful approach to obtain novel AMPs with increased antimicrobial activity but minimized cytotoxicity. The hybrid peptide cecropin A (1–8)-LL37 (17–30) (C-L) combining the hydrophobic N-terminal fragment of cecropin A (C) with the core antimicrobial fragment of LL37 (L) was designed and synthesized. C-L showed higher antibacterial activity against all indicator strains than C and L, and no hemolytic activity to sheep erythrocytes was observed. C-L kills bacterial cells and causes disruption of surface structure, as determined by scanning electron microscopy. Synergistic effects were observed in the combination of C-L with several antibiotics (chloramphenicol, thiamphenicol, or neomycin sulfate) against Escherichia coli and Staphylococcus aureus. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 2029 KiB

Open AccessArticle

The X-ray Structures of Six Octameric RNA Duplexes in the Presence of Different Di- and Trivalent Cations

by Michelle F. Schaffer¹, Guanya Peng², Bernhard Spingler¹, Joachim Schnabl¹

, Meitian Wang², Vincent Olieric² and Roland K. O. Sigel^1,*

¹ Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zürich CH-8057, Switzerland

² Swiss Light Source, Paul Scherrer Institute, Villigen CH-5232, Switzerland

Int. J. Mol. Sci. 2016, 17(7), 988; https://doi.org/10.3390/ijms17070988 - 27 Jun 2016

Cited by 7 | Viewed by 6793

Abstract

Due to the polyanionic nature of RNA, the principles of charge neutralization and electrostatic condensation require that cations help to overcome the repulsive forces in order for RNA to adopt a three-dimensional structure. A precise structural knowledge of RNA-metal ion interactions is crucial [...] Read more.

Due to the polyanionic nature of RNA, the principles of charge neutralization and electrostatic condensation require that cations help to overcome the repulsive forces in order for RNA to adopt a three-dimensional structure. A precise structural knowledge of RNA-metal ion interactions is crucial to understand the mechanism of metal ions in the catalytic or regulatory activity of RNA. We solved the crystal structure of an octameric RNA duplex in the presence of the di- and trivalent metal ions Ca²⁺, Mn²⁺, Co²⁺, Cu²⁺, Sr²⁺, and Tb³⁺. The detailed investigation reveals a unique innersphere interaction to uracil and extends the knowledge of the influence of metal ions for conformational changes in RNA structure. Furthermore, we could demonstrate that an accurate localization of the metal ions in the X-ray structures require the consideration of several crystallographic and geometrical parameters as well as the anomalous difference map. Full article

(This article belongs to the Special Issue Applied Bioinorganic Chemistry and Selected Papers from 13th ISABC)

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10 pages, 2399 KiB

Open AccessArticle

Cytotoxicity and Apoptotic Effects of Polyphenols from Sugar Beet Molasses on Colon Carcinoma Cells in Vitro

by Mingshun Chen¹

, Zhengang Zhao^1,* and Shujuan Yu^1,2,*

¹ College of Light Industry and Food Sciences, South China University of Technology, Guangzhou 510640, China

² Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China

Int. J. Mol. Sci. 2016, 17(7), 993; https://doi.org/10.3390/ijms17070993 - 23 Jun 2016

Cited by 16 | Viewed by 6798

Abstract

Three polyphenols were isolated and purified from sugar beet molasses by ultrasonic-aid extraction and various chromatographic techniques, and their structures were elucidated by spectral analysis. Cytotoxicity and the molecular mechanism were measured by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry, caspase-3 activity assay [...] Read more.

Three polyphenols were isolated and purified from sugar beet molasses by ultrasonic-aid extraction and various chromatographic techniques, and their structures were elucidated by spectral analysis. Cytotoxicity and the molecular mechanism were measured by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry, caspase-3 activity assay and Western blot assay. The results showed that gallic acid, cyanidin-3-O-glucoside chloride and epicatechin have cytotoxicity to the human colon, hepatocellular and breast cancer cells. Cyanidin-3-O-glucoside chloride showed its cytotoxicity against various tumor cell lines, particularly against colon cancer Caco-2 cells with half maximal inhibitory concentration (IC₅₀) value of 23.21 ± 0.14 μg/mL in vitro. Cyanidin-3-O-glucoside chloride may be a potential candidate for the treatment of colon cancer. In the mechanism study, cyanidin-3-O-glucoside chloride increased the ratio of cell cycle at G₀/G₁ phase and reduced cyclin D1 expression on Caco-2 cells. Cyanidin-3-O-glucoside chloride decreased mutant p21 expression, and increased the ratio of Bax/Bcl-2 and the activation of caspase-3 to induce apoptosis. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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11 pages, 2852 KiB

Open AccessArticle

Conductive Hybrid Crystal Composed from Polyoxomolybdate and Deprotonatable Ionic-Liquid Surfactant

by Jun Kobayashi¹, Ryosuke Kawahara², Sayaka Uchida², Shinichi Koguchi¹ and Takeru Ito^1,*

¹ Department of Chemistry, School of Science, Tokai University, 4-1-1 Kitakaname, Hiratsuka 259-1292, Japan

² Department of Basic Science, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan

Int. J. Mol. Sci. 2016, 17(7), 994; https://doi.org/10.3390/ijms17070994 - 23 Jun 2016

Cited by 13 | Viewed by 6721

Abstract

A polyoxomolybdate inorganic-organic hybrid crystal was synthesized with deprotonatable ionic-liquid surfactant. 1-dodecylimidazolium cation was employed for its synthesis. The hybrid crystal contained δ-type octamolybdate (Mo₈) isomer, and possessed alternate stacking of Mo₈ monolayers and interdigitated surfactant bilayers. The crystal structure [...] Read more.

A polyoxomolybdate inorganic-organic hybrid crystal was synthesized with deprotonatable ionic-liquid surfactant. 1-dodecylimidazolium cation was employed for its synthesis. The hybrid crystal contained δ-type octamolybdate (Mo₈) isomer, and possessed alternate stacking of Mo₈ monolayers and interdigitated surfactant bilayers. The crystal structure was compared with polyoxomolybdate hybrid crystals comprising 1-dodecyl-3-methylimidazolium surfactant, which preferred β-type Mo₈ isomer. The less bulky hydrophilic moiety of the 1-dodecylimidazolium interacted with the δ-Mo₈ anion by N–H···O hydrogen bonds, which presumably induced the formation of the δ-Mo₈ anion. Anhydrous conductivity of the hybrid crystal was estimated to be 5.5 × 10⁻⁶ S·cm⁻¹ at 443 K by alternating current (AC) impedance spectroscopy. Full article

(This article belongs to the Special Issue Ionic Liquids 2016 and Selected Papers from ILMAT III)

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12 pages, 4112 KiB

Open AccessArticle

Dexmedetomidine Protects Rat Liver against Ischemia-Reperfusion Injury Partly by the α_2A-Adrenoceptor Subtype and the Mechanism Is Associated with the TLR4/NF-κB Pathway

by Yiheng Wang^1,2,†

, Shan Wu^1,†, Xiaofang Yu³, Shaoli Zhou¹, Mian Ge¹, Xinjin Chi^1,* and Jun Cai^1,*

¹ Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou 510630, China

² Department of Anesthesiology, The First Affiliated Hospital, University of South China, Hengyang 421001, China

³ Department of Anesthesiology, Fujian Provincial Hospital, Fuzhou 350000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 995; https://doi.org/10.3390/ijms17070995 - 23 Jun 2016

Cited by 59 | Viewed by 6769

Abstract

Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via α₂-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The [...] Read more.

Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via α₂-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The authors aimed to examine whether pretreatment with Dex produces hepatic protection and investigate the influence of Dex on TLR4/NF-κB signaling. Dex was given via intraperitoneal injection 30 min prior to orthotopic autologous liver transplantation (OALT) in rats, and three α₂-adrenoceptor antagonists including atipamezole (a nonselective α₂ receptor blocker), ARC-239 (a specific α_2B/C blocker) and BRL-44408 (a specific α_2A blocker) were injected intraperitoneally 10 min before Dex administration. Histopathologic evaluation of the liver and the measurement of serum alanine aminotransferase activity, TLR4/NF-κB expression in the liver, and pro-inflammatory factors (serum tumor necrosis factor-α, interleukin-1β and hepatic myeloperoxidase) concentrations were performed 8 h after OALT. Dex ameliorated liver injury after OALT probably by suppressing the TLR4/NF-κB pathway and decreasing inflammatory mediator levels. The protective effects of Dex were reversed by atipamezole and BRL-44408, but not by ARC-239, suggesting that these effects were mediated in part by the α_2A subtype. In conclusion, Dex attenuates liver injury partly via the α_2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB pathway. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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15 pages, 245 KiB

Open AccessReview

Chitosan Effects on Plant Systems

by Massimo Malerba¹ and Raffaella Cerana^2,*

¹ Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy

² Dipartimento di Scienze dell’Ambiente e del Territorio e di Scienze della Terra, Università degli Studi di Milano-Bicocca, Piazza della Scienza 1, 20126 Milano, Italy

Int. J. Mol. Sci. 2016, 17(7), 996; https://doi.org/10.3390/ijms17070996 - 23 Jun 2016

Cited by 377 | Viewed by 15608

Abstract

Chitosan (CHT) is a natural, safe, and cheap product of chitin deacetylation, widely used by several industries because of its interesting features. The availability of industrial quantities of CHT in the late 1980s enabled it to be tested in agriculture. CHT has been [...] Read more.

Chitosan (CHT) is a natural, safe, and cheap product of chitin deacetylation, widely used by several industries because of its interesting features. The availability of industrial quantities of CHT in the late 1980s enabled it to be tested in agriculture. CHT has been proven to stimulate plant growth, to protect the safety of edible products, and to induce abiotic and biotic stress tolerance in various horticultural commodities. The stimulating effect of different enzyme activities to detoxify reactive oxygen species suggests the involvement of hydrogen peroxide and nitric oxide in CHT signaling. CHT could also interact with chromatin and directly affect gene expression. Recent innovative uses of CHT include synthesis of CHT nanoparticles as a valuable delivery system for fertilizers, herbicides, pesticides, and micronutrients for crop growth promotion by a balanced and sustained nutrition. In addition, CHT nanoparticles can safely deliver genetic material for plant transformation. This review presents an overview on the status of the use of CHT in plant systems. Attention was given to the research that suggested the use of CHT for sustainable crop productivity. Full article

(This article belongs to the Special Issue Frontiers of Marine Biomaterials)

13 pages, 2952 KiB

Open AccessArticle

Brusatol Enhances the Radiosensitivity of A549 Cells by Promoting ROS Production and Enhancing DNA Damage

by Xiaohui Sun, Qin Wang^*, Yan Wang, Liqing Du, Chang Xu and Qiang Liu^*

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China

Int. J. Mol. Sci. 2016, 17(7), 997; https://doi.org/10.3390/ijms17070997 - 24 Jun 2016

Cited by 90 | Viewed by 8974

Abstract

NF-E2-related factor 2 (Nrf2) has been identified as a master regulatory factor in the protection of cells from oxidative and electrophilic stress. However, overexpression of Nrf2 in lung cancer may cause chemoresistance, as well as radioresistance. In this study, we examined the relationship [...] Read more.

NF-E2-related factor 2 (Nrf2) has been identified as a master regulatory factor in the protection of cells from oxidative and electrophilic stress. However, overexpression of Nrf2 in lung cancer may cause chemoresistance, as well as radioresistance. In this study, we examined the relationship between radioresistance and Nrf2 protein levels in H1299, A549, and H460 cells, and finally chose the A549 cell line to continue with due to its strong radioresistance and high Nrf2 protein levels. We found that the Nrf2 inhibitor, brusatol, could prevent the increase and accumulation of Nrf2 after exposure to irradiation. Additionally, following treatment with 80 nM brusatol, A549 cells became sensitive to irradiation, suffering severe DNA damage. Combination treatment with brusatol and ionizing radiation (IR) can distinctly increase the level of reactive oxygen species in A549 cells, causing a 1.8-fold increase compared with the control, and a 1.4-fold increase compared with IR alone. In fact, in the treatment with both brusatol and IR, lung cancer cell proliferation is halted, gradually leading to cell death. Because Nrf2 is closely linked to DNA damage repair, inhibiting the function of Nrf2, as in brusatol treatment, may increase the DNA damage caused by radiotherapy or chemotherapy, possibly enhancing the efficacy of chemotherapeutic drugs. Our study is the first to demonstrate brusatol’s ability to enhance the responsiveness of lung cancer cells to irradiation, and its potential application as a natural sensitizer in radiotherapy. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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22 pages, 4017 KiB

Open AccessArticle

Profiling Taste and Aroma Compound Metabolism during Apricot Fruit Development and Ripening

by Wanpeng Xi^1,2,*, Huiwen Zheng¹, Qiuyun Zhang¹ and Wenhui Li³

¹ College of Horticulture and Landscape Architecture, Southwest University, Chongqing 400716, China

² Key Laboratory of Horticulture Science for Southern Mountainous Regions, Ministry of Education, Chongqing 400715, China

³ National Fruit Tree Germplasm Repository, Xinjiang Academy of Agricultural Sciences, Luntai, Xinjiang 841600, China

Int. J. Mol. Sci. 2016, 17(7), 998; https://doi.org/10.3390/ijms17070998 - 24 Jun 2016

Cited by 94 | Viewed by 12313

Abstract

Sugars, organic acids and volatiles of apricot were determined by HPLC and GC-MS during fruit development and ripening, and the key taste and aroma components were identified by integrating flavor compound contents with consumers’ evaluation. Sucrose and glucose were the major sugars in [...] Read more.

Sugars, organic acids and volatiles of apricot were determined by HPLC and GC-MS during fruit development and ripening, and the key taste and aroma components were identified by integrating flavor compound contents with consumers’ evaluation. Sucrose and glucose were the major sugars in apricot fruit. The contents of all sugars increased rapidly, and the accumulation pattern of sugars converted from glucose-predominated to sucrose-predominated during fruit development and ripening. Sucrose synthase (SS), sorbitol oxidase (SO) and sorbitol dehydrogenase (SDH) are under tight developmental control and they might play important roles in sugar accumulation. Almost all organic acids identified increased during early development and then decrease rapidly. During early development, fruit mainly accumulated quinate and malate, with the increase of citrate after maturation, and quinate, malate and citrate were the predominant organic acids at the ripening stage. The odor activity values (OAV) of aroma volatiles showed that 18 aroma compounds were the characteristic components of apricot fruit. Aldehydes and terpenes decreased significantly during the whole development period, whereas lactones and apocarotenoids significantly increased with fruit ripening. The partial least squares regression (PLSR) results revealed that β-ionone, γ-decalactone, sucrose and citrate are the key characteristic flavor factors contributing to consumer acceptance. Carotenoid cleavage dioxygenases (CCD) may be involved in β-ionone formation in apricot fruit. Full article

(This article belongs to the Section Molecular Plant Sciences)

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10 pages, 212 KiB

Open AccessReview

Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives

by Antonio Simone Laganà^1,*

, Salvatore Giovanni Vitale¹

, Angela Nigro², Vincenza Sofo³, Francesca Maria Salmeri³

, Paola Rossetti², Agnese Maria Chiara Rapisarda⁴, Sandro La Vignera⁵

, Rosita Angela Condorelli⁵, Gianluca Rizzo⁶

and Massimo Buscema²

¹ Unit of Gynecology and Obstetrics, Department of Human Pathology in Adulthood and Childhood ‘‘G. Barresi’’, University of Messina, Via Consolare Valeria 1, Messina 98125, Italy

² Unit of Diabetology and Endocrino-Metabolic Diseases, Hospital for Emergency Cannizzaro, Via Messina 829, Catania 95126, Italy

³ Department of Biomedical Sciences, Dentistry and Morphological and Functional Imaging, University of Messina, Via Consolare Valeria 1, Messina 98100, Italy

⁴ Department of General Surgery and Medical Surgical Specialties, University of Catania, Via S. Sofia 78, Catania 95124, Italy

⁵ Department of Clinical and Experimental Medicine—CRAMD (Research Centre of Motor Activity and Metabolic Rehabilitation in Diabetes), University of Catania, Via S. Sofia 78, Catania 95124, Italy

⁶ Independent Researcher, Catania 95124, Italy

Int. J. Mol. Sci. 2016, 17(7), 999; https://doi.org/10.3390/ijms17070999 - 24 Jun 2016

Cited by 132 | Viewed by 8613

Abstract

Background: Peroxisome proliferator-activated receptors (PPARs) have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The [...] Read more.

Background: Peroxisome proliferator-activated receptors (PPARs) have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The purpose of this review is to describe the effects of PPARs, their action and their future prospective; Methods: Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; Results: PPARs play a key role in metabolic diseases, which include several cardiovascular diseases, insulin resistance, type 2 diabetes, metabolic syndrome, impaired immunity and the increasing risk of cancer; in particular, PPARα and PPARβ/δ mainly enable energy combustion, while PPARγ contributes to energy storage by enhancing adipogenesis; Conclusion: PPAR agonists could represent interesting types of molecules that can treat not only metabolic diseases, but also inflammation and cancer. Additional research is needed for the identification of high-affinity, high-specificity agonists for the treatment of obesity, type 2 diabetes (T2DM) and other metabolic diseases. Further studies are needed also to elucidate the role of PPARs in cancer. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

11 pages, 862 KiB

Open AccessReview

Site-Specific Genome Engineering in Human Pluripotent Stem Cells

by Sylvia Merkert^1,2,3 and Ulrich Martin^1,2,3,*

¹ Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany

² Regenerative Biology and Reconstructive Therapies (REBIRTH), Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany

³ Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, 30625 Hannover, Germany

Int. J. Mol. Sci. 2016, 17(7), 1000; https://doi.org/10.3390/ijms17071000 - 24 Jun 2016

Cited by 20 | Viewed by 12153

Abstract

The possibility to generate patient-specific induced pluripotent stem cells (iPSCs) offers an unprecedented potential of applications in clinical therapy and medical research. Human iPSCs and their differentiated derivatives are tools for diseases modelling, drug discovery, safety pharmacology, and toxicology. Moreover, they allow for [...] Read more.

The possibility to generate patient-specific induced pluripotent stem cells (iPSCs) offers an unprecedented potential of applications in clinical therapy and medical research. Human iPSCs and their differentiated derivatives are tools for diseases modelling, drug discovery, safety pharmacology, and toxicology. Moreover, they allow for the engineering of bioartificial tissue and are promising candidates for cellular therapies. For many of these applications, the ability to genetically modify pluripotent stem cells (PSCs) is indispensable, but efficient site-specific and safe technologies for genetic engineering of PSCs were developed only recently. By now, customized engineered nucleases provide excellent tools for targeted genome editing, opening new perspectives for biomedical research and cellular therapies. Full article

(This article belongs to the Special Issue Genome Editing)

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16 pages, 8750 KiB

Open AccessArticle

Platelet-Rich Plasma-Loaded Poly(d,l-lactide)-Poly(ethylene glycol)-Poly(d,l-lactide) Hydrogel Dressing Promotes Full-Thickness Skin Wound Healing in a Rodent Model

by Manle Qiu^1,†, Daoyun Chen^1,†, Chaoyong Shen^2,†, Ji Shen¹, Huakun Zhao¹ and Yaohua He^1,*

¹ Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China

² Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1001; https://doi.org/10.3390/ijms17071001 - 24 Jun 2016

Cited by 52 | Viewed by 8685

Abstract

Traditional therapeutic methods for skin wounds have many disadvantages, and new wound dressings that can facilitate the healing process are thus urgently needed. Platelet-rich plasma (PRP) contains multiple growth factors (GFs) and shows a significant capacity to heal soft tissue wounds. However, these [...] Read more.

Traditional therapeutic methods for skin wounds have many disadvantages, and new wound dressings that can facilitate the healing process are thus urgently needed. Platelet-rich plasma (PRP) contains multiple growth factors (GFs) and shows a significant capacity to heal soft tissue wounds. However, these GFs have a short half-life and deactivate rapidly; we therefore need a sustained delivery system to overcome this shortcoming. In this study, poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA: PLEL) hydrogel was successfully created as delivery vehicle for PRP GFs and was evaluated systematically. PLEL hydrogel was injectable at room temperature and exhibited a smart thermosensitive in situ gel-formation behavior at body temperature. In vitro cell culture showed PRP-loaded PLEL hydrogel (PRP/PLEL) had little cytotoxicity, and promoted EaHy926 proliferation, migration and tube formation; the factor release assay additionally indicated that PLEL realized the controlled release of PRP GFs for as long as 14 days. When employed to treat rodents’ full-thickness skin defects, PRP/PLEL showed a significantly better ability to raise the number of both newly formed and mature blood vessels compared to the control, PLEL and PRP groups. Furthermore, the PRP/PLEL-treated group displayed faster wound closure, better reepithelialization and collagen formation. Taken together, PRP/PLEL provides a promising strategy for promoting angiogenesis and skin wound healing, which extends the potential of this dressing for clinical application. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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17 pages, 264 KiB

Open AccessReview

Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

by J. Abraham Domínguez-Avila¹

, Gustavo A. González-Aguilar¹

, Emilio Alvarez-Parrilla²

and Laura A. De la Rosa^2,*

¹ Coordinación de Tecnología de Alimentos de Origen Vegetal, Centro de Investigación en Alimentación y Desarrollo A. C., Carretera a La Victoria km 0.6, AP 1735, CP 83304 Hermosillo, Sonora, Mexico

² Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Anillo Envolvente del PRONAF y Estocolmo s/n, CP 32310 Ciudad Juárez, Chihuahua, Mexico

Int. J. Mol. Sci. 2016, 17(7), 1002; https://doi.org/10.3390/ijms17071002 - 29 Jun 2016

Cited by 61 | Viewed by 7635

Abstract

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs [...] Read more.

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

24 pages, 2767 KiB

Open AccessArticle

The Role of Genetic Polymorphisms as Related to One-Carbon Metabolism, Vitamin B6, and Gene–Nutrient Interactions in Maintaining Genomic Stability and Cell Viability in Chinese Breast Cancer Patients

by Xiayu Wu¹, Weijiang Xu¹

, Tao Zhou¹, Neng Cao¹, Juan Ni¹, Tianning Zou², Ziqing Liang¹, Xu Wang^1,* and Michael Fenech^3,*

¹ School of Life Sciences, The Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, Yunnan Normal University, Kunming 650500, Yunnan, China

² Third Affiliated Hospital of Kunming Medical College, Kunming 650101, Yunnan, China

³ Genome Health and Personalized Nutrition, CSIRO Food and Nutrition, P.O. Box 10041, Adelaide SA 5000, Australia

Int. J. Mol. Sci. 2016, 17(7), 1003; https://doi.org/10.3390/ijms17071003 - 24 Jun 2016

Cited by 11 | Viewed by 8181

Abstract

Folate-mediated one-carbon metabolism (FMOCM) is linked to DNA synthesis, methylation, and cell proliferation. Vitamin B6 (B6) is a cofactor, and genetic polymorphisms of related key enzymes, such as serine hydroxymethyltransferase (SHMT), methionine synthase reductase (MTRR), and methionine synthase (MS), in FMOCM may govern [...] Read more.

Folate-mediated one-carbon metabolism (FMOCM) is linked to DNA synthesis, methylation, and cell proliferation. Vitamin B6 (B6) is a cofactor, and genetic polymorphisms of related key enzymes, such as serine hydroxymethyltransferase (SHMT), methionine synthase reductase (MTRR), and methionine synthase (MS), in FMOCM may govern the bioavailability of metabolites and play important roles in the maintenance of genomic stability and cell viability (GSACV). To evaluate the influences of B6, genetic polymorphisms of these enzymes, and gene–nutrient interactions on GSACV, we utilized the cytokinesis-block micronucleus assay (CBMN) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques in the lymphocytes from female breast cancer cases and controls. GSACV showed a significantly positive correlation with B6 concentration, and 48 nmol/L of B6 was the most suitable concentration for maintaining GSACV in vitro. The GSACV indexes showed significantly different sensitivity to B6 deficiency between cases and controls; the B6 effect on the GSACV variance contribution of each index was significantly higher than that of genetic polymorphisms and the sample state (tumor state). SHMT C1420T mutations may reduce breast cancer susceptibility, whereas MTRR A66G and MS A2756G mutations may increase breast cancer susceptibility. The role of SHMT, MS, and MTRR genotype polymorphisms in GSACV is reduced compared with that of B6. The results appear to suggest that the long-term lack of B6 under these conditions may increase genetic damage and cell injury and that individuals with various genotypes have different sensitivities to B6 deficiency. FMOCM metabolic enzyme gene polymorphism may be related to breast cancer susceptibility to a certain extent due to the effect of other factors such as stress, hormones, cancer therapies, psychological conditions, and diet. Adequate B6 intake may be good for maintaining genome health and preventing breast cancer. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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16 pages, 3780 KiB

Open AccessArticle

Genome-Wide Identification, Evolutionary Analysis, and Stress Responses of the GRAS Gene Family in Castor Beans

by Wei Xu^1,2,3,†, Zexi Chen^1,†, Naeem Ahmed^2,4

, Bing Han^2,3, Qinghua Cui^1,* and Aizhong Liu^2,*

¹ College of Life Sciences, Yunnan University, Kunming 650091, China

² Department of Economic Plants and Biotechnology, Yunnan Key Laboratory for Wild Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China

³ University of the Chinese Academy of Sciences, Beijing 100049, China

⁴ Department of Botany, University of Karachi, Karachi-75270, Pakistan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1004; https://doi.org/10.3390/ijms17071004 - 24 Jun 2016

Cited by 74 | Viewed by 9281

Abstract

Plant-specific GRAS transcription factors play important roles in regulating growth, development, and stress responses. Castor beans (Ricinus communis) are important non-edible oilseed plants, cultivated worldwide for its seed oils and its adaptability to growth conditions. In this study, we identified and [...] Read more.

Plant-specific GRAS transcription factors play important roles in regulating growth, development, and stress responses. Castor beans (Ricinus communis) are important non-edible oilseed plants, cultivated worldwide for its seed oils and its adaptability to growth conditions. In this study, we identified and characterized a total of 48 GRAS genes based on the castor bean genome. Combined with phylogenetic analysis, the castor bean GRAS members were divided into 13 distinct groups. Functional divergence analysis revealed the presence of mostly Type-I functional divergence. The gene structures and conserved motifs, both within and outside the GRAS domain, were characterized. Gene expression analysis, performed in various tissues and under a range of abiotic stress conditions, uncovered the potential functions of GRAS members in regulating plant growth development and stress responses. The results obtained from this study provide valuable information toward understanding the potential molecular mechanisms of GRAS proteins in castor beans. These findings also serve as a resource for identifying the genes that allow castor beans to grow in stressful conditions and to enable further breeding and genetic improvements in agriculture. Full article

(This article belongs to the Section Molecular Plant Sciences)

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4 pages, 152 KiB

Open AccessEditorial

Stem Cell Activation in Adult Organisms

by Wilhelm Bloch

Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Am Sportpark Muengersdorf 6, Cologne 50933, Germany

Int. J. Mol. Sci. 2016, 17(7), 1005; https://doi.org/10.3390/ijms17071005 - 24 Jun 2016

Cited by 1 | Viewed by 4714

Abstract

Stem cells are responsible for the organ and tissue development, growth and maintenance from embryonic stage up to late adult life.[...] Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)

13 pages, 1465 KiB

Open AccessArticle

Echinacoside Inhibits Glutamate Release by Suppressing Voltage-Dependent Ca²⁺ Entry and Protein Kinase C in Rat Cerebrocortical Nerve Terminals

by Cheng Wei Lu^1,2

, Tzu Yu Lin^1,2

, Shu Kuei Huang¹ and Su Jane Wang^3,*

¹ Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan

² Department of Mechanical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan

³ School of Medicine, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei 24205, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1006; https://doi.org/10.3390/ijms17071006 - 24 Jun 2016

Cited by 23 | Viewed by 5963

Abstract

The glutamatergic system may be involved in the effects of neuroprotectant therapies. Echinacoside, a phenylethanoid glycoside extracted from the medicinal Chinese herb Herba Cistanche, has neuroprotective effects. This study investigated the effects of echinacoside on 4-aminopyridine-evoked glutamate release in rat cerebrocortical nerve [...] Read more.

The glutamatergic system may be involved in the effects of neuroprotectant therapies. Echinacoside, a phenylethanoid glycoside extracted from the medicinal Chinese herb Herba Cistanche, has neuroprotective effects. This study investigated the effects of echinacoside on 4-aminopyridine-evoked glutamate release in rat cerebrocortical nerve terminals (synaptosomes). Echinacoside inhibited Ca²⁺-dependent, but not Ca²⁺-independent, 4-aminopyridine-evoked glutamate release in a concentration-dependent manner. Echinacoside also reduced the 4-aminopyridine-evoked increase in cytoplasmic free Ca²⁺ concentration but did not alter the synaptosomal membrane potential. The inhibitory effect of echinacoside on 4-aminopyridine-evoked glutamate release was prevented by ω-conotoxin MVIIC, a wide-spectrum blocker of Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but was insensitive to the intracellular Ca²⁺ release-inhibitors dantrolene and 7-chloro-5-(2-chloropheny)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP37157). Furthermore, echinacoside decreased the 4-aminopyridine-induced phosphorylation of protein kinase C, and protein kinase C inhibitors abolished the effect of echinacoside on glutamate release. According to these results, we suggest that the inhibitory effect of echinacoside on evoked glutamate release is associated with reduced voltage-dependent Ca²⁺ entry and subsequent suppression of protein kinase C activity. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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9 pages, 1138 KiB

Open AccessArticle

PBK/TOPK Expression Predicts Prognosis in Oral Cancer

by Chin-Fang Chang^1,2,†, Sung-Lang Chen^3,4,†, Wen-Wei Sung^1,3,5,6, Ming-Ju Hsieh^7,8,9, Hui-Ting Hsu^1,3,10, Li-Hsin Chen³, Mu-Kuan Chen^3,11, Jiunn-Liang Ko¹, Chih-Jung Chen^3,6,10,* and Ming-Chih Chou^1,3,*

¹ Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan

² Department of Otorhinolaryngology, Head and Neck Surgery, Jen-Ai Hospital, Taichung 400, Taiwan

³ School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan

⁴ Department of Urology, Chung Shan Medical University Hospital, Taichung 402, Taiwan

⁵ Department of Medical Education, Chung Shan Medical University Hospital, Taichung 402, Taiwan

⁶ Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan

⁷ Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan

⁸ School of Optometry, Chung Shan Medical University, Taichung 402, Taiwan

⁹ Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan

¹⁰ Department of Surgical Pathology, Changhua Christian Hospital, Changhua 500, Taiwan

¹¹ Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua 500, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2016, 17(7), 1007; https://doi.org/10.3390/ijms17071007 - 24 Jun 2016

Cited by 37 | Viewed by 5540

Abstract

Oral cancer is a common cancer with poor prognosis. We evaluated the expression of PBK/TOPK (PDZ-binding kinase/T-LAK cell-originated protein kinase) and its prognostic significance in oral cancer. PBK/TOPK expression was measured by immunohistochemical staining of samples from 287 patients with oral cancer. The [...] Read more.

Oral cancer is a common cancer with poor prognosis. We evaluated the expression of PBK/TOPK (PDZ-binding kinase/T-LAK cell-originated protein kinase) and its prognostic significance in oral cancer. PBK/TOPK expression was measured by immunohistochemical staining of samples from 287 patients with oral cancer. The association between PBK/TOPK expression and clinicopathological features was analyzed. The prognostic value of PBK/TOPK for overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. A high PBK/TOPK expression level was correlated with long overall survival. The prognostic role of PBK/TOPK expression was significant in young patients (p < 0.05), patients with smoking habits (p < 0.05), and late stage disease (p < 0.05). Our results suggest that PBK/TOPK expression is enhanced in oral cancer. High PBK/TOPK expression, either alone or in subgroups according to clinicopathological features, may serve as a favorable prognostic marker for patients with oral cancer. Full article

(This article belongs to the Special Issue Kinase Signal Transduction)

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14 pages, 3002 KiB

Open AccessCommunication

Computational Analysis of Single Nucleotide Polymorphisms Associated with Altered Drug Responsiveness in Type 2 Diabetes

by Valerio Costa¹

, Antonio Federico^1,2

, Carla Pollastro^1,2, Carmela Ziviello¹, Simona Cataldi¹, Pietro Formisano³ and Alfredo Ciccodicola^1,2,*

¹ Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy

² DiST, Department of Science and Technology, University of Naples “Parthenope”, 80134 Naples, Italy

³ Department of Translational Medical Sciences, University of Naples “Federico II”, 80131 Naples, Italy

Int. J. Mol. Sci. 2016, 17(7), 1008; https://doi.org/10.3390/ijms17071008 - 25 Jun 2016

Cited by 10 | Viewed by 7034

Abstract

Type 2 diabetes (T2D) is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual [...] Read more.

Type 2 diabetes (T2D) is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9) or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG). However, most genome-wide association studies did not provide clues about the contribution of DNA variations to impaired drug responsiveness. Thus, characterizing T2D drug responsiveness variants is needed to guide clinicians toward tailored therapeutic approaches. Here, we extensively investigated polymorphisms associated with altered drug response in T2D, predicting their effects in silico. Combining different computational approaches, we focused on the expression pattern of genes correlated to drug resistance and inferred evolutionary conservation of polymorphic residues, computationally predicting the biochemical properties of polymorphic proteins. Using RNA-Sequencing followed by targeted validation, we identified and experimentally confirmed that two nucleotide variations in the CAPN10 gene—currently annotated as intronic—fall within two new transcripts in this locus. Additionally, we found that a Single Nucleotide Polymorphism (SNP), currently reported as intergenic, maps to the intron of a new transcript, harboring CAPN10 and GPR35 genes, which undergoes non-sense mediated decay. Finally, we analyzed variants that fall into non-coding regulatory regions of yet underestimated functional significance, predicting that some of them can potentially affect gene expression and/or post-transcriptional regulation of mRNAs affecting the splicing. Full article

(This article belongs to the Special Issue Diabetic Complications: Pathophysiology, Mechanisms, and Therapies)

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67 pages, 2134 KiB

Open AccessReview

Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis—Masters of Survival and Clonality?

by Lisa Pleyer^1,2,3,*, Peter Valent⁴

and Richard Greil^1,2,3

¹ 3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria

² Center for Clinical Cancer and Immunology Trials at Salzburg Cancer Research Institute, 5020 Salzburg, Austria

³ 3rd Medical Department, Cancer Cluster Salzburg, 5020 Salzburg, Austria

⁴ Department of Internal Medicine I, Division of Hematology and Hemostaseology & Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Vienna, Austria

Int. J. Mol. Sci. 2016, 17(7), 1009; https://doi.org/10.3390/ijms17071009 - 27 Jun 2016

Cited by 37 | Viewed by 19216

Abstract

Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including [...] Read more.

Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts. MSCs have potent immunomodulatory capacities and communicate with diverse immune cells, but also interact with various other cellular components of the microenvironment as well as with normal and leukemic stem and progenitor cells. Moreover, compared to normal MSCs, MSCs in MDS and AML often exhibit altered gene expression profiles, an aberrant phenotype, and abnormal functional properties. These alterations supposedly contribute to the “reprogramming” of the stem cell niche into a disease-permissive microenvironment where an altered immune system, abnormal stem cell niche interactions, and an impaired growth control lead to disease progression. The current article also reviews molecular targets that play a role in such cellular interactions and possibilities to interfere with abnormal stem cell niche interactions by using specific targeted drugs. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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18 pages, 2811 KiB

Open AccessArticle

Synthesis, Characterization, and Cytotoxicity of the First Oxaliplatin Pt(IV) Derivative Having a TSPO Ligand in the Axial Position

by Salvatore Savino¹, Nunzio Denora², Rosa Maria Iacobazzi^2,3, Letizia Porcelli³, Amalia Azzariti³, Giovanni Natile¹ and Nicola Margiotta^1,*

¹ Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy

² Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy

³ Istituto Tumori IRCCS Giovanni Paolo II, viale O. Flacco 65, 70124 Bari, Italy

Int. J. Mol. Sci. 2016, 17(7), 1010; https://doi.org/10.3390/ijms17071010 - 25 Jun 2016

Cited by 20 | Viewed by 9286

Abstract

The first Pt(IV) derivative of oxaliplatin carrying a ligand for TSPO (the 18-kDa mitochondrial translocator protein) has been developed. The expression of the translocator protein in the brain and liver of healthy humans is usually low, oppositely to steroid-synthesizing and rapidly proliferating tissues, [...] Read more.

The first Pt(IV) derivative of oxaliplatin carrying a ligand for TSPO (the 18-kDa mitochondrial translocator protein) has been developed. The expression of the translocator protein in the brain and liver of healthy humans is usually low, oppositely to steroid-synthesizing and rapidly proliferating tissues, where TSPO is much more abundant. The novel Pt(IV) complex, cis,trans,cis-[Pt(ethanedioato)Cl{2-(2-(4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenoxy)acetate)-ethanolato}(1R,2R-DACH)] (DACH = diaminocyclohexane), has been fully characterized by spectroscopic and spectrometric techniques and tested in vitro against human MCF7 breast carcinoma, U87 glioblastoma, and LoVo colon adenocarcinoma cell lines. In addition, affinity for TSPO (IC₅₀ = 18.64 nM), cellular uptake (ca. 2 times greater than that of oxaliplatin in LoVo cancer cells, after 24 h treatment), and perturbation of cell cycle progression were investigated. Although the new compound was less active than oxaliplatin and did not exploit a synergistic proapoptotic effect due to the presence of the TSPO ligand, it appears to be promising in a receptor-mediated drug targeting context towards TSPO-overexpressing tumors, in particular colorectal cancer (IC₅₀ = 2.31 μM after 72 h treatment). Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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14 pages, 2041 KiB

Open AccessArticle

Extraction, Characterization and Immunological Activity of Polysaccharides from Rhizoma gastrodiae

by Juncheng Chen¹, Shan Tian¹, Xiaoying Shu¹, Hongtao Du^1,2, Na Li¹ and Junru Wang^1,*

¹ Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Sciences, Northwest A & F University, Yangling 712100, Shaanxi, China

² College of Plant Protection, Northwest A & F University, Yangling 712100, Shaanxi, China

Int. J. Mol. Sci. 2016, 17(7), 1011; https://doi.org/10.3390/ijms17071011 - 25 Jun 2016

Cited by 45 | Viewed by 6444

Abstract

A response surface and Box-Behnken design approach was applied to augment polysaccharide extraction from the residue of Rhizoma gastrodiae. Statistical analysis revealed that the linear and quadratic terms for three variables during extraction exhibited obvious effects on extraction yield. The optimum conditions [...] Read more.

A response surface and Box-Behnken design approach was applied to augment polysaccharide extraction from the residue of Rhizoma gastrodiae. Statistical analysis revealed that the linear and quadratic terms for three variables during extraction exhibited obvious effects on extraction yield. The optimum conditions were determined to be a liquid-to-solid ratio of 54 mL/g, an extraction temperature of 74 °C, an extraction time of 66 min, and three extractions. These conditions resulted in a maximum Rhizoma gastrodiae polysaccharide (RGP) extraction yield of 6.11% ± 0.13%. Two homogeneous polysaccharides (RGP-1a and RGP-1b) were obtained using DEAE cellulose-52 and Sephadex G-100 columns. The preliminary characterization of RGP-1a and RGP-1b was performed using HPLC-RID, HPGPC, and FTIR. Tests of the immunological activity in vitro showed that the two polysaccharides could significantly stimulate macrophages to release NO and enhance phagocytosis in a dose-dependent manner. In particular, RGP-1b (200 μg/mL) and LPS (2 μg/mL) had almost the same influence on the NO production and phagocytic activity of RAW 264.7 macrophages (p > 0.05). All the data obtained indicate that RGP-1a and RGP-1b have the potential to be developed as a health food. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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10 pages, 1202 KiB

Open AccessArticle

Characterization and Genomic Analysis of a Highly Efficient Dibutyl Phthalate-Degrading Bacterium Gordonia sp. Strain QH-12

by Decai Jin¹, Xiao Kong¹, Huijun Liu², Xinxin Wang³, Ye Deng^1,*

, Minghong Jia^2,* and Xiangyang Yu⁴

¹ CAS Key Laboratory of Environmental Biotechnology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China

² Beijing Key Laboratory of Detection and Control of Spoilage Organisms and Pesticide Residues in Agricultural Products, Beijing University of Agriculture, Beijing 102206, China

³ China Offshore Environmental Service Co., Ltd., Tianjin 300452, China

⁴ Institute of Food Quality and Safety, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China

Int. J. Mol. Sci. 2016, 17(7), 1012; https://doi.org/10.3390/ijms17071012 - 25 Jun 2016

Cited by 26 | Viewed by 5552

Abstract

A bacterial strain QH-12 isolated from activated sludge was identified as Gordonia sp. based on analysis of 16S rRNA gene sequence and was found to be capable of utilizing dibutyl phthalate (DBP) and other common phthalate esters (PAEs) as the sole carbon and [...] Read more.

A bacterial strain QH-12 isolated from activated sludge was identified as Gordonia sp. based on analysis of 16S rRNA gene sequence and was found to be capable of utilizing dibutyl phthalate (DBP) and other common phthalate esters (PAEs) as the sole carbon and energy source. The degradation kinetics of DBP under different concentrations by the strain QH-12 fit well with the modified Gompertz model (R² > 0.98). However, strain QH-12 could not utilize the major intermediate product phthalate (phthalic acid; PA) as the sole carbon and energy source, and only a little amount of PA was detected. The QH-12 genome analysis revealed the presence of putative hydrolase/esterase genes involved in PAEs-degradation but no phthalic acid catabolic gene cluster was found, suggesting that a novel degradation pathway of PAEs was present in Gordonia sp. QH-12. This information will be valuable for obtaining a more holistic understanding on diverse genetic mechanisms of PAEs-degrading Gordonia sp. strains. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 2757 KiB

Open AccessArticle

Hypoxia Potentiates Anabolic Effects of Exogenous Hyaluronic Acid in Rat Articular Cartilage

by Shohei Ichimaru¹, Shuji Nakagawa¹, Yuji Arai^2,*, Tsunao Kishida³, Masaharu Shin-Ya³, Kuniaki Honjo¹, Shinji Tsuchida¹, Hiroaki Inoue¹, Hiroyoshi Fujiwara¹, Seiji Shimomura¹, Osam Mazda³ and Toshikazu Kubo¹

¹ Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan

² Department of Sports and Para-Sports Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan

³ Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan

Int. J. Mol. Sci. 2016, 17(7), 1013; https://doi.org/10.3390/ijms17071013 - 25 Jun 2016

Cited by 13 | Viewed by 6248

Abstract

Hyaluronic acid (HA) is used clinically to treat osteoarthritis (OA), but its pharmacological effects under hypoxic conditions remain unclear. Articular chondrocytes in patients with OA are exposed to a hypoxic environment. This study investigated whether hypoxia could potentiate the anabolic effects of exogenous [...] Read more.

Hyaluronic acid (HA) is used clinically to treat osteoarthritis (OA), but its pharmacological effects under hypoxic conditions remain unclear. Articular chondrocytes in patients with OA are exposed to a hypoxic environment. This study investigated whether hypoxia could potentiate the anabolic effects of exogenous HA in rat articular cartilage and whether these mechanisms involved HA receptors. HA under hypoxic conditions significantly enhanced the expression of extracellular matrix genes and proteins in explant culture, as shown by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and dimethylmethylene blue (DMMB) assays. Staining with Safranin-O and immunohistochemical staining with antibody to type II collagen were also enhanced in pellet culture. The expression of CD44 was increased by hypoxia and significantly suppressed by transfection with siRNAs targeting hypoxia-inducible factor 1 alpha (siHIF-1α). These findings indicate that hypoxia potentiates the anabolic effects of exogenous HA by a mechanism in which HIF-1α positively regulates the expression of CD44, enhancing the binding affinity for exogenous HA. The anabolic effects of exogenous HA may increase as OA progresses. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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17 pages, 1445 KiB

Open AccessArticle

Oenocarpus bacaba and Oenocarpus bataua Leaflets and Roots: A New Source of Antioxidant Compounds

by Louis-Jérôme Leba^†, Christel Brunschwig^†, Mona Saout, Karine Martial, Didier Bereau and Jean-Charles Robinson^*

¹ Université de Guyane, UMR QUALITROP, Campus Universitaire de Troubiran, P.O. Box 792, 97337 Cayenne Cedex, French Guiana, France

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1014; https://doi.org/10.3390/ijms17071014 - 27 Jun 2016

Cited by 19 | Viewed by 7428

Abstract

Native palm trees fruit from the Amazonian rainforest, Oenocarpus bacaba and Oenocarpus bataua, are very often used in the diet of local communities, but the biological activities of their roots and leaflets remain poorly known. Total phenolic content (TPC) and antioxidant activity [...] Read more.

Native palm trees fruit from the Amazonian rainforest, Oenocarpus bacaba and Oenocarpus bataua, are very often used in the diet of local communities, but the biological activities of their roots and leaflets remain poorly known. Total phenolic content (TPC) and antioxidant activity of root and leaflet extracts from Oenocarpus bacaba and Oenocarpus bataua were assessed by using different chemical assays, the oxygèn radical absorbance capacity (ORAC), the 2,2-diphenyl-l-picrylhydrazyl (DPPH) free radical-scavenging capacity and the ferric-reducing ability of plasma (FRAP). Cellular antioxidant activity and cytotoxicity were also measured in Normal Human Dermal Fibroblasts. The polyphenolic composition of Oenocarpus extracts was investigated by LC-MSⁿ. Oenocarpus leaflet extracts were more antioxidant than root extracts, being at least as potent as Euterpe oleracea berries known as superfruit. Oenocarpus root extracts were characterized by hydroxycinnamic acids (caffeoylquinic and caffeoylshikimic acids), while leaflet extracts contained mainly caffeoylquinic acids and C-glycosyl flavones. These results suggest that leaflets of both Oenocarpus species could be valorized as a new non-cytotoxic source of antioxidants from Amazonia, containing hydroxycinnamic acids and flavonoids, in the pharmaceutical, cosmetic or agri-food industry. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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19 pages, 4299 KiB

Open AccessArticle

A Homogeneous Polysaccharide from Fructus Schisandra chinensis (Turz.) Baill Induces Mitochondrial Apoptosis through the Hsp90/AKT Signalling Pathway in HepG2 Cells

by Yonglin Chen^1,2,3, Songshan Shi^1,2,3, Huijun Wang^1,2,3, Ning Li^1,2,3, Juan Su^1,2,3, Guixin Chou^1,2,3,* and Shunchun Wang^1,2,3,*

¹ The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

² The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

³ Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

Int. J. Mol. Sci. 2016, 17(7), 1015; https://doi.org/10.3390/ijms17071015 - 28 Jun 2016

Cited by 20 | Viewed by 6533

Abstract

According to the potential anti-hepatoma therapeutic effect of Schisandra chinensis polysaccharides presented in previous studies, a bioactive constituent, homogeneous Schisandra chinensis polysaccharide-0-1 (SCP-0-1), molecular weight (M_W) circa 69.980 kDa, was isolated and purified. We assessed the efficacy of SCP-0-1 against [...] Read more.

According to the potential anti-hepatoma therapeutic effect of Schisandra chinensis polysaccharides presented in previous studies, a bioactive constituent, homogeneous Schisandra chinensis polysaccharide-0-1 (SCP-0-1), molecular weight (M_W) circa 69.980 kDa, was isolated and purified. We assessed the efficacy of SCP-0-1 against human hepatocellular liver carcinoma (HepG2) cells to investigate the effects of its antitumour activity and molecular mechanisms. Anticancer activity was evaluated using microscopy, 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyltetrazolium bromide (MTT) assay, Hoechst 33258 staining, acridine orange (AO) staining, flow cytometry (FCM), and cell-cycle analysis. SCP-0-1 inhibited the HepG2 cells’ growth via inducing apoptosis and second gap/mitosis (G2/M) arrest dose-dependently, with a half maximal inhibitory concentration (IC₅₀) value of 479.63 µg/mL. Western blotting of key proteins revealed the apoptotic and autophagic potential of SCP-0-1. Besides, SCP-0-1 upregulated Bcl-2 Associated X Protein (Bax) and downregulated B-cell leukemia/lymphoma 2 (Bcl-2) in the HepG2 cells. The expression of caspase-3, -8, and -9; poly (ADP-ribose) polymerase (PARP); cytochrome c (Cyt C); tumor protein 53 (p53); survivin; sequestosome 1 (p62); microtubule-associated protein 1 light chain-3B (LC3B); mitogen-activated protein kinase p38 (p38); extracellular regulated protein kinases (ERK); c-Jun N-terminal kinase (JNK); protein kinase B (AKT); and heat shock protein 90 (Hsp90) were evaluated using Western blotting. Our findings demonstrate a novel mechanism through which SCP-0-1 exerts its antiproliferative activity and induces mitochondrial apoptosis rather than autophagy. The induction of mitochondrial apoptosis was attributed to the inhibition of the Hsp90/AKT signalling pathway in an extracellular signal-regulated kinase-independent manner. The results also provide initial evidence on a molecular basis that SCP-0-1 can be used as an anti-hepatocellular carcinoma therapeutic agent in the future. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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12 pages, 1349 KiB

Open AccessCommunication

Screening of α-Tocopherol Transfer Protein Sensitive Genes in Human Hepatoma Cells (HepG2)

by Yang-Hua Qu^†, Jun-Cai Fu^†, Kun Liu, Zhao-Yun Zuo, Hui-Na Jia, Yong Ma and Hai-Ling Luo^*

¹ State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China

^† The authors contributed equally to the work.

Int. J. Mol. Sci. 2016, 17(7), 1016; https://doi.org/10.3390/ijms17071016 - 27 Jun 2016

Cited by 3 | Viewed by 4841

Abstract

α-Tocopherol transfer protein (α-TTP) is a ~32 kDa protein expressed mainly in hepatocytes. The major function of the protein is to bind specifically to α-tocopherol and, together, the complex transfers from late lysosomes to the cell membrane. A previous study indicated that some [...] Read more.

α-Tocopherol transfer protein (α-TTP) is a ~32 kDa protein expressed mainly in hepatocytes. The major function of the protein is to bind specifically to α-tocopherol and, together, the complex transfers from late lysosomes to the cell membrane. A previous study indicated that some factors might be required in the transferring process. However, there is little information available about the potential transferring factors. In addition, there remains much to learn about other physiological processes which α-TTP might participate in. Thus, in this study a human α-TTP eukaryotic expression vector was successfully constructed and expressed in human hepatoma cells (HepG2). The sensitive genes related to α-TTP were then screened by microarray technology. Results showed that expression of the vector in HepG2 cells led to the identification of 323 genes showing differential expression. The differentially expressed transcripts were divided into four main categories, including (1) cell inflammation; (2) cell cycle and cell apoptosis; (3) cell signaling and gene regulation; and (4) cellular movement. A few cellular movement related transcripts were selected and verified by quantitative real-time PCR. Expressions of some were significantly increased in α-TTP-expressed group, which indicated that these factors were likely to play a role in the transferring process. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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20 pages, 2462 KiB

Open AccessArticle

Stable Isotope-Assisted Evaluation of Different Extraction Solvents for Untargeted Metabolomics of Plants

by Maria Doppler^1,2,†, Bernhard Kluger^1,2,†, Christoph Bueschl^1,2

, Christina Schneider^1,2, Rudolf Krska^1,2

, Sylvie Delcambre³, Karsten Hiller³, Marc Lemmens^1,2 and Rainer Schuhmacher^1,2,*

¹ Center for Analytical Chemistry, Department of Agrobiotechnology (IFA-Tulln), University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad-Lorenz-Strasse 20, 3430 Tulln, Austria

² Institute for Biotechnology in Plant Production, Department of Agrobiotechnology (IFA-Tulln), University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad-Lorenz-Strasse 20, 3430 Tulln, Austria

³ Luxembourg Centre for Systems Biomedicine, University of Luxembourg Campus Belval, Avenue du Swing 6, 4367 Esch-Belval, Luxembourg

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1017; https://doi.org/10.3390/ijms17071017 - 28 Jun 2016

Cited by 80 | Viewed by 9147

Abstract

The evaluation of extraction protocols for untargeted metabolomics approaches is still difficult. We have applied a novel stable isotope-assisted workflow for untargeted LC-HRMS-based plant metabolomics , which allows for the first time every detected feature to be considered for method evaluation. The efficiency [...] Read more.

The evaluation of extraction protocols for untargeted metabolomics approaches is still difficult. We have applied a novel stable isotope-assisted workflow for untargeted LC-HRMS-based plant metabolomics , which allows for the first time every detected feature to be considered for method evaluation. The efficiency and complementarity of commonly used extraction solvents, namely 1 + 3 (v/v) mixtures of water and selected organic solvents (methanol, acetonitrile or methanol/acetonitrile 1 + 1 (v/v)), with and without the addition of 0.1% (v/v) formic acid were compared. Four different wheat organs were sampled, extracted and analysed by LC-HRMS. Data evaluation was performed with the in-house-developed MetExtract II software and R. With all tested solvents a total of 871 metabolites were extracted in ear, 785 in stem, 733 in leaf and 517 in root samples, respectively. Between 48% (stem) and 57% (ear) of the metabolites detected in a particular organ were found with all extraction mixtures, and 127 of 996 metabolites were consistently shared between all extraction agent/organ combinations. In aqueous methanol, acidification with formic acid led to pronounced pH dependency regarding the precision of metabolite abundance and the number of detectable metabolites, whereas extracts of acetonitrile-containing mixtures were less affected. Moreover, methanol and acetonitrile have been found to be complementary with respect to extraction efficiency. Interestingly, the beneficial properties of both solvents can be combined by the use of a water-methanol-acetonitrile mixture for global metabolite extraction instead of aqueous methanol or aqueous acetonitrile alone. Full article

(This article belongs to the Special Issue Metabolomics in the Plant Sciences)

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45 pages, 14637 KiB

Open AccessReview

Structure and Functional Diversity of GCN5-Related N-Acetyltransferases (GNAT)

by Abu Iftiaf Md Salah Ud-Din¹

, Alexandra Tikhomirova¹ and Anna Roujeinikova^1,2,*

¹ Infection and Immunity Program, Monash Biomedicine Discovery Institute; Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia

² Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia

Int. J. Mol. Sci. 2016, 17(7), 1018; https://doi.org/10.3390/ijms17071018 - 28 Jun 2016

Cited by 135 | Viewed by 13427

Abstract

General control non-repressible 5 (GCN5)-related N-acetyltransferases (GNAT) catalyze the transfer of an acyl moiety from acyl coenzyme A (acyl-CoA) to a diverse group of substrates and are widely distributed in all domains of life. This review of the currently available data acquired [...] Read more.

General control non-repressible 5 (GCN5)-related N-acetyltransferases (GNAT) catalyze the transfer of an acyl moiety from acyl coenzyme A (acyl-CoA) to a diverse group of substrates and are widely distributed in all domains of life. This review of the currently available data acquired on GNAT enzymes by a combination of structural, mutagenesis and kinetic methods summarizes the key similarities and differences between several distinctly different families within the GNAT superfamily, with an emphasis on the mechanistic insights obtained from the analysis of the complexes with substrates or inhibitors. It discusses the structural basis for the common acetyltransferase mechanism, outlines the factors important for the substrate recognition, and describes the mechanism of action of inhibitors of these enzymes. It is anticipated that understanding of the structural basis behind the reaction and substrate specificity of the enzymes from this superfamily can be exploited in the development of novel therapeutics to treat human diseases and combat emerging multidrug-resistant microbial infections. Full article

(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)

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14 pages, 4050 KiB

Open AccessArticle

The NAD-Dependent Deacetylase Sirtuin-1 Regulates the Expression of Osteogenic Transcriptional Activator Runt-Related Transcription Factor 2 (Runx2) and Production of Matrix Metalloproteinase (MMP)-13 in Chondrocytes in Osteoarthritis

by Koh Terauchi¹, Hajime Kobayashi¹, Kanaka Yatabe¹

, Naoko Yui¹, Hiroto Fujiya¹, Hisateru Niki², Haruki Musha¹ and Kazuo Yudoh^3,*

¹ Department of Sports Medicine, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8511, Japan

² Department of Orthopaedic Surgery, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8512, Japan

³ Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8512, Japan

Int. J. Mol. Sci. 2016, 17(7), 1019; https://doi.org/10.3390/ijms17071019 - 28 Jun 2016

Cited by 24 | Viewed by 6977

Abstract

Aging is one of the major pathologic factors associated with osteoarthritis (OA). Recently, numerous reports have demonstrated the impact of sirtuin-1 (Sirt1), which is the NAD-dependent deacetylase, on human aging. It has been demonstrated that Sirt1 induces osteogenic and chondrogenic differentiation of mesenchymal [...] Read more.

Aging is one of the major pathologic factors associated with osteoarthritis (OA). Recently, numerous reports have demonstrated the impact of sirtuin-1 (Sirt1), which is the NAD-dependent deacetylase, on human aging. It has been demonstrated that Sirt1 induces osteogenic and chondrogenic differentiation of mesenchymal stem cells. However, the role of Sirt1 in the OA chondrocytes still remains unknown. We postulated that Sirt1 regulates a hypertrophic chondrocyte lineage and degeneration of articular cartilage through the activation of osteogenic transcriptional activator Runx2 and matrix metalloproteinase (MMP)-13 in OA chondrocytes. To verify whether sirtuin-1 (Sirt1) regulates chondrocyte activity in OA, we studied expressions of Sirt1, Runx2 and production of MMP-13, and their associations in human OA chondrocytes. The expression of Sirt1 was ubiquitously observed in osteoarthritic chondrocytes; in contrast, Runx2 expressed in the osteophyte region in patients with OA and OA model mice. OA relating catabolic factor IL-1βincreased the expression of Runx2 in OA chondrocytes. OA chondrocytes, which were pretreated with Sirt1 inhibitor, inhibited the IL-1β-induced expression of Runx2 compared to the control. Since the Runx2 is a promotor of MMP-13 expression, Sirt1 inactivation may inhibit the Runx2 expression and the resultant down-regulation of MMP-13 production in chondrocytes. Our findings suggest thatSirt1 may regulate the expression of Runx2, which is the osteogenic transcription factor, and the production of MMP-13 from chondrocytes in OA. Since Sirt1 activity is known to be affected by several stresses, including inflammation and oxidative stress, as well as aging, SIRT may be involved in the development of OA. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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43 pages, 11386 KiB

Open AccessArticle

Computational Identification of the Paralogs and Orthologs of Human Cytochrome P450 Superfamily and the Implication in Drug Discovery

by Shu-Ting Pan^1,†, Danfeng Xue^1,†, Zhi-Ling Li², Zhi-Wei Zhou³, Zhi-Xu He⁴, Yinxue Yang⁵, Tianxin Yang⁶, Jia-Xuan Qiu^1,* and Shu-Feng Zhou^7,*

¹ Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital of Nanchang University, Nanchang 330003, China

² Department of Pharmacy, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai 200040, China

³ Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA

⁴ Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang 550004, China

⁵ Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, China

⁶ Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT 84132, USA

⁷ Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian, China

^† These two authors contributed to this work equally.

Int. J. Mol. Sci. 2016, 17(7), 1020; https://doi.org/10.3390/ijms17071020 - 28 Jun 2016

Cited by 23 | Viewed by 10539

Abstract

The human cytochrome P450 (CYP) superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been [...] Read more.

The human cytochrome P450 (CYP) superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been shown to expand itself through gene duplication, and some of them become pseudogenes due to gene mutations. Orthologs and paralogs are homologous genes resulting from speciation or duplication, respectively. To explore the evolutionary and functional relationships of human CYPs, we conducted this bioinformatic study to identify their corresponding paralogs, homologs, and orthologs. The functional implications and implications in drug discovery and evolutionary biology were then discussed. GeneCards and Ensembl were used to identify the paralogs of human CYPs. We have used a panel of online databases to identify the orthologs of human CYP genes: NCBI, Ensembl Compara, GeneCards, OMA (“Orthologous MAtrix”) Browser, PATHER, TreeFam, EggNOG, and Roundup. The results show that each human CYP has various numbers of paralogs and orthologs using GeneCards and Ensembl. For example, the paralogs of CYP2A6 include CYP2A7, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 2R1, 2S1, 2U1, and 2W1; CYP11A1 has 6 paralogs including CYP11B1, 11B2, 24A1, 27A1, 27B1, and 27C1; CYP51A1 has only three paralogs: CYP26A1, 26B1, and 26C1; while CYP20A1 has no paralog. The majority of human CYPs are well conserved from plants, amphibians, fishes, or mammals to humans due to their important functions in physiology and xenobiotic disposition. The data from different approaches are also cross-validated and validated when experimental data are available. These findings facilitate our understanding of the evolutionary relationships and functional implications of the human CYP superfamily in drug discovery. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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0 pages, 154 KiB

Open AccessRetraction

RETRACTED: Amedei et al. Multiple Sclerosis: The Role of Cytokines in Pathogenesis and in Therapies. Int. J. Mol. Sci. 2012, 13, 13438–13460

by International Journal of Molecular Sciences Editorial Office

MDPI AG, Klybeckstrasse 64, 4057 Basel, Switzerland

Int. J. Mol. Sci. 2016, 17(7), 1021; https://doi.org/10.3390/ijms17071021 - 4 Jul 2016

Viewed by 4199

Abstract

We have been made aware that the title paper [1] contains text taken verbatim from previously published articles by Shyi-Jou Chen et al. [2] and Ghislain Opdenakker and Jo Van Damme [3].[...] Full article

20 pages, 5885 KiB

Open AccessArticle

Mechanisms Underlying Activation of α₁-Adrenergic Receptor-Induced Trafficking of AQP5 in Rat Parotid Acinar Cells under Isotonic or Hypotonic Conditions

by Aneta M. Bragiel¹, Di Wang^1,†, Tomasz D. Pieczonka¹, Masayuki Shono² and Yasuko Ishikawa^1,*

¹ Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8504, Japan

² Support Center for Advanced Medical Sciences, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8504, Japan

^† Present address: Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China

Int. J. Mol. Sci. 2016, 17(7), 1022; https://doi.org/10.3390/ijms17071022 - 28 Jun 2016

Cited by 8 | Viewed by 6281

Abstract

Defective cellular trafficking of aquaporin-5 (AQP5) to the apical plasma membrane (APM) in salivary glands is associated with the loss of salivary fluid secretion. To examine mechanisms of α₁-adrenoceptor (AR)-induced trafficking of AQP5, immunoconfocal microscopy and Western blot analysis were used [...] Read more.

Defective cellular trafficking of aquaporin-5 (AQP5) to the apical plasma membrane (APM) in salivary glands is associated with the loss of salivary fluid secretion. To examine mechanisms of α₁-adrenoceptor (AR)-induced trafficking of AQP5, immunoconfocal microscopy and Western blot analysis were used to analyze AQP5 localization in parotid tissues stimulated with phenylephrine under different osmolality. Phenylephrine-induced trafficking of AQP5 to the APM and lateral plasma membrane (LPM) was mediated via the α_1A-AR subtype, but not the α_1B- and α_1D-AR subtypes. Phenylephrine-induced trafficking of AQP5 was inhibited by ODQ and KT5823, inhibitors of nitric oxide (NO)-stimulated guanylcyclase (GC) and protein kinase (PK) G, respectively, indicating the involvement of the NO/ soluble (c) GC/PKG signaling pathway. Under isotonic conditions, phenylephrine-induced trafficking was inhibited by La³⁺, implying the participation of store-operated Ca²⁺ channel. Under hypotonic conditions, phenylephrine-induced trafficking of AQP5 to the APM was higher than that under isotonic conditions. Under non-stimulated conditions, hypotonicity-induced trafficking of AQP5 to the APM was inhibited by ruthenium red and La³⁺, suggesting the involvement of extracellular Ca²⁺ entry. Thus, α_1A-AR activation induced the trafficking of AQP5 to the APM and LPM via the Ca²⁺/ cyclic guanosine monophosphate (cGMP)/PKG signaling pathway, which is associated with store-operated Ca²⁺ entry. Full article

(This article belongs to the Special Issue Aquaporin)

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27 pages, 3768 KiB

Open AccessReview

Roles of d-Amino Acids on the Bioactivity of Host Defense Peptides

by Hao Li¹, Nuttapat Anuwongcharoen¹, Aijaz Ahmad Malik¹, Virapong Prachayasittikul², Jarl E. S. Wikberg³ and Chanin Nantasenamat^1,*

¹ Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand

² Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand

³ Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden

Int. J. Mol. Sci. 2016, 17(7), 1023; https://doi.org/10.3390/ijms17071023 - 30 Jun 2016

Cited by 67 | Viewed by 10295

Abstract

Host defense peptides (HDPs) are positively-charged and amphipathic components of the innate immune system that have demonstrated great potential to become the next generation of broad spectrum therapeutic agents effective against a vast array of pathogens and tumor. As such, many approaches have [...] Read more.

Host defense peptides (HDPs) are positively-charged and amphipathic components of the innate immune system that have demonstrated great potential to become the next generation of broad spectrum therapeutic agents effective against a vast array of pathogens and tumor. As such, many approaches have been taken to improve the therapeutic efficacy of HDPs. Amongst these methods, the incorporation of d-amino acids (d-AA) is an approach that has demonstrated consistent success in improving HDPs. Although, virtually all HDP review articles briefly mentioned about the role of d-AA, however it is rather surprising that no systematic review specifically dedicated to this topic exists. Given the impact that d-AA incorporation has on HDPs, this review aims to fill that void with a systematic discussion of the impact of d-AA on HDPs. Full article

(This article belongs to the Special Issue Molecule- and Cell-Targeted Drug Design and Screening and Identification of Natural Product)

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14 pages, 1744 KiB

Open AccessArticle

Fourier Transform Mass Spectrometry and Nuclear Magnetic Resonance Analysis for the Rapid and Accurate Characterization of Hexacosanoylceramide

by Charles W. Ross^1,*, William J. Simonsick^2,†, Michael J. Bogusky¹, Recep W. Celikay^2,‡, James P. Guare¹ and Randall C. Newton¹

¹ Merck & Co. Inc., Merck Research Laboratories, Dept. of Medicinal Chemistry, West Point, PA 19486, USA

² DuPont Marshall R & D Laboratories, Philadelphia, PA 19146, USA

^† Current Address: Lubrizol Advanced Materials, Inc., 9911 Brecksville Rd., Brecksville, OH 44141-3201, USA

^‡ Current Address: DuPont Corporate Center for Analytical Sciences, DuPont Experimental Station, 200 Powder Mill Rd., PO Box 8352, Wilmington, DE 19803, USA

Int. J. Mol. Sci. 2016, 17(7), 1024; https://doi.org/10.3390/ijms17071024 - 28 Jun 2016

Cited by 1 | Viewed by 6176

Abstract

Ceramides are a central unit of all sphingolipids which have been identified as sites of biological recognition on cellular membranes mediating cell growth and differentiation. Several glycosphingolipids have been isolated, displaying immunomodulatory and anti-tumor activities. These molecules have generated considerable interest as potential [...] Read more.

Ceramides are a central unit of all sphingolipids which have been identified as sites of biological recognition on cellular membranes mediating cell growth and differentiation. Several glycosphingolipids have been isolated, displaying immunomodulatory and anti-tumor activities. These molecules have generated considerable interest as potential vaccine adjuvants in humans. Accurate analyses of these and related sphingosine analogues are important for the characterization of structure, biological function, and metabolism. We report the complementary use of direct laser desorption ionization (DLDI), sheath flow electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) and high-field nuclear magnetic resonance (NMR) analysis for the rapid, accurate identification of hexacosanoylceramide and starting materials. DLDI does not require stringent sample preparation and yields representative ions. Sheath-flow ESI yields ions of the product and byproducts and was significantly better than monospray ESI due to improved compound solubility. Negative ion sheath flow ESI provided data of starting materials and products all in one acquisition as hexacosanoic acid does not ionize efficiently when ceramides are present. NMR provided characterization of these lipid molecules complementing the results obtained from MS analyses. NMR data was able to differentiate straight chain versus branched chain alkyl groups not easily obtained from mass spectrometry. Full article

(This article belongs to the Special Issue Fourier Transform Mass Spectrometry in Molecular Sciences)

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12 pages, 1860 KiB

Open AccessArticle

CD133 Modulate HIF-1α Expression under Hypoxia in EMT Phenotype Pancreatic Cancer Stem-Like Cells

by Koki Maeda^1,2, Qiang Ding^1,3, Makoto Yoshimitsu⁴

, Taisaku Kuwahata^1,2, Yumi Miyazaki¹, Koichirou Tsukasa¹, Tomomi Hayashi², Hiroyuki Shinchi²

, Shoji Natsugoe² and Sonshin Takao^5,6,*

¹ Division of Cancer and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

² Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

³ Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Tronto, ON M5T 3M7, Canada

⁴ Department of Hematology and Immunology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

⁵ Center for Innovative Therapy Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

⁶ Tanegashima Medical Center, 7463 Nishi-no-omote, Nishi-no-omote 891-3198, Japan

Int. J. Mol. Sci. 2016, 17(7), 1025; https://doi.org/10.3390/ijms17071025 - 28 Jun 2016

Cited by 36 | Viewed by 8577

Abstract

Although CD133 is a known representative cancer stem cell marker, its function in tumor aggressiveness under hypoxia is not fully known. The aim of this study is to demonstrate that CD133 regulates hypoxia inducible factor (HIF)-1α expression with tumor migration. The CD133⁺ [...] Read more.

Although CD133 is a known representative cancer stem cell marker, its function in tumor aggressiveness under hypoxia is not fully known. The aim of this study is to demonstrate that CD133 regulates hypoxia inducible factor (HIF)-1α expression with tumor migration. The CD133⁺ pancreatic cancer cell line, Capan1M9, was compared with the CD133⁻ cell line, shCD133M9, under hypoxia. HIF-1α expression levels were compared by Western blot, HIF-1α nucleus translocation assay and real-time (RT)-PCR. The hypoxia responsive element (HRE) was observed by luciferase assay. The migration ability was analyzed by migration and wound healing assays. Epithelial mesenchymal transition (EMT) related genes were analyzed by real-time RT-PCR. HIF-1α was highly expressed in Capan1M9 compared to shCD133M9 under hypoxia because of the high activation of HRE. Furthermore, the migration ability of Capan1M9 was higher than that of shCD133M9 under hypoxia, suggesting higher expression of EMT related genes in Capan1M9 compared to shCD133M9. Conclusion: HIF-1α expression under hypoxia in CD133⁺ pancreatic cancer cells correlated with tumor cell migration through EMT gene expression. Understanding the function of CD133 in cancer aggressiveness provides a novel therapeutic approach to eradicate pancreatic cancer stem cells. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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21 pages, 3429 KiB

Open AccessReview

Fernblock (Polypodium leucotomos Extract): Molecular Mechanisms and Pleiotropic Effects in Light-Related Skin Conditions, Photoaging and Skin Cancers, a Review

by Concepcion Parrado¹, Marta Mascaraque², Yolanda Gilaberte³, Angeles Juarranz²

and Salvador Gonzalez^4,5,*

¹ Pathology Department, School of Medicine, Universidad de Málaga, Malaga 29071, Spain

² Biology Department, Sciences School, Universidad Autónoma de Madrid, Madrid 28049, Spain

³ Dermatology Service, Hospital San Jorge, Huesca 22004, Spain

⁴ Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA

⁵ Medicine Department, Alcalá University, Madrid 28805, Spain

Int. J. Mol. Sci. 2016, 17(7), 1026; https://doi.org/10.3390/ijms17071026 - 29 Jun 2016

Cited by 79 | Viewed by 19488

Abstract

Healthier life styles include increased outdoors time practicing sports and walking. This means increased exposure to the sun, leading to higher risk of sunburn, photoaging and skin cancer. In addition to topical barrier products, oral supplementations of various botanicals endowed with antioxidant activity [...] Read more.

Healthier life styles include increased outdoors time practicing sports and walking. This means increased exposure to the sun, leading to higher risk of sunburn, photoaging and skin cancer. In addition to topical barrier products, oral supplementations of various botanicals endowed with antioxidant activity are emerging as novel method of photoprotection. Polypodium leucotomos extract (PL, commercial name Fernblock^®, IFC Group, Spain) is a powerful antioxidant due to its high content of phenolic compounds. PL is administered orally, with proven safety, and it can also be used topically. Its mechanisms include inhibition of the generation and release of reactive oxygen species (ROS) by ultraviolet (UV) light. It also prevents UV- and ROS-induced DNA damage with inhibition of AP1 and NF-κB and protection of natural antioxidant enzyme systems. At the cellular level, PL decreases cellular apoptosis and necrosis mediated UV and inhibits abnormal extracellular matrix remodeling. PL reduces inflammation, prevents immunosuppression, activates tumor suppressor p53 and inhibits UV-induced cyclooxygenase-2 (COX-2) enzyme expression. In agreement with increased p53 activity, PL decreased UV radiation-induced cell proliferation. PL also prevents common deletions mitochondrial DNA damage induced by UVA, and MMP-1 expression induced Visible Light and Infrared Radiation. These cellular and molecular effects are reflected in inhibitions of carcinogenesis and photoaging. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food)

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13 pages, 1185 KiB

Open AccessArticle

Use of Different Proteases to Obtain Flaxseed Protein Hydrolysates with Antioxidant Activity

by Magdalena Karamać^1,*

, Agnieszka Kosińska-Cagnazzo^1,2 and Anna Kulczyk¹

¹ Department of Chemical and Physical Properties of Food, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10 Str., 10-748 Olsztyn, Poland

² Institute of Life Technologies, University of Applied Sciences and Arts Western Switzerland, Route du Rawyl 47, 1950 Sion, Switzerland

Int. J. Mol. Sci. 2016, 17(7), 1027; https://doi.org/10.3390/ijms17071027 - 29 Jun 2016

Cited by 95 | Viewed by 9334

Abstract

The antioxidant activity of flaxseed protein hydrolysates obtained using five different enzymes was evaluated. Proteins were isolated from flaxseed cake and were separately treated with papain, trypsin, pancreatin, Alcalase and Flavourzyme. The degree of hydrolysis (DH) was determined as the percentage of cleaved [...] Read more.

The antioxidant activity of flaxseed protein hydrolysates obtained using five different enzymes was evaluated. Proteins were isolated from flaxseed cake and were separately treated with papain, trypsin, pancreatin, Alcalase and Flavourzyme. The degree of hydrolysis (DH) was determined as the percentage of cleaved peptide bonds using a spectrophotometric method with o-phthaldialdehyde. The distribution of the molecular weights (MW) of the hydrolysis products was profiled using Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Tricine-SDS-PAGE) and size exclusion-high performance liquid chromatography (SE-HPLC) separations. The antioxidant activities of the protein isolate and hydrolysates were probed for their radical scavenging activity using 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) radical cation (ABTS^•+) and photochemiluminescence (PCL-ACL) assays, and for their ferric reducing antioxidant power (FRAP) and ability to bind Fe²⁺. The hydrolysates were more effective as antioxidants than the protein isolate in all systems. The PCL-ACL values of the hydrolysates ranged from 7.2 to 35.7 μmol Trolox/g. Both the FRAP and ABTS^•+ scavenging activity differed among the hydrolysates to a lower extent, with the ranges of 0.20–0.24 mmol Fe²⁺/g and 0.17–0.22 mmol Trolox/g, respectively. The highest chelating activity (71.5%) was noted for the pancreatin hydrolysate. In general, the hydrolysates obtained using Alcalase and pancreatin had the highest antioxidant activity, even though their DH (15.4% and 29.3%, respectively) and the MW profiles of the peptides varied substantially. The O₂^•− scavenging activity and the ability to chelate Fe²⁺ of the Flavourzyme hydrolysate were lower than those of the Alcalase and pancreatin hydrolysates. Papain was the least effective in releasing the peptides with antioxidant activity. The study showed that the type of enzyme used for flaxseed protein hydrolysis determines the antioxidant activity of the hydrolysates. Full article

(This article belongs to the Special Issue Macro- and Micro-nutrient Antioxidants)

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16 pages, 2134 KiB

Open AccessArticle

TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being

by Eleonora Da Pozzo

, Chiara Giacomelli, Barbara Costa

, Chiara Cavallini, Sabrina Taliani

, Elisabetta Barresi, Federico Da Settimo

and Claudia Martini^*

Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy

Int. J. Mol. Sci. 2016, 17(7), 1028; https://doi.org/10.3390/ijms17071028 - 29 Jun 2016

Cited by 38 | Viewed by 6250

Abstract

The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA) class were evaluated for their potential [...] Read more.

The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA) class were evaluated for their potential ability to affect the cellular Oxidative Metabolism Activity/Proliferation index, which is used as a measure of astrocyte well-being. The most active PIGA ligands were also assessed for steroidogenic activity in terms of pregnenolone production, and the values were related to the metabolic index in rat and human models. The results showed a positive correlation between the increase in the Oxidative Metabolism Activity/Proliferation index and the pharmacologically induced stimulation of steroidogenesis. The specific involvement of steroid molecules in mediating the metabolic effects of the PIGA ligands was demonstrated using aminoglutethimide, a specific inhibitor of the first step of steroid biosynthesis. The most promising steroidogenic PIGA ligands were the 2-naphthyl derivatives that showed a long residence time to the target, in agreement with our previous data. In conclusion, TSPO ligand-induced neurosteroidogenesis was involved in astrocyte well-being. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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18 pages, 723 KiB

Open AccessReview

Aquaporins and Brain Tumors

by Rosario Maugeri¹, Gabriella Schiera²

, Carlo Maria Di Liegro²

, Anna Fricano^1,2, Domenico Gerardo Iacopino¹ and Italia Di Liegro^1,*

¹ Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Palermo I-90127, Italy

² Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo (UNIPA), Palermo I-90128, Italy

Int. J. Mol. Sci. 2016, 17(7), 1029; https://doi.org/10.3390/ijms17071029 - 29 Jun 2016

Cited by 71 | Viewed by 7726

Abstract

Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate [...] Read more.

Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate throughout the brain and to stimulate angiogenesis, by inducing brain capillary endothelial cell proliferation. This in turn causes loss of tight junctions and fragility of the blood–brain barrier, which becomes leaky. As a consequence, the most serious clinical complication of glioblastoma is the vasogenic brain edema. Both glioma cell migration and edema have been correlated with modification of the expression/localization of different isoforms of aquaporins (AQPs), a family of water channels, some of which are also involved in the transport of other small molecules, such as glycerol and urea. In this review, we discuss relationships among expression/localization of AQPs and brain tumors/edema, also focusing on the possible role of these molecules as both diagnostic biomarkers of cancer progression, and therapeutic targets. Finally, we will discuss the possibility that AQPs, together with other cancer promoting factors, can be exchanged among brain cells via extracellular vesicles (EVs). Full article

(This article belongs to the Special Issue Aquaporin)

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21 pages, 1078 KiB

Open AccessReview

The Immunogenicity of Colorectal Cancer in Relation to Tumor Development and Treatment

by Natasja L. De Vries^1,2, Marloes Swets¹, Alexander L. Vahrmeijer¹, Marianne Hokland^2,† and Peter J. K. Kuppen^1,*,†

¹ Department of Surgery, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands

² Department of Biomedicine, Aarhus University, Bartholins Allé 6, Build. 1242, DK-8000 Aarhus, Denmark

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1030; https://doi.org/10.3390/ijms17071030 - 29 Jun 2016

Cited by 42 | Viewed by 7472

Abstract

Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important [...] Read more.

Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important implications for the design of novel immune-based therapies. Natural immune responses, but also therapeutic interventions, can modulate the tumor phenotype due to selective outgrowth of resistant subtypes. This is the result of heterogeneity of tumors, with genetic instability as a driving force, and obviously changes the immunogenicity of tumors. In this review, we discuss the immunogenicity of colorectal cancer (CRC) in relation to tumor development and treatment. As most tumors, CRC activates the immune system in various ways, and is also capable of escaping recognition and elimination by the immune system. Tumor-immune system interactions underlie the balance between immune control and immune escape, and may differ in primary tumors, in the circulation, and in liver metastases of CRC. Since CRC immunogenicity varies between tumors and individuals, novel immune-based therapeutic strategies should not only anticipate the molecular profile, but also the immunological profile of a specific tumor. Full article

(This article belongs to the Special Issue Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy)

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14 pages, 4601 KiB

Open AccessArticle

A WDR Gene Is a Conserved Member of a Chitin Synthase Gene Cluster and Influences the Cell Wall in Aspergillus nidulans

by Gea Guerriero^1,2,*,†

, Lucia Silvestrini^1,†, Michael Obersriebnig³, Jean-Francois Hausman²

, Joseph Strauss^1,4 and Inés Ezcurra^5,*

¹ Department of Applied Genetics and Cell Biology, Fungal Genetics and Genomics Unit, University of Natural Resources and Life Sciences Vienna (BOKU), Bioresources and Technologies Campus Tulln-Technopol, Tulln/Donau A-3430, Austria

² Environmental Research and Innovation (ERIN), Luxembourg Institute of Science and Technology (LIST), Esch/Alzette L-4362, Luxembourg

³ Institute of Wood Science and Technology, University of Natural Resources and Life Sciences Vienna (BOKU), Bioresources and Technologies Campus Tulln-Technopol, Tulln/Donau A-3430, Austria

⁴ Health and Environment Department, Austrian Institute of Technology GmbH—AIT, University and Research Center Campus Tulln-Technopol, Tulln/Donau A-3430, Austria

⁵ KTH, School of Biotechnology, Albanova, Stockholm SE-10691, Sweden

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1031; https://doi.org/10.3390/ijms17071031 - 29 Jun 2016

Cited by 6 | Viewed by 7044

Abstract

WD40 repeat (WDR) proteins are pleiotropic molecular hubs. We identify a WDR gene that is a conserved genomic neighbor of a chitin synthase gene in Ascomycetes. The WDR gene is unique to fungi and plants, and was called Fungal Plant WD (FPWD [...] Read more.

WD40 repeat (WDR) proteins are pleiotropic molecular hubs. We identify a WDR gene that is a conserved genomic neighbor of a chitin synthase gene in Ascomycetes. The WDR gene is unique to fungi and plants, and was called Fungal Plant WD (FPWD). FPWD is within a cell wall metabolism gene cluster in the Ascomycetes (Pezizomycotina) comprising chsD, a Chs activator and a GH17 glucanase. The FPWD, AN1556.2 locus was deleted in Aspergillus nidulans strain SAA.111 by gene replacement and only heterokaryon transformants were obtained. The re-annotation of Aspergilli genomes shows that AN1556.2 consists of two tightly linked separate genes, i.e., the WDR gene and a putative beta-flanking gene of unknown function. The WDR and the beta-flanking genes are conserved genomic neighbors localized within a recently identified metabolic cell wall gene cluster in genomes of Aspergilli. The heterokaryons displayed increased susceptibility to drugs affecting the cell wall, and their phenotypes, observed by optical, confocal, scanning electron and atomic force microscopy, suggest cell wall alterations. Quantitative real-time PCR shows altered expression of some cell wall-related genes. The possible implications on cell wall biosynthesis are discussed. Full article

(This article belongs to the Special Issue Microbial Genomics and Metabolomics)

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10 pages, 226 KiB

Open AccessArticle

Plasma Folate and Vitamin B₁₂ Levels in Patients with Hepatocellular Carcinoma

by Lian-Hua Cui^1,*,†, Zhen-Yu Quan^2,†, Jin-Mei Piao¹, Ting-Ting Zhang^1,3, Meng-Hui Jiang¹, Min-Ho Shin⁴ and Jin-Su Choi⁴

¹ Department of Public Health, Qingdao University Medical College, No. 38 Dengzhou Road, Qingdao 266021, China

² Department of Public Health, Yanbian University Medical College, No. 977 Gongyuan Road, Yanji 133002, China

³ Department of Oncology, Shengli Oil-Field Central Hospital, No. 31 Jinan Road, Dongying 257000, China

⁴ Department of Preventive Medicine, Chonnam National University Medical School, Gwangju 501-746, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1032; https://doi.org/10.3390/ijms17071032 - 30 Jun 2016

Cited by 27 | Viewed by 5653

Abstract

Folate and vitamin B₁₂ involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 [...] Read more.

Folate and vitamin B₁₂ involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B₁₂ in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients’ clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B₁₂ levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15–0.60), 0.33 (0.17–0.65), and 0.19 (0.09–0.38). Compared to the subjects in the lowest quartile of plasma vitamin B₁₂, only the subjects in the highest quartile of vitamin B₁₂ exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02–3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B₁₂ levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B₁₂ than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B₁₂ levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results. Full article

(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)

13 pages, 4000 KiB

Open AccessArticle

Effect of Antimicrobial Denture Base Resin on Multi-Species Biofilm Formation

by Keke Zhang¹, Biao Ren¹

, Xuedong Zhou^1,2, Hockin H. K. Xu³, Yu Chen⁴, Qi Han¹, Bolei Li^1,2, Michael D. Weir³, Mingyun Li¹, Mingye Feng^1,* and Lei Cheng^1,2,*

¹ State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China

² Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China

³ Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Dental School, Baltimore, MD 21201, USA

⁴ Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China

Int. J. Mol. Sci. 2016, 17(7), 1033; https://doi.org/10.3390/ijms17071033 - 29 Jun 2016

Cited by 47 | Viewed by 7394

Abstract

Our aims of the research were to study the antimicrobial effect of dimethylaminododecyl methacrylate (DMADDM) modified denture base resin on multi-species biofilms and the biocompatibility of this modified dental material. Candida albicans (C. albicans), Streptococcus mutans (S. mutans), Streptococcus [...] Read more.

Our aims of the research were to study the antimicrobial effect of dimethylaminododecyl methacrylate (DMADDM) modified denture base resin on multi-species biofilms and the biocompatibility of this modified dental material. Candida albicans (C. albicans), Streptococcus mutans (S. mutans), Streptococcus sanguinis (S. sanguinis), as well as Actinomyces naeslundii (A. naeslundii) were used for biofilm formation on denture base resin. Colony forming unit (CFU) counts, microbial viability staining, and 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) array were used to evaluate the antimicrobial effect of DMADDM. C. albicans staining and Real-time PCR were used to analyze the morphology and expression of virulence genes of C. albicans in biofilm. Lactate dehydrogenase (LDH) array and Real-time PCR were conducted to examine the results after biofilm co-cultured with epithelial cell. Hematoxylin and eosin (HE) staining followed by histological evaluation were used to study the biocompatibility of this modified material. We found that DMADDM containing groups reduced both biomass and metabolic activity of the biofilm significantly. DMADDM can also inhibit the virulence of C. albicans by means of inhibiting the hyphal development and downregulation of two virulence related genes. DMADDM significantly reduced the cell damage caused by multi-species biofilm according to the LDH activity and reduced the expression of IL-18 gene of the cells simultaneously. The in vivo histological evaluation proved that the addition of DMADDM less than 6.6% in denture material did not increase the inflammatory response (p > 0.05). Therefore, we proposed that the novel denture base resin containing DMADDM may be considered as a new promising therapeutic system against problems caused by microbes on denture base such as denture stomatitis. Full article

(This article belongs to the Special Issue Molecular Research on Dental Materials and Biomaterials)

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19 pages, 3467 KiB

Open AccessArticle

Evaluation of Housekeeping Genes for Quantitative Real-Time PCR Analysis of Bradysia odoriphaga (Diptera: Sciaridae)

by Caihua Shi^1,†

, Fengshan Yang^2,†, Xun Zhu³, Erxia Du⁴, Yuting Yang¹, Shaoli Wang³, Qingjun Wu³ and Youjun Zhang^3,*

¹ College of Agriculture, Yangtze University, Jingzhou 434025, China

² College of Life Science, Heilongjiang University, Harbin 150080, China

³ Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China

⁴ Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA

^† These authors contribute equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1034; https://doi.org/10.3390/ijms17071034 - 7 Jul 2016

Cited by 64 | Viewed by 7253

Abstract

The soil insect Bradysia odoriphaga (Diptera: Sciaridae) causes substantial damage to Chinese chive. Suitable reference genes in B. odoriphaga (Bradysia odoriphaga) have yet to be identified for normalizing target gene expression among samples by quantitative real-time PCR (qRT-PCR). This study was [...] Read more.

The soil insect Bradysia odoriphaga (Diptera: Sciaridae) causes substantial damage to Chinese chive. Suitable reference genes in B. odoriphaga (Bradysia odoriphaga) have yet to be identified for normalizing target gene expression among samples by quantitative real-time PCR (qRT-PCR). This study was focused on identifying the expression stability of 12 candidate housekeeping genes in B. odoriphaga under various experiment conditions. The final stability ranking of 12 housekeeping genes was obtained with RefFinder, and the most suitable number of reference genes was analyzed by GeNorm. The results revealed that the most appropriate sets of internal controls were RPS15, RPL18, and RPS18 across developmental phases; RPS15, RPL28, and GAPDH across temperatures; RPS15 and RPL18 across pesticide treatments; RSP5, RPS18, and SDHA across photoperiods; ACTb, RPS18, and RPS15 across diets; RPS13 and RPL28 across populations; and RPS15, ACTb, and RPS18 across all samples. The use of the most suitable reference genes versus an arbitrarily selected reference gene resulted in significant differences in the analysis of a target gene expression. HSP23 in B. odoriphaga was found to be up-regulated under low temperatures. These results will contribute to the standardization of qRT-PCR and will also be valuable for further research on gene function in B. odoriphaga. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 1374 KiB

Open AccessArticle

Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer’s Disease

by Ivana Cacciatore¹

, Lisa Marinelli¹, Erika Fornasari¹, Laura S. Cerasa¹, Piera Eusepi¹, Hasan Türkez^1,2, Cristina Pomilio^1,3, Marcella Reale⁴, Chiara D’Angelo⁴

, Erica Costantini⁴

and Antonio Di Stefano^1,*

¹ Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy

² Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25240, Turkey

³ Dompé Farmaceutici S.p.A.,Via Campo di Pile, 67100 L’Aquila (AQ), Italy

⁴ Department of Medical Oral and Biotechnological Sciences, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy

Int. J. Mol. Sci. 2016, 17(7), 1035; https://doi.org/10.3390/ijms17071035 - 30 Jun 2016

Cited by 33 | Viewed by 7069

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived [...] Read more.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL4–9) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)-α-lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and Aβ(25–35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1β and TNF-α in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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15 pages, 2998 KiB

Open AccessArticle

Demethyleneberberine Protects against Hepatic Fibrosis in Mice by Modulating NF-κB Signaling

by Yongchen Wang^1,2, Zheng Zhao³, Yan Yan¹, Xiaoyan Qiang¹, Cuisong Zhou¹, Ruiyan Li¹, Huan Chen¹ and Yubin Zhang^1,4,*

¹ State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China

² Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA

³ Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210009, China

⁴ Department of Biochemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China

Int. J. Mol. Sci. 2016, 17(7), 1036; https://doi.org/10.3390/ijms17071036 - 30 Jun 2016

Cited by 75 | Viewed by 6641

Abstract

Demethyleneberberine (DMB) is an essential metabolite of Berberine (BBR) in vivo. Recent reports have revealed multiple novel therapeutic applications of BBR. However, the pharmacological activities of DMB remain to be elucidated. This study aimed to demonstrate the hepatoprotective and anti-fibrotic effects of DMB [...] Read more.

Demethyleneberberine (DMB) is an essential metabolite of Berberine (BBR) in vivo. Recent reports have revealed multiple novel therapeutic applications of BBR. However, the pharmacological activities of DMB remain to be elucidated. This study aimed to demonstrate the hepatoprotective and anti-fibrotic effects of DMB both in vitro and in vivo. Here we showed that DMB protects against thioacetamide (TAA)-induced hepatic fibrosis in mice and exhibits a higher safety profile as compared to BBR. Flow cytometry and Western blotting analysis showed that DMB is able to suppress the activation of hepatic stellate cells (HSCs) and induce cell apoptosis through the nuclear factor-κB (NF-κB) cascade. Immunohistochemical (IHC) and quantitative polymerase chain reaction (qPCR) analysis indicated that DMB also has inhibitory effects on collagen synthesis and is able to increase collagen degradation by blocking the transforming growth factor β 1 (TGF-β1)-Smad signaling and reducing the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs). These findings indicate that DMB has the potential to attenuate hepatic fibrosis via suppressing HSC activation. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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14 pages, 509 KiB

Open AccessReview

The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy

by Shudong Wang¹

, Lijuan Ding², Honglei Ji¹, Zheng Xu¹, Quan Liu^1,* and Yang Zheng^1,*

¹ Cardiovascular Center, The First Hospital of Jilin University, Changchun 130021, China

² Department of Radiation Oncology, the First Hospital of Jilin University, Changchun 130021, China

Int. J. Mol. Sci. 2016, 17(7), 1037; https://doi.org/10.3390/ijms17071037 - 30 Jun 2016

Cited by 99 | Viewed by 11016

Abstract

Diabetic cardiomyopathy (DCM) is a major complication of diabetes that contributes to an increase in mortality. A number of mechanisms potentially explain the development of DCM including oxidative stress, inflammation and extracellular fibrosis. Mitogen-activated protein kinase (MAPK)-mediated signaling pathways are common among these [...] Read more.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes that contributes to an increase in mortality. A number of mechanisms potentially explain the development of DCM including oxidative stress, inflammation and extracellular fibrosis. Mitogen-activated protein kinase (MAPK)-mediated signaling pathways are common among these pathogenic responses. Among the diverse array of kinases, extensive attention has been given to p38 MAPK due to its capacity for promoting or inhibiting the translation of target genes. Growing evidence has indicated that p38 MAPK is aberrantly expressed in the cardiovascular system, including the heart, under both experimental and clinical diabetic conditions and, furthermore, inhibition of p38 MAPK activation in transgenic animal model or with its pharmacologic inhibitor significantly prevents the development of DCM, implicating p38 MAPK as a novel diagnostic indicator and therapeutic target for DCM. This review summarizes our current knowledge base to provide an overview of the impact of p38 MAPK signaling in diabetes-induced cardiac remodeling and dysfunction. Full article

(This article belongs to the Special Issue Diabetic Complications: Pathophysiology, Mechanisms, and Therapies)

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6 pages, 717 KiB

Open AccessEditorial

Natural Bioactive Compounds: The Way Shown by Professor Maurizio Battino and His Group in an Italian Cutting-Edge Laboratory

by International Journal of Molecular Sciences Editorial Office

MDPI AG, Klybeckstrasse 64, CH-4057 Basel, Switzerland

Int. J. Mol. Sci. 2016, 17(7), 1038; https://doi.org/10.3390/ijms17071038 - 5 Jul 2016

Viewed by 8925

Abstract

Maurizio Battino, Ph.D., Associate Professor of Biochemistry in the Department of Clinical Sciences, Faculty of Medicine, Università Politecnica delle Marche (Italy), is the Director of the Centre for Health and Nutrition, Universidad Europea del Atlantico (Santander, Spain) and Director of Nutrition and Health [...] Read more.

Maurizio Battino, Ph.D., Associate Professor of Biochemistry in the Department of Clinical Sciences, Faculty of Medicine, Università Politecnica delle Marche (Italy), is the Director of the Centre for Health and Nutrition, Universidad Europea del Atlantico (Santander, Spain) and Director of Nutrition and Health projects and Master courses at FUNIBER on-line platform (Barcelona, Spain).[...] Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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9 pages, 201 KiB

Open AccessArticle

Prognostic Value of Affective Symptoms in First-Admission Psychotic Patients

by Marta Arrasate^1,*, Itxaso González-Ortega², Adriana García-Alocén², Susana Alberich², Iñaki Zorrilla² and Ana González-Pinto²

¹ RSMB-Algorta-Vizcaya, Osakidetza, University of the Basque Country (EHU/UPV), Leioa 48940, Vizcaya, Spain

² CIBERSAM, BIOARABA Health Research Institute, OSI Araba, Department of Psychiatry, Araba University Hospital-Santiago, University of the Basque Country (EHU/UPV), Vitoria 01004, Alava, Spain

Int. J. Mol. Sci. 2016, 17(7), 1039; https://doi.org/10.3390/ijms17071039 - 30 Jun 2016

Cited by 17 | Viewed by 5565

Abstract

Background: Very little research has been conducted in patients with first-episode psychosis using a dimensional approach. Affective dimensional representations might be useful to predict the clinical course and treatment needs in such patients. Methods: Weincluded 112 patients with first-episode psychosis in a longitudinal-prospective [...] Read more.

Background: Very little research has been conducted in patients with first-episode psychosis using a dimensional approach. Affective dimensional representations might be useful to predict the clinical course and treatment needs in such patients. Methods: Weincluded 112 patients with first-episode psychosis in a longitudinal-prospective study with a five-year follow-up (N = 82). Logistic analyses were performed to determine the predictive factors associated with depressive, manic, activation, and dysphoric dimensions. Results: High scores on the depressive dimension were associated with the best prognosis. On the other hand, high scores on the activation dimension and the manic dimension were associated with a poorer prognosis in terms of relapses. Only the dysphoric dimension was not associated with syndromic or functional prognosis. Conclusion: Ourresults suggest that the pattern of baseline affective symptoms helps to predict the course of psychotic illness. Therefore, the systematic assessment of affective symptoms would enable us to draw important conclusions regarding patients’ prognosis. Interventions for patients with high scores on manic or activation dimensions could be beneficial in decreasing relapses in first-episode psychosis. Full article

(This article belongs to the Special Issue Big Data Analysis and QSAR/QSPR Research in Chemistry, Bio-Medical, and Network Sciences)

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26 pages, 1717 KiB

Open AccessReview

Cell Models and Their Application for Studying Adipogenic Differentiation in Relation to Obesity: A Review

by Francisco Javier Ruiz-Ojeda^1,2

, Azahara Iris Rupérez¹, Carolina Gomez-Llorente^1,2,3

, Angel Gil^1,2,3

and Concepción María Aguilera^1,2,3,*

¹ Department of Biochemistry and Molecular Biology II, School of Pharmacy, Campus de Cartuja s/n, 18071, Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, Avenida del Conocimiento s/n, 18016, University of Granada, Granada 18071, Spain

² Instituto de Investigación Biosanitaria ibs, Complejo Hospitalario Universitario de Granada/Universidad de Granada, Granada 18014, Spain

³ CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain

Int. J. Mol. Sci. 2016, 17(7), 1040; https://doi.org/10.3390/ijms17071040 - 30 Jun 2016

Cited by 299 | Viewed by 19762

Abstract

Over the last several years, the increasing prevalence of obesity has favored an intense study of adipose tissue biology and the precise mechanisms involved in adipocyte differentiation and adipogenesis. Adipocyte commitment and differentiation are complex processes, which can be investigated thanks to the [...] Read more.

Over the last several years, the increasing prevalence of obesity has favored an intense study of adipose tissue biology and the precise mechanisms involved in adipocyte differentiation and adipogenesis. Adipocyte commitment and differentiation are complex processes, which can be investigated thanks to the development of diverse in vitro cell models and molecular biology techniques that allow for a better understanding of adipogenesis and adipocyte dysfunction associated with obesity. The aim of the present work was to update the different animal and human cell culture models available for studying the in vitro adipogenic differentiation process related to obesity and its co-morbidities. The main characteristics, new protocols, and applications of the cell models used to study the adipogenesis in the last five years have been extensively revised. Moreover, we depict co-cultures and three-dimensional cultures, given their utility to understand the connections between adipocytes and their surrounding cells in adipose tissue. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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7 pages, 347 KiB

Open AccessCommunication

Usefulness of Aquaporin 1 as a Prognostic Marker in a Prospective Cohort of Malignant Mesotheliomas

by Jack Driml¹, Emily Pulford¹, David Moffat², Christos Karapetis³, Steven Kao⁴, Kim Griggs¹, Douglas Warrington Henderson²

and Sonja Klebe^1,2,*

¹ Department of Anatomical Pathology, Flinders University of South Australia, Bedford Park, South Australia 5042, Australia

² Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Bedford Park, South Australia 5042, Australia

³ Medical Oncology, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia

⁴ Asbestos Diseases Research Institute, Bernie Banton Centre, Concord Repatriation General Hospital, Concord 2139 Sydney, Australia

Int. J. Mol. Sci. 2016, 17(7), 1041; https://doi.org/10.3390/ijms17071041 - 30 Jun 2016

Cited by 10 | Viewed by 4391

Abstract

(1) Background: Malignant mesothelioma (MM) is an aggressive tumour of the serosal membranes, associated with exposure to asbestos. Survival is generally poor, but prognostication for individual patients is difficult. We recently described Aquaporin 1 (AQP1) as independent prognostic factor in two separate retrospective [...] Read more.

(1) Background: Malignant mesothelioma (MM) is an aggressive tumour of the serosal membranes, associated with exposure to asbestos. Survival is generally poor, but prognostication for individual patients is difficult. We recently described Aquaporin 1 (AQP1) as independent prognostic factor in two separate retrospective cohorts of MM patients. Here we assess the usefulness of AQP1 prospectively, and determine the inter-observer agreement in assessing AQP1 scores; (2) Methods: A total of 104 consecutive cases of MM were included. Sufficient tissue for immunohistochemistry was available for 100 cases, and these cases were labelled for AQP1. Labelling was assessed by two pathologists. Complete clinical information and follow up was available for 91 cases; (3) Results: Labelling of ≥50% of tumour cells for AQP indicated improved prognosis in a univariate model (median survival 13 versus 8 months, p = 0.008), but the significance was decreased in a multivariate analysis. Scoring for AQP1 was robust, with an inter-observer kappa value of 0.722, indicating substantial agreement between observers; (4) Conclusion: AQP1 is a useful prognostic marker that can be easily incorporated in existing diagnostic immunohistochemical panels and which can be reliably interpreted by different pathologists. Full article

(This article belongs to the Special Issue Aquaporin)

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15 pages, 3441 KiB

Open AccessArticle

Analysis of the Interaction of Dp44mT with Human Serum Albumin and Calf Thymus DNA Using Molecular Docking and Spectroscopic Techniques

by Zhongjie Xu^1,†, Youxun Liu^2,†, Sufeng Zhou², Yun Fu² and Changzheng Li^2,3,*

¹ College of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China

² Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453003, China

³ Henan Collaborative Innovation Center of Molecular Diagnostics and Laboratory Medicine, Xinxiang 453003, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1042; https://doi.org/10.3390/ijms17071042 - 30 Jun 2016

Cited by 19 | Viewed by 5355 | Correction

Abstract

Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) exhibits significant antitumor activity. However, the mechanism of its pharmacological interaction with human serum albumin (HSA) and DNA remains poorly understood. Here, we aimed to elucidate the interactions of Dp44mT with HSA and DNA using MTT assays, spectroscopic methods, and molecular [...] Read more.

Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) exhibits significant antitumor activity. However, the mechanism of its pharmacological interaction with human serum albumin (HSA) and DNA remains poorly understood. Here, we aimed to elucidate the interactions of Dp44mT with HSA and DNA using MTT assays, spectroscopic methods, and molecular docking analysis. Our results indicated that addition of HSA at a ratio of 1:1 did not alter the cytotoxicity of Dp44mT, but did affect the cytotoxicity of the Dp44mT-Cu complex. Data from fluorescence quenching and UV-VIS absorbance measurements demonstrated that Dp44mT could bind to HSA with a moderate affinity (K_a = approximately 10⁴ M⁻¹). CD spectra revealed that Dp44mT could slightly disrupt the secondary structure of HSA. Dp44mT could also interact with Ct-DNA, but had a moderate binding constant (K_EB = approximately 10⁴ M⁻¹). Docking studies indicated that the IB site of HSA, but not the IIA and IIIA sites, could be favorable for Dp44mT and that binding of Dp44mT to HSA involved hydrogen bonds and hydrophobic force, consistent with thermodynamic results from spectral investigations. Thus, the moderate binding affinity of Dp44mT with HSA and DNA partially contributed to its antitumor activity and may be preferable in drug design approaches. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 233 KiB

Open AccessReview

Clinical Application of Human Urinary Extracellular Vesicles in Kidney and Urologic Diseases

by Giuseppe De Palma^1,2

, Fabio Sallustio³

and Francesco Paolo Schena^2,*

¹ C.A.R.S.O. Consortium, University of Bari, Valenzano 70010, Italy

² Schena Foundation—European Research Center for Kidney Diseases, Valenzano 70010, Italy

³ Department of Emergency and Organ Transplantation, University of Bari, DETO, Bari 70124, Italy

Int. J. Mol. Sci. 2016, 17(7), 1043; https://doi.org/10.3390/ijms17071043 - 30 Jun 2016

Cited by 24 | Viewed by 6037

Abstract

Extracellular vesicles (EVs) have been isolated in different body fluids, including urine. The cargo of urinary EVs is composed of nucleic acids and proteins reflecting the physiological and possibly pathophysiological state of cells lining the nephron and the urinary tract. Urinary EVs have [...] Read more.

Extracellular vesicles (EVs) have been isolated in different body fluids, including urine. The cargo of urinary EVs is composed of nucleic acids and proteins reflecting the physiological and possibly pathophysiological state of cells lining the nephron and the urinary tract. Urinary EVs have been confirmed to contain low amounts of various types of RNA that play a role in intercellular communication by transferring genetic information. This communication through EV RNAs includes both continuation of normal physiological processes and conditioning in disease mechanisms. Although proteins included in urinary EVs represent only 3% of the whole-urine proteome, urinary EVs can influence cells in the renal epithelia not only by delivering RNA cargo, but also by delivering a wide range of proteins. Since urine is a readily available biofluid, the discovery of EVs has opened a new field of biomarker research. The potential use of urinary EV RNAs and proteins as diagnostic biomarkers for various kidney and urologic diseases is currently being explored. Here, we review recent studies that deal in identifying biomarker candidates for human kidney and urologic diseases using urinary EVs and might help to understand the pathophysiology. Full article

(This article belongs to the Special Issue Focus on Extracellular Vesicles)

14 pages, 2224 KiB

Open AccessArticle

The Effect and Action Mechanisms of Oligochitosan on Control of Stem Dry Rot of Zanthoxylum bungeanum

by Peiqin Li^1,*, Zhimin Cao¹, Zhou Wu¹, Xing Wang² and Xiuhong Li³

¹ Department of Forest Protection, College of Forestry, Northwest A&F University, Yangling 712100, China

² Department of Chemistry and Chemical Biology & the Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA

³ Department of Chemical Processing of Forest Products, College of Forestry, Northwest A&F University, Yangling 712100, China

Int. J. Mol. Sci. 2016, 17(7), 1044; https://doi.org/10.3390/ijms17071044 - 30 Jun 2016

Cited by 12 | Viewed by 5108

Abstract

In this report, the effects of two oligochitosans, i.e., oligochitosan A (OCHA) and oligochitosan B (OCHB), on control of dry rot of Zanthoxylum bungeanum (Z. bungeanum) caused by Fusarium sambucinum (F. sambucinum) were evaluated. First, both oligochitosans show desirable [...] Read more.

In this report, the effects of two oligochitosans, i.e., oligochitosan A (OCHA) and oligochitosan B (OCHB), on control of dry rot of Zanthoxylum bungeanum (Z. bungeanum) caused by Fusarium sambucinum (F. sambucinum) were evaluated. First, both oligochitosans show desirable ability to decrease the infection of F. sambucinum. Second, the oligochitosans strongly inhibit the radial colony and submerged biomass growth of F. sambucinum. Lastly, these oligochitosans are capable of increasing the activities of phenylalanine ammonia lyase (PAL), polyphenoloxidase (PPO) and peroxidase (POD) significantly, as well as enhancing the content of total phenolics in Z. bungeanum stems. These findings indicate that the protective effects of OCHA and OCHB on Z. bungeanum stems against dry rot may be associated with the direct fungitoxic function against pathogen and the elicitation of biochemical defensive responses in Z. bungeanum stems. The outcome of this report suggests that oligochitosans may serve as a promising natural fungicide to substitute, at least partially, for synthetic fungicides in the disease management of Z. bungeanum. Full article

(This article belongs to the Section Molecular Plant Sciences)

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14 pages, 1292 KiB

Open AccessReview

Role of Aquaporins in a Composite Model of Water Transport in the Leaf

by Adi Yaaran and Menachem Moshelion^*

Faculty of Agriculture, Food and Environment, The Robert H. Smith Institute of Plant Sciences and Genetics in Agriculture, The Hebrew University of Jerusalem, Rehovot 76100, Israel

Int. J. Mol. Sci. 2016, 17(7), 1045; https://doi.org/10.3390/ijms17071045 - 30 Jun 2016

Cited by 15 | Viewed by 6169

Abstract

Water-transport pathways through the leaf are complex and include several checkpoints. Some of these checkpoints exhibit dynamic behavior that may be regulated by aquaporins (AQPs). To date, neither the relative weight of the different water pathways nor their molecular mechanisms are well understood. [...] Read more.

Water-transport pathways through the leaf are complex and include several checkpoints. Some of these checkpoints exhibit dynamic behavior that may be regulated by aquaporins (AQPs). To date, neither the relative weight of the different water pathways nor their molecular mechanisms are well understood. Here, we have collected evidence to support a putative composite model of water pathways in the leaf and the distribution of water across those pathways. We describe how water moves along a single transcellular path through the parenchyma and continues toward the mesophyll and stomata along transcellular, symplastic and apoplastic paths. We present evidence that points to a role for AQPs in regulating the relative weight of each path in the overall leaf water-transport system and the movement of water between these paths as a result of the integration of multiple signals, including transpiration demand, water potential and turgor. We also present a new theory, the hydraulic fuse theory, to explain effects of the leaf turgor-loss-point on water paths alternation and the subsequent reduction in leaf hydraulic conductivity. An improved understating of leaf water-balance management may lead to the development of crops that use water more efficiently, and responds better to environmental changes. Full article

(This article belongs to the Section Molecular Plant Sciences)

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3 pages, 822 KiB

Open AccessCommentary

PD-L1 Immunohistochemical Detection in Tumor Cells and Tumor Microenvironment: Main Considerations on the Use of Tissue Micro Arrays

by Gerardo Botti, Giosuè Scognamiglio and Monica Cantile^*

Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, via Mariano Semmola, 80131 Napoli, Italy

Int. J. Mol. Sci. 2016, 17(7), 1046; https://doi.org/10.3390/ijms17071046 - 30 Jun 2016

Cited by 21 | Viewed by 5521

Abstract

PD-1/PD-L1 (programmed death 1/programmed death ligand 1) pathway plays a critical role in immune escape of tumor cells. Recent studies have described that PD-L1 is heterogeneously expressed in various types of cancer, although its prognostic/predictive value is still uncertain. These problems are partly [...] Read more.

PD-1/PD-L1 (programmed death 1/programmed death ligand 1) pathway plays a critical role in immune escape of tumor cells. Recent studies have described that PD-L1 is heterogeneously expressed in various types of cancer, although its prognostic/predictive value is still uncertain. These problems are partly due to a not well defined operating protocol for its detection by immunohistochemistry, but also because most of the studies conducted on large case series were made by Tissue Micro Array (TMA). We are going to discuss this latter point, to highlight that TMA must be set up in an appropriate manner, especially for some markers, such as PD-L1, which, besides being poorly expressed in tumor cells, can be expressed by cells of the tumor microenvironment. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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8 pages, 1746 KiB

Open AccessCommunication

In Situ Electron Microscopy of Lactomicroselenium Particles in Probiotic Bacteria

by Gabor Nagy¹, Gyula Pinczes¹, Gabor Pinter¹, Istvan Pocsi¹, Jozsef Prokisch² and Gaspar Banfalvi^1,*

¹ Department of Biotechnology and Microbiology, University of Debrecen, Debrecen 4010, Hungary

² Department of Animal Breeding, University of Debrecen, Debrecen 4010, Hungary

Int. J. Mol. Sci. 2016, 17(7), 1047; https://doi.org/10.3390/ijms17071047 - 30 Jun 2016

Cited by 24 | Viewed by 7668

Abstract

Electron microscopy was used to test whether or not (a) in statu nascendi synthesized, and in situ measured, nanoparticle size does not differ significantly from the size of nanoparticles after their purification; and (b) the generation of selenium is detrimental to the bacterial [...] Read more.

Electron microscopy was used to test whether or not (a) in statu nascendi synthesized, and in situ measured, nanoparticle size does not differ significantly from the size of nanoparticles after their purification; and (b) the generation of selenium is detrimental to the bacterial strains that produce them. Elemental nano-sized selenium produced by probiotic latic acid bacteria was used as a lactomicroselenium (lactomicroSel) inhibitor of cell growth in the presence of lactomicroSel, and was followed by time-lapse microscopy. The size of lactomicroSel produced by probiotic bacteria was measured in situ and after isolation and purification. For these measurements the TESLA BS 540 transmission electron microscope was converted from analog (aTEM) to digital processing (dTEM), and further to remote-access internet electron microscopy (iTEM). Lactobacillus acidophilus produced fewer, but larger, lactomicroSel nanoparticles (200–350 nm) than Lactobacillus casei (L. casei), which generated many, smaller lactomicroSel particles (85–200 nm) and grains as a cloudy, less electrodense material. Streptococcus thermophilus cells generated selenoparticles (60–280 nm) in a suicidic manner. The size determined in situ in lactic acid bacteria was significantly lower than those measured by scanning electron microscopy after the isolation of lactomicroSel particles obtained from lactobacilli (100–500 nm), but higher relative to those isolated from Streptococcus thermopilus (50–100 nm). These differences indicate that smaller lactomicroSel particles could be more toxic to the producing bacteria themselves and discrepancies in size could have implications with respect to the applications of selenium nanoparticles as prebiotics. Full article

(This article belongs to the Special Issue Inorganic Nanostructures in Biological Systems)

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11 pages, 1137 KiB

Open AccessArticle

The Salicylic Acid-Mediated Release of Plant Volatiles Affects the Host Choice of Bemisia tabaci

by Xiaobin Shi^1,2

, Gong Chen¹, Lixia Tian¹, Zhengke Peng¹, Wen Xie¹, Qingjun Wu¹, Shaoli Wang¹, Xuguo Zhou³ and Youjun Zhang^1,*

¹ Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China

² Plant Protection Institute, Hunan Academy of Agricultural Sciences, Changsha 410125, China

³ Department of Entomology, University of Kentucky, Lexington, KY 40546, USA

Int. J. Mol. Sci. 2016, 17(7), 1048; https://doi.org/10.3390/ijms17071048 - 30 Jun 2016

Cited by 35 | Viewed by 6948

Abstract

The whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) causes serious crop losses worldwide by transmitting viruses. We have previously shown that salicylic acid (SA)-related plant defenses directly affect whiteflies. In this study, we applied exogenous SA to tomato plants in order to investigate the [...] Read more.

The whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) causes serious crop losses worldwide by transmitting viruses. We have previously shown that salicylic acid (SA)-related plant defenses directly affect whiteflies. In this study, we applied exogenous SA to tomato plants in order to investigate the interaction between SA-induced plant volatiles and nonviruliferous B. tabaci B and Q or B- and Q-carrying tomato yellow leaf curl virus (TYLCV). The results showed that exogenous SA caused plants to repel nonviruliferous whiteflies, but the effect was reduced when the SA concentration was low and when the whiteflies were viruliferous. Exogenous SA increased the number and quantity of plant volatiles—especially the quantity of methyl salicylate and δ-limonene. In Y-tube olfactometer assays, methyl salicylate and δ-limonene repelled the whiteflies, but the repellency was reduced for viruliferous Q. We suggest that the release of plant volatiles as mediated by SA affects the interaction between whiteflies, plants, and viruses. Further studies are needed to determine why viruliferous Q is less sensitive than nonviruliferous Q to repellent plant volatiles. Full article

(This article belongs to the Special Issue Plant-Insect Interactions)

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18 pages, 4613 KiB

Open AccessArticle

Analysis of the Mitochondrial Genome in Hypomyces aurantius Reveals a Novel Twintron Complex in Fungi

by Youjin Deng^1,2, Qihui Zhang³, Ray Ming³, Longji Lin¹, Xiangzhi Lin¹, Yiying Lin¹, Xiao Li¹, Baogui Xie¹ and Zhiqiang Wen^1,*

¹ Mycological Research Center, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China

² Center for Genomics and Biotechnology, Haixia Institute of Science and Technology, Fujian Agriculture and Forestry University, Fuzhou 350002, China

³ Gutian Edible Fungal Research and Development Center, Ningde 352200, China

Int. J. Mol. Sci. 2016, 17(7), 1049; https://doi.org/10.3390/ijms17071049 - 30 Jun 2016

Cited by 26 | Viewed by 7933

Abstract

Hypomyces aurantius is a mycoparasite that causes cobweb disease, a most serious disease of cultivated mushrooms. Intra-species identification is vital for disease control, however the lack of genomic data makes development of molecular markers challenging. Small size, high copy number, and high mutation [...] Read more.

Hypomyces aurantius is a mycoparasite that causes cobweb disease, a most serious disease of cultivated mushrooms. Intra-species identification is vital for disease control, however the lack of genomic data makes development of molecular markers challenging. Small size, high copy number, and high mutation rate of fungal mitochondrial genome makes it a good candidate for intra and inter species differentiation. In this study, the mitochondrial genome of H. H.a0001 was determined from genomic DNA using Illumina sequencing. The roughly 72 kb genome shows all major features found in other Hypocreales: 14 common protein genes, large and small subunit rRNAs genes and 27 tRNAs genes. Gene arrangement comparison showed conserved gene orders in Hypocreales mitochondria are relatively conserved, with the exception of Acremonium chrysogenum and Acremonium implicatum. Mitochondrial genome comparison also revealed that intron length primarily contributes to mitogenome size variation. Seventeen introns were detected in six conserved genes: five in cox1, four in rnl, three in cob, two each in atp6 and cox3, and one in cox2. Four introns were found to contain two introns or open reading frames: cox3-i2 is a twintron containing two group IA type introns; cox2-i1 is a group IB intron encoding two homing endonucleases; and cox1-i4 and cox1-i3 both contain two open reading frame (ORFs). Analyses combining secondary intronic structures, insertion sites, and similarities of homing endonuclease genes reveal two group IA introns arranged side by side within cox3-i2. Mitochondrial data for H. aurantius provides the basis for further studies relating to population genetics and species identification. Full article

(This article belongs to the Section Biochemistry)

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10 pages, 209 KiB

Open AccessArticle

Age-Specific Lipid and Fatty Acid Profiles of Atlantic Salmon Juveniles in the Varzuga River

by Svetlana A. Murzina^*, Zinaida A. Nefedova, Svetlana N. Pekkoeva

, Alexey E. Veselov, Denis A. Efremov and Nina N. Nemova

Institute of Biology, Karelian Research Centre of the Russian Academy of Sciences, Petrozavodsk 185910, Russia

Int. J. Mol. Sci. 2016, 17(7), 1050; https://doi.org/10.3390/ijms17071050 - 30 Jun 2016

Cited by 10 | Viewed by 4614

Abstract

The age-specific lipid and fatty acid profiles of juvenile Atlantic salmon at different ages (0+, 1+, and 2+ years) after hatching from nests located in the mainstream of a large Arctic River, the Varzuga River, and resettling to the favorable Sobachji shoal in [...] Read more.

The age-specific lipid and fatty acid profiles of juvenile Atlantic salmon at different ages (0+, 1+, and 2+ years) after hatching from nests located in the mainstream of a large Arctic River, the Varzuga River, and resettling to the favorable Sobachji shoal in autumn before overwinter are herein presented. The contemporary methods of the lipid analysis were used: thin layer chromatography and gas chromatography. The results show that the stability of the regulation of important functions in developing organisms is maintained through structural alterations in lipids. These alterations can be considered as a sequence of the modifications and changes in the ratios of certain lipid classes and fatty acids constituents. In general, changes in the lipids and fatty acids (FAs) maintained the physiological limits and controls through the adaptive systems of the organism. The mechanisms of juvenile fish biochemical adaptation to the environmental conditions in the studied biotope include the modification of the energy metabolism and anabolism, and here belongs to the energy characteristics of metabolic processes. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

19 pages, 3109 KiB

Open AccessArticle

Stanniocalcin-1 Protects a Mouse Model from Renal Ischemia-Reperfusion Injury by Affecting ROS-Mediated Multiple Signaling Pathways

by Dajun Liu^*, Huiping Shang and Ying Liu

Department of Nephrology, Shengjing Affiliated Hospital of China Medical University, Shenyang 110036, China

Int. J. Mol. Sci. 2016, 17(7), 1051; https://doi.org/10.3390/ijms17071051 - 12 Jul 2016

Cited by 43 | Viewed by 7688

Abstract

Stanniocalcin-1 (STC-1) protects against renal ischemia-reperfusion injury (RIRI). However, the molecular mechanisms remain widely unknown. STC-1 inhibits reactive oxygen species (ROS), whereas most ROS-mediated pathways are associated with ischemic injury. Therefore, to explore the mechanism, the effects of STC-1 on ROS-medicated pathways were [...] Read more.

Stanniocalcin-1 (STC-1) protects against renal ischemia-reperfusion injury (RIRI). However, the molecular mechanisms remain widely unknown. STC-1 inhibits reactive oxygen species (ROS), whereas most ROS-mediated pathways are associated with ischemic injury. Therefore, to explore the mechanism, the effects of STC-1 on ROS-medicated pathways were studied. Non-traumatic vascular clamps were used to establish RIRI mouse models. The serum levels of STC-1, interleukin-6 (IL-6), interferon (IFN) γ, P53, and capase-3 were measured by ELISA kits. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by fluorescence spectrofluorometer. All these molecules changed significantly in a RIRI model mouse when compared with those in a sham control. Kidney cells were isolated from sham and model mice. STC-1 was overexpressed or knockout in these kidney cells. The molecules in ROS-medicated pathways were measured by real-time quantitative PCR and Western blot. The results showed that STC-1 is an effective ROS scavenger. The serum levels of STC-1, MDA and SOD activity were increased while the serum levels of IL-6, iIFN-γ, P53, and capase-3 were decreased in a model group when compared with a sham control (p < 0.05). Furthermore, the levels of STC-1,p53, phosphorylated mitogen-activated protein kinase kinase (p-MEKK-1), c-Jun N-terminal kinase (p-JNK), extracellular signal-regulated kinase (p-ERK), IkB kinase (p-IKK), nuclear factor (NF) κB, apoptosis signal-regulating kinase 1 (ASK-1) and caspase-3 changed significantly in kidney cells isolated from a RIRI model when compared to those isolated from a sham control (p < 0.05). Meanwhile, STC-1 overexpression or silence caused significant changes of the levels of these ROS-mediated molecules. Therefore, STC-1 maybe improve anti-inflammation, anti-oxidant and anti-apoptosis activities by affecting ROS-mediated pathways, especially the phospho-modifications of the respective proteins, resulting in the increase of SOD and reduce of capase-3, p53, IL-6 and IFN-γ. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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30 pages, 1199 KiB

Open AccessReview

Diet Quality and Cancer Outcomes in Adults: A Systematic Review of Epidemiological Studies

by Jennifer Potter¹, Leanne Brown^2,3

, Rebecca L. Williams^1,3, Julie Byles^4,5

and Clare E. Collins^1,3,*

¹ School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Callaghan 2308, Australia

² Department of Rural Health, University of Newcastle, Tamworth 2308, Australia

³ Priority Research Centre for Physical Activity and Nutrition, University of Newcastle, Callaghan 2308, Australia

⁴ Priority Research Centre for Gender, Health and Ageing, University of Newcastle, Callaghan 2308, Australia

⁵ School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan 2308, Australia

Int. J. Mol. Sci. 2016, 17(7), 1052; https://doi.org/10.3390/ijms17071052 - 5 Jul 2016

Cited by 43 | Viewed by 8168

Abstract

Dietary patterns influence cancer risk. However, systematic reviews have not evaluated relationships between a priori defined diet quality scores and adult cancer risk and mortality. The aims of this systematic review are to (1) describe diet quality scores used in cohort or cross-sectional [...] Read more.

Dietary patterns influence cancer risk. However, systematic reviews have not evaluated relationships between a priori defined diet quality scores and adult cancer risk and mortality. The aims of this systematic review are to (1) describe diet quality scores used in cohort or cross-sectional research examining cancer outcomes; and (2) describe associations between diet quality scores and cancer risk and mortality. The protocol was registered in Prospero, and a systematic search using six electronic databases was conducted through to December 2014. Records were assessed for inclusion by two independent reviewers, and quality was evaluated using a validated tool. Sixty-four studies met inclusion criteria from which 55 different diet quality scores were identified. Of the 35 studies investigating diet quality and cancer risk, 60% (n = 21) found a positive relationship. Results suggest no relationship between diet quality scores and overall cancer risk. Inverse associations were found for diet quality scores and risk of postmenopausal breast, colorectal, head, and neck cancer. No consistent relationships between diet quality scores and cancer mortality were found. Diet quality appears to be related to site-specific adult cancer risk. The relationship with cancer mortality is less conclusive, suggesting additional factors impact overall cancer survival. Development of a cancer-specific diet quality score for application in prospective epidemiology and in public health is warranted. Full article

(This article belongs to the Special Issue Advances in Nutritional Epidemiology)

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15 pages, 2343 KiB

Open AccessArticle

Determination of Free-Form and Peptide Bound Pyrraline in the Commercial Drinks Enriched with Different Protein Hydrolysates

by Zhili Liang¹, Lin Li^1,2,3,*, Haiping Qi¹, Xia Zhang¹, Zhenbo Xu^1,4

and Bing Li^1,2,*

¹ School of Food Sciences and Engineering, South China University of Technology, Guangzhou 510640, China

² Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China

³ University Affairs Committee, Dongguan University of Technology, Dongguan 523808, China

⁴ Department of Microbial Pathogenesis, Dental School, University of Maryland, Baltimore, MD 21201, USA

Int. J. Mol. Sci. 2016, 17(7), 1053; https://doi.org/10.3390/ijms17071053 - 4 Jul 2016

Cited by 10 | Viewed by 6851

Abstract

Pyrraline, a causative factor for the recent epidemics of diabetes and cardiovascular disease, is also employed as an indicator to evaluate heat damage and formation of advanced glycation end-products (AGEs) in foods. Peptide-enriched drinks (PEDs) are broadly consumed worldwide due to rapid rate [...] Read more.

Pyrraline, a causative factor for the recent epidemics of diabetes and cardiovascular disease, is also employed as an indicator to evaluate heat damage and formation of advanced glycation end-products (AGEs) in foods. Peptide-enriched drinks (PEDs) are broadly consumed worldwide due to rapid rate of absorption and perceived health effects. It can be hypothesized that PED is an important source of pyrraline, especially peptide bound pyrraline (Pep-Pyr). In this study we determined free-form pyrraline (Free-Pyr) and Pep-Pyr in drinks enriched with whey protein hydrolysate (WPH), soy protein hydrolysate (SPH) and collagen protein hydrolysate (CPH). A detection method was developed using ultrahigh-performance liquid chromatography with UV-visible detector coupled with tandem mass spectrometry after solid-phase extraction (SPE). The SPE led to excellent recovery rates ranging between 93.2% and 98.5% and a high reproducibility with relative standard deviations (RSD) of <5%. The limits of detection and quantification obtained were 30.4 and 70.3 ng/mL, respectively. Pep-Pyr was identified as the most abundant form (above 96 percent) of total pyrraline, whereas Free-Pyr was present in a small proportion (less than four percent) of total pyrraline. The results indicate that PED is an important extrinsic source of pyrraline, especially Pep-Pyr. As compared with CPH- and SPH-enriched drinks, WPH-enriched drinks contained high content of Pep-Pyr. The Pep-Pyr content is associated with the distribution of peptide lengths and the amino acid compositions of protein in PEDs. Full article

(This article belongs to the Special Issue Lipidomics and Glycomics: New Advances in Food Science and Nutrition)

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13 pages, 3767 KiB

Open AccessArticle

Compound K Attenuates the Development of Atherosclerosis in ApoE^−/− Mice via LXRα Activation

by Li Zhou^1,2,†, Yu Zheng¹, Zhuoying Li³, Lingxia Bao¹, Yin Dou¹, Yuan Tang¹, Jianxiang Zhang¹, Jianzhi Zhou¹, Ya Liu¹, Yi Jia^1,*,† and Xiaohui Li^1,*

¹ Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China

² Department of pharmacy, Xinqiao Hospital & The Second Affiliated Hospital, Third Military Medical University, Shapingba, Chongqing 400037, China

³ Department of Outpatient, Logistical Engineering University of PLA, Shapingba, Chongqing 401311, China

^† These authors contributed equally to this work

Int. J. Mol. Sci. 2016, 17(7), 1054; https://doi.org/10.3390/ijms17071054 - 8 Jul 2016

Cited by 41 | Viewed by 6278

Abstract

Background: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K [...] Read more.

Background: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K. Methods: We treated the atherosclerotic model animals (apoE^−/− mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments. Results: Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K. Conclusion: These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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14 pages, 5306 KiB

Open AccessArticle

Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer

by Jianzong Li^1,†, Haiyang Wang^1,†, Junjie Li¹, Jinku Bao^1,2,3,* and Chuanfang Wu^1,*

¹ School of Life Sciences and Key Laboratory of Ministry of Education for Bio-Resources and Bio-Environment, Sichuan University, Chengdu 610064, China

² State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China

³ State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu 610041, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1055; https://doi.org/10.3390/ijms17071055 - 1 Jul 2016

Cited by 30 | Viewed by 8948

Abstract

Breast cancer is one of the most lethal types of cancer in women worldwide due to the late stage detection and resistance to traditional chemotherapy. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. [...] Read more.

Breast cancer is one of the most lethal types of cancer in women worldwide due to the late stage detection and resistance to traditional chemotherapy. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Even though a substantial effort has been made to develop HER2 inhibitors, only lapatinib has been approved by the U.S. Food and Drug Administration (FDA). Side effects were observed in a majority of the patients within one year of treatment initiation. Here, we took advantage of bioinformatics tools to identify novel effective HER2 inhibitors. The structure-based virtual screening combined with ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction was explored. In total, 11,247 natural compounds were screened. The top hits were evaluated by an in vitro HER2 kinase inhibition assay. The cell proliferation inhibition effect of identified inhibitors was evaluated in HER2-overexpressing SKBR3 and BT474 cell lines. We found that ZINC15122021 showed favorable ADMET properties and attained high binding affinity against HER2. Moreover, ZINC15122021 showed high kinase inhibition activity against HER2 and presented outstanding cell proliferation inhibition activity against both SKBR3 and BT474 cell lines. Results reveal that ZINC15122021 can be a potential HER2 inhibitor. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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9 pages, 849 KiB

Open AccessArticle

Increased Efficacy of Brentuximab Vedotin (SGN-35) in Combination with Cytokine-Induced Killer Cells in Lymphoma

by Laura Esser¹, Hans Weiher² and Ingo Schmidt-Wolf^1,*

¹ Center for Integrated Oncology (CIO), Medizinische Klinik und Poliklinik III, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany

² Hochschule Bonn-Rhein-Sieg, 53359 Rheinbach, Germany

Int. J. Mol. Sci. 2016, 17(7), 1056; https://doi.org/10.3390/ijms17071056 - 1 Jul 2016

Cited by 10 | Viewed by 6425

Abstract

Brentuximab vedotin (SGN-35) is an antibody–drug conjugate with a high selectivity against CD30⁺ cell lines and more than 300-fold less activity against antigen-negative cells. In the last years, the results of many in vitro and in vivo studies have led to the [...] Read more.

Brentuximab vedotin (SGN-35) is an antibody–drug conjugate with a high selectivity against CD30⁺ cell lines and more than 300-fold less activity against antigen-negative cells. In the last years, the results of many in vitro and in vivo studies have led to the fast approval of this drug to treat lymphoma patients. Another innovative method to treat tumor cells including lymphoma cells is the use cytokine-induced killer (CIK) cells, which have also been approved and proven to be a safe treatment with only minor adverse events. In this study, a possible additive effect when combining SGN-35 with CIK cells was investigated. The combinational treatment showed that it reduces the viability of CD30⁺ cell lines significantly in vitro. Additionally, the amount of lymphoma cells was significantly reduced when exposed to CIK cells as well as when exposed to SGN-35. A significant negative effect of SGN-35 on the function of CIK cells could be excluded. These results lead to the assumption that SGN-35 and CIK cells in combination might achieve better results in an in vitro setting compared to the single use of SGN-35 and CIK cells. Further investigations in in vivo models must be conducted to obtain a better understanding of the exact mechanisms of both treatments when applied in combination. Full article

(This article belongs to the Special Issue Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy)

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9 pages, 616 KiB

Open AccessReview

Effects and Mechanisms of Low-Intensity Pulsed Ultrasound for Chronic Prostatitis and Chronic Pelvic Pain Syndrome

by Guiting Lin¹

, Amanda B. Reed-Maldonado¹, Maofan Lin², Zhongcheng Xin² and Tom F. Lue^1,*

¹ Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA

² Department of Urology, Peking University First Hospital and the Institute of Urology, Peking University, Beijing 100009, China

Int. J. Mol. Sci. 2016, 17(7), 1057; https://doi.org/10.3390/ijms17071057 - 1 Jul 2016

Cited by 56 | Viewed by 9829

Abstract

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is one of the most common urologic diseases, and no curative treatments have been identified. Low-intensity pulsed ultrasound (LIPUS) has been successfully used in promoting tissue healing, inhibiting inflammation and pain, differentiating stem cells, and stimulating nerve [...] Read more.

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is one of the most common urologic diseases, and no curative treatments have been identified. Low-intensity pulsed ultrasound (LIPUS) has been successfully used in promoting tissue healing, inhibiting inflammation and pain, differentiating stem cells, and stimulating nerve regeneration/muscle regeneration, as well as enhancing angiogenesis. Very recently, LIPUS has been proven an effective approach for CP/CPPS. This review summarizes the possible mechanisms responsible for the therapeutic effect of LIPUS for CP/CPPS. To search publications relevant to the topics of this review, the search engine for life sciences of Entrez was used. We reviewed the available evidence from 1954 through 2015 concerning LIPUS for CP/CPPS. According to the literature, both transrectal and transperineal approaches of LIPUS are effective for CP/CPPS. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 5297 KiB

Open AccessArticle

Transcriptome Sequencing Analyses between the Cytoplasmic Male Sterile Line and Its Maintainer Line in Welsh Onion (Allium fistulosum L.)

by Qianchun Liu^1,†, Yanping Lan^2,†, Changlong Wen¹, Hong Zhao¹, Jian Wang¹ and Yongqin Wang^1,*

¹ Beijing Vegetable Research Center, Beijing Academy of Agriculture and Forestry Sciences/Key Laboratory of Biology and Genetic Improvement of Horticultural Crops (North China), Ministry of Agriculture, Beijing 100097, China

² Institute of Agricultural Integrated Development, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1058; https://doi.org/10.3390/ijms17071058 - 1 Jul 2016

Cited by 29 | Viewed by 6578

Abstract

Cytoplasmic male sterility (CMS) is important for exploiting heterosis in crop plants and also serves as a model for investigating nuclear–cytoplasmic interaction. The molecular mechanism of cytoplasmic male sterility and fertility restoration was investigated in several important economic crops but remains poorly understood [...] Read more.

Cytoplasmic male sterility (CMS) is important for exploiting heterosis in crop plants and also serves as a model for investigating nuclear–cytoplasmic interaction. The molecular mechanism of cytoplasmic male sterility and fertility restoration was investigated in several important economic crops but remains poorly understood in the Welsh onion. Therefore, we compared the differences between the CMS line 64-2 and its maintainer line 64-1 using transcriptome sequencing with the aim of determining critical genes and pathways associated with male sterility. This study combined two years of RNA-seq data; there were 1504 unigenes (in May 2013) and 2928 unigenes (in May 2014) that were differentially expressed between the CMS and cytoplasmic male maintainer Welsh onion varieties. Known CMS-related genes were found in the set of differentially expressed genes and checked by qPCR. These genes included F-type ATPase, NADH dehydrogenase, cytochrome c oxidase, etc. Overall, this study demonstrated that the CMS regulatory genes and pathways may be associated with the mitochondria and nucleus in the Welsh onion. We believe that this transcriptome dataset will accelerate the research on CMS gene clones and other functional genomics research on A. fistulosum L. Full article

(This article belongs to the Section Molecular Plant Sciences)

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27 pages, 1915 KiB

Open AccessReview

Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins

by Francisco Andrés Peralta and Juan Pablo Huidobro-Toro^*

Laboratorio de Farmacología de Nucleótidos, Laboratorio de Farmacología, Departamento de Biología, Facultad de Química y Biología, y Centro para el Desarrollo de Nanociencias y Nanotecnología (CEDENNA), Universidad de Santiago de Chile, Alameda Libertador B. O’Higgins, 3363 Santiago, Chile

Int. J. Mol. Sci. 2016, 17(7), 1059; https://doi.org/10.3390/ijms17071059 - 2 Jul 2016

Cited by 38 | Viewed by 8945

Abstract

Zinc is an essential metal to life. This transition metal is a structural component of many proteins and is actively involved in the catalytic activity of cell enzymes. In either case, these zinc-containing proteins are metalloproteins. However, the amino acid residues that serve [...] Read more.

Zinc is an essential metal to life. This transition metal is a structural component of many proteins and is actively involved in the catalytic activity of cell enzymes. In either case, these zinc-containing proteins are metalloproteins. However, the amino acid residues that serve as ligands for metal coordination are not necessarily the same in structural proteins compared to enzymes. While crystals of structural proteins that bind zinc reveal a higher preference for cysteine sulfhydryls rather than histidine imidazole rings, catalytic enzymes reveal the opposite, i.e., a greater preference for the histidines over cysteines for catalysis, plus the influence of carboxylic acids. Based on this paradigm, we reviewed the putative ligands of zinc in ionotropic receptors, where zinc has been described as an allosteric modulator of channel receptors. Although these receptors do not strictly qualify as metalloproteins since they do not normally bind zinc in structural domains, they do transitorily bind zinc at allosteric sites, modifying transiently the receptor channel’s ion permeability. The present contribution summarizes current information showing that zinc allosteric modulation of receptor channels occurs by the preferential metal coordination to imidazole rings as well as to the sulfhydryl groups of cysteine in addition to the carboxyl group of acid residues, as with enzymes and catalysis. It is remarkable that most channels, either voltage-sensitive or transmitter-gated receptor channels, are susceptible to zinc modulation either as positive or negative regulators. Full article

(This article belongs to the Special Issue Metalloproteins)

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18 pages, 3511 KiB

Open AccessArticle

Molecular Signals Controlling the Inhibition of Nodulation by Nitrate in Medicago truncatula

by Giel E. Van Noorden^†, Rob Verbeek^†,‡

, Quy Dung Dinh^§, Jian Jin^‖, Alexandra Green, Jason Liang Pin Ng and Ulrike Mathesius^*

¹ Division of Plant Science, Research School of Biology, Australian National University, Canberra ACT 2601, Australia

^† These authors contributed equally to this work.

^‡ Current address: Medtronic Bakken Research Centre B.V., 6229 GW Maastricht, The Netherlands

^§ Current address: Wageningen UR Plant Breeding, P.O. Box 386, 6700 AJ Wageningen, The Netherlands

^‖ Current address: Key Laboratory of Mollisols Agroecology, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Harbin 150081, China

Int. J. Mol. Sci. 2016, 17(7), 1060; https://doi.org/10.3390/ijms17071060 - 2 Jul 2016

Cited by 34 | Viewed by 8085

Abstract

The presence of nitrogen inhibits legume nodule formation, but the mechanism of this inhibition is poorly understood. We found that 2.5 mM nitrate and above significantly inhibited nodule initiation but not root hair curling in Medicago trunatula. We analyzed protein abundance in [...] Read more.

The presence of nitrogen inhibits legume nodule formation, but the mechanism of this inhibition is poorly understood. We found that 2.5 mM nitrate and above significantly inhibited nodule initiation but not root hair curling in Medicago trunatula. We analyzed protein abundance in M. truncatula roots after treatment with either 0 or 2.5 mM nitrate in the presence or absence of its symbiont Sinorhizobium meliloti after 1, 2 and 5 days following inoculation. Two-dimensional gel electrophoresis combined with mass spectrometry was used to identify 106 differentially accumulated proteins responding to nitrate addition, inoculation or time point. While flavonoid-related proteins were less abundant in the presence of nitrate, addition of Nod gene-inducing flavonoids to the Sinorhizobium culture did not rescue nodulation. Accumulation of auxin in response to rhizobia, which is also controlled by flavonoids, still occurred in the presence of nitrate, but did not localize to a nodule initiation site. Several of the changes included defense- and redox-related proteins, and visualization of reactive oxygen species indicated that their induction in root hairs following Sinorhizobium inoculation was inhibited by nitrate. In summary, the presence of nitrate appears to inhibit nodulation via multiple pathways, including changes to flavonoid metabolism, defense responses and redox changes. Full article

(This article belongs to the Special Issue Molecular Signals in Nodulation Control)

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14 pages, 2041 KiB

Open AccessReview

Aberrant Lipid Metabolism Promotes Prostate Cancer: Role in Cell Survival under Hypoxia and Extracellular Vesicles Biogenesis

by Gagan Deep¹ and Isabel R. Schlaepfer^2,*

¹ Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA

² Division of Medical Oncology, Genitourinary Cancer Program, University of Colorado School of Medicine, Aurora, CO 80045, USA

Int. J. Mol. Sci. 2016, 17(7), 1061; https://doi.org/10.3390/ijms17071061 - 2 Jul 2016

Cited by 79 | Viewed by 13636

Abstract

Prostate cancer (PCa) is the leading malignancy among men in United States. Recent studies have focused on the identification of novel metabolic characteristics of PCa, aimed at devising better preventive and therapeutic approaches. PCa cells have revealed unique metabolic features such as higher [...] Read more.

Prostate cancer (PCa) is the leading malignancy among men in United States. Recent studies have focused on the identification of novel metabolic characteristics of PCa, aimed at devising better preventive and therapeutic approaches. PCa cells have revealed unique metabolic features such as higher expression of several enzymes associated with de novo lipogenesis, fatty acid up-take and β-oxidation. This aberrant lipid metabolism has been reported to be important for PCa growth, hormone-refractory progression and treatment resistance. Furthermore, PCa cells effectively use lipid metabolism under adverse environmental conditions for their survival advantage. Specifically, hypoxic cancer cells accumulate higher amount of lipids through a combination of metabolic alterations including high glutamine and fatty acid uptake, as well as decreased fatty acid oxidation. These stored lipids serve to protect cancer cells from oxidative and endoplasmic reticulum stress, and play important roles in fueling cancer cell proliferation following re-oxygenation. Lastly, cellular lipids have also been implicated in extracellular vesicle biogenesis, which play a vital role in intercellular communication. Overall, the new understanding of lipid metabolism in recent years has offered several novel targets to better target and manage clinical PCa. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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6 pages, 1004 KiB

Open AccessCommunication

Mechanisms Underlying the Immune Response Generated by an Oral Vibrio cholerae Vaccine

by Danylo Sirskyj^1,2, Ashok Kumar^1,2,3 and Ali Azizi^3,*

¹ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada

² Children’s Hospital of Eastern Ontario (CHEO)-Research Institute, Ottawa, ON K1H 5B2, Canada

³ Department of Pathology and Laboratory Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada

Int. J. Mol. Sci. 2016, 17(7), 1062; https://doi.org/10.3390/ijms17071062 - 2 Jul 2016

Cited by 7 | Viewed by 4912

Abstract

Mechanistic details underlying the resulting protective immune response generated by mucosal vaccines remain largely unknown. We investigated the involvement of Toll-like receptor signaling in the induction of humoral immune responses following oral immunization with Dukoral, comparing wild type mice with TLR-2-, TLR-4-, MyD88- [...] Read more.

Mechanistic details underlying the resulting protective immune response generated by mucosal vaccines remain largely unknown. We investigated the involvement of Toll-like receptor signaling in the induction of humoral immune responses following oral immunization with Dukoral, comparing wild type mice with TLR-2-, TLR-4-, MyD88- and Trif-deficient mice. Although all groups generated similar levels of IgG antibodies, the proliferation of CD4+ T-cells in response to V. cholerae was shown to be mediated via MyD88/TLR signaling, and independently of Trif signaling. The results demonstrate differential requirements for generation of immune responses. These results also suggest that TLR pathways may be modulators of the quality of immune response elicited by the Dukoral vaccine. Determining the critical signaling pathways involved in the induction of immune response to this vaccine would be beneficial, and could contribute to more precisely-designed versions of other oral vaccines in the future. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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15 pages, 1783 KiB

Open AccessArticle

Digital Gene Expression Analysis of Ponkan Mandarin (Citrus reticulata Blanco) in Response to Asia Citrus Psyllid-Vectored Huanglongbing Infection

by Yun Zhong^1,†

, Chunzhen Cheng^1,2,†

, Bo Jiang^1,3, Nonghui Jiang^1,3, Yongyan Zhang², Minlun Hu^1,3 and Guangyan Zhong^1,3,*

¹ Institute of Fruit Tree Research, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China

² Institute of Horticultural Biotechnology, Fujian Agriculture and Forestry University, Fuzhou 350002, China

³ Key Laboratory of South Subtropical Fruit Biology and Genetic Resource Utilization Ministry of Agriculture, Guangzhou 510640, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1063; https://doi.org/10.3390/ijms17071063 - 2 Jul 2016

Cited by 23 | Viewed by 6241

Abstract

Citrus Huanglongbing (HLB), the most destructive citrus disease, can be transmitted by psyllids and diseased budwoods. Although the final symptoms of the two main HLB transmission ways were similar and hard to distinguish, the host responses might be different. In this study, the [...] Read more.

Citrus Huanglongbing (HLB), the most destructive citrus disease, can be transmitted by psyllids and diseased budwoods. Although the final symptoms of the two main HLB transmission ways were similar and hard to distinguish, the host responses might be different. In this study, the global gene changes in leaves of ponkan (Citrus reticulata) mandarin trees following psyllid-transmission of HLB were analyzed at the early symptomatic stage (13 weeks post inoculation, wpi) and late symptomatic stage (26 wpi) using digital gene expression (DGE) profiling. At 13 wpi, 2452 genes were downregulated while only 604 genes were upregulated in HLB infected ponkan leaves but no pathway enrichment was identified. Gene function analysis showed impairment in defense at the early stage of infection. At late stage of 26 wpi, however, differentially expressed genes (DEGs) involved in carbohydrate metabolism, plant defense, hormone signaling, secondary metabolism, transcription regulation were overwhelmingly upregulated, indicating that the defense reactions were eventually activated. The results indicated that HLB bacterial infection significantly influenced ponkan gene expression, and a delayed response of the host to the fast growing bacteria might be responsible for its failure in fighting against the bacteria. Full article

(This article belongs to the Special Issue Plant Innate Immunity)

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13 pages, 385 KiB

Open AccessArticle

Intra-Articular Injections of Platelet-Rich Plasma versus Hyaluronic Acid in the Treatment of Osteoarthritic Knee Pain: A Randomized Clinical Trial in the Context of the Spanish National Health Care System

by Elvira Montañez-Heredia^1,*

, Sofia Irízar¹, Pedro J. Huertas¹, Esperanza Otero², Marta Del Valle², Isidro Prat³, Macarena S. Díaz-Gallardo³, Macarena Perán^4,5, Juan A. Marchal^5,6,7

and María Del Carmen Hernandez-Lamas³

¹ Department of Orthopedic Surgery and Traumatology, Virgen de la Victoria University Hospital, Málaga E-29010, Spain

² Department of Anestesiology. Pain’s Treatment Unit. Virgen de la Victoria University Hospital, MálagaE-29010, Spain

³ Málaga Tissue Bank, Regional Blood Center, Málaga E-29009, Spain

⁴ Department of Health Sciences, University of Jaén, Jaén E-23071, Spain

⁵ Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18071, Spain

⁶ Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada E-18016, Spain

⁷ Biosanitary Institute of Granada (ibs. GRANADA), University Hospitals of Granada-University of Granada, Granada, Granada E-18016, Spain

Int. J. Mol. Sci. 2016, 17(7), 1064; https://doi.org/10.3390/ijms17071064 - 2 Jul 2016

Cited by 111 | Viewed by 11038

Abstract

Intra-articular injection of platelet-rich plasma (PRP) has been established as a suitable treatment for knee osteoarthritis. Here, we present a double-blind randomized controlled clinical trial, conducted in a public Hospital of the Spanish National Health Care System, to evaluate the efficacy of injecting [...] Read more.

Intra-articular injection of platelet-rich plasma (PRP) has been established as a suitable treatment for knee osteoarthritis. Here, we present a double-blind randomized controlled clinical trial, conducted in a public Hospital of the Spanish National Health Care System, to evaluate the efficacy of injecting autologous PRP versus hyaluronic acid (HA) in knee osteoarthritis. PRP was manufactured in Malaga’s Regional Blood Center (Spain). Patients that met the eligibility criteria were randomized into a PRP group or a HA group. Pain and functional improvements were assessed pre- and post-treatment (three and six months follow-up) using the Visual Analogue Scale (VAS); the Knee and Osteoarthritis Outcome System (KOOS) scale and the European Quality of Life scale (EUROQOL). Both groups presented pain reduction at six months. The VAS scores for the PRP group improved by at least 50% from their initial value, particularly at three months following the final infiltration, with results resembling those of the HA group at six months. PRP was more effective in patients with lower osteoarthritis grades. Both treatments improved pain in knee osteoarthritis patients without statistically significant differences between them. However, PRP injection was proved to improve pain three months after the final infiltration and to be more effective in lower osteoarthritis grades. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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22 pages, 570 KiB

Open AccessReview

Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

by Maria Francisca Coutinho^*

, Juliana Inês Santos and Sandra Alves

Department of Human Genetics, Research and Development Unit, National Health Institute Doutor Ricardo Jorge, Rua Alexandre Herculano, 321 4000-055 Porto, Portugal

Int. J. Mol. Sci. 2016, 17(7), 1065; https://doi.org/10.3390/ijms17071065 - 4 Jul 2016

Cited by 101 | Viewed by 13025 | Correction

Abstract

Lysosomal storage diseases (LSDs) are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally, [...] Read more.

Lysosomal storage diseases (LSDs) are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally, efforts have been mainly targeting the functional loss of the enzyme, by injection of a recombinant formulation, in a process called enzyme replacement therapy (ERT), with no impact on neuropathology. This ineffectiveness, together with its high cost and lifelong dependence is amongst the main reasons why additional therapeutic approaches are being (and have to be) investigated: chaperone therapy; gene enhancement; gene therapy; and, alternatively, substrate reduction therapy (SRT), whose aim is to prevent storage not by correcting the original enzymatic defect but, instead, by decreasing the levels of biosynthesis of the accumulating substrate(s). Here we review the concept of substrate reduction, highlighting the major breakthroughs in the field and discussing the future of SRT, not only as a monotherapy but also, especially, as complementary approach for LSDs. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond)

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11 pages, 2314 KiB

Open AccessArticle

Anti-Cancer Effect of Lambertianic Acid by Inhibiting the AR in LNCaP Cells

by Myoung-Sun Lee, Seon-Ok Lee, Sung-Hoon Kim

, Eun-Ok Lee and Hyo-Jeong Lee^*

Department of Cancer Preventive Material Development, Graduate School, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea

Int. J. Mol. Sci. 2016, 17(7), 1066; https://doi.org/10.3390/ijms17071066 - 7 Jul 2016

Cited by 10 | Viewed by 8264

Abstract

Lambertianic acid (LA) is known to have anti-allergic and antibacterial effects. However, the anticancer activities and mechanism of action of LA have not been investigated. Therefore, the anticancer effects and mechanism of LA are investigated in this study. LA decreased not only AR [...] Read more.

Lambertianic acid (LA) is known to have anti-allergic and antibacterial effects. However, the anticancer activities and mechanism of action of LA have not been investigated. Therefore, the anticancer effects and mechanism of LA are investigated in this study. LA decreased not only AR protein levels, but also cellular and secretory levels of PSA. Furthermore, LA inhibited nuclear translocation of the AR induced by mibolerone. LA suppressed cell proliferation by inducing G₁ arrest, downregulating CDK4/6 and cyclin D1 and activating p53 and its downstream molecules, p21 and p27. LA induced apoptosis and the expression of related proteins, including cleaved caspase-9 and -3, c-PARP and BAX, and inhibited BCl-2. The role of AR in LA-induced apoptosis was assessed by using siRNA. Collectively, these findings suggest that LA exerts the anticancer effect by inhibiting AR and is a valuable therapeutic agent in prostate cancer treatment. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 1240 KiB

Open AccessArticle

Transformation of Litchi Pericarp-Derived Condensed Tannin with Aspergillus awamori

by Sen Lin^1,†, Qing Li^2,†, Bao Yang¹, Xuewu Duan¹, Mingwei Zhang³, John Shi⁴ and Yueming Jiang^1,*

¹ Key Laboratory of Plant Resource Conservation and Sustainable Utilization/Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China

² Wenzhou Institute of Biomaterials and Engineering (in Preparation), Chinese Academy of Science, Wenzhou 325000, China

³ Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China

⁴ Guelph Research and Development Center, Agriculture and Agri-Food Canada, Guelph, ON N1G 5C9, Canada

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1067; https://doi.org/10.3390/ijms17071067 - 12 Jul 2016

Cited by 7 | Viewed by 5107

Abstract

Condensed tannin is a ubiquitous polyphenol in plants that possesses substantial antioxidant capacity. In this study, we have investigated the polyphenol extraction recovery and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity of the extracted polyphenol after litchi pericarp is treated with Aspergillus awamori, Aspergillus sojae [...] Read more.

Condensed tannin is a ubiquitous polyphenol in plants that possesses substantial antioxidant capacity. In this study, we have investigated the polyphenol extraction recovery and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity of the extracted polyphenol after litchi pericarp is treated with Aspergillus awamori, Aspergillus sojae or Aspergillus oryzae. We have further explored the activity of A. awamori in the formation of condensed tannin. The treatment of A. awamori appeared to produce the highest antioxidant activity of polyphenol from litchi pericarp. Further studies suggested that the treatment of A. awamori releases the non-extractable condensed tannin from cell walls of litchi pericarp. The total extractable tannin in the litchi pericarp residue after a six-time extraction with 60% ethanol increased from 199.92 ± 14.47–318.38 ± 7.59 μg/g dry weight (DW) after the treatment of A. awamori. The ESI-TOF-MS and HPLC-MS² analyses further revealed that treatment of A. awamori degraded B-type condensed tannin (condensed flavan-3-ol via C4–C8 linkage), but exhibited a limited capacity to degrade the condensed tannin containing A-type linkage subunits (C4–C8 coupled C2–O–C7 linkage). These results suggest that the treatment of A. awamori can significantly improve the production of condensed tannin from litchi pericarp. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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13 pages, 2415 KiB

Open AccessArticle

Prodifferentiation Activity of Novel Vitamin D₂ Analogs PRI-1916 and PRI-1917 and Their Combinations with a Plant Polyphenol in Acute Myeloid Leukemia Cells

by Matan Nachliely¹, Ehud Sharony¹, Narasimha Rao Bolla², Andrzej Kutner² and Michael Danilenko^1,*

¹ Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beer Sheva 841051, Israel

² Department of Chemistry and Department of Pharmacology, Pharmaceutical Research Institute, Warsaw 01-793, Poland

Int. J. Mol. Sci. 2016, 17(7), 1068; https://doi.org/10.3390/ijms17071068 - 5 Jul 2016

Cited by 12 | Viewed by 6173

Abstract

1α,25-dihydroxyvitamin D₃ (1,25D3) is a powerful differentiation inducer for acute myeloid leukemia (AML) cells. However, 1,25D3 doses required for differentiation of AML cells may cause lethal hypercalcemia in vivo. There is evidence that vitamin D₂ is less toxic than vitamin D [...] Read more.

1α,25-dihydroxyvitamin D₃ (1,25D3) is a powerful differentiation inducer for acute myeloid leukemia (AML) cells. However, 1,25D3 doses required for differentiation of AML cells may cause lethal hypercalcemia in vivo. There is evidence that vitamin D₂ is less toxic than vitamin D₃ in animals. Here, we determined the differentiation effects of novel analogs of 1α,25-dihydroxyvitamin D₂ (1,25D2), PRI-1916 and PRI-1917, in which the extended side chains of their previously reported precursors (PRI-1906 and PRI-1907, respectively) underwent further 24Z (24-cis) modification. Using four human AML cell lines representing different stages of myeloid maturation (KG-1a, HL60, U937, and MOLM-13), we found that the potency of PRI-1916 was slightly higher or equal to that of PRI-1906 while PRI-1917 was significantly less potent than PRI-1907. We also demonstrated that 1,25D2 was a less effective differentiation agent than 1,25D3 in these cell lines. Irrespective of their differentiation potency, all the vitamin D₂ derivatives tested were less potent than 1,25D3 in transactivating the DR3-type vitamin D response elements. However, similar to 1,25D3, both 1,25D2 and its analogs could strongly cooperate with the plant polyphenol carnosic acid in inducing cell differentiation and inhibition of G1–S cell cycle transition. These results indicate that the 24Z modification has contrasting effects on the differentiation ability of PRI-1906 and PRI-1907 and that the addition of a plant polyphenol could result in a similar extent of cell differentiation induced by different vitamin D compounds. The enhanced antileukemic effects of the tested combinations may constitute the basis for the development of novel approaches for differentiation therapy of AML. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

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13 pages, 1936 KiB

Open AccessArticle

The Effect of Resveratrol and Quercetin Treatment on PPAR Mediated Uncoupling Protein (UCP-) 1, 2, and 3 Expression in Visceral White Adipose Tissue from Metabolic Syndrome Rats

by Vicente Castrejón-Tellez^1,†

, José Manuel Rodríguez-Pérez^2,†

, Israel Pérez-Torres³

, Nonanzit Pérez-Hernández²

, Alfredo Cruz-Lagunas⁴, Verónica Guarner-Lans¹

, Gilberto Vargas-Alarcón²

and María Esther Rubio-Ruiz^1,*

¹ Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Tlalpan, Mexico City 14080, Mexico

² Department of Molecular Biology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Tlalpan, Mexico City 14080, Mexico

³ Department of Pathology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Tlalpan, Mexico City 14080, Mexico

⁴ Department of Immunology Research, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Calzada de Tlalpan 4502, Tlalpan, Mexico City 14080, Mexico

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1069; https://doi.org/10.3390/ijms17071069 - 5 Jul 2016

Cited by 44 | Viewed by 6946

Abstract

Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier superfamily involved in the control of body temperature and energy balance regulation. They are currently proposed as therapeutic targets for treating obesity and metabolic syndrome (MetS). We studied the gene expression regulation of [...] Read more.

Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier superfamily involved in the control of body temperature and energy balance regulation. They are currently proposed as therapeutic targets for treating obesity and metabolic syndrome (MetS). We studied the gene expression regulation of UCP1, -2, and -3 in abdominal white adipose tissue (WAT) from control and MetS rats treated with two doses of a commercial mixture of resveratrol (RSV) and quercetin (QRC). We found that UCP2 was the predominantly expressed isoform, UCP3 was present at very low levels, and UCP1 was undetectable. The treatment with RSV + QRC did not modify UCP3 levels; however, it significantly increased UCP2 mRNA in control and MetS rats in association with an increase in oleic and linoleic fatty acids. WAT from MetS rats showed a significantly increased expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ when compared to the control group. Furthermore, PPAR-α protein levels were increased by the highest dose of RSV + QRC in the control and MetS groups. PPAR-γ expression was only increased in the control group. We conclude that the RSV + QRC treatment leads to overexpression of UCP2, which is associated with an increase in MUFA and PUFA, which might increase PPAR-α expression. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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15 pages, 3125 KiB

Open AccessArticle

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

by Ping Meng¹, Suxian Zhao¹, Xuemin Niu¹, Na Fu¹, Shanshan Su¹, Rongqi Wang¹, Yuguo Zhang¹, Liang Qiao^2,* and Yuemin Nan^1,*

¹ Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China

² Storr Liver Centre, Westmead Institute for Medical Research (WIMR), the University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia

Int. J. Mol. Sci. 2016, 17(7), 1070; https://doi.org/10.3390/ijms17071070 - 15 Jul 2016

Cited by 23 | Viewed by 6409 | Correction

Abstract

Interleukin-23 (IL-23) and its downstream factor IL-17 are the key cytokines involved in immune and inflammatory response in chronic liver diseases. This study aimed to investigate the role and molecular mechanisms of the IL-23/Th17 axis in chronic hepatitis C virus (HCV) infection, and [...] Read more.

Interleukin-23 (IL-23) and its downstream factor IL-17 are the key cytokines involved in immune and inflammatory response in chronic liver diseases. This study aimed to investigate the role and molecular mechanisms of the IL-23/Th17 axis in chronic hepatitis C virus (HCV) infection, and the efficacy of IL-23/Th17 modulation in response to anti-HCV therapy. Sixty-six HCV-infected patients and 20 healthy controls were enrolled. The patients received PegIFNa-2a and ribavirin therapy for at least 48 weeks. The plasma level of IL-23 and the number of IL-17A-, IFN-γ-, and IL-21-producing peripheral blood mononuclear cells (PBMCs) at baseline and 12, 24, and 48 weeks following treatment were determined. The mRNA level of Th17 immune-associated molecules in PBMCs was evaluated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) following treatment with IL-23 agonist or antagonist. Our data showed that, compared to healthy controls, HCV-infected patients had an increased plasma level of IL-23 and increased frequencies of IL-17A- and IFN-γ-producing PBMCs, whereas the HCV patients exhibited a reduced number of IL-21-producing PBMCs. However, the baseline frequencies of IL-21-producing PBMCs were markedly higher in HCV patients who achieved rapid virological response (RVR) than those without RVR. Additionally, the mRNA expressions of IL-21, IFN-γ, myxovirus resistance protein A (MxA), and suppressor of cytokine signaling 3 (SOCS3) were significantly upregulated in PBMCs, while FoxP3 expression was suppressed by IL-23 agonist. Thus, the IL-23/Th17 axis plays an important role in development of chronic HCV infection and antiviral response. IL-23 may enhance the antiviral activity of interferon-based therapy by modulating the expression of Th17 cells-associated molecules in HCV-infected patients. Full article

(This article belongs to the Special Issue Hepatitis Virus Infection and Research)

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15 pages, 3747 KiB

Open AccessArticle

Protonation Sites, Tandem Mass Spectrometry and Computational Calculations of o-Carbonyl Carbazolequinone Derivatives

by Maximiliano Martínez-Cifuentes^1,*

, Graciela Clavijo-Allancan², Pamela Zuñiga-Hormazabal², Braulio Aranda², Andrés Barriga³, Boris Weiss-López² and Ramiro Araya-Maturana^4,*

¹ Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Casilla 9845, Santiago 7800003, Chile

² Departamento de Química, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Casilla 653, Santiago 7800003, Chile

³ Unidad de Espectrometría de Masas, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Casilla 233, Santiago 8380494, Chile

⁴ Instituto de Química de Recursos Naturales, Universidad de Talca, Av. Lircay s/n, Casilla 747, Talca 3460000, Chile

Int. J. Mol. Sci. 2016, 17(7), 1071; https://doi.org/10.3390/ijms17071071 - 5 Jul 2016

Cited by 4 | Viewed by 6254

Abstract

A series of a new type of tetracyclic carbazolequinones incorporating a carbonyl group at the ortho position relative to the quinone moiety was synthesized and analyzed by tandem electrospray ionization mass spectrometry (ESI/MS-MS), using Collision-Induced Dissociation (CID) to dissociate the protonated species. Theoretical [...] Read more.

A series of a new type of tetracyclic carbazolequinones incorporating a carbonyl group at the ortho position relative to the quinone moiety was synthesized and analyzed by tandem electrospray ionization mass spectrometry (ESI/MS-MS), using Collision-Induced Dissociation (CID) to dissociate the protonated species. Theoretical parameters such as molecular electrostatic potential (MEP), local Fukui functions and local Parr function for electrophilic attack as well as proton affinity (PA) and gas phase basicity (GB), were used to explain the preferred protonation sites. Transition states of some main fragmentation routes were obtained and the energies calculated at density functional theory (DFT) B3LYP level were compared with the obtained by ab initio quadratic configuration interaction with single and double excitation (QCISD). The results are in accordance with the observed distribution of ions. The nature of the substituents in the aromatic ring has a notable impact on the fragmentation routes of the molecules. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2016)

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16 pages, 1977 KiB

Open AccessArticle

Staphylococcal Superantigen-Like Protein 1 and 5 (SSL1 & SSL5) Limit Neutrophil Chemotaxis and Migration through MMP-Inhibition

by Kirsten J. Koymans^*, Adinda Bisschop, Mignon M. Vughs, Kok P. M. Van Kessel, Carla J. C. De Haas and Jos A. G. Van Strijp

Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands

Int. J. Mol. Sci. 2016, 17(7), 1072; https://doi.org/10.3390/ijms17071072 - 5 Jul 2016

Cited by 30 | Viewed by 6365

Abstract

Matrix metalloproteinases (MMPs) are endopeptidases that degrade components of the extracellular matrix, but also modulate inflammation. During bacterial infections, MMPs are important in the recruitment and migration of inflammatory cells. Besides facilitating cell migration by degrading extracellular matrix components, they potentiate the action [...] Read more.

Matrix metalloproteinases (MMPs) are endopeptidases that degrade components of the extracellular matrix, but also modulate inflammation. During bacterial infections, MMPs are important in the recruitment and migration of inflammatory cells. Besides facilitating cell migration by degrading extracellular matrix components, they potentiate the action of several inflammatory molecules, including cytokines, chemokines, and antimicrobial peptides. Staphylococcus aureus secretes an arsenal of immune evasion molecules that interfere with immune cell functioning and hamper proper immune responses. An earlier study identified staphylococcal superantigen-like protein 5 (SSL5) as an MMP9 inhibitor. Since multiple MMPs are involved in neutrophil recruitment, we set up an in-depth search for additional MMP inhibitors by testing a panel of over 70 secreted staphylococcal proteins on the inhibition of the two main neutrophil MMPs: MMP8 (neutrophil collagenase) and MMP9 (neutrophil gelatinase B). We identified SSL1 and SSL5 as potent inhibitors of both neutrophil MMPs and show that they are actually broad range MMP inhibitors. SSL1 and SSL5 prevent MMP-induced cleavage and potentiation of IL-8 and inhibit the migration of neutrophils through collagen. Thus, through MMP-inhibition, SSL1 and SSL5 interfere with neutrophil activation, chemotaxis, and migration, all vital neutrophil functions in bacterial clearance. Studies on MMP-SSL interactions can have therapeutic potential and SSL based derivatives might prove useful in treatment of cancer and destructive inflammatory diseases. Full article

(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)

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12 pages, 6544 KiB

Open AccessArticle

Bone Marrow Mesenchymal Stem Cells Expressing Baculovirus-Engineered Bone Morphogenetic Protein-7 Enhance Rabbit Posterolateral Fusion

by Jen-Chung Liao

Department of Orthopedic Surgery, Bone and Joint Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1073; https://doi.org/10.3390/ijms17071073 - 5 Jul 2016

Cited by 8 | Viewed by 6174

Abstract

Previous studies have suggested that bone marrow-derived mesenchymal stem cells (BMDMSCs) genetically modified with baculoviral bone morphogenetic protein-2 (Bac-BMP-2) vectors could achieve successful fusion in a femur defect model or in a spinal fusion model. In this study, BMDMSCs expressing BMP-7 (Bac-BMP-7-BMDMSCs) were [...] Read more.

Previous studies have suggested that bone marrow-derived mesenchymal stem cells (BMDMSCs) genetically modified with baculoviral bone morphogenetic protein-2 (Bac-BMP-2) vectors could achieve successful fusion in a femur defect model or in a spinal fusion model. In this study, BMDMSCs expressing BMP-7 (Bac-BMP-7-BMDMSCs) were generated. We hypothesized that Bac-BMP-7-BMDMSCs could secrete more BMP-7 than untransduced BMDMSCs in vitro and achieve spinal posterolateral fusion in a rabbit model. Eighteen rabbits underwent posterolateral fusion at L4-5. Group I (n = 6) was implanted with collagen-β-tricalcium phosphate (TCP)-hydroxyapatite (HA), Group II (n = 6) was implanted with collagen-β-TCP-HA plus BMDMSCs, and Group III (n = 6) was implanted with collagen-β-TCP-HA plus Bac-BMP-7-BMDMSCs. In vitro production of BMP-7 was quantified with an enzyme-linked immunosorbent assay (ELISA). Spinal fusion was examined using computed tomography (CT), manual palpation, and histological analysis. ELISA demonstrated that Bac-BMP-7-BMDMSCs produced four-fold to five-fold more BMP-7 than did BMDMSCs. In the CT results, 6 fused segments were observed in Group I (50%, 6/12), 8 in Group II (67%, 8/12), and 12 in Group III (100%, 12/12). The fusion rate, determined by manual palpation, was 0% (0/6) in Group I, 0% (0/6) in Group II, and 83% (5/6) in Group III. Histology showed that Group III had more new bone and matured marrow formation. In conclusion, BMDMSCs genetically transduced with the Bac-BMP-7 vector could express more BMP-7 than untransduced BMDMSCs. These Bac-BMP-7-BMDMSCs on collagen-β-TCP-HA scaffolds were able to induce successful spinal fusion in rabbits. Full article

(This article belongs to the Special Issue Advances in Cell Transplantation)

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12 pages, 223 KiB

Open AccessReview

Molecular Targeted Therapies for the Treatment of Leptomeningeal Carcinomatosis: Current Evidence and Future Directions

by Dae-Won Lee¹, Kyung-Hun Lee^1,2, Jin Wook Kim³ and Bhumsuk Keam^1,2,*

¹ Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea

² Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea

³ Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea

Int. J. Mol. Sci. 2016, 17(7), 1074; https://doi.org/10.3390/ijms17071074 - 5 Jul 2016

Cited by 28 | Viewed by 7106

Abstract

Leptomeningeal carcinomatosis (LMC) is the multifocal seeding of cerebrospinal fluid and leptomeninges by malignant cells. The incidence of LMC is approximately 5% in patients with malignant tumors overall and the rate is increasing due to increasing survival time of cancer patients. Eradication of [...] Read more.

Leptomeningeal carcinomatosis (LMC) is the multifocal seeding of cerebrospinal fluid and leptomeninges by malignant cells. The incidence of LMC is approximately 5% in patients with malignant tumors overall and the rate is increasing due to increasing survival time of cancer patients. Eradication of the disease is not yet possible, so the treatment goals of LMC are to improve neurologic symptoms and to prolong survival. A standard treatment for LMC has not been established due to low incidences of LMC, the rapidly progressing nature of the disease, heterogeneous populations with LMC, and a lack of randomized clinical trial results. Treatment options for LMC include intrathecal chemotherapy, systemic chemotherapy, and radiation therapy, but the prognoses remain poor with a median survival of <3 months. Recently, molecular targeted agents have been applied in the clinic and have shown groundbreaking results in specific patient groups epidermal growth factor receptor (EGFR)-targeted therapy or an anaplastic lymphoma kinase (ALK) inhibitor in lung cancer, human epidermal growth factor receptor 2 (HER2)-directed therapy in breast cancer, and CD20-targeted therapy in B cell lymphoma). Moreover, there are results indicating that the use of these agents under proper dose and administration routes can be effective for managing LMC. In this article, we review molecular targeted agents for managing LMC. Full article

(This article belongs to the Special Issue Brain Metastasis 2016)

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11 pages, 467 KiB

Open AccessArticle

MMP-9 Serum Levels in Schizophrenic Patients during Treatment Augmentation with Sarcosine (Results of the PULSAR Study)

by Dominik Strzelecki^1,*

, Olga Kałużyńska¹, Justyna Szyburska¹ and Adam Wysokiński²

¹ Department of Affective and Psychotic Disorders, Medical University of Łódź, Central Clinical Hospital, Czechosłowacka 8/10, 92-216 Łódź, Poland

² Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Łódź, Central Clinical Hospital, Czechosłowacka 8/10, 92-216 Łódź, Poland

Int. J. Mol. Sci. 2016, 17(7), 1075; https://doi.org/10.3390/ijms17071075 - 9 Jul 2016

Cited by 10 | Viewed by 5315

Abstract

Aim: Find changes in matrix metallopeptidase-9 (MMP-9) levels during augmentation of antipsychotic treatment with sarcosine and a relationship between schizophrenia symptoms severity and initial level of MMP-9. Method: Fifty-eight patients with diagnosis of schizophrenia with predominant negative symptoms participated in a six-month prospective [...] Read more.

Aim: Find changes in matrix metallopeptidase-9 (MMP-9) levels during augmentation of antipsychotic treatment with sarcosine and a relationship between schizophrenia symptoms severity and initial level of MMP-9. Method: Fifty-eight patients with diagnosis of schizophrenia with predominant negative symptoms participated in a six-month prospective RCT (randomized controlled trial). The patients received two grams of sarcosine (n = 28) or placebo (n = 30) daily. At the beginning, after six weeks and after six months MMP-9 levels were measured. Severity of symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS). Results: MMP-9 serum levels were stable after six weeks and six months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group compared to placebo; however, there was no correlations between serum MMP-9 concentrations and PANSS scores in all assessments. Initial serum MMP-9 concentrations cannot be used as an improvement predictor acquired during sarcosine augmentation. Conclusions: Our results indicate that either MMP-9 is not involved in the N-methyl-d-aspartate (NMDA)-dependent mechanism of sarcosine action in terms of clinical parameters or sarcosine induced changes in peripheral MMP-9 concentrations cannot be detected in blood assessments. Full article

(This article belongs to the Special Issue Metalloproteins)

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13 pages, 4516 KiB

Open AccessArticle

MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways

by Yuhan Chen¹, Zhaochong Zeng^1,*, Xiaoyun Shen¹, Zhifeng Wu¹, Yinying Dong¹ and Jason Chia-Hsien Cheng²

¹ Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China

² Division of Radiation Oncology, Departments of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1076; https://doi.org/10.3390/ijms17071076 - 7 Jul 2016

Cited by 63 | Viewed by 8159

Abstract

Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this [...] Read more.

Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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18 pages, 2296 KiB

Open AccessArticle

Interspecies and Intraspecies Analysis of Trehalose Contents and the Biosynthesis Pathway Gene Family Reveals Crucial Roles of Trehalose in Osmotic-Stress Tolerance in Cassava

by Bingying Han^†, Lili Fu^†, Dan Zhang^†, Xiuquan He, Qiang Chen, Ming Peng and Jiaming Zhang^*

¹ Institute of Tropical Bioscience and Biotechnology, Key Laboratory of Tropical Crops Biology and Genetic Resources, Ministry of Agriculture, Hainan Bioenergy Center, Chinese Academy of Tropical Agricultural Sciences (CATAS), Xueyuan Road 4, Haikou 571101, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1077; https://doi.org/10.3390/ijms17071077 - 13 Jul 2016

Cited by 50 | Viewed by 6654

Abstract

Trehalose is a nonreducing α,α-1,1-disaccharide in a wide range of organisms, and has diverse biological functions that range from serving as an energy source to acting as a protective/signal sugar. However, significant amounts of trehalose have rarely been detected in higher plants, and [...] Read more.

Trehalose is a nonreducing α,α-1,1-disaccharide in a wide range of organisms, and has diverse biological functions that range from serving as an energy source to acting as a protective/signal sugar. However, significant amounts of trehalose have rarely been detected in higher plants, and the function of trehalose in the drought-tolerant crop cassava (Manihot esculenta Crantz) is unclear. We measured soluble sugar concentrations of nine plant species with differing levels of drought tolerance and 41 cassava varieties using high-performance liquid chromatography with evaporative light-scattering detector (HPLC-ELSD). Significantly high amounts of trehalose were identified in drought-tolerant crops cassava, Jatropha curcas, and castor bean (Ricinus communis). All cassava varieties tested contained high amounts of trehalose, although their concentrations varied from 0.23 to 1.29 mg·g⁻¹ fresh weight (FW), and the trehalose level was highly correlated with dehydration stress tolerance of detached leaves of the varieties. Moreover, the trehalose concentrations in cassava leaves increased 2.3–5.5 folds in response to osmotic stress simulated by 20% PEG 6000. Through database mining, 24 trehalose pathway genes, including 12 trehalose-6-phosphate synthases (TPS), 10 trehalose-6-phosphate phosphatases (TPP), and two trehalases were identified in cassava. Phylogenetic analysis indicated that there were four cassava TPS genes (MeTPS1–4) that were orthologous to the solely active TPS gene (AtTPS1 and OsTPS1) in Arabidopsis and rice, and a new TPP subfamily was identified in cassava, suggesting that the trehalose biosynthesis activities in cassava had potentially been enhanced in evolutionary history. RNA-seq analysis indicated that MeTPS1 was expressed at constitutionally high level before and after osmotic stress, while other trehalose pathway genes were either up-regulated or down-regulated, which may explain why cassava accumulated high level of trehalose under normal conditions. MeTPS1 was then transformed into tobacco (Nicotiana benthamiana). Results indicated that transgenic tobacco lines accumulated significant level of trehalose and possessed improved drought stress tolerance. In conclusion, cassava accumulated significantly high amount of trehalose under normal conditions due to multiplied trehalose biosynthesis gene families and constant expression of the active MeTPS1 gene. High levels of trehalose subsequently contributed to high drought stress tolerance. Full article

(This article belongs to the Section Molecular Plant Sciences)

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13 pages, 6654 KiB

Open AccessArticle

Exploring the Molecular Basis for Binding of Inhibitors by Threonyl-tRNA Synthetase from Brucella abortus: A Virtual Screening Study

by Ming Li^1,2,†, Fang Wen^1,2,†, Shengguo Zhao^1,2,†

, Pengpeng Wang^1,2, Songli Li^1,2, Yangdong Zhang^1,2

, Nan Zheng^1,2,3,* and Jiaqi Wang^1,2,3

¹ Ministry of Agriculture Laboratory of Quality & Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China

² Ministry of Agriculture—Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China

³ State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1078; https://doi.org/10.3390/ijms17071078 - 19 Jul 2016

Cited by 3 | Viewed by 5918

Abstract

Targeting threonyl-tRNA synthetase (ThrRS) of Brucella abortus is a promising approach to developing small-molecule drugs against bovine brucellosis. Using the BLASTp algorithm, we identified ThrRS from Escherichia coli (EThrRS, PDB ID 1QF6), which is 51% identical to ThrRS from Brucella abortus (BaThrRS) at [...] Read more.

Targeting threonyl-tRNA synthetase (ThrRS) of Brucella abortus is a promising approach to developing small-molecule drugs against bovine brucellosis. Using the BLASTp algorithm, we identified ThrRS from Escherichia coli (EThrRS, PDB ID 1QF6), which is 51% identical to ThrRS from Brucella abortus (BaThrRS) at the amino acid sequence level. EThrRS was used as the template to construct a BaThrRS homology model which was optimized using molecular dynamics simulations. To determine the residues important for substrate ATP binding, we identified the ATP-binding regions of BaThrRS, docked ATP to the protein, and identified the residues whose side chains surrounded bound ATP. We then used the binding site of ATP to virtually screen for BaThrRS inhibitors and got seven leads. We further characterized the BaThrRS-binding site of the compound with the highest predicted inhibitory activity. Our results should facilitate future experimental effects to find novel drugs for use against bovine brucellosis. Full article

(This article belongs to the Collection Computational, Structural and Spectroscopic Studies of Enzyme Mechanisms, Inhibition and Dynamics)

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12 pages, 444 KiB

Open AccessArticle

Endometriosis Might Be Inversely Associated with Developing Chronic Kidney Disease: A Population-Based Cohort Study in Taiwan

by Ben-Shian Huang^1,2, Wen-Hsun Chang^3,4, Kuan-Chin Wang⁵, Nicole Huang⁶, Chao-Yu Guo⁶, Yiing-Jen Chou⁶, Hsin-Yi Huang⁷, Tzeng-Ji Chen⁸

, Wen-Ling Lee^5,9,* and Peng-Hui Wang^2,4,10,*

¹ Department of Obstetrics and Gynecology, Yang-Ming University Hospital, Ilan 260, Taiwan

² Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei 112, Taiwan

³ Department of Nursing, Taipei Veterans General Hospital, Taipei 112, Taiwan

⁴ Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan

⁵ Department of Nursing, Oriental Institute of Technology, New Taipei City 220, Taiwan

⁶ Institute of Public Health, National Yang-Ming University, Taipei 112, Taiwan

⁷ Biostatics Task Force, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan

⁸ Department of Family Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan

⁹ Department of Medicine, Cheng-Hsin General Hospital, Taipei 112, Taiwan

¹⁰ Department of Medical Research, China Medical University Hospital, Taichung 440, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1079; https://doi.org/10.3390/ijms17071079 - 7 Jul 2016

Cited by 14 | Viewed by 5322

Abstract

This study was conducted to determine the risk of chronic kidney disease (CKD) among women with endometriosis in Taiwan. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan. A total of 27,973 women with a diagnosis of [...] Read more.

This study was conducted to determine the risk of chronic kidney disease (CKD) among women with endometriosis in Taiwan. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan. A total of 27,973 women with a diagnosis of endometriosis and 27,973 multivariable-matched controls (1:1) from 2000 to 2010 were selected. Cox regression and computed hazard ratios (HR) with 95% confidence intervals (95% CI) were used to determine the risk of CKD among women with endometriosis. The incidence rates (IR, per 10,000 person-years) of CKD among women with and without endometriosis were 4.64 and 7.01, respectively, with a significantly decreased risk of CKD (crude HR 0.65, 95% CI 0.53–0.81; adjusted HR 0.69, 95% CI 0.56–0.86) among women with endometriosis. The IR of CKD progressively increased with age, but the trend of lower CKD risk among women with endometriosis was consistent. However, the lower risk of CKD in women with endometriosis was no longer statistically significant after adjusting for menopausal status (adjusted HR 0.85, 95% CI 0.65–1.10). The results suggest that endometriosis is inversely associated with CKD, but this effect was mediated by menopause. The possible mechanism of this association is worthy of further evaluation. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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14 pages, 1948 KiB

Open AccessArticle

The Systemic Profile of Soluble Immune Mediators in Patients with Myelodysplastic Syndromes

by Astrid Olsnes Kittang^1,2,*,†, Kristoffer Sand^1,†, Annette Katharina Brenner¹, Kristin Paulsen Rye¹ and Øystein Bruserud^1,2

¹ Department of Clinical Science, University of Bergen, Bergen N-5021, Norway

² Division for Hematology, Department of Medicine, Haukeland University Hospital, Bergen N-5021, Norway

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1080; https://doi.org/10.3390/ijms17071080 - 5 Jul 2016

Cited by 17 | Viewed by 5457

Abstract

Introduction: Myelodysplastic syndromes (MDS) are characterized by bone marrow failure due to disturbed bone marrow maturation. MDS is associated with increased risk of transformation to acute myeloid leukemia (AML) and features of immunological dysregulation. Materials and methods: Serum levels of 47 soluble immune [...] Read more.

Introduction: Myelodysplastic syndromes (MDS) are characterized by bone marrow failure due to disturbed bone marrow maturation. MDS is associated with increased risk of transformation to acute myeloid leukemia (AML) and features of immunological dysregulation. Materials and methods: Serum levels of 47 soluble immune mediators were examined in samples derived from 49 MDS patients (35 low-risk and 14 high-risk) and 23 healthy adults. Our patients represent an unselected population-based cohort. The mediators included cytokines, soluble adhesion proteins, matrix metalloproteases, and tissue inhibitors of proteases. Levels were determined using Luminex assays. Patients were classified as low- and high-risk based on the international prognostic scoring system (IPSS) score. Results: When comparing the serum levels of single mediators the MDS patients showed a relatively wide variation range for several mediators compared with healthy adults, especially interleukin 6 (IL-6), IL-8/CXCL8, CCL3, and CCL4. The high-risk patients had lower levels of epidermal growth factor (EGF), cluster of differentiation 40 ligand (CD40L), CCL5, CCL11, CXCL5, matrix metalloproteinase 1 (MMP-1), MMP-9, and tissue inhibitor of metalloproteinases 2 (TIMP-2) compared with low-risk patients. Unsupervised hierarchical cluster analysis visualized marked serum mediator profile differences between MDS patients; based on this analysis three patient subsets could be identified. The healthy adults were also included in this analysis and, as expected, they formed their own separate cluster, except for one outlier. Both low- and high-risk patients showed considerable heterogeneity with regard to serum profile, and this heterogeneity seems stable over time (one year follow-up). Finally, very few mediators differed between low- and high-risk patients, but hierarchical clustering based both on all mediators, as well as five selected mediators (EGF, CCL11, TIMP-2, MMP-1, and MMP-9) identified subsets of patients with significantly increased frequency of high-risk disease (χ-square test p = 0.0158 and p = 0.0148). Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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13 pages, 1251 KiB

Open AccessReview

Control of Appetite and Food Preference by NMDA Receptor and Its Co-Agonist d-Serine

by Tsutomu Sasaki^*

, Sho Matsui and Tadahiro Kitamura

Laboratory for Metabolic Signaling, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan

Int. J. Mol. Sci. 2016, 17(7), 1081; https://doi.org/10.3390/ijms17071081 - 7 Jul 2016

Cited by 18 | Viewed by 7709

Abstract

Obesity causes a significant negative impact on health of human beings world-wide. The main reason for weight gain, which eventually leads to obesity, is excessive ingestion of energy above the body’s homeostatic needs. Therefore, the elucidation of detailed mechanisms for appetite control is [...] Read more.

Obesity causes a significant negative impact on health of human beings world-wide. The main reason for weight gain, which eventually leads to obesity, is excessive ingestion of energy above the body’s homeostatic needs. Therefore, the elucidation of detailed mechanisms for appetite control is necessary to prevent and treat obesity. N-methyl-d-aspartate (NMDA) receptor is a post-synaptic glutamate receptor and is important for excitatory neurotransmission. It is expressed throughout the nervous system, and is important for long-term potentiation. It requires both ligand (glutamate) and co-agonist (d-serine or glycine) for efficient opening of the channel to allow calcium influx. d-serine is contained in fermented foods and marine invertebrates, and brain d-serine level is maintained by synthesis in vivo and supply from food and gut microbiota. Although the NMDA receptor has been reported to take part in the central regulation of appetite, the role of d-serine had not been addressed. We recently reported that exogenous d-serine administration can suppress appetite and alter food preference. In this review, we will discuss how NMDA receptor and its co-agonist d-seine participate in the control of appetite and food preference, and elaborate on how this system could possibly be manipulated to suppress obesity. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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12 pages, 3226 KiB

Open AccessArticle

Promotion of Survival and Engraftment of Transplanted Adipose Tissue-Derived Stromal and Vascular Cells by Overexpression of Manganese Superoxide Dismutase

by Silvia Baldari^1,†

, Giuliana Di Rocco^1,†, Angelo Trivisonno², Daniela Samengo³, Giovambattista Pani³ and Gabriele Toietta^1,*

¹ Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, via E. Chianesi 53, Rome 00144, Italy

² Department of Surgical Science, Policlinico Umberto I, University of Rome “La Sapienza”, Viale Regina Elena 324, Rome 00161, Italy

³ Institute of General Pathology, Laboratory of Cell Signaling, Università Cattolica School of Medicine, Largo F. Vito 1, Rome 00168, Italy

^† These authors contributed equally to this work

Int. J. Mol. Sci. 2016, 17(7), 1082; https://doi.org/10.3390/ijms17071082 - 7 Jul 2016

Cited by 23 | Viewed by 6261

Abstract

Short-term persistence of transplanted cells during early post-implant period limits clinical efficacy of cell therapy. Poor cell survival is mainly due to the harsh hypoxic microenvironment transplanted cells face at the site of implantation and to anoikis, driven by cell adhesion loss. We [...] Read more.

Short-term persistence of transplanted cells during early post-implant period limits clinical efficacy of cell therapy. Poor cell survival is mainly due to the harsh hypoxic microenvironment transplanted cells face at the site of implantation and to anoikis, driven by cell adhesion loss. We evaluated the hypothesis that viral-mediated expression of a gene conferring hypoxia resistance to cells before transplant could enhance survival of grafted cells in early stages after implant. We used adipose tissue as cell source because it consistently provides high yields of adipose-tissue-derived stromal and vascular cells (ASCs), suitable for regenerative purposes. Luciferase positive cells were transduced with lentiviral vectors expressing either green fluorescent protein as control or human manganese superoxide dismutase (SOD2). Cells were then exposed in vitro to hypoxic conditions, mimicking cell transplantation into an ischemic site. Cells overexpressing SOD2 displayed survival rates significantly greater compared to mock transduced cells. Similar results were also obtained in vivo after implantation into syngeneic mice and assessment of cell engraftment by in vivo bioluminescent imaging. Taken together, these findings suggest that ex vivo gene transfer of SOD2 into ASCs before implantation confers a cytoprotective effect leading to improved survival and engraftment rates, therefore enhancing cell therapy regenerative potential. Full article

(This article belongs to the Special Issue Advances in Cell Transplantation)

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11 pages, 1745 KiB

Open AccessArticle

Molecular Dynamics Simulation Study of the Selectivity of a Silica Polymer for Ibuprofen

by Riccardo Concu^* and M. Natalia D. S. Cordeiro^*

REQUIMTE/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal

Int. J. Mol. Sci. 2016, 17(7), 1083; https://doi.org/10.3390/ijms17071083 - 7 Jul 2016

Cited by 7 | Viewed by 6443

Abstract

In the past few years, the sol-gel polycondensation technique has been increasingly employed with great success as an alternative approach to the preparation of molecularly imprinted materials (MIMs). The main aim of this study was to study, through a series of molecular dynamics [...] Read more.

In the past few years, the sol-gel polycondensation technique has been increasingly employed with great success as an alternative approach to the preparation of molecularly imprinted materials (MIMs). The main aim of this study was to study, through a series of molecular dynamics (MD) simulations, the selectivity of an imprinted silica xerogel towards a new template—the (±)-2-(P-Isobutylphenyl) propionic acid (Ibuprofen, IBU). We have previously demonstrated the affinity of this silica xerogel toward a similar molecule. In the present study, we simulated the imprinting process occurring in a sol-gel mixture using the Optimized Potentials for Liquid Simulations-All Atom (OPLS-AA) force field, in order to evaluate the selectivity of this xerogel for a template molecule. In addition, for the first time, we have developed and verified a new parameterisation for the Ibuprofen^® based on the OPLS-AA framework. To evaluate the selectivity of the polymer, we have employed both the radial distribution functions, interaction energies and cluster analyses. Full article

(This article belongs to the Special Issue Big Data Analysis and QSAR/QSPR Research in Chemistry, Bio-Medical, and Network Sciences)

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16 pages, 3344 KiB

Open AccessArticle

Comparative Analysis of the Chloroplast Genomic Information of Cunninghamia lanceolata (Lamb.) Hook with Sibling Species from the Genera Cryptomeria D. Don, Taiwania Hayata, and Calocedrus Kurz

by Weiwei Zheng^1,2, Jinhui Chen¹, Zhaodong Hao¹ and Jisen Shi^1,*

¹ Collaborative Innovation Center of Sustainable Forestry in Southern China; Key Laboratory of Forestry Genetics and Biotechnology, Ministry of Education, Nanjing Forestry University, Longpan Road 159, Nanjing 210037, China

² College of Electronics and Information Science, Fujian Jiangxia University, Fuzhou 350108, China

Int. J. Mol. Sci. 2016, 17(7), 1084; https://doi.org/10.3390/ijms17071084 - 7 Jul 2016

Cited by 24 | Viewed by 5654

Abstract

Chinese fir (Cunninghamia lanceolata (Lamb.) Hook) is an important coniferous tree species for timber production, which accounts for ~40% of log supply from plantations in southern China. Chloroplast genetic engineering is an exciting field to engineer several valuable tree traits. In this [...] Read more.

Chinese fir (Cunninghamia lanceolata (Lamb.) Hook) is an important coniferous tree species for timber production, which accounts for ~40% of log supply from plantations in southern China. Chloroplast genetic engineering is an exciting field to engineer several valuable tree traits. In this study, we revisited the published complete Chinese fir (NC_021437) and four other coniferous species chloroplast genome sequence in Taxodiaceae. Comparison of their chloroplast genomes revealed three unique inversions found in the downstream of the gene clusters and evolutionary divergence were found, although overall the chloroplast genomic structure of the Cupressaceae linage was conserved. We also investigated the phylogenetic position of Chinese fir among conifers by examining gene functions, selection forces, substitution rates, and the full chloroplast genome sequence. Consistent with previous molecular systematics analysis, the results provided a well-supported phylogeny framework for the Cupressaceae that strongly confirms the “basal” position of Cunninghamia lanceolata. The structure of the Cunninghamia lanceolata chloroplast genome showed a partial lack of one IR copy, rearrangements clearly occurred and slight evolutionary divergence appeared among the cp genome of C. lanceolata, Taiwania cryptomerioides, Taiwania flousiana, Calocedrus formosana and Cryptomeria japonica. The information from sequence divergence and length variation of genes could be further considered for bioengineering research. Full article

(This article belongs to the Section Molecular Plant Sciences)

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10 pages, 1199 KiB

Open AccessArticle

Synthesis and Evaluation of Tricarbonyl ^99mTc-Labeled 2-(4-Chloro)phenyl-imidazo[1,2-a]pyridine Analogs as Novel SPECT Imaging Radiotracer for TSPO-Rich Cancer

by Ji Young Choi^1,2, Rosa Maria Iacobazzi^3,4, Mara Perrone³, Nicola Margiotta⁵

, Annalisa Cutrignelli³, Jae Ho Jung¹, Do Dam Park¹, Byung Seok Moon¹, Nunzio Denora^3,*, Sang Eun Kim^1,2,6 and Byung Chul Lee^1,6,*

¹ Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea

² Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 16229, Korea

³ Department of Pharmacy–Drug Sciences, University of Bari “Aldo Moro”, Bari 70125, Italy

⁴ Istituto Tumori IRCCS “Giovanni Paolo II”, Flacco, St. 65, Bari 70124, Italy

⁵ Department of Chemistry, University of Bari “Aldo Moro”, Bari 70125, Italy

⁶ Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon 16229, Korea

Int. J. Mol. Sci. 2016, 17(7), 1085; https://doi.org/10.3390/ijms17071085 - 7 Jul 2016

Cited by 13 | Viewed by 6403

Abstract

The 18-kDa translocator protein (TSPO) levels are associated with brain, breast, and prostate cancer progression and have emerged as viable targets for cancer therapy and imaging. In order to develop highly selective and active ligands with a high affinity for TSPO, imidazopyridine-based TSPO [...] Read more.

The 18-kDa translocator protein (TSPO) levels are associated with brain, breast, and prostate cancer progression and have emerged as viable targets for cancer therapy and imaging. In order to develop highly selective and active ligands with a high affinity for TSPO, imidazopyridine-based TSPO ligand (CB256, 3) was prepared as the precursor. ^99mTc- and Re-CB256 (1 and 2, respectively) were synthesized in high radiochemical yield (74.5% ± 6.4%, decay-corrected, n = 5) and chemical yield (65.6%) by the incorporation of the [^99mTc(CO)₃(H₂O)₃]⁺ and (NEt₄)₂[Re(CO)₃Br₃] followed by HPLC separation. Radio-ligand 1 was shown to be stable (>99%) when incubated in human serum for 4 h at 37 °C with a relatively low lipophilicity (logD = 2.15 ± 0.02). The rhenium-185 and -187 complex 2 exhibited a moderate affinity (K_i = 159.3 ± 8.7 nM) for TSPO, whereas its cytotoxicity evaluated on TSPO-rich tumor cell lines was lower than that observed for the precursor. In vitro uptake studies of 1 in C6 and U87-MG cells for 60 min was found to be 9.84% ± 0.17% and 7.87% ± 0.23% ID, respectively. Our results indicated that ^99mTc-CB256 can be considered as a potential new TSPO-rich cancer SPECT imaging agent and provides the foundation for further in vivo evaluation. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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15 pages, 11954 KiB

Open AccessArticle

Dual-Labeled Near-Infrared/^99mTc Imaging Probes Using PAMAM-Coated Silica Nanoparticles for the Imaging of HER2-Expressing Cancer Cells

by Haruka Yamaguchi^1,†

, Makoto Tsuchimochi^1,2,3,*, Kazuhide Hayama², Tomoyuki Kawase^3,4

and Norio Tsubokawa^3,5

¹ Quantitative Diagnostic Imaging Program, Graduate School of Life Dentistry at Niigata, The Nippon Dental University, Niigata 951-8580, Japan

² Department of Oral and Maxillofacial Radiology, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan

³ Advanced Research Center, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan

⁴ Division of Oral Bioengineering, Institute of Medicine and Dentistry, Niigata University, Niigata 951-8514, Japan

⁵ Faculty of Engineering, Niigata University, Niigata 950-2181, Japan

^† Current address: Haruka Yamaguchi-Takezawa, Department of Life Science Dentistry, The Nippon Dental University, Niigata 951-8580, Japan

Int. J. Mol. Sci. 2016, 17(7), 1086; https://doi.org/10.3390/ijms17071086 - 7 Jul 2016

Cited by 34 | Viewed by 8157

Abstract

We sought to develop dual-modality imaging probes using functionalized silica nanoparticles to target human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer cells and achieve efficient target imaging of HER2-expressing tumors. Polyamidoamine-based functionalized silica nanoparticles (PCSNs) for multimodal imaging were synthesized with near-infrared [...] Read more.

We sought to develop dual-modality imaging probes using functionalized silica nanoparticles to target human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer cells and achieve efficient target imaging of HER2-expressing tumors. Polyamidoamine-based functionalized silica nanoparticles (PCSNs) for multimodal imaging were synthesized with near-infrared (NIR) fluorescence (indocyanine green (ICG)) and technetium-99m (^99mTc) radioactivity. Anti-HER2 antibodies were bound to the labeled PCSNs. These dual-imaging probes were tested to image HER2-overexpressing breast carcinoma cells. In vivo imaging was also examined in breast tumor xenograft models in mice. SK-BR3 (HER2 positive) cells were imaged with stronger NIR fluorescent signals than that in MDA-MB231 (HER2 negative) cells. The increased radioactivity of the SK-BR3 cells was also confirmed by phosphor imaging. NIR images showed strong fluorescent signals in the SK-BR3 tumor model compared to muscle tissues and the MDA-MB231 tumor model. Automatic well counting results showed increased radioactivity in the SK-BR3 xenograft tumors. We developed functionalized silica nanoparticles loaded with ^99mTc and ICG for the targeting and imaging of HER2-expressing cells. The dual-imaging probes efficiently imaged HER2-overexpressing cells. Although further studies are needed to produce efficient isotope labeling, the results suggest that the multifunctional silica nanoparticles are a promising vehicle for imaging specific components of the cell membrane in a dual-modality manner. Full article

(This article belongs to the Special Issue Inorganic Nanostructures in Biological Systems)

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23 pages, 3146 KiB

Open AccessReview

Chemical Structure-Biological Activity Models for Pharmacophores’ 3D-Interactions

by Mihai V. Putz^1,2,*,†, Corina Duda-Seiman^1,†, Daniel Duda-Seiman^3,†, Ana-Maria Putz^1,4,†, Iulia Alexandrescu^5,†, Maria Mernea⁵ and Speranta Avram^5,†

¹ Laboratory of Computational and Structural Physical-Chemistry for Nanosciences and QSAR, Department of Biology-Chemistry, West University of Timişoara, Pestalozzi Str. 16, RO-300115 Timisoara, Romania

² Laboratory of Renewable Energies-Photovoltaics, R & D National Institute for Electrochemistry and Condensed Matter, Dr. A. Paunescu Podeanu Str. No. 144, RO-300569 Timisoara, Romania

³ Department of Medical Ambulatory, and Medical Emergencies, University of Medicine and Pharmacy “Victor Babes”, Avenue C. D. Loga No. 49, RO-300020 Timisoara, Romania

⁴ Institute of Chemistry Timișoara of the Romanian Academy, 24 Mihai Viteazul Bld., RO-300223 Timisoara, Romania

⁵ Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Str. 91-95th Independentei, RO-050095 Bucharest, Romania

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1087; https://doi.org/10.3390/ijms17071087 - 8 Jul 2016

Cited by 32 | Viewed by 6922

Abstract

Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the [...] Read more.

Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the present review exposes three of the fertile directions in approaching the biological activity by chemical structural causes: the special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) offering the full analytical counterpart for multi-variate computational regression, the minimal topological difference (MTD) as the revived precursor for comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analysis (CoMSIA); all of these methods and algorithms were presented, discussed and exemplified on relevant chemical medicinal systems as proton pump inhibitors belonging to the 4-indolyl,2-guanidinothiazole class of derivatives blocking the acid secretion from parietal cells in the stomach, the 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine congeners’ (HEPT ligands) antiviral activity against Human Immunodeficiency Virus of first type (HIV-1) and new pharmacophores in treating severe genetic disorders (like depression and psychosis), respectively, all involving 3D pharmacophore interactions. Full article

(This article belongs to the Special Issue Computational Eco, Bio, and Pharmaco-Toxicity 2016)

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12 pages, 1615 KiB

Open AccessArticle

MALDI Mass Spectrometry Imaging Reveals Decreased CK5 Levels in Vulvar Squamous Cell Carcinomas Compared to the Precursor Lesion Differentiated Vulvar Intraepithelial Neoplasia

by Chao Zhang^1,2,†, Georgia Arentz^1,2,†, Lyron Winderbaum^1,†, Noor A. Lokman^1,3

, Manuela Klingler-Hoffmann^1,2, Parul Mittal^1,2, Christopher Carter⁴, Martin K. Oehler^3,5 and Peter Hoffmann^1,2,*

¹ Adelaide Proteomics Centre, School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia

² Institute for Photonics and Advanced Sensing (IPAS), The University of Adelaide, Adelaide 5005, Australia

³ Discipline of Obstetrics and Gynaecology, School of Medicine, Research Centre for Reproductive Health, Robinson Institute, Adelaide 5005, Australia

⁴ Department of Cytopathology, SA Pathology, Adelaide 5005, Australia

⁵ Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide 5005, Australia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1088; https://doi.org/10.3390/ijms17071088 - 8 Jul 2016

Cited by 12 | Viewed by 6211

Abstract

Vulvar cancer is the fourth most common gynecological cancer worldwide. However, limited studies have been completed on the molecular characterization of vulvar squamous cell carcinoma resulting in a poor understanding of the disease initiation and progression. Analysis and early detection of the precursor [...] Read more.

Vulvar cancer is the fourth most common gynecological cancer worldwide. However, limited studies have been completed on the molecular characterization of vulvar squamous cell carcinoma resulting in a poor understanding of the disease initiation and progression. Analysis and early detection of the precursor lesion of HPV-independent vulvar squamous cell carcinoma (VSCC), differentiated vulvar intraepithelial neoplasia (dVIN), is of great importance given dVIN lesions have a high level of malignant potential. Here we present an examination of adjacent normal vulvar epithelium, dVIN, and VSCC from six patients by peptide Matrix-assisted laser desorption/ionization Mass Spectrometry Imaging (MALDI-MSI). The results reveal the differential expression of multiple peptides from the protein cytokeratin 5 (CK5) across the three vulvar tissue types. The difference observed in the relative abundance of CK5 by MALDI-MSI between the healthy epithelium, dVIN, and VSCC was further analyzed by immunohistochemistry (IHC) in tissue from eight VSCC patients. A decrease in CK5 immunostaining was observed in the VSCC compared to the healthy epithelium and dVIN. These results provide an insight into the molecular fingerprint of the vulvar intraepithelial neoplasia that appears to be more closely related to the healthy epithelium than the VSCC. Full article

(This article belongs to the Special Issue Cancer Molecular Imaging in the Era of Precision Medicine)

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8 pages, 632 KiB

Open AccessArticle

Liver Fat Measured by MR Spectroscopy: Estimate of Imprecision and Relationship with Serum Glycerol, Caeruloplasmin and Non-Esterified Fatty Acids

by Michael France^1,*, See Kwok², Handrean Soran³, Steve Williams⁴, Jan Hoong Ho^3,*, Safwaan Adam⁴, Dexter Canoy⁵, Yifen Liu⁶ and Paul N. Durrington⁶

¹ Department of Clinical Biochemistry, Cobbett House, Central Manchester Foundation Trust, Oxford Road, Manchester M13 9WL, UK

² Cardiovascular Trials Unit, The Old St Mary’s Hospital, Hathersage Road, Oxford Road, Manchester M13 9WL, UK

³ Department of Medicine, Central Manchester Foundation Trust, Oxford Road, Manchester M13 9WL, UK

⁴ Department of Imaging Science, University of Manchester, Oxford Road, Manchester M13 9PT, UK

⁵ Cancer Epidemiology Unit, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, UK

⁶ School of Biomedicine, 3rd floor, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK

Int. J. Mol. Sci. 2016, 17(7), 1089; https://doi.org/10.3390/ijms17071089 - 8 Jul 2016

Cited by 4 | Viewed by 6171

Abstract

Magnetic resonance spectroscopy (MRS) is a non-invasive method for quantitative estimation of liver fat. Knowledge of its imprecision, which comprises biological variability and measurement error, is required to design therapeutic trials with measurement of change. The role of adipocyte lipolysis in ectopic fat [...] Read more.

Magnetic resonance spectroscopy (MRS) is a non-invasive method for quantitative estimation of liver fat. Knowledge of its imprecision, which comprises biological variability and measurement error, is required to design therapeutic trials with measurement of change. The role of adipocyte lipolysis in ectopic fat accumulation remains unclear. We examined the relationship between liver fat content and indices of lipolysis, and determine whether lipolysis reflects insulin resistance or metabolic liver disease. Imprecision of measurement of liver fat was estimated from duplicate measurements by MRS at one month intervals. Patients provided fasting blood samples and we examined the correlation of liver fat with indices of insulin resistance, lipolysis and metabolic liver disease using Kendall Tau statistics. The coefficient of variation of liver fat content was 14.8%. Liver fat was positively related to serum insulin (T = 0.48, p = 0.042), homeostasis model assessment (HOMA)-B% (T = −0.48, p = 0.042), and body mass index (BMI) (T = 0.59, p = 0.012); and inversely related to HOMA-S% (T = −0.48, p = 0.042), serum glycerol (T = −0.59, p = 0.014), and serum caeruloplasmin (T = 0.055, p = 0.047). Our estimate of total variability in liver fat content (14.8%) is nearly twice that of the reported procedural variability (8.5%). We found that liver fat content was significantly inversely related to serum glycerol but not to non-esterified fatty acids (NEFA), suggesting progressive suppression of lipolysis. Reduction of caeruloplasmin with increasing liver fat may be a consequence or a cause of hepatic steatosis. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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13 pages, 1970 KiB

Open AccessArticle

The Prognostic and Predictive Role of Epidermal Growth Factor Receptor in Surgical Resected Pancreatic Cancer

by Meng Guo^1,2,3,†

, Guopei Luo^1,2,3,*,†, Chen Liu^1,2,3,†, He Cheng^1,2,3, Yu Lu^1,2,3, Kaizhou Jin^1,2,3, Zuqiang Liu^1,2,3, Jiang Long^1,2,3, Liang Liu^1,2,3, Jin Xu^1,2,3, Dan Huang^3,4, Quanxing Ni^1,2,3 and Xianjun Yu^1,2,3,*

¹ Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China

² Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China

³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

⁴ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1090; https://doi.org/10.3390/ijms17071090 - 8 Jul 2016

Cited by 17 | Viewed by 5713

Abstract

The data regarding the prognostic significance of EGFR (epidermal growth factor receptor) expression and adjuvant therapy in patients with resected pancreatic cancer are insufficient. We retrospectively investigated EGFR status in 357 resected PDAC (pancreatic duct adenocarcinoma) patients using tissue immunohistochemistry and validated the [...] Read more.

The data regarding the prognostic significance of EGFR (epidermal growth factor receptor) expression and adjuvant therapy in patients with resected pancreatic cancer are insufficient. We retrospectively investigated EGFR status in 357 resected PDAC (pancreatic duct adenocarcinoma) patients using tissue immunohistochemistry and validated the possible role of EGFR expression in predicting prognosis. The analysis was based on excluding the multiple confounding parameters. A negative association was found between overall EGFR status and postoperative survival (p = 0.986). Remarkably, adjuvant chemotherapy and radiotherapy were significantly associated with favorable postoperative survival, which prolonged median overall survival (OS) for 5.8 and 10.2 months (p = 0.009 and p = 0.006, respectively). Kaplan–Meier analysis showed that adjuvant chemotherapy correlated with an obvious survival benefit in the EGFR-positive subgroup rather than in the EGFR-negative subgroup. In the subgroup analyses, chemotherapy was highly associated with increased postoperative survival in the EGFR-positive subgroup (p = 0.002), and radiotherapy had a significant survival benefit in the EGFR-negative subgroup (p = 0.029). This study demonstrated that EGFR expression is not correlated with outcome in resected pancreatic cancer patients. Adjuvant chemotherapy and radiotherapy were significantly associated with improved survival in contrary EGFR expressing subgroup. Further studies of EGFR as a potential target for pancreatic cancer treatment are warranted. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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19 pages, 4558 KiB

Open AccessArticle

Piriformospora indica Stimulates Root Metabolism of Arabidopsis thaliana

by Nadine Strehmel^1,*, Susann Mönchgesang¹

, Siska Herklotz¹, Sylvia Krüger¹, Jörg Ziegler² and Dierk Scheel^1,*

¹ Department of Stress and Developmental Biology, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany

² Department of Molecular Signal Processing, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany

Int. J. Mol. Sci. 2016, 17(7), 1091; https://doi.org/10.3390/ijms17071091 - 8 Jul 2016

Cited by 36 | Viewed by 12094

Abstract

Piriformospora indica is a root-colonizing fungus, which interacts with a variety of plants including Arabidopsis thaliana. This interaction has been considered as mutualistic leading to growth promotion of the host. So far, only indolic glucosinolates and phytohormones have been identified as key [...] Read more.

Piriformospora indica is a root-colonizing fungus, which interacts with a variety of plants including Arabidopsis thaliana. This interaction has been considered as mutualistic leading to growth promotion of the host. So far, only indolic glucosinolates and phytohormones have been identified as key players. In a comprehensive non-targeted metabolite profiling study, we analyzed Arabidopsis thaliana’s roots, root exudates, and leaves of inoculated and non-inoculated plants by ultra performance liquid chromatography/electrospray ionization quadrupole-time-of-flight mass spectrometry (UPLC/(ESI)-QTOFMS) and gas chromatography/electron ionization quadrupole mass spectrometry (GC/EI-QMS), and identified further biomarkers. Among them, the concentration of nucleosides, dipeptides, oligolignols, and glucosinolate degradation products was affected in the exudates. In the root profiles, nearly all metabolite levels increased upon co-cultivation, like carbohydrates, organic acids, amino acids, glucosinolates, oligolignols, and flavonoids. In the leaf profiles, we detected by far less significant changes. We only observed an increased concentration of organic acids, carbohydrates, ascorbate, glucosinolates and hydroxycinnamic acids, and a decreased concentration of nitrogen-rich amino acids in inoculated plants. These findings contribute to the understanding of symbiotic interactions between plant roots and fungi of the order of Sebacinales and are a valid source for follow-up mechanistic studies, because these symbioses are particular and clearly different from interactions of roots with mycorrhizal fungi or dark septate endophytes Full article

(This article belongs to the Special Issue Metabolomics in the Plant Sciences)

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10 pages, 5069 KiB

Open AccessArticle

miR-494-3p Induces Cellular Senescence and Enhances Radiosensitivity in Human Oral Squamous Carcinoma Cells

by Jui-Hung Weng¹, Cheng-Chia Yu^2,3,4,†, Yueh-Chun Lee^5,6,†

, Cheng-Wei Lin⁷, Wen-Wei Chang^7,8,*

and Yu-Liang Kuo^9,10,*

¹ Department of Nuclear Medicine, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

² School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan

³ Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

⁴ Institute of Oral Science, Chung Shan Medical University, Taichung 40201, Taiwan

⁵ Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

⁶ Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan

⁷ School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung 40201, Taiwan

⁸ Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

⁹ Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201, Taiwan

¹⁰ Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2016, 17(7), 1092; https://doi.org/10.3390/ijms17071092 - 8 Jul 2016

Cited by 53 | Viewed by 6194

Abstract

Oral squamous cell carcinoma (OSCC) is the most common malignancy of head and neck. Although radiotherapy is used for OSCC treatment, the occurrence of radioresistant cancer cells limits its efficiency. MicroRNAs (miRNAs) are non-coding RNAs with lengths of 18–25 base pairs and known [...] Read more.

Oral squamous cell carcinoma (OSCC) is the most common malignancy of head and neck. Although radiotherapy is used for OSCC treatment, the occurrence of radioresistant cancer cells limits its efficiency. MicroRNAs (miRNAs) are non-coding RNAs with lengths of 18–25 base pairs and known to be involved in carcinogenesis. We previously demonstrated that by targeting B lymphoma Mo-MLV insertion region 1 homolog (Bmi1), miR-494-3p functions as a putative tumor suppressor miRNA in OSCC. In this study, we further discovered that miR-494-3p could enhance the radiosensitivity of SAS OSCC cells and induce cellular senescence. The overexpression of miR-494-3p in SAS cells increased the population of senescence-associated β-galactosidase positive cells, the expression of p16^INK4a and retinoblastoma 1 (RB1), as well as downregulated Bmi1. The knockdown of Bmi1 by lentiviral-mediated delivery of specific short hairpin RNAs (shRNAs) also enhanced the radiosensitivity of SAS cells and the activation of the senescence pathway. Furthermore, the inverse correlation between Bmi1 and miR-494-3p expression was observed among OSCC tissues. Results suggest that miR-494-3p could increase the radiosensitivity of OSCC cells through the induction of cellular senescence caused by the downregulation of Bmi1. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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9 pages, 1790 KiB

Open AccessArticle

Expression of Tenascin C, EGFR, E-Cadherin, and TTF-1 in Medullary Thyroid Carcinoma and the Correlation with RET Mutation Status

by Florian Steiner¹, Cornelia Hauser-Kronberger¹, Gundula Rendl², Margarida Rodrigues² and Christian Pirich^2,*

¹ Department of Pathology, Paracelsus Medical University Salzburg, Müllner Hauptstrasse 48, A-5020 Salzburg, Austria

² Department of Nuclear Medicine and Endocrinology, Paracelsus Medical University Salzburg, Müllner Hauptstrasse 48, A-5020 Salzburg, Austria

Int. J. Mol. Sci. 2016, 17(7), 1093; https://doi.org/10.3390/ijms17071093 - 9 Jul 2016

Cited by 8 | Viewed by 5301

Abstract

Tenascin C expression correlates with tumor grade and indicates worse prognosis in several tumors. Epidermal growth factor receptor (EGFR) plays an important role in driving proliferation in many tumors. Loss of E-cadherin function is associated with tumor invasion and metastasis. Thyroid transcription factor-1 [...] Read more.

Tenascin C expression correlates with tumor grade and indicates worse prognosis in several tumors. Epidermal growth factor receptor (EGFR) plays an important role in driving proliferation in many tumors. Loss of E-cadherin function is associated with tumor invasion and metastasis. Thyroid transcription factor-1 (TTF-1) is involved in rearranged during transfection (RET) transcription in Hirschsprung’s disease. Tenascin C, EGFR, E-cadherin, TTF-1-expression, and their correlations with RET mutation status were investigated in 30 patients with medullary thyroid carcinoma (MTC) (n = 26) or C-cell hyperplasia (n = 4). Tenascin C was found in all, EGFR in 4/26, E-cadherin in 23/26, and TTF-1 in 25/26 MTC. Tenascin C correlated significantly with tumor proliferation (overall, r = 0.61, p < 0.005; RET-mutated, r = 0.81, p < 0.01). E-cadherin showed weak correlation, whereas EGFR and TTF-1 showed no significant correlation with tumor proliferation. EGFR, E-cadherin, and TTF-1 showed weak correlation with proliferation of RET-mutated tumors. Correlation between TTF-1 and tenascin C, E-cadherin, and EGFR was r = −0.10, 0.37, and 0.21, respectively. In conclusion, MTC express tenascin C, E-cadherin, and TTF-1. Tenascin C correlates significantly with tumor proliferation, especially in RET-mutated tumors. EGFR is low, and tumors expressing EGFR do not exhibit higher proliferation. TTF-1 does not correlate with RET mutation status and has a weak correlation with tenascin C, E-cadherin, and EGFR expression. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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14 pages, 411 KiB

Open AccessArticle

Replacement of Oxygen by Sulfur in Small Organic Molecules. 3. Theoretical Studies on the Tautomeric Equilibria of the 2OH and 4OH-Substituted Oxazole and Thiazole and the 3OH and 4OH-Substituted Isoxazole and Isothiazole in the Isolated State and in Solution

by Peter I. Nagy

Center for Drug Design and Development, The University of Toledo, Toledo, OH 43606, USA

Int. J. Mol. Sci. 2016, 17(7), 1094; https://doi.org/10.3390/ijms17071094 - 9 Jul 2016

Cited by 5 | Viewed by 6593

Abstract

This follow-up paper completes the author’s investigations to explore the in-solution structural preferences and relative free energies of all OH-substituted oxazole, thiazole, isoxazole, and isothiazole systems. The polarizable continuum dielectric solvent method calculations in the integral-equation formalism (IEF-PCM) were performed at the DFT/B97D/aug-cc-pv(q+(d))z [...] Read more.

This follow-up paper completes the author’s investigations to explore the in-solution structural preferences and relative free energies of all OH-substituted oxazole, thiazole, isoxazole, and isothiazole systems. The polarizable continuum dielectric solvent method calculations in the integral-equation formalism (IEF-PCM) were performed at the DFT/B97D/aug-cc-pv(q+(d))z level for the stable neutral tautomers with geometries optimized in dichloromethane and aqueous solution. With the exception of the predictions for the predominant tautomers of the 3OH isoxazole and isothiazole, the results of the IEF-PCM calculations for identifying the most stable tautomer of the given species in the two selected solvents agreed with those from experimental investigations. The calculations predict that the hydroxy proton, with the exception for the 4OH isoxazole and 4OH isothiazole, moves preferentially to the ring nitrogen or to a ring carbon atom in parallel with the development of a C=O group. The remaining, low-fraction OH tautomers will not be observable in the equilibrium compositions. Relative solvation free energies obtained by the free energy perturbation method implemented in Monte Carlo simulations are in moderate accord with the IEF-PCM results, but consideration of the ΔG_solv/MC values in calculating ΔG^s_tot maintains the tautomeric preferences. It was revealed from the Monte Carlo solution structure analyses that the S atom is not a hydrogen-bond acceptor in any OH-substituted thiazole or isothiazole, and the OH-substituted isoxazole and oxazole ring oxygens may act as a weak hydrogen-bond acceptor at most. The molecules form 1.0−3.4 solute−water hydrogen bonds in generally unexplored numbers at some specific solute sites. Nonetheless, hydrogen-bond formation is favorable with the NH, C=O and OH groups. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2016)

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9 pages, 1178 KiB

Open AccessArticle

Regulation of Intestinal Epithelial Calcium Transport Proteins by Stanniocalcin-1 in Caco2 Cells

by Jinmei Xiang^1,2,†, Rui Guo^3,†, Chunyun Wan^1,4,†, Liming Wu¹, Shijin Yang¹ and Dingzong Guo^1,*

¹ College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, China

² Department of Animal Science, Hubei Vocational College Of Bio-Technology, Wuhan 430070, Hubei, China

³ Hubei Key Laboratory of Embryo and Molecular Breeding, Hubei Academy of Agricultural Sciences, Wuhan 430064, Hubei, China

⁴ College of Animal Science, Yangtze University, Jingzhou 434023, Hubei, China

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2016, 17(7), 1095; https://doi.org/10.3390/ijms17071095 - 9 Jul 2016

Cited by 15 | Viewed by 6107

Abstract

Stanniocalcin-1 (STC1) is a calcium and phosphate regulatory hormone. However, the exact molecular mechanisms underlying how STC1 affects Ca²⁺ uptake remain unclear. Here, the expression levels of the calcium transport proteins involved in transcellular transport in Caco2 cells were examined following over-expression [...] Read more.

Stanniocalcin-1 (STC1) is a calcium and phosphate regulatory hormone. However, the exact molecular mechanisms underlying how STC1 affects Ca²⁺ uptake remain unclear. Here, the expression levels of the calcium transport proteins involved in transcellular transport in Caco2 cells were examined following over-expression or inhibition of STC1. These proteins include the transient receptor potential vanilloid members (TRPV) 5 and 6, the plasma membrane calcium ATPase 1b (PMCA1b), the sodium/calcium exchanger (NCX1), and the vitamin D receptor (VDR). Both gene and protein expressions of TRPV5 and TRPV6 were attenuated in response to over-expression of STC1, and the opposite trend was observed in cells treated with siRNA_STC1. To further investigate the ability of STC1 to influence TRPV6 expression, cells were treated with 100 ng/mL of recombinant human STC1 (rhSTC1) for 4 h following pre-transfection with siRNA_STC1 for 48 h. Intriguingly, the increase in the expression of TRPV6 resulting from siRNA_STC1 was reversed by rhSTC1. No significant effect of STC1 on the expression of PMCA1b, NCX1 or VDR was observed in this study. In conclusion, the effect of STC1 on calcium transport in intestinal epithelia is due to, at least in part, its negative regulation of the epithelial channels TRPV5/6 that mediate calcium influx. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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20 pages, 2867 KiB

Open AccessReview

Hepatocyte and Sertoli Cell Aquaporins, Recent Advances and Research Trends

by Raquel L. Bernardino¹, Raul A. Marinelli², Anna Maggio³, Patrizia Gena³, Ilaria Cataldo³, Marco G. Alves⁴

, Maria Svelto³, Pedro F. Oliveira^1,5,*

and Giuseppe Calamita^3,*

¹ Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal

² Instituto de Fisiología Experimental-CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario, 531 S2002LRK Rosario, Santa Fe, Argentina

³ Department of Biosciences, Biotechnologies and Biopharnaceutics, University of Bari “Aldo Moro”, 70125 Bari, Italy

⁴ CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal

⁵ Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal

Int. J. Mol. Sci. 2016, 17(7), 1096; https://doi.org/10.3390/ijms17071096 - 9 Jul 2016

Cited by 27 | Viewed by 12035

Abstract

Aquaporins (AQPs) are proteinaceous channels widespread in nature where they allow facilitated permeation of water and uncharged through cellular membranes. AQPs play a number of important roles in both health and disease. This review focuses on the most recent advances and research trends [...] Read more.

Aquaporins (AQPs) are proteinaceous channels widespread in nature where they allow facilitated permeation of water and uncharged through cellular membranes. AQPs play a number of important roles in both health and disease. This review focuses on the most recent advances and research trends regarding the expression and modulation, as well as physiological and pathophysiological functions of AQPs in hepatocytes and Sertoli cells (SCs). Besides their involvement in bile formation, hepatocyte AQPs are involved in maintaining energy balance acting in hepatic gluconeogenesis and lipid metabolism, and in critical processes such as ammonia detoxification and mitochondrial output of hydrogen peroxide. Roles are played in clinical disorders including fatty liver disease, diabetes, obesity, cholestasis, hepatic cirrhosis and hepatocarcinoma. In the seminiferous tubules, particularly in SCs, AQPs are also widely expressed and seem to be implicated in the various stages of spermatogenesis. Like in hepatocytes, AQPs may be involved in maintaining energy homeostasis in these cells and have a major role in the metabolic cooperation established in the testicular tissue. Altogether, this information represents the mainstay of current and future investigation in an expanding field. Full article

(This article belongs to the Special Issue Aquaporin)

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10 pages, 381 KiB

Open AccessArticle

Common Genetic Variation in CYP17A1 and Response to Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer

by Moritz Binder¹

, Ben Y. Zhang², David W. Hillman³, Rhea Kohli⁴, Tanvi Kohli⁴, Adam Lee⁵ and Manish Kohli^2,*

¹ Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

² Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

³ Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

⁴ Mayo High School, 1420 11th Avenue SE, Rochester, MN 55904, USA

⁵ Experimental and Clinical Pharmacology Department, University of Minnesota, 515 Delaware St. SE, Minneapolis, MN 55455, USA

Int. J. Mol. Sci. 2016, 17(7), 1097; https://doi.org/10.3390/ijms17071097 - 9 Jul 2016

Cited by 20 | Viewed by 5351

Abstract

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a [...] Read more.

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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9 pages, 759 KiB

Open AccessReview

Angiotensin A/Alamandine/MrgD Axis: Another Clue to Understanding Cardiovascular Pathophysiology

by Jaroslav Hrenak^1,2

, Ludovit Paulis^1,3

and Fedor Simko^1,4,5,*

¹ Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia

² 1st Clinic of Medicine, Donauisar Klinikum, 944 69 Deggendorf, Germany

³ Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, 814 38 Bratislava, Slovakia

⁴ 3rd Clinic of Medicine, Faculty of Medicine, Comenius University, 833 05 Bratislava, Slovakia

⁵ Institute of Experimental Endocrinology, BMC, Slovak Academy of Sciences, 814 38 Bratislava, Slovakia

Int. J. Mol. Sci. 2016, 17(7), 1098; https://doi.org/10.3390/ijms17071098 - 20 Jul 2016

Cited by 81 | Viewed by 10381

Abstract

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension [...] Read more.

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension of the RAS is thus far from complete. The RAS represents an ingenious system of “checks and balances”. It incorporates vasoconstrictive, pro-proliferative, and pro-inflammatory compounds on one hand and molecules with opposing action on the other hand. The list of these molecules is still not definitive because new biological properties can be achieved by minor alteration of the molecular structure. The angiotensin A/alamandine-MrgD cascade associates the deleterious and protective branches of the RAS. Its identification provided a novel clue to the understanding of the RAS. Angiotensin A (Ang A) is positioned at the “crossroad” in this system since it either elicits direct vasoconstrictive and pro-proliferative actions or it is further metabolized to alamandine, triggering opposing effects. Alamandine, the central molecule of this cascade, can be generated both from the “deleterious” Ang A as well as from the “protective” angiotensin 1–7. This pathway modulates peripheral and central blood pressure regulation and cardiovascular remodeling. Further research will elucidate its interactions in cardiovascular pathophysiology and its possible therapeutic implications. Full article

(This article belongs to the Special Issue Molecular Research on Hypertension)

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24 pages, 6016 KiB

Open AccessArticle

Identification of Pathways in Liver Repair Potentially Targeted by Secretory Proteins from Human Mesenchymal Stem Cells

by Sandra Winkler¹, Madlen Hempel¹, Sandra Brückner¹, Hans-Michael Tautenhahn¹, Roland Kaufmann² and Bruno Christ^1,*

¹ Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany

² Department of General, Visceral and Vascular Surgery, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany

Int. J. Mol. Sci. 2016, 17(7), 1099; https://doi.org/10.3390/ijms17071099 - 9 Jul 2016

Cited by 22 | Viewed by 7326

Abstract

Background: The beneficial impact of mesenchymal stem cells (MSC) on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order [...] Read more.

Background: The beneficial impact of mesenchymal stem cells (MSC) on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order to delineate liver repair pathways potentially targeted by MSC. Methods: Secreted factors were determined by protein arrays and related pathways identified by biomathematical analyses. Results: MSC from adipose tissue and bone marrow expressed a similar pattern of surface markers. After hepatocytic differentiation, CD54 (intercellular adhesion molecule 1, ICAM-1) increased and CD166 (activated leukocyte cell adhesion molecule, ALCAM) decreased. MSC secreted different factors before and after differentiation. These comprised cytokines involved in innate immunity and growth factors regulating liver regeneration. Pathway analysis revealed cytokine-cytokine receptor interactions, chemokine signalling pathways, the complement and coagulation cascades as well as the Januskinase-signal transducers and activators of transcription (JAK-STAT) and nucleotide-binding oligomerization domain-like receptor (NOD-like receptor) signalling pathways as relevant networks. Relationships to transforming growth factor β (TGF-β) and hypoxia-inducible factor 1-α (HIF1-α) signalling seemed also relevant. Conclusion: MSC secreted proteins, which differed depending on cell source and degree of differentiation. The factors might address inflammatory and growth factor pathways as well as chemo-attraction and innate immunity. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration. Full article

(This article belongs to the Special Issue Advances in Cell Transplantation)

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13 pages, 3253 KiB

Open AccessArticle

Neuroprotective Effects of Inhibiting Fyn S-Nitrosylation on Cerebral Ischemia/Reperfusion-Induced Damage to CA1 Hippocampal Neurons

by Lingyun Hao^1,2,†, Xuewen Wei^1,3,†, Peng Guo¹, Guangyi Zhang^1,‡ and Suhua Qi^1,*

¹ Research Center for Biochemistry and Molecular Biology, and Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou 221002, China

² Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou 221002, China

³ Department of Laboratory Medicine, Affiliated Municipal Hospital of Xuzhou Medical University, Xuzhou 221002, China

^† These authors contributed equally to this work.

^‡ This author has passed away.

Int. J. Mol. Sci. 2016, 17(7), 1100; https://doi.org/10.3390/ijms17071100 - 12 Jul 2016

Cited by 11 | Viewed by 5790

Abstract

Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the [...] Read more.

Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the effects of Fyn S-nitrosylation on brain damage. In vitro, Fyn could be S-nitrosylated by S-nitrosoglutathione (GSNO, an exogenous NO donor), and in vivo, endogenous NO synthesized by NO synthases (NOS) could enhance Fyn S-nitrosylation. Application of GSNO, 7-nitroindazole (7-NI, an inhibitor of neuronal NOS) and hydrogen maleate (MK-801, the N-methyl-d-aspartate receptor (NMDAR) antagonist) could decrease the S-nitrosylation and phosphorylation of Fyn induced by cerebral ischemia/reperfusion (I/R). Cresyl violet staining validated that these compounds exerted neuroprotective effects against the cerebral I/R-induced damage to hippocampal CA1 neurons. Taken together, in this study, we demonstrated that Fyn can be S-nitrosylated both in vitro and in vivo and that inhibiting S-nitrosylation can exert neuroprotective effects against cerebral I/R injury, potentially via NMDAR-mediated mechanisms. These findings may lead to a new field of inquiry to investigate the underlying pathogenesis of stroke and the development of novel treatment strategies. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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9 pages, 2420 KiB

Open AccessArticle

Prolonged Starvation Causes Up-Regulation of AQP1 in Adipose Tissue Capillaries of AQP7 Knock-Out Mice

by Mariusz T. Skowronski^1,*

, Agnieszka Skowronska², Aleksandra Rojek³, Michal K. Oklinski³ and Søren Nielsen³

¹ Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn 10-752, Poland

² Department of Human Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn 10-752, Poland

³ Department of Health Science and Technology, Aalborg University, Aalborg 9220, Denmark

Int. J. Mol. Sci. 2016, 17(7), 1101; https://doi.org/10.3390/ijms17071101 - 22 Jul 2016

Cited by 10 | Viewed by 5859

Abstract

Aquaporins (AQPs) are membrane proteins involved in the regulation of cellular transport and the balance of water and glycerol and cell volume in the white adipose tissue (WAT). In our previous study, we found the co-expression of the AQP1 water channel and AQP7 [...] Read more.

Aquaporins (AQPs) are membrane proteins involved in the regulation of cellular transport and the balance of water and glycerol and cell volume in the white adipose tissue (WAT). In our previous study, we found the co-expression of the AQP1 water channel and AQP7 in the mouse WAT. In our present study, we aimed to find out whether prolonged starvation influences the AQP1 expression of AQP7 knock-out mice (AQP7 KO) in the WAT. To resolve this hypothesis, immunoperoxidase, immunoblot and immunogold microscopy were used. AQP1 expression was found with the use of immunohistochemistry and was confirmed by immunogold microscopy in the vessels of mouse WAT of all studied groups. Semi-quantitative immunoblot and quantitative immunogold microscopy showed a significant increase (by 2.5- to 3-fold) in the abundance of AQP1 protein expression in WAT in the 72 h starved AQP7 KO mice as compared to AQP7+/+ (p < 0.05) and AQP7−/− (p < 0.01) controls, respectively. In conclusion, the AQP1 water channel located in the vessels of WAT is up-regulated in response to prolonged starvation in the WAT of AQP7 KO mice. The present data suggest that an interaction of different AQP isoforms is required for maintaining proper water homeostasis within the mice WAT. Full article

(This article belongs to the Special Issue Aquaporin)

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10 pages, 2244 KiB

Open AccessArticle

Inhibition of AQP1 Hampers Osteosarcoma and Hepatocellular Carcinoma Progression Mediated by Bone Marrow-Derived Mesenchymal Stem Cells

by Alessandra Pelagalli^1,2,*

, Anna Nardelli², Raffaela Fontanella² and Antonella Zannetti^2,*

¹ Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli “Federico II”, Via Pansini No. 5, 80131 Napoli, Italy

² Istituto di Biostrutture e Bioimmagini-CNR, Via De Amicis No. 95, 80145 Napoli, Italy

Int. J. Mol. Sci. 2016, 17(7), 1102; https://doi.org/10.3390/ijms17071102 - 11 Jul 2016

Cited by 43 | Viewed by 7423

Abstract

The complex cross-talk between tumor cells and their surrounding stromal environment plays a key role in the pathogenesis of cancer. Among several cell types that constitute the tumor stroma, bone marrow-derived mesenchymal stem cells (BM-MSCs) selectively migrate toward the tumor microenvironment and contribute [...] Read more.

The complex cross-talk between tumor cells and their surrounding stromal environment plays a key role in the pathogenesis of cancer. Among several cell types that constitute the tumor stroma, bone marrow-derived mesenchymal stem cells (BM-MSCs) selectively migrate toward the tumor microenvironment and contribute to the active formation of tumor-associated stroma. Therefore, here we elucidate the involvement of BM-MSCs to promote osteosarcoma (OS) and hepatocellular carcinoma (HCC) cells migration and invasion and deepening the role of specific pathways. We analyzed the function of aquaporin 1 (AQP1), a water channel known to promote metastasis and neoangiogenes. AQP1 protein levels were analyzed in OS (U2OS) and HCC (SNU-398) cells exposed to conditioned medium from BM-MSCs. Tumor cell migration and invasion in response to BM-MSC conditioned medium were evaluated through a wound healing assay and Boyden chamber, respectively. The results showed that the AQP1 level was increased in both tumor cell lines after treatment with BM-MSC conditioned medium. Moreover, BM-MSCs-mediated tumor cell migration and invasion were hampered after treatment with AQP1 inhibitor. These data suggest that the recruitment of human BM-MSCs into the tumor microenvironment might cause OS and HCC cell migration and invasion through involvement of AQP1. Full article

(This article belongs to the Special Issue Aquaporin)

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14 pages, 993 KiB

Open AccessArticle

Strawberry Achenes Are an Important Source of Bioactive Compounds for Human Health

by María Teresa Ariza^1,*

, Patricia Reboredo-Rodríguez², Luca Mazzoni³, Tamara Yuliett Forbes-Hernández⁴

, Francesca Giampieri⁴

, Sadia Afrin⁴

, Massimiliano Gasparrini⁴

, Carmen Soria¹, Elsa Martínez-Ferri¹

, Maurizio Battino⁴

and Bruno Mezzetti^3,*

¹ Instituto Andaluz de Investigación y Formación Agraria y Pesquera (IFAPA), Consejería de Agricultura, Pesca y Desarrollo Rural, Junta de Andalucía, IFAPA de Churriana, Cortijo de la Cruz s/n, Churriana, 29140 Málaga, Spain

² Área de Nutrición y Bromatología, Departamento de Química Analítica y Alimentaria, Universidad de Vigo, Campus de Ourense, E-32004 Ourense, Spain

³ Dipartimento di Scienze Agrarie, Alimentari e Ambientali, Università Politecnica delle Marche, Ancona 60131, Italy

⁴ Department of Clinical Sciences, Faculty of Medicine, Polytechnic University of Marche, Ancona 60131, Italy

Int. J. Mol. Sci. 2016, 17(7), 1103; https://doi.org/10.3390/ijms17071103 - 11 Jul 2016

Cited by 61 | Viewed by 9139

Abstract

Strawberries are highly appreciated for their taste, nutritional value and antioxidant compounds, mainly phenolics. Fruit antioxidants derive from achenes and flesh, but achene contribution to the total fruit antioxidant capacity and to the bioaccessibility after intake is still unknown. In this work, the [...] Read more.

Strawberries are highly appreciated for their taste, nutritional value and antioxidant compounds, mainly phenolics. Fruit antioxidants derive from achenes and flesh, but achene contribution to the total fruit antioxidant capacity and to the bioaccessibility after intake is still unknown. In this work, the content of total phenolic compounds, flavonoids, anthocyanins and antioxidant capacity (TEAC, FRAP and DPPH) of achenes and flesh were compared in non-digested as well as in gastric and intestinal extracts after in vitro digestion. Results showed that, despite strawberry achenes represent a small fraction of the fruit, their contribution to total fruit antioxidant content was more than 41% and accounted for 81% of antioxidant capacity (TEAC). Achenes have higher quantity and different quality of antioxidants in non-digested and digested extracts. Antioxidant release was higher in the in vitro gastric digested extracts, but digestion conditions did not only affect quantity but quality, resulting in differences in antioxidant capacity and highlighting the importance of simulating physiological-like extraction conditions for assessing fruit antioxidant properties on human health. These results give new insights into the use of strawberry achenes as a source of bioactive compounds to be considered in strawberry breeding programs for improving human health. Full article

(This article belongs to the Special Issue Macro- and Micro-nutrient Antioxidants)

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16 pages, 4784 KiB

Open AccessArticle

Bacteria-Templated NiO Nanoparticles/Microstructure for an Enzymeless Glucose Sensor

by Settu Vaidyanathan¹, Jong-Yuh Cherng^1,*, An-Cheng Sun²

and Chien-Yen Chen^3,*

¹ Department of Chemistry and Biochemistry, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 62102, Taiwan

² Department of Chemical Engineering & Materials Science, Yuan Ze University. No. 135 Yuandong Road, Zhongli District, Taoyuan City 320, Taiwan

³ Department of Earth and Environmental Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 62102, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1104; https://doi.org/10.3390/ijms17071104 - 11 Jul 2016

Cited by 23 | Viewed by 7813

Abstract

The bacterial-induced hollow cylinder NiO (HCNiO) nanomaterial was utilized for the enzymeless (without GOx) detection of glucose in basic conditions. The determination of glucose in 0.05 M NaOH solution with high sensitivity was performed using cyclic voltammetry (CV) and amperometry (i–t). The fundamental [...] Read more.

The bacterial-induced hollow cylinder NiO (HCNiO) nanomaterial was utilized for the enzymeless (without GOx) detection of glucose in basic conditions. The determination of glucose in 0.05 M NaOH solution with high sensitivity was performed using cyclic voltammetry (CV) and amperometry (i–t). The fundamental electrochemical parameters were analyzed and the obtained values of diffusion coefficient (D), heterogeneous rate constant (k_s), electroactive surface coverage (Г), and transfer coefficient (alpha-α) are 1.75 × 10⁻⁶ cm²/s, 57.65 M⁻¹·s⁻¹, 1.45 × 10⁻¹⁰ mol/cm², and 0.52 respectively. The peak current of the i–t method shows two dynamic linear ranges of calibration curves 0.2 to 3.5 µM and 0.5 to 250 µM for the glucose electro-oxidation. The Ni²⁺/Ni³⁺ couple with the HCNiO electrode and the electrocatalytic properties were found to be sensitive to the glucose oxidation. The green chemistry of NiO preparation from bacteria and the high catalytic ability of the oxyhydroxide (NiOOH) is the good choice for the development of a glucose sensor. The best obtained sensitivity and limit of detection (LOD) for this sensor were 3978.9 µA mM⁻¹·cm⁻² and 0.9 µM, respectively. Full article

(This article belongs to the Special Issue Inorganic Nanostructures in Biological Systems)

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12 pages, 986 KiB

Open AccessReview

Nuclear Receptor Regulation of Aquaporin-2 in the Kidney

by Xiao-Yan Zhang^1,2,*, Bing Wang¹ and You-Fei Guan^1,3

¹ Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China

² Department of Physiology, AstraZeneca–Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen 518060, China

³ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

Int. J. Mol. Sci. 2016, 17(7), 1105; https://doi.org/10.3390/ijms17071105 - 11 Jul 2016

Cited by 31 | Viewed by 14837

Abstract

Aquaporin-2 (AQP2) is a vasopressin-regulated water channel responsible for regulating water reabsorption through the apical plasma membrane of the principal cells of renal collecting ducts. It has been found that dysregulation and dysfunction of AQP2 cause many disorders related to water balance in [...] Read more.

Aquaporin-2 (AQP2) is a vasopressin-regulated water channel responsible for regulating water reabsorption through the apical plasma membrane of the principal cells of renal collecting ducts. It has been found that dysregulation and dysfunction of AQP2 cause many disorders related to water balance in people and animals, including polyuria and dilutional hyponatremia. Classically, AQP2 mRNA and protein expression and its membrane translocation are regulated by systemic vasopressin involving short-term regulation of AQP2 trafficking to and from the apical plasma membrane and long-term regulation of the total amount of the AQP2 protein in the cell. Recently, increasing evidence has demonstrated that collecting duct AQP2 expression and membrane translocation are also under the control of many other local factors, especially nuclear receptors. Here, we briefly review the progress of studies in this area and discuss the role of nuclear receptors in the regulation of water reabsorption via affecting AQP2 expression and function. Full article

(This article belongs to the Special Issue Aquaporin)

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13 pages, 232 KiB

Open AccessReview

Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED): A “Rare” Manifestation in a “Rare” Disease

by Alessandra Fierabracci

Infectivology and Clinical Trials Area, Children’s Hospital Bambino Gesù, Rome 00146, Italy

Int. J. Mol. Sci. 2016, 17(7), 1106; https://doi.org/10.3390/ijms17071106 - 12 Jul 2016

Cited by 35 | Viewed by 6084

Abstract

Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator [...] Read more.

Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes) has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

10 pages, 2146 KiB

Open AccessArticle

MAL Daylight Photodynamic Therapy for Actinic Keratosis: Clinical and Imaging Evaluation by 3D Camera

by Carmen Cantisani^1,*

, Giovanni Paolino¹

, Giovanni Pellacani², Dario Didona¹

, Marco Scarno³, Valentina Faina¹, Tommaso Gobello⁴ and Stefano Calvieri¹

¹ Department of Dermatology, Policlinico Umberto I, “Sapienza” University of Rome, Rome 00185, Italy

² Department of Dermatology, University of Modena and Reggio Emilia, Modena 41121, Italy

³ Interuniversity Consortium for Supercomputing (CINECA), Rome 00185, Italy

⁴ Istituto Dermopatico dell’Immacolata (IDI) Hospital, Rome 00195, Italy

Int. J. Mol. Sci. 2016, 17(7), 1108; https://doi.org/10.3390/ijms17071108 - 11 Jul 2016

Cited by 13 | Viewed by 6558

Abstract

Non-melanoma skin cancer is the most common skin cancer with an incidence that varies widely worldwide. Among them, actinic keratosis (AK), considered by some authors as in situ squamous cell carcinoma (SCC), are the most common and reflect an abnormal multistep skin cell [...] Read more.

Non-melanoma skin cancer is the most common skin cancer with an incidence that varies widely worldwide. Among them, actinic keratosis (AK), considered by some authors as in situ squamous cell carcinoma (SCC), are the most common and reflect an abnormal multistep skin cell development due to the chronic ultraviolet (UV) light exposure. No ideal treatment exists, but the potential risk of their development in a more invasive form requires prompt treatment. As patients usually present with multiple AK on fields of actinic damage, there is a need for effective, safe, simple and short treatments which allow the treatment of large areas. To achieve this, daylight photodynamic therapy (DL-PDT) is an innovative treatment for multiple mild actinic keratosis, well tolerated by patients. Patients allocated to the PDT unit, affected by multiple mild−moderate and severe actinic keratosis on sun-exposed areas treated with DL-PDT, were clinically evaluated at baseline and every three months with an Antera 3D, Miravex^© camera. Clinical and 3D images were performed at each clinical check almost every three months. In this retrospective study, 331 patients (56.7% male, 43.3% female) were treated with DL-PDT. We observed a full clearance in more than two-thirds of patients with one or two treatments. Different responses depend on the number of lesions and on their severity; for patients with 1–3 lesions and with grade I or II AK, a full clearance was reached in 85% of cases with a maximum of two treatments. DL-PDT in general improved skin tone and erased sun damage. Evaluating each Antera 3D images, hemoglobin concentration and pigmentation, a skin color and tone improvement in 310 patients was observed. DL-PDT appears as a promising, effective, simple, tolerable and practical treatment for actinic damage associated with AK, and even treatment of large areas can be with little or no pain. The 3D imaging allowed for quantifying in real time the aesthetic benefits of DL-PDT’s increasing compliance. Full article

(This article belongs to the Special Issue Advances in Photodynamic Therapy)

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13 pages, 3070 KiB

Open AccessArticle

Neuroprotective Effect of Puerarin on Glutamate-Induced Cytotoxicity in Differentiated Y-79 Cells via Inhibition of ROS Generation and Ca²⁺ Influx

by Ke Wang¹, Xue Zhu¹, Kai Zhang¹, Zhifeng Wu^2,*, Song Sun^2,*, Fanfan Zhou³ and Ling Zhu⁴

¹ Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China

² Department of Ophthalmology, Wuxi No.2 People’s Hospital, Nanjing Medical University, Wuxi 214002, China

³ Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia

⁴ Save Sight Institute, University of Sydney, Sydney, NSW 2000, Australia

Int. J. Mol. Sci. 2016, 17(7), 1109; https://doi.org/10.3390/ijms17071109 - 11 Jul 2016

Cited by 27 | Viewed by 6225

Abstract

Glutamate toxicity is estimated to be the key cause of photoreceptor degeneration in the pathogenesis of retinal degenerative diseases. Oxidative stress and Ca²⁺ influx induced by glutamate are responsible for the apoptosis process of photoreceptor degeneration. Puerarin, a primary component of Kudzu [...] Read more.

Glutamate toxicity is estimated to be the key cause of photoreceptor degeneration in the pathogenesis of retinal degenerative diseases. Oxidative stress and Ca²⁺ influx induced by glutamate are responsible for the apoptosis process of photoreceptor degeneration. Puerarin, a primary component of Kudzu root, has been widely used in the clinical treatment of retinal degenerative diseases in China for decades; however, the detailed molecular mechanism underlying this effect remains unclear. In this study, the neuroprotective effect of puerarin against glutamate-induced cytotoxicity in the differentiated Y-79 cells was first investigated through cytotoxicity assay. Then the molecular mechanism of this effect regarding anti-oxidative stress and Ca²⁺ hemostasis was further explored with indirect immunofluorescence, flow cytometric analysis and western blot analysis. Our study showed that glutamate induced cell viability loss, excessive reactive oxygen species (ROS) generation, calcium overload and up-regulated cell apoptosis in differentiated Y-79 cells, which effect was significantly attenuated with the pre-treatment of puerarin in a dose-dependent manner. Furthermore, our data indicated that the neuroprotective effect of puerarin was potentially mediated through the inhibition of glutamate-induced activation of mitochondrial-dependent signaling pathway and calmodulin-dependent protein kinase II (CaMKII)-dependent apoptosis signal-regulating kinase 1(ASK-1)/c-Jun N-terminal kinase (JNK)/p38 signaling pathway. The present study supports the notion that puerarin may be a promising neuroprotective agent in the prevention of retinal degenerative diseases. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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17 pages, 5353 KiB

Open AccessArticle

De Novo Assembly and Characterization of the Transcriptome of Grasshopper Shirakiacris shirakii

by Zhongying Qiu¹, Fei Liu^1,2, Huimeng Lu³, Hao Yuan¹, Qin Zhang¹ and Yuan Huang^1,*

¹ College of Life Sciences, Shaanxi Normal University, Xi’an 710062, China

² College of Life Sciences and Food Engineering, Shaanxi Xueqian Normal University, Xi’an 710061, China

³ Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China

Int. J. Mol. Sci. 2016, 17(7), 1110; https://doi.org/10.3390/ijms17071110 - 22 Jul 2016

Cited by 10 | Viewed by 6039

Abstract

Background: The grasshopper Shirakiacris shirakii is an important agricultural pest and feeds mainly on gramineous plants, thereby causing economic damage to a wide range of crops. However, genomic information on this species is extremely limited thus far, and transcriptome data relevant to insecticide [...] Read more.

Background: The grasshopper Shirakiacris shirakii is an important agricultural pest and feeds mainly on gramineous plants, thereby causing economic damage to a wide range of crops. However, genomic information on this species is extremely limited thus far, and transcriptome data relevant to insecticide resistance and pest control are also not available. Methods: The transcriptome of S. shirakii was sequenced using the Illumina HiSeq platform, and we de novo assembled the transcriptome. Results: Its sequencing produced a total of 105,408,878 clean reads, and the de novo assembly revealed 74,657 unigenes with an average length of 680 bp and N50 of 1057 bp. A total of 28,173 unigenes were annotated for the NCBI non-redundant protein sequences (Nr), NCBI non-redundant nucleotide sequences (Nt), a manually-annotated and reviewed protein sequence database (Swiss-Prot), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Based on the Nr annotation results, we manually identified 79 unigenes encoding cytochrome P450 monooxygenases (P450s), 36 unigenes encoding carboxylesterases (CarEs) and 36 unigenes encoding glutathione S-transferases (GSTs) in S. shirakii. Core RNAi components relevant to miroRNA, siRNA and piRNA pathways, including Pasha, Loquacious, Argonaute-1, Argonaute-2, Argonaute-3, Zucchini, Aubergine, enhanced RNAi-1 and Piwi, were expressed in S. shirakii. We also identified five unigenes that were homologous to the Sid-1 gene. In addition, the analysis of differential gene expressions revealed that a total of 19,764 unigenes were up-regulated and 4185 unigenes were down-regulated in larvae. In total, we predicted 7504 simple sequence repeats (SSRs) from 74,657 unigenes. Conclusions: The comprehensive de novo transcriptomic data of S. shirakii will offer a series of valuable molecular resources for better studying insecticide resistance, RNAi and molecular marker discovery in the transcriptome. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 3661 KiB

Open AccessArticle

Nanodiamonds for Medical Applications: Interaction with Blood in Vitro and in Vivo

by Lin-Wei Tsai¹, Yu-Chung Lin¹, Elena Perevedentseva¹, Andrei Lugovtsov², Alexander Priezzhev^2,3 and Chia-Liang Cheng^1,*

¹ Department of Physics, National Dong Hwa University, Hualien 97401, Taiwan

² International Laser Center, M.V. Lomonosov Moscow State University, Moscow 119991, Russia

³ Physics Department, M.V. Lomonosov Moscow State University, Moscow 119991, Russia

Int. J. Mol. Sci. 2016, 17(7), 1111; https://doi.org/10.3390/ijms17071111 - 12 Jul 2016

Cited by 87 | Viewed by 8419

Abstract

Nanodiamonds (ND) have emerged to be a widely-discussed nanomaterial for their applications in biological studies and for medical diagnostics and treatment. The potentials have been successfully demonstrated in cellular and tissue models in vitro. For medical applications, further in vivo studies on various [...] Read more.

Nanodiamonds (ND) have emerged to be a widely-discussed nanomaterial for their applications in biological studies and for medical diagnostics and treatment. The potentials have been successfully demonstrated in cellular and tissue models in vitro. For medical applications, further in vivo studies on various applications become important. One of the most challenging possibilities of ND biomedical application is controllable drug delivery and tracing. That usually assumes ND interaction with the blood system. In this work, we study ND interaction with rat blood and analyze how the ND surface modification and coating can optimize the ND interaction with the blood. It was found that adsorption of a low concentration of ND does not affect the oxygenation state of red blood cells (RBC). The obtained in vivo results are compared to the results of in vitro studies of nanodiamond interaction with rat and human blood and blood components, such as red blood cells and blood plasma. An in vivo animal model shows ND injected in blood attach to the RBC membrane and circulate with blood for more than 30 min; and ND do not stimulate an immune response by measurement of proinflammatory cytokine TNF-α with ND injected into mice via the caudal vein. The results further confirm nanodiamonds’ safety in organisms, as well as the possibility of their application without complicating the blood’s physiological conditions. Full article

(This article belongs to the Special Issue Inorganic Nanostructures in Biological Systems)

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9 pages, 1491 KiB

Open AccessCommunication

(Salen)Mn(III) Catalyzed Asymmetric Epoxidation Reactions by Hydrogen Peroxide in Water: A Green Protocol

by Francesco Paolo Ballistreri¹

, Chiara M. A. Gangemi¹, Andrea Pappalardo^1,2, Gaetano A. Tomaselli^1,*

, Rosa Maria Toscano^1,* and Giuseppe Trusso Sfrazzetto^1,*

¹ Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy

² I.N.S.T.M. UdR of Catania, Viale A. Doria 6, 95125 Catania, Italy

Int. J. Mol. Sci. 2016, 17(7), 1112; https://doi.org/10.3390/ijms17071112 - 12 Jul 2016

Cited by 30 | Viewed by 6906

Abstract

Enantioselective epoxidation reactions of some chosen reactive alkenes by a chiral Mn(III) salen catalyst were performed in H₂O employing H₂O₂ as oxidant and diethyltetradecylamine N-oxide (AOE-14) as surfactant. This procedure represents an environmentally benign protocol which leads [...] Read more.

Enantioselective epoxidation reactions of some chosen reactive alkenes by a chiral Mn(III) salen catalyst were performed in H₂O employing H₂O₂ as oxidant and diethyltetradecylamine N-oxide (AOE-14) as surfactant. This procedure represents an environmentally benign protocol which leads to e.e. values ranging from good to excellent (up to 95%). Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2016)

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20 pages, 1870 KiB

Open AccessArticle

Cellular Stress and p53-Associated Apoptosis by Juniperus communis L. Berry Extract Treatment in the Human SH-SY5Y Neuroblastoma Cells

by Tiina A. Lantto¹, Into Laakso¹, H. J. Damien Dorman¹, Timo Mauriala¹, Raimo Hiltunen^1,†, Sulev Kõks² and Atso Raasmaja^3,4,*

¹ Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Post Office Box 56 (Viikinkaari 5E), Helsinki 00014, Finland

² Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, Tartu 50411, Estonia

³ Division of Pharmacology & Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Post Office Box 56 (Viikinkaari 5E), Helsinki 00014, Finland

⁴ Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, Tartu 50411, Estonia

^† Deceased.

Int. J. Mol. Sci. 2016, 17(7), 1113; https://doi.org/10.3390/ijms17071113 - 13 Jul 2016

Cited by 33 | Viewed by 7853

Abstract

Plant phenolics have shown to activate apoptotic cell death in different tumourigenic cell lines. In this study, we evaluated the effects of juniper berry extract (Juniperus communis L.) on p53 protein, gene expression and DNA fragmentation in human neuroblastoma SH-SY5Y cells. In [...] Read more.

Plant phenolics have shown to activate apoptotic cell death in different tumourigenic cell lines. In this study, we evaluated the effects of juniper berry extract (Juniperus communis L.) on p53 protein, gene expression and DNA fragmentation in human neuroblastoma SH-SY5Y cells. In addition, we analyzed the phenolic composition of the extract. We found that juniper berry extract activated cellular relocalization of p53 and DNA fragmentation-dependent cell death. Differentially expressed genes between treated and non-treated cells were evaluated with the cDNA-RDA (representational difference analysis) method at the early time point of apoptotic process when p53 started to be activated and no caspase activity was detected. Twenty one overexpressed genes related to cellular stress, protein synthesis, cell survival and death were detected. Interestingly, they included endoplasmic reticulum (ER) stress inducer and sensor HSPA5 and other ER stress-related genes CALM2 and YKT6 indicating that ER stress response was involved in juniper berry extract mediated cell death. In composition analysis, we identified and quantified low concentrations of fifteen phenolic compounds. The main groups of them were flavones, flavonols, phenolic acids, flavanol and biflavonoid including glycosides of quercetin, apigenin, isoscutellarein and hypolaetin. It is suggested that juniper berry extract induced the p53-associated apoptosis through the potentiation and synergism by several phenolic compounds. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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13 pages, 4176 KiB

Open AccessArticle

BML-111 Protected LPS/D-GalN-Induced Acute Liver Injury in Rats

by Dan Yan^1,2,†, Hai-Ling Liu^3,†, Zhong-Jian Yu^1,4, Yong-Hong Huang^3,5, Dian Gao⁶

, Hua Hao⁷, Shou-Sheng Liao⁷, Fang-Yun Xu³ and Xiao-Yan Zhou^3,5,*

¹ Department of Pharmacology, Medical College of Nanchang University, Nanchang 330006, China

² Department of Pharmacy, Jiangxi Province Cancer Hospital, Nanchang 330006, China

³ Department of Pathophysiology, Medical College of Nanchang University, Nanchang 330006, China

⁴ Department of Science and Education, Jiangxi Province Cancer Hospital, Nanchang 330006, China

⁵ Jiangxi Province Key Laboratory of Tumor Etiology and Molecular Pathology, Nanchang 330006, China

⁶ Department of Human Parasitology, Medical College of Nanchang University, Nanchang 330006, China

⁷ Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang 330006, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1114; https://doi.org/10.3390/ijms17071114 - 13 Jul 2016

Cited by 28 | Viewed by 6408

Abstract

Lipoxins (LXs) display unique pro-resolving and anti-inflammatory functions in a variety of inflammatory conditions. The present study was undertaken to investigate the effects of BML-111 (5(S),6(R),7-trihydroxyheptanoic acid methyl ester), the agonist of lipoxin A₄ receptor, in a model [...] Read more.

Lipoxins (LXs) display unique pro-resolving and anti-inflammatory functions in a variety of inflammatory conditions. The present study was undertaken to investigate the effects of BML-111 (5(S),6(R),7-trihydroxyheptanoic acid methyl ester), the agonist of lipoxin A₄ receptor, in a model of Lipopolysaccharides (LPS) and d-Galactosamine (d-GalN) induced acute liver injury, and to explore the mechanisms. Histopathological analyses were carried out to quantify liver injury degree. The activities of myeloperoxidase (MPO) were examined to evaluate the levels of neutrophil infiltration. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were detected to evaluate the functions of the liver. The amounts of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and interleukin-1β (IL-1β) were measured using enzyme-linked immunosorbent assay (ELISA), and the expression levels of transforming growth factor-β1(TGF-β1) and cyclooxygenase-2 (COX-2) were examined using Western blotting. The antioxidant capacity, the activities of inducible nitric oxide synthase (iNOS), the contents of malondialdehyde (MDA) and nitric oxide (NO) were analyzed with the kits via biochemical analysis. We established the model of acute liver injury with lipopolysaccharide and d-Galactosamine (LPS/d-GalN): (1) histopathological results and MPO activities, with the activities of AST and ALT in serum, consistently demonstrated LPS and d-GalN challenge could cause severe liver damage, but BML-111 could prevent pathological changes, inhibit neutrophil infiltration, and improve the hepatic function; (2) LPS/d-GalN increased TNF-α, IL-1β, COX-2, and IL-10, while decreasing TGF-β1. However, BML-111 could repress LPS/d-GalN -induced TNF-α, IL-1β and COX-2, meanwhile increasing the expression levels of TGF-β1 and IL-10; (3) LPS/d-GalN inhibited the activities of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (T-AOC), and hydroxyl radical-scavenging ability, simultaneously increasing the levels of MDA and NO, so also the activity of iNOS. Otherwise, BML-111 could reverse all the phenomena. In a word, BML-111 played a protective role in acute liver injury induced by LPS and d-GalN in rats, through improving antioxidant capacity and regulating the balance of inflammatory cytokines. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 4530 KiB

Open AccessArticle

Structural Characterization and Evolutionary Relationship of High-Molecular-Weight Glutenin Subunit Genes in Roegneria nakaii and Roegneria alashanica

by Lujun Zhang^1,2

, Zhixin Li^1,3, Renchun Fan¹, Bo Wei¹ and Xiangqi Zhang^1,*

¹ State Key Laboratory of Plant Cell and Chromosome Engineering, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China

² University of Chinese Academy of Sciences, Beijing 100049, China

³ College of Agriculture, Yangtze University, Jingzhou 434023, Hubei, China

Int. J. Mol. Sci. 2016, 17(7), 1115; https://doi.org/10.3390/ijms17071115 - 19 Jul 2016

Cited by 17 | Viewed by 4223

Abstract

The Roegneria of Triticeae is a large genus including about 130 allopolyploid species. Little is known about its high-molecular-weight glutenin subunits (HMW-GSs). Here, we reported six novel HMW-GS genes from R. nakaii and R. alashanica. Sequencing indicated that Rny1, Rny3, [...] Read more.

The Roegneria of Triticeae is a large genus including about 130 allopolyploid species. Little is known about its high-molecular-weight glutenin subunits (HMW-GSs). Here, we reported six novel HMW-GS genes from R. nakaii and R. alashanica. Sequencing indicated that Rny1, Rny3, and Ray1 possessed intact open reading frames (ORFs), whereas Rny2, Rny4, and Ray2 harbored in-frame stop codons. All of the six genes possessed a similar primary structure to known HMW-GS, while showing some unique characteristics. Their coding regions were significantly shorter than Glu-1 genes in wheat. The amino acid sequences revealed that all of the six genes were intermediate towards the y-type. The phylogenetic analysis showed that the HMW-GSs from species with St, StY, or StH genome(s) clustered in an independent clade, varying from the typical x- and y-type clusters. Thus, the Glu-1 locus in R. nakaii and R. alashanica is a very primitive glutenin locus across evolution. The six genes were phylogenetically split into two groups clustered to different clades, respectively, each of the two clades included the HMW-GSs from species with St (diploid and tetraploid species), StY, and StH genomes. Hence, it is concluded that the six Roegneria HMW-GS genes are from two St genomes undergoing slight differentiation. Full article

(This article belongs to the Section Molecular Plant Sciences)

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13 pages, 5061 KiB

Open AccessReview

Cytoskeletal Regulation of Inflammation and Its Impact on Skin Blistering Disease Epidermolysis Bullosa Acquisita

by Zlatko Kopecki^1,*, Ralf J. Ludwig² and Allison J. Cowin¹

¹ Future Industries Institute, Regenerative Medicine, University of South Australia, Mawson Lakes 5095, Adelaide, Australia

² Institute of Experimental Dermatology, University of Lubeck, Lubeck 23562, Germany

Int. J. Mol. Sci. 2016, 17(7), 1116; https://doi.org/10.3390/ijms17071116 - 13 Jul 2016

Cited by 16 | Viewed by 8734

Abstract

Actin remodelling proteins regulate cytoskeletal cell responses and are important in both innate and adaptive immunity. These responses play a major role in providing a fine balance in a cascade of biological events that results in either protective acute inflammation or chronic inflammation [...] Read more.

Actin remodelling proteins regulate cytoskeletal cell responses and are important in both innate and adaptive immunity. These responses play a major role in providing a fine balance in a cascade of biological events that results in either protective acute inflammation or chronic inflammation that leads to a host of diseases including autoimmune inflammation mediated epidermolysis bullosa acquisita (EBA). This review describes the role of the actin cytoskeleton and in particular the actin remodelling protein called Flightless I (Flii) in regulating cellular inflammatory responses and its subsequent effect on the autoimmune skin blistering disease EBA. It also outlines the potential of an antibody based therapy for decreasing Flii expression in vivo to ameliorate the symptoms associated with EBA. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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13 pages, 3309 KiB

Open AccessArticle

Edwardsiella tarda Outer Membrane Protein C: An Immunogenic Protein Induces Highly Protective Effects in Flounder (Paralichthys olivaceus) against Edwardsiellosis

by Fuguo Liu¹, Xiaoqian Tang¹, Xiuzhen Sheng¹, Jing Xing¹ and Wenbin Zhan^1,2,*

¹ Laboratory of Pathology and Immunology of Aquatic Animals, Ocean University of China, 5 Yushan Road, Qingdao 266003, China

² Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, No. 1 Wenhai Road, Aoshanwei Town, Jimo, Qingdao 266071, China

Int. J. Mol. Sci. 2016, 17(7), 1117; https://doi.org/10.3390/ijms17071117 - 12 Jul 2016

Cited by 60 | Viewed by 8355

Abstract

Outer membrane protein C of Edwardsiella tarda is a major cell surface antigen and it was identified to be an immunogenic protein by Western blot using flounder (Paralichthys olivaceus) anti-recombinant OmpC (rOmpC), and anti-E. tarda antibodies. rOmpC tested the immune [...] Read more.

Outer membrane protein C of Edwardsiella tarda is a major cell surface antigen and it was identified to be an immunogenic protein by Western blot using flounder (Paralichthys olivaceus) anti-recombinant OmpC (rOmpC), and anti-E. tarda antibodies. rOmpC tested the immune protective effect against E. tarda challenge in a flounder model and produced a relative percentage of survival rate of 85%. The immune response of flounder induced by rOmpC was investigated, and the results showed that: (1) the levels of specific serum antibodies induced by rOmpC were significantly higher than the control group after the second week after immunization, and the peak level occurred at week five after immunization; (2) rOmpC could induce the proliferation of sIg+ lymphocytes, and the peak levels of sIg+ lymphocytes in blood, spleen, and pronephros occurred at 4–5 weeks after immunization; and (3) the MHCIIα, CD4-1, IL-1β, IL-6 and TNF-α genes were significantly induced after being injected with rOmpC. Taken together, these results demonstrated that rOmpC could evoke highly protective effects against E. tarda challenge and induce strong innate immune response and humoral immune response of flounder, which indicated that OmpC was a promising vaccine candidate against E. tarda infection. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 1196 KiB

Open AccessReview

Cell Fusion in the War on Cancer: A Perspective on the Inception of Malignancy

by Jeffrey L. Platt^*

, Xiaofeng Zhou, Adam R. Lefferts and Marilia Cascalho

Departments of Surgery and of Microbiology & Immunology, University of Michigan, A520B Medical Sciences Research Building I, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-5656, USA

Int. J. Mol. Sci. 2016, 17(7), 1118; https://doi.org/10.3390/ijms17071118 - 13 Jul 2016

Cited by 27 | Viewed by 6276

Abstract

Cell fusion occurs in development and in physiology and rarely in those settings is it associated with malignancy. However, deliberate fusion of cells and possibly untoward fusion of cells not suitably poised can eventuate in aneuploidy, DNA damage and malignant transformation. How often [...] Read more.

Cell fusion occurs in development and in physiology and rarely in those settings is it associated with malignancy. However, deliberate fusion of cells and possibly untoward fusion of cells not suitably poised can eventuate in aneuploidy, DNA damage and malignant transformation. How often cell fusion may initiate malignancy is unknown. However, cell fusion could explain the high frequency of cancers in tissues with low underlying rates of cell proliferation and mutation. On the other hand, cell fusion might also engage innate and adaptive immune surveillance, thus helping to eliminate or retard malignancies. Here we consider whether and how cell fusion might weigh on the overall burden of cancer in modern societies. Full article

(This article belongs to the Special Issue Cell Fusion in Cancer)

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18 pages, 5087 KiB

Open AccessReview

Human Aquaporin-4 and Molecular Modeling: Historical Perspective and View to the Future

by Giuseppe Felice Mangiatordi¹, Domenico Alberga², Daniela Trisciuzzi¹, Gianluca Lattanzi^3,*

and Orazio Nicolotti^1,*

¹ Dipartimento di Farmacia-Scienze del Farmaco, Via Orabona, 4, University of Bari ”Aldo Moro”, 70126 Bari, Italy

² Institut de Recherche de Chimie Paris CNRS Chimie ParisTech, PSL Research University, 11 rue P. et M. Curie, F-75005 Paris, France

³ INFN-Sez. di Bari and Dipartimento di Medicina Clinica e Sperimentale, University of Foggia, Viale Pinto, 71122 Foggia, Italy

Int. J. Mol. Sci. 2016, 17(7), 1119; https://doi.org/10.3390/ijms17071119 - 13 Jul 2016

Cited by 11 | Viewed by 6086

Abstract

Among the different aquaporins (AQPs), human aquaporin-4 (hAQP4) has attracted the greatest interest in recent years as a new promising therapeutic target. Such a membrane protein is, in fact, involved in a multiple sclerosis-like immunopathology called Neuromyelitis Optica (NMO) and in several disorders [...] Read more.

Among the different aquaporins (AQPs), human aquaporin-4 (hAQP4) has attracted the greatest interest in recent years as a new promising therapeutic target. Such a membrane protein is, in fact, involved in a multiple sclerosis-like immunopathology called Neuromyelitis Optica (NMO) and in several disorders resulting from imbalanced water homeostasis such as deafness and cerebral edema. The gap of knowledge in its functioning and dynamics at the atomistic level of detail has hindered the development of rational strategies for designing hAQP4 modulators. The application, lately, of molecular modeling has proved able to fill this gap providing a breeding ground to rationally address compounds targeting hAQP4. In this review, we give an overview of the important advances obtained in this field through the application of Molecular Dynamics (MD) and other complementary modeling techniques. The case studies presented herein are discussed with the aim of providing important clues for computational chemists and biophysicists interested in this field and looking for new challenges. Full article

(This article belongs to the Special Issue Aquaporin)

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17 pages, 1273 KiB

Open AccessReview

MicroRNAs in Valvular Heart Diseases: Potential Role as Markers and Actors of Valvular and Cardiac Remodeling

by Cécile Oury^1,2,*, Laurence Servais^1,2, Nassim Bouznad^1,2,3, Alexandre Hego^1,2, Alain Nchimi^1,2 and Patrizio Lancellotti^1,2,4

¹ GIGA-Cardiovascular Sciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liège, 4000 Liège, Belgium

² Department of Cardiology, University of Liège Hospital, 4000 Liège, Belgium

³ Experimental and Molecular Pathology Laboratory, Insitute of Pathology Ludwig Maximilians, University Munich, 80331 Munich, Germany

⁴ Gruppo Villa Maria Care and Research, Anthea Hospital, 70124 Bari, Italy

Int. J. Mol. Sci. 2016, 17(7), 1120; https://doi.org/10.3390/ijms17071120 - 13 Jul 2016

Cited by 41 | Viewed by 11656

Abstract

miRNAs are a class of over 5000 noncoding RNAs that regulate more than half of the protein-encoding genes by provoking their degradation or preventing their translation. miRNAs are key regulators of complex biological processes underlying several cardiovascular disorders, including left ventricular hypertrophy, ischemic [...] Read more.

miRNAs are a class of over 5000 noncoding RNAs that regulate more than half of the protein-encoding genes by provoking their degradation or preventing their translation. miRNAs are key regulators of complex biological processes underlying several cardiovascular disorders, including left ventricular hypertrophy, ischemic heart disease, heart failure, hypertension and arrhythmias. Moreover, circulating miRNAs herald promise as biomarkers in acute myocardial infarction and heart failure. In this context, this review gives an overview of studies that suggest that miRNAs could also play a role in valvular heart diseases. This area of research is still at its infancy, and further investigations in large patient cohorts and cellular or animal models are needed to provide strong data. Most studies focused on aortic stenosis, one of the most common valvular diseases in developed countries. Profiling and functional analyses indicate that miRNAs could contribute to activation of aortic valve interstitial cells to a myofibroblast phenotype, leading to valvular fibrosis and calcification, and to pressure overload-induced myocardial remodeling and hypertrophy. Data also indicate that specific miRNA signatures, in combination with clinical and functional imaging parameters, could represent useful biomarkers of disease progression or recovery after aortic valve replacement. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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18 pages, 462 KiB

Open AccessReview

Astrocyte Aquaporin Dynamics in Health and Disease

by Maja Potokar^1,2,†, Jernej Jorgačevski^1,2,† and Robert Zorec^1,2,*

¹ Laboratory of Neuroendocrinology—Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia

² Celica Biomedical, Tehnološki Park 24, 1000 Ljubljana, Slovenia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1121; https://doi.org/10.3390/ijms17071121 - 13 Jul 2016

Cited by 64 | Viewed by 7895

Abstract

The family of aquaporins (AQPs), membrane water channels, consists of diverse types of proteins that are mainly permeable to water; some are also permeable to small solutes, such as glycerol and urea. They have been identified in a wide range of organisms, from [...] Read more.

The family of aquaporins (AQPs), membrane water channels, consists of diverse types of proteins that are mainly permeable to water; some are also permeable to small solutes, such as glycerol and urea. They have been identified in a wide range of organisms, from microbes to vertebrates and plants, and are expressed in various tissues. Here, we focus on AQP types and their isoforms in astrocytes, a major glial cell type in the central nervous system (CNS). Astrocytes have anatomical contact with the microvasculature, pia, and neurons. Of the many roles that astrocytes have in the CNS, they are key in maintaining water homeostasis. The processes involved in this regulation have been investigated intensively, in particular regulation of the permeability and expression patterns of different AQP types in astrocytes. Three aquaporin types have been described in astrocytes: aquaporins AQP1 and AQP4 and aquaglyceroporin AQP9. The aim here is to review their isoforms, subcellular localization, permeability regulation, and expression patterns in the CNS. In the human CNS, AQP4 is expressed in normal physiological and pathological conditions, but astrocytic expression of AQP1 and AQP9 is mainly associated with a pathological state. Full article

(This article belongs to the Special Issue Aquaporin)

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12 pages, 3831 KiB

Open AccessArticle

Niemann-Pick Type C2 Protein Mediates Hepatic Stellate Cells Activation by Regulating Free Cholesterol Accumulation

by Yuh-Ching Twu¹

, Tzong-Shyuan Lee², Yun-Lian Lin³, Shih-Ming Hsu⁴, Yuan-Hsi Wang⁵, Chia-Yu Liao⁵, Chung-Kwe Wang⁶, Yu-Chih Liang⁵

and Yi-Jen Liao^5,*

¹ Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, 112 Taipei, Taiwan

² Department & Institute of Physiology, National Yang-Ming University, 112 Taipei, Taiwan

³ College of Biopharmaceutical and Food Sciences, China Medical University, 404 Taichung, Taiwan

⁴ Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, 112 Taipei, Taiwan

⁵ School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 110 Taipei, Taiwan

⁶ Department of International Medicine, Taipei City Hospital Ranai Branch, 106 Taipei, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1122; https://doi.org/10.3390/ijms17071122 - 13 Jul 2016

Cited by 24 | Viewed by 6889

Abstract

In chronic liver diseases, regardless of their etiology, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hepatic stellate cells (HSCs) are the main profibrogenic cells that promote the pathogenesis of liver fibrosis, and [...] Read more.

In chronic liver diseases, regardless of their etiology, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hepatic stellate cells (HSCs) are the main profibrogenic cells that promote the pathogenesis of liver fibrosis, and so it is important to identify the molecules that regulate HSCs activation and liver fibrosis. Niemann-Pick type C2 (NPC2) protein plays an important role in the regulation of intracellular cholesterol homeostasis by directly binding with free cholesterol. However, the roles of NPC2 in HSCs activation and liver fibrosis have not been explored in detail. Since a high-cholesterol diet exacerbates liver fibrosis progression in both rodents and humans, we propose that the expression of NPC2 affects free cholesterol metabolism and regulates HSCs activation. In this study, we found that NPC2 is decreased in both thioacetamide- and carbon tetrachloride-induced liver fibrosis tissues. In addition, NPC2 is expressed in quiescent HSCs, but its activation status is down-regulated. Knockdown of NPC2 in HSC-T6 cells resulted in marked increases in transforming growth factor-β1 (TGF-β1)-induced collagen type 1 α1 (Col1a1), α-smooth muscle actin (α-SMA) expression, and Smad2 phosphorylation. In contrast, NPC2 overexpression decreased TGF-β1-induced HSCs activation. We further demonstrated that NPC2 deficiency significantly increased the accumulation of free cholesterol in HSCs, increasing Col1a1 and α-SMA expression and activating Smad2, and leading to sensitization of HSCs to TGF-β1 activation. In contrast, overexpression of NPC2 decreased U18666A-induced free cholesterol accumulation and inhibited the subsequent HSCs activation. In conclusion, our study has demonstrated that NPC2 plays an important role in HSCs activation by regulating the accumulation of free cholesterol. NPC2 overexpression may thus represent a new treatment strategy for liver fibrosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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19 pages, 4812 KiB

Open AccessArticle

Methylsulfonylmethane Induces p53 Independent Apoptosis in HCT-116 Colon Cancer Cells

by Arzu Zeynep Karabay^1,*, Asli Koc^2,*, Tulin Ozkan^3,*, Yalda Hekmatshoar³, Asuman Sunguroglu³, Fugen Aktan¹ and Zeliha Buyukbingol¹

¹ Faculty of Pharmacy, Department of Biochemistry, Ankara University, 06100 Ankara, Turkey

² Faculty of Pharmacy, Ankara University, 06100 Ankara, Turkey

³ Faculty of Medicine, Department of Medical Biology, Ankara University, 06560 Ankara, Turkey

Int. J. Mol. Sci. 2016, 17(7), 1123; https://doi.org/10.3390/ijms17071123 - 15 Jul 2016

Cited by 23 | Viewed by 11165

Abstract

Methylsulfonylmethane (MSM) is an organic sulfur-containing compound which has been used as a dietary supplement for osteoarthritis. MSM has been shown to reduce oxidative stress and inflammation, as well as exhibit apoptotic or anti-apoptotic effects depending on the cell type or activating stimuli. [...] Read more.

Methylsulfonylmethane (MSM) is an organic sulfur-containing compound which has been used as a dietary supplement for osteoarthritis. MSM has been shown to reduce oxidative stress and inflammation, as well as exhibit apoptotic or anti-apoptotic effects depending on the cell type or activating stimuli. However, there are still a lot of unknowns about the mechanisms of actions of MSM. In this study, MSM was tested on colon cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis revealed that MSM inhibited cell viability and increased apoptotic markers in both HCT-116 p53 +/+ and HCT-116 p53 −/− colon cancer cells. Increased poly (ADP-ribose) polymerase (PARP) fragmentation and caspase-3 activity by MSM also supported these findings. MSM also modulated the expression of various apoptosis-related genes and proteins. Moreover, MSM was found to increase c-Jun N-terminal kinases (JNK) phosphorylation in both cell lines, dose-dependently. In conclusion, our results show for the first time that MSM induces apoptosis in HCT-116 colon cancer cells regardless of their p53 status. Since p53 is defective in >50% of tumors, the ability of MSM to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy. Moreover, the remarkable effect of MSM on Bim, an apoptotic protein, also suggests its potential use as a novel chemotherapeutic agent for Bim-targeted anti-cancer therapies. Full article

(This article belongs to the Special Issue Kinase Signal Transduction)

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10 pages, 2232 KiB

Open AccessArticle

Immunogenic Human Papillomavirus Pseudovirus-Mediated Suicide-Gene Therapy for Bladder Cancer

by Rim Hojeij¹, Sonia Domingos-Pereira¹, Marianne Nkosi¹, Dalila Gharbi¹, Laurent Derré¹, John T. Schiller², Patrice Jichlinski¹ and Denise Nardelli-Haefliger^1,*

¹ Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1011, Switzerland

² Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

Int. J. Mol. Sci. 2016, 17(7), 1125; https://doi.org/10.3390/ijms17071125 - 14 Jul 2016

Cited by 17 | Viewed by 6242

Abstract

Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral [...] Read more.

Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral resection of the lesion. However, this treatment is associated with significant side-effects and treatment failures, highlighting the necessity of novel strategies. One potent approach is the suicide-gene mediated therapy/prodrug combination, provided tumor-specificity can be ensured and anti-tumor immune responses induced. Using the mouse syngeneic orthotopic MB49-bladder tumor model, here we show that IVES human papillomavirus non-replicative pseudovirions (PsV) can pseudoinfect tumors with a ten-fold higher efficacy than normal bladders. In addition, PsV carrying the suicide-gene herpes-simplex virus thymidine kinase (PsV-TK) combined to Ganciclovir (GCV) led to immunogenic cell-death of tumor cells in vitro and to MB49-specific CD8 T-cells in vivo. This was associated with reduction in bladder-tumor growth and increased mice survival. Altogether, our data show that IVES PsV-TK/GCV may be a promising alternative or combinatory treatment for NMIBC. Full article

(This article belongs to the Special Issue Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy)

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14 pages, 5805 KiB

Open AccessArticle

Correlation between Gene Expression and Osteoarthritis Progression in Human

by Leilei Zhong^†, Xiaobin Huang^†

, Marcel Karperien

and Janine N. Post^*

¹ Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1126; https://doi.org/10.3390/ijms17071126 - 14 Jul 2016

Cited by 89 | Viewed by 8369

Abstract

Osteoarthritis (OA) is a multifactorial disease characterized by gradual degradation of joint cartilage. This study aimed to quantify major pathogenetic factors during OA progression in human cartilage. Cartilage specimens were isolated from OA patients and scored 0–5 according to the Osteoarthritis Research Society [...] Read more.

Osteoarthritis (OA) is a multifactorial disease characterized by gradual degradation of joint cartilage. This study aimed to quantify major pathogenetic factors during OA progression in human cartilage. Cartilage specimens were isolated from OA patients and scored 0–5 according to the Osteoarthritis Research Society International (OARSI) guidelines. Protein and gene expressions were measured by immunohistochemistry and qPCR, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used to detect apoptotic cells. Cartilage degeneration in OA is a gradual progress accompanied with gradual loss of collagen type II and a gradual decrease in mRNA expression of SOX9, ACAN and COL2A1. Expression of WNT antagonists DKK1 and FRZB was lost, while hypertrophic markers (RUNX2, COL10A1 and IHH) increased during OA progression. Moreover, DKK1 and FRZB negatively correlated with OA grading, while RUNX2 and IHH showed a significantly positive correlation with OA grading. The number of apoptotic cells was increased with the severity of OA. Taken together, our results suggested that genetic profiling of the gene expression could be used as markers for staging OA at the molecular level. This helps to understand the molecular pathology of OA and may lead to the development of therapies based on OA stage. Full article

(This article belongs to the Special Issue Transcriptome Profiling in Human Diseases)

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11 pages, 1840 KiB

Open AccessReview

Molecular Mechanisms Elicited by d-Aspartate in Leydig Cells and Spermatogonia

by Maria Maddalena Di Fiore^1,*, Alessandra Santillo¹, Sara Falvo¹, Salvatore Longobardi² and Gabriella Chieffi Baccari¹

¹ Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy

² Medical Affairs Fertility, Merck KGaA, Frankfurter Straße 250, 64293 Darmstadt, Germany

Int. J. Mol. Sci. 2016, 17(7), 1127; https://doi.org/10.3390/ijms17071127 - 14 Jul 2016

Cited by 52 | Viewed by 8894

Abstract

A bulk of evidence suggests that d-aspartate (d-Asp) regulates steroidogenesis and spermatogenesis in vertebrate testes. This review article focuses on intracellular signaling mechanisms elicited by d-Asp possibly via binding to the N-methyl-d-aspartate receptor (NMDAR) in both [...] Read more.

A bulk of evidence suggests that d-aspartate (d-Asp) regulates steroidogenesis and spermatogenesis in vertebrate testes. This review article focuses on intracellular signaling mechanisms elicited by d-Asp possibly via binding to the N-methyl-d-aspartate receptor (NMDAR) in both Leydig cells, and spermatogonia. In Leydig cells, the amino acid upregulates androgen production by eliciting the adenylate cyclase-cAMP and/or mitogen-activated protein kinase (MAPK) pathways. d-Asp treatment enhances gene and protein expression of enzymes involved in the steroidogenic cascade. d-Asp also directly affects spermatogonial mitotic activity. In spermatogonial GC-1 cells, d-Asp induces phosphorylation of MAPK and AKT serine-threonine kinase proteins, and stimulates expression of proliferating cell nuclear antigen (PCNA) and aurora kinase B (AURKB). Further stimulation of spermatogonial GC-1 cell proliferation might come from estradiol/estrogen receptor β (ESR2) interaction. d-Asp modulates androgen and estrogen levels as well as the expression of their receptors in the rat epididymis by acting on mRNA levels of Srd5a1 and Cyp19a1 enzymes, hence suggesting involvement in spermatozoa maturation. Full article

(This article belongs to the Special Issue Kinase Signal Transduction)

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17 pages, 2574 KiB

Open AccessArticle

Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

by Chun-Hung Chiu^1,†, Chun-Chao Chang^2,3,†, Shiang-Ting Lin¹, Charng-Cherng Chyau^1,* and Robert Y. Peng^1,4,*

¹ Research Institute of Biotechnology, Hungkuang University, Taichung City 43302, Taiwan

² Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan

³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

⁴ Research Institute of Medical Sciences, Taipei Medical University, Taipei 11031, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1128; https://doi.org/10.3390/ijms17071128 - 14 Jul 2016

Cited by 61 | Viewed by 6615

Abstract

Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an [...] Read more.

Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA) apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group) were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10) for seven days and then were LPS-challenged (i.p., 5 mg/kg). The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), creatinine (CRE), hepatic malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS), suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day). Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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17 pages, 8736 KiB

Open AccessArticle

Dermal Lipogenesis Inhibits Adiponectin Production in Human Dermal Fibroblasts while Exogenous Adiponectin Administration Prevents against UVA-Induced Dermal Matrix Degradation in Human Skin

by Chien-Liang Fang¹, Ling-Hung Huang², Hung-Yueh Tsai² and Hsin-I Chang^2,*

¹ Division of Plastic and Reconstructive Surgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, No. 539, Zhongxiao Rd., Chiayi City 60002, Taiwan

² Department of Biochemical Science and Technology, National Chia Yi University, No. 300, Syuefu Rd., Chiayi City 60004, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1129; https://doi.org/10.3390/ijms17071129 - 14 Jul 2016

Cited by 14 | Viewed by 7417

Abstract

Adiponectin is one of the most abundant adipokines from the subcutaneous fat, and regulates multiple activities through endocrine, paracrine, or autocrine mechanisms. However, its expression in adipogenic induced fibroblasts, and the potential role in photoaging has not been determined. Here, human dermal fibroblasts, [...] Read more.

Adiponectin is one of the most abundant adipokines from the subcutaneous fat, and regulates multiple activities through endocrine, paracrine, or autocrine mechanisms. However, its expression in adipogenic induced fibroblasts, and the potential role in photoaging has not been determined. Here, human dermal fibroblasts, Hs68, were presented as a cell model of dermal lipogenesis through stimulation of adipogenic differentiation medium (ADM). Similar to other studies in murine pre-adipocyte models (i.e., 3T3-L1), Hs68 fibroblasts showed a tendency to lipogenesis based on lipid accumulation, triglyceride formation, and the expressions of PPAR-γ, lipoprotein lipase (LPL), and FABP4 mRNA. As expected, ADM-treated fibroblasts displayed a reduction on adiponectin expression. Next, we emphasized the photoprotective effects of adiponectin against UVA-induced damage in Hs68 fibroblasts. UVA radiation can downregulate cell adhesion strength and elastic modulus of Hs68 fibroblasts. Moreover, UVA radiation could induce the mRNA expressions of epidermal growth factor receptor (EGFR), adiponectin receptor 1 (AdipoR1), matrix metalloproteinase-1 (MMP-1), MMP-3, and cyclooxygenase-2 (COX-2), but downregulate the mRNA expressions of type I and type III collagen. On the other hand, post-treatment of adiponectin can partially overcome UVA-induced reduction in the cell adhesion strength of Hs68 fibroblasts through the activation of AdipoR1 and the suppression of EGF-R. In addition, post-treatment of adiponectin indicated the increase of type III collagen and elastin mRNA expression and the decrease of MMP-1 and MMP-3 mRNA expression, but a limited degree of recovery of elastic modulus on UVA-irradiated Hs68 fibroblasts. Overall, these results suggest that dermal lipogenesis may inhibit the expression of adiponectin while exogenous adiponectin administration prevents against UVA-induced dermal matrix degradation in Hs68 fibroblasts. Full article

(This article belongs to the Section Biochemistry)

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9 pages, 927 KiB

Open AccessArticle

Molecular Rearrangement of an Aza-Scorpiand Macrocycle Induced by pH: A Computational Study

by Jesus Vicente De Julián-Ortiz^1,2,*, Begoña Verdejo³, Víctor Polo⁴, Emili Besalú⁵

and Enrique García-España³

¹ ProtoQSAR SL, Parc Cientíﬁc, 46980 Paterna, València, Spain

² Departament de Química Física, Facultat de Farmàcia, Universitat de València, Av V. Andrés Estellés 0, 46100 Burjassot, València, Spain

³ Institut de Ciència Molecular, Universitat de València, 46980 Paterna, València, Spain

⁴ Departamento de Química Física, Universidad de Zaragoza, 50009 Zaragoza, Spain

⁵ Institut de Química Computacional i Catàlisi, Universitat de Girona, 17003 Girona, Spain

Int. J. Mol. Sci. 2016, 17(7), 1131; https://doi.org/10.3390/ijms17071131 - 14 Jul 2016

Cited by 5 | Viewed by 4537

Abstract

Rearrangements and their control are a hot topic in supramolecular chemistry due to the possibilities that these phenomena open in the design of synthetic receptors and molecular machines. Macrocycle aza-scorpiands constitute an interesting system that can reorganize their spatial structure depending on pH [...] Read more.

Rearrangements and their control are a hot topic in supramolecular chemistry due to the possibilities that these phenomena open in the design of synthetic receptors and molecular machines. Macrocycle aza-scorpiands constitute an interesting system that can reorganize their spatial structure depending on pH variations or the presence of metal cations. In this study, the relative stabilities of these conformations were predicted computationally by semi-empirical and density functional theory approximations, and the reorganization from closed to open conformations was simulated by using the Monte Carlo multiple minimum method. Full article

(This article belongs to the Special Issue Big Data Analysis and QSAR/QSPR Research in Chemistry, Bio-Medical, and Network Sciences)

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18 pages, 8124 KiB

Open AccessArticle

Effect of Medium Supplements on Agrobacterium rhizogenes Mediated Hairy Root Induction from the Callus Tissues of Camellia sinensis var. sinensis

by Mohammad M. Rana^1,2, Zhuo-Xiao Han¹, Da-Peng Song¹, Guo-Feng Liu¹, Da-Xiang Li¹, Xiao-Chun Wan¹, Alagarsamy Karthikeyan¹ and Shu Wei^1,*

¹ State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, 130 Changjiang Blvd West, Hefei 230036, China

² Agronomy Division, Bangladesh Tea Research Institute, Srimangal-3210, Moulvibazar, Bangladesh

Int. J. Mol. Sci. 2016, 17(7), 1132; https://doi.org/10.3390/ijms17071132 - 15 Jul 2016

Cited by 33 | Viewed by 7254

Abstract

Tea (Camellia sinensis L.) is recalcitrant to Agrobacterium-mediated genetic transformation largely due to the bactericidal effects of tea polyphenols and phenolics oxidation induced by necrosis of explant tissue over the process of transformation. In this study, different antioxidants/adsorbents were added as [...] Read more.

Tea (Camellia sinensis L.) is recalcitrant to Agrobacterium-mediated genetic transformation largely due to the bactericidal effects of tea polyphenols and phenolics oxidation induced by necrosis of explant tissue over the process of transformation. In this study, different antioxidants/adsorbents were added as supplements to the co-cultivation and post co-cultivation media to overcome these problems for the transformation improvement. Tea-cotyledon-derived calli were used as explants and Agrobacterium rhizognes strain ATCC 15834 was used as a mediator. Results showed that Agrobacterium growth, virulence (vir) gene expression and browning of explant tissue were greatly influenced by different supplements. Murashige and Skoog (MS) basal salts medium supplemented with 30 g·L⁻¹ sucrose, 0.1 g·L⁻¹ l-glutamine and 5 g·L⁻¹ polyvinylpolypyrrolidone (PVPP) as co-cultivation and post co-cultivation media could maintain these parameters better that ultimately led to significant improvement of hairy root generation efficiency compared to that in the control (MS + 30 g·L⁻¹ sucrose). Additionally, the reporter genes β-glucuronidase (gusA) and cyan fluorescent protein (cfp) were also stably expressed in the transgenic hairy roots. Our study would be helpful in establishing a feasible approach for tea biological studies and genetic improvement of tea varieties. Full article

(This article belongs to the Section Molecular Plant Sciences)

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15 pages, 3168 KiB

Open AccessArticle

Human Aquaporin 4 Gating Dynamics under Perpendicularly-Oriented Electric-Field Impulses: A Molecular Dynamics Study

by Paolo Marracino^1,*, Micaela Liberti^1,*, Erika Trapani¹, Christian J. Burnham^2,*, Massimiliano Avena^1,†, José-Antonio Garate^3,4, Francesca Apollonio^1,* and Niall J. English^2,*

¹ Department of Information Engineering, Electronics and Telecommunications, La Sapienza University, 00184 Rome, Italy

² School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, D4 Dublin, Ireland

³ Computational Biology Laboratory, Life Sciences Foundation, 7750000 Santiago, Chile

⁴ Centro Interdisciplinario de neurociencia de Valparaiso, Universidad de Valparaiso, 05101 Valparaiso, Chile

^† Current address: Deloitte Business Analytics, 00196 Rome, Italy

Int. J. Mol. Sci. 2016, 17(7), 1133; https://doi.org/10.3390/ijms17071133 - 14 Jul 2016

Cited by 22 | Viewed by 5327

Abstract

Human aquaporin 4 has been studied using molecular dynamics (MD) simulations in the absence and presence of pulses of external static electric fields. The pulses were 10 ns in duration and 0.012–0.065 V/Å in intensity acting along both directions perpendicular to the pores. [...] Read more.

Human aquaporin 4 has been studied using molecular dynamics (MD) simulations in the absence and presence of pulses of external static electric fields. The pulses were 10 ns in duration and 0.012–0.065 V/Å in intensity acting along both directions perpendicular to the pores. Water permeability and the dipolar response of all residues of interest (including the selectivity filter) within the pores have been studied. Results showed decreased levels of water osmotic permeability within aquaporin channels during orthogonally-oriented field impulses, although care must be taken with regard to statistical certainty. This can be explained observing enhanced “dipolar flipping” of certain key residues, especially serine 211, histidine 201, arginine 216, histidine 95 and cysteine 178. These residues are placed at the extracellular end of the pore (serine 211, histidine 201, and arginine 216) and at the cytoplasm end (histidine 95 and cysteine 178), with the key role in gating mechanism, hence influencing water permeability. Full article

(This article belongs to the Special Issue Aquaporin)

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14 pages, 974 KiB

Open AccessReview

Modifications in Glass Ionomer Cements: Nano-Sized Fillers and Bioactive Nanoceramics

by Shariq Najeeb¹

, Zohaib Khurshid²

, Muhammad Sohail Zafar³

, Abdul Samad Khan⁴, Sana Zohaib⁵

, Juan Manuel Nuñez Martí⁶, Salvatore Sauro⁷

, Jukka Pekka Matinlinna⁸ and Ihtesham Ur Rehman^9,*

¹ Department of Restorative Dental Sciences, Al-Farabi Colleges, P.O Box 361724, Riyadh 11313, Saudi Arabia

² Department of Dental Biomaterials, College of Dentistry, King Faisal University, P.O. Box 400, Al-Hofuf 31982, Saudi Arabia

³ Department of Restorative Dentistry, College of Dentistry, Taibah University, Madina Munawwarrah 41311, Saudi Arabia

⁴ Interdisciplinary Research Centre in Biomedical Materials, COMSATS Institute of Information Technology, Defence Road, off Raiwind Road, Lahore 54000, Pakistan

⁵ Department of Biomedical Engineering, College of Engineering, King Faisal University, Al-Hofuf 31982, Saudia Arabia

⁶ Preventive and Minimally Invasive Dentistry (Spanish Course), Departamento de Odontología, Facultad de Ciencias de la Salud, Universidad CEU-Cardenal Herrera, Valencia 46115, Spain

⁷ Dental Biomaterials, Preventive and Minimally Invasive Dentistry (Bilingual course), Departamento de Odontología, Facultad de Ciencias de la Salud, Universidad CEU-Cardenal Herrera, Valencia 46115, Spain

⁸ The University of Hong Kong, Faculty of Dentistry, Dental Materials Science, Hong Kong, China

⁹ Department of Materials Science and Engineering, The Kroto Research Institute, The University of Sheffield, North Campus, Broad Lane, Sheffield S3 7HQ, UK

Int. J. Mol. Sci. 2016, 17(7), 1134; https://doi.org/10.3390/ijms17071134 - 14 Jul 2016

Cited by 152 | Viewed by 21358

Abstract

Glass ionomer cements (GICs) are being used for a wide range of applications in dentistry. In order to overcome the poor mechanical properties of glass ionomers, several modifications have been introduced to the conventional GICs. Nanotechnology involves the use of systems, modifications or [...] Read more.

Glass ionomer cements (GICs) are being used for a wide range of applications in dentistry. In order to overcome the poor mechanical properties of glass ionomers, several modifications have been introduced to the conventional GICs. Nanotechnology involves the use of systems, modifications or materials the size of which is in the range of 1–100 nm. Nano-modification of conventional GICs and resin modified GICs (RMGICs) can be achieved by incorporation of nano-sized fillers to RMGICs, reducing the size of the glass particles, and introducing nano-sized bioceramics to the glass powder. Studies suggest that the commercially available nano-filled RMGIC does not hold any significant advantage over conventional RMGICs as far as the mechanical and bonding properties are concerned. Conversely, incorporation of nano-sized apatite crystals not only increases the mechanical properties of conventional GICs, but also can enhance fluoride release and bioactivity. By increasing the crystallinity of the set matrix, apatites can make the set cement chemically more stable, insoluble, and improve the bond strength with tooth structure. Increased fluoride release can also reduce and arrest secondary caries. However, due to a lack of long-term clinical studies, the use of nano-modified glass ionomers is still limited in daily clinical dentistry. In addition to the in vitro and in vivo studies, more randomized clinical trials are required to justify the use of these promising materials. The aim of this paper is to review the modification performed in GIC-based materials to improve their physicochemical properties. Full article

(This article belongs to the Special Issue Molecular Research on Dental Materials and Biomaterials)

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17 pages, 2906 KiB

Open AccessArticle

Transcriptome and Metabolome Analyses of Glucosinolates in Two Broccoli Cultivars Following Jasmonate Treatment for the Induction of Glucosinolate Defense to Trichoplusia ni (Hübner)

by Kang-Mo Ku^1,2

, Talon M. Becker²

and John A. Juvik^2,*

¹ Division of Plant and Soil Sciences, West Virginia University, Morgantown, WV 26505, USA

² Department of Crop Sciences, University of Illinois at Urbana–Champaign, Urbana, IL 61801, USA

Int. J. Mol. Sci. 2016, 17(7), 1135; https://doi.org/10.3390/ijms17071135 - 15 Jul 2016

Cited by 30 | Viewed by 6104

Abstract

Lepidopteran larvae growth is influenced by host plant glucosinolate (GS) concentrations, which are, in turn, influenced by the phytohormone jasmonate (JA). In order to elucidate insect resistance biomarkers to lepidopteran pests, transcriptome and metabolome analyses following JA treatments were conducted with two broccoli [...] Read more.

Lepidopteran larvae growth is influenced by host plant glucosinolate (GS) concentrations, which are, in turn, influenced by the phytohormone jasmonate (JA). In order to elucidate insect resistance biomarkers to lepidopteran pests, transcriptome and metabolome analyses following JA treatments were conducted with two broccoli cultivars, Green Magic and VI-158, which have differentially induced indole GSs, neoglucobrassicin and glucobrassicin, respectively. To test these two inducible GSs on growth of cabbage looper (Trichoplusia ni), eight neonate cabbage looper larvae were placed onto each of three plants per JA treatments (0, 100, 200, 400 µM) three days after treatment. After five days of feeding, weight of larvae and their survival rate was found to decrease with increasing JA concentrations in both broccoli cultivars. JA-inducible GSs were measured by high performance liquid chromatography. Neoglucobrassicin in Green Magic and glucobrassicin in VI-158 leaves were increased in a dose-dependent manner. One or both of these glucosinolates and/or their hydrolysis products showed significant inverse correlations with larval weight and survival (five days after treatment) while being positively correlated with the number of days to pupation. This implies that these two JA-inducible glucosinolates can influence the growth and survival of cabbage looper larvae. Transcriptome profiling supported the observed changes in glucosinolate and their hydrolysis product concentrations following JA treatments. Several genes related to GS metabolism differentiate the two broccoli cultivars in their pattern of transcriptional response to JA treatments. Indicative of the corresponding change in indole GS concentrations, transcripts of the transcription factor MYB122, core structure biosynthesis genes (CYP79B2, UGT74B1, SUR1, SOT16, SOT17, and SOT18), an indole glucosinolate side chain modification gene (IGMT1), and several glucosinolate hydrolysis genes (TGG1, TGG2, and ESM1) were significantly increased in Green Magic (statistically significant in most cases at 400 µM) while UGT74B1 and MYB122 were significantly increased in VI-158. Therefore, these metabolite and transcript biomarker results indicate that transcriptome profiling can identify genes associated with the formation of two different indole GS and their hydrolysis products. Therefore, these metabolite and transcript biomarkers could be useful in an effective marker-assisted breeding strategy for resistance to generalist lepidopteran pests in broccoli and potentially other Brassica vegetables. Full article

(This article belongs to the Section Molecular Plant Sciences)

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8 pages, 1451 KiB

Open AccessConcept Paper

“On-The-Spot” Arresting of Chondroitin Sulphate Proteoglycans: Implications for Ovarian Adenocarcinoma Recognition and Intervention

by Priyamvada Pradeep, Yahya E. Choonara

, Pradeep Kumar

and Viness Pillay^*

Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa

Int. J. Mol. Sci. 2016, 17(7), 1136; https://doi.org/10.3390/ijms17071136 - 18 Jul 2016

Cited by 2 | Viewed by 4515

Abstract

Ovarian Cancer (OC) is one of the leading causes of cancer-associated death among women. The underlying biochemical cause of OC proliferation is usually attributed to the over-expression of Chondroitin Sulphate Proteoglycans (CSPGs) wherein the CS-E subgroup plays a major role in tumor cell [...] Read more.

Ovarian Cancer (OC) is one of the leading causes of cancer-associated death among women. The underlying biochemical cause of OC proliferation is usually attributed to the over-expression of Chondroitin Sulphate Proteoglycans (CSPGs) wherein the CS-E subgroup plays a major role in tumor cell proliferation by over-expressing vascular endothelial growth factor (VEGF). We hereby hypothesize that by targeting the OC extracellular matrix using a CS-E-specific antibody, GD3G7, we could provide spatial delivery of crosslinkers and anti-VEGF agents to firstly induce in vivo crosslinking and complexation (arresting) of CS-E into a “biogel mass” for efficient and effective detection, detachment and reduction of tumorous tissue, and secondly inhibit angiogenesis in OC. It is further proposed that the antibody-assisted targeted delivery of CS-E crosslinkers can bind to highly anionic CS-E to form a polyelectrolyte complex to inhibit the formation of ovarian tumor spheroids that are responsible for spheroid-induced mesothelial clearance and progression of OC. The hypothesis also describes the potential in vivo “On-The-Spot” CSPG crosslinkers such as sodium trimetaphosphate (physical crosslinker), 1,12-diaminododecane (chemical crosslinker), poly(ethylene glycol) diglycidyl ether (synthetic polymer), and chitosan (natural polyelectrolyte-forming agent). In conclusion, this hypothesis proposes in vivo spatial crosslinking of CSPGs as a potential theranostic intervention strategy for OC—a first in the field of cancer research. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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11 pages, 1151 KiB

Open AccessArticle

Mitochondrial Protein Profile in Mice with Low or Excessive Selenium Diets

by Lianmei Hu^1,2, Congcong Wang¹, Qin Zhang¹, Hao Yan¹, Ying Li¹, Jiaqiang Pan¹ and Zhaoxin Tang^1,*

¹ College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China

² Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou 510642, China

Int. J. Mol. Sci. 2016, 17(7), 1137; https://doi.org/10.3390/ijms17071137 - 15 Jul 2016

Cited by 12 | Viewed by 4268

Abstract

Dietary selenium putatively prevents oxidative damage, whereas excessive selenium may lead to animal disorder. In this study, we investigated the effects of low and excessive levels of dietary selenium on oxidative stress and mitochondrial proteins in mouse liver. Six to eight week old [...] Read more.

Dietary selenium putatively prevents oxidative damage, whereas excessive selenium may lead to animal disorder. In this study, we investigated the effects of low and excessive levels of dietary selenium on oxidative stress and mitochondrial proteins in mouse liver. Six to eight week old mice were fed a diet with low, excessive, or moderate (control) levels of selenium (sodium selenite). The selenium concentration and oxidative stress-related parameters in hepatic mitochondria were evaluated. Two-dimensional electrophoresis and mass spectrometry were applied to identify the differentially-expressed proteins associated with dietary selenium. The selenium content of the livers in mice with the low selenium diet was significantly lower than that of the control, while that of mice fed excessive levels was significantly higher. In both groups oxidative stress in hepatic mitochondria was found; accompanied by lower superoxide dismutase (SOD) and glutathione peroxidase (GPX) levels and higher malondialdehyde (MDA) content, compared with the control group. Furthermore, ten proteins in the hepatic mitochondria of the selenium-low or -excessive groups with more than two-fold differences in abundance compared with the control group were identified. The differentially-expressed proteins in hepatic mitochondria may be associated with dietary (low or excessive) selenium-induced oxidative stress. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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15 pages, 806 KiB

Open AccessArticle

Genome-Wide Analysis of Codon Usage Bias in Epichloë festucae

by Xiuzhang Li, Hui Song, Yu Kuang, Shuihong Chen, Pei Tian, Chunjie Li^* and Zhibiao Nan

State Key Laboratory of Grassland Agro-Ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China

Int. J. Mol. Sci. 2016, 17(7), 1138; https://doi.org/10.3390/ijms17071138 - 15 Jul 2016

Cited by 31 | Viewed by 6873

Abstract

Analysis of codon usage data has both practical and theoretical applications in understanding the basics of molecular biology. Differences in codon usage patterns among genes reflect variations in local base compositional biases and the intensity of natural selection. Recently, there have been several [...] Read more.

Analysis of codon usage data has both practical and theoretical applications in understanding the basics of molecular biology. Differences in codon usage patterns among genes reflect variations in local base compositional biases and the intensity of natural selection. Recently, there have been several reports related to codon usage in fungi, but little is known about codon usage bias in Epichloë endophytes. The present study aimed to assess codon usage patterns and biases in 4870 sequences from Epichloë festucae, which may be helpful in revealing the constraint factors such as mutation or selection pressure and improving the bioreactor on the cloning, expression, and characterization of some special genes. The GC content with 56.41% is higher than the AT content (43.59%) in E. festucae. The results of neutrality and effective number of codons plot analyses showed that both mutational bias and natural selection play roles in shaping codon usage in this species. We found that gene length is strongly correlated with codon usage and may contribute to the codon usage patterns observed in genes. Nucleotide composition and gene expression levels also shape codon usage bias in E. festucae. E. festucae exhibits codon usage bias based on the relative synonymous codon usage (RSCU) values of 61 sense codons, with 25 codons showing an RSCU larger than 1. In addition, we identified 27 optimal codons that end in a G or C. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 2582 KiB

Open AccessArticle

Global Transcriptomic Analysis Reveals the Mechanism of Phelipanche aegyptiaca Seed Germination

by Zhaoqun Yao, Fang Tian, Xiaolei Cao, Ying Xu, Meixiu Chen, Benchun Xiang and Sifeng Zhao^*

Key Laboratory at Universities of Xinjiang Uygur Autonomous Region for Oasis Agricultural Pest Management and Plant Protection Resource Utilization, Shihezi University, Shihezi 832003, China

Int. J. Mol. Sci. 2016, 17(7), 1139; https://doi.org/10.3390/ijms17071139 - 15 Jul 2016

Cited by 26 | Viewed by 6194

Abstract

Phelipanche aegyptiaca is one of the most destructive root parasitic plants of Orobanchaceae. This plant has significant impacts on crop yields worldwide. Conditioned and host root stimulants, in particular, strigolactones, are needed for unique seed germination. However, no extensive study on this phenomenon [...] Read more.

Phelipanche aegyptiaca is one of the most destructive root parasitic plants of Orobanchaceae. This plant has significant impacts on crop yields worldwide. Conditioned and host root stimulants, in particular, strigolactones, are needed for unique seed germination. However, no extensive study on this phenomenon has been conducted because of insufficient genomic information. Deep RNA sequencing, including de novo assembly and functional annotation was performed on P. aegyptiaca germinating seeds. The assembled transcriptome was used to analyze transcriptional dynamics during seed germination. Key gene categories involved were identified. A total of 274,964 transcripts were determined, and 53,921 unigenes were annotated according to the NR, GO, COG, KOG, and KEGG databases. Overall, 5324 differentially expressed genes among dormant, conditioned, and GR24-treated seeds were identified. GO and KEGG enrichment analyses demonstrated numerous DEGs related to DNA, RNA, and protein repair and biosynthesis, as well as carbohydrate and energy metabolism. Moreover, ABA and ethylene were found to play important roles in this process. GR24 application resulted in dramatic changes in ABA and ethylene-associated genes. Fluridone, a carotenoid biosynthesis inhibitor, alone could induce P. aegyptiaca seed germination. In addition, conditioning was probably not the indispensable stage for P. aegyptiaca, because the transcript level variation of MAX2 and KAI2 genes (relate to strigolactone signaling) was not up-regulated by conditioning treatment. Full article

(This article belongs to the Section Molecular Plant Sciences)

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11 pages, 484 KiB

Open AccessReview

Pneumococcus and the Elderly in Italy: A Summary of Available Evidence Regarding Carriage, Clinical Burden of Lower Respiratory Tract Infections and On-Field Effectiveness of PCV13 Vaccination

by Andrea Orsi^1,2,*, Filippo Ansaldi^1,2, Cecilia Trucchi¹, Roberto Rosselli³

and Giancarlo Icardi^1,2

¹ Department of Health Sciences (DiSSal), University of Genoa, 16132 Genoa, Italy

² IRCCS AOU San Martino-IST, 16132 Genoa, Italy

³ ASL3 Genovese, 16132 Genoa, Italy

Int. J. Mol. Sci. 2016, 17(7), 1140; https://doi.org/10.3390/ijms17071140 - 15 Jul 2016

Cited by 17 | Viewed by 5388

Abstract

Streptococcus pneumoniae is currently the leading cause of community-acquired pneumonia (CAP) and lower respiratory tract infections (LRTI) in adults, elderly and high-risk subjects worldwide. The clear benefits of pneumococcal conjugate vaccination in childhood have been accompanied by a decrease of vaccine-serotype invasive diseases [...] Read more.

Streptococcus pneumoniae is currently the leading cause of community-acquired pneumonia (CAP) and lower respiratory tract infections (LRTI) in adults, elderly and high-risk subjects worldwide. The clear benefits of pneumococcal conjugate vaccination in childhood have been accompanied by a decrease of vaccine-serotype invasive diseases among adults in several countries, mainly due to the herd effect mediated by the reduction of vaccine-serotype nasopharyngeal colonization in both age groups, but this reduction in the incidence of pneumonia has not been observed. The “Community Acquired Pneumonia Immunization Trial in Adults” (CAPITA) study provided conclusive evidence about 13-valent pneumococcal conjugate vaccine (PCV13) efficacy in preventing CAP in adults and led Western countries to issue new recommendations for pneumococcal immunization targeting subjects >50 years and high-risk groups, with marked differences with respect to age and/or risk groups immunized, eligibility for reimbursement and national, regional or local implementation. Several Italian regions implemented PCV13 immunization programs in adults and interesting data have been come available in the last years, especially from Liguria, a Northern region with a high and long-lasting pneumococcal vaccine immunological pressure in infants. In this review, currently available evidence from Italy and Liguria regarding pneumococcal carriage, burden of CAP and LRTI, and on-field effectiveness of PCV13 immunization in adults and elderly will be summarized. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

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10 pages, 1871 KiB

Open AccessArticle

Ligand and Structure-Based Approaches for the Identification of Peptide Deformylase Inhibitors as Antibacterial Drugs

by Jian Gao^1,2,*

, Li Liang¹, Yasheng Zhu¹, Shengzhi Qiu¹, Tao Wang¹ and Ling Zhang¹

¹ Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China

² Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China

Int. J. Mol. Sci. 2016, 17(7), 1141; https://doi.org/10.3390/ijms17071141 - 15 Jul 2016

Cited by 33 | Viewed by 6941

Abstract

Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins, which makes it an important antibacterial drug target. Given the importance of PDF inhibitors like actinonin in antibacterial drug discovery, several reported potent PDF inhibitors were [...] Read more.

Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins, which makes it an important antibacterial drug target. Given the importance of PDF inhibitors like actinonin in antibacterial drug discovery, several reported potent PDF inhibitors were used to develop pharmacophore models using the Galahad module of Sybyl 7.1 software. Generated pharmacophore models were composed of two donor atom centers, four acceptor atom centers and two hydrophobic groups. Model-1 was screened against the Zinc database and several compounds were retrieved as hits. Compounds with Qfit values of more than 60 were employed to perform a molecular docking study with the receptor Escherichia coli PDF, then compounds with docking score values of more than 6 were used to predict the in silico pharmacokinetic and toxicity risk via OSIRIS property explorer. Two known PDF inhibitors were also used to perform a molecular docking study with E. coli PDF as reference molecules. The results of the molecular docking study were validated by reproducing the crystal structure of actinonin. Molecular docking and in silico pharmacokinetic and toxicity prediction studies suggested that ZINC08740166 has a relatively high docking score of 7.44 and a drug score of 0.78. Full article

(This article belongs to the Collection Computational, Structural and Spectroscopic Studies of Enzyme Mechanisms, Inhibition and Dynamics)

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14 pages, 10498 KiB

Open AccessArticle

Silkworm Gut Fiber of Bombyx mori as an Implantable and Biocompatible Light-Diffusing Fiber

by Jose Luis Cenis¹, Salvador D. Aznar-Cervantes¹

, Antonio Abel Lozano-Pérez^1,*

, Marta Rojo², Juan Muñoz², Luis Meseguer-Olmo^3,4

and Aurelio Arenas²

¹ Department of Biotechnology, Instituto Murciano de Investigación y Desarrollo Agrario y Alimentario (IMIDA), Murcia 30150, Spain

² Departamento de Electromagnetismo y Electrónica, Universidad de Murcia, Murcia 30003, Spain

³ Biomaterials & Tissue Engineering Unit & Orthopedic Surgery Service, V. Arrixaca University Hospital, Murcia 30120, Spain

⁴ Department of Health Sciences, UCAM-Catholic University of Murcia, Murcia 30107, Spain

Int. J. Mol. Sci. 2016, 17(7), 1142; https://doi.org/10.3390/ijms17071142 - 16 Jul 2016

Cited by 10 | Viewed by 8213

Abstract

This work describes a new approach to the delivery of light in deeper tissues, through a silk filament that is implantable, biocompatible, and biodegradable. In the present work, silkworm gut fibers (SGFs) of Bombyx mori L., are made by stretching the silk glands. [...] Read more.

This work describes a new approach to the delivery of light in deeper tissues, through a silk filament that is implantable, biocompatible, and biodegradable. In the present work, silkworm gut fibers (SGFs) of Bombyx mori L., are made by stretching the silk glands. Morphological, structural, and optical properties of the fibers have been characterized and the stimulatory effect of red laser light diffused from the fiber was assayed in fibroblast cultures. SGFs are formed by silk fibroin (SF) mainly in a β-sheet conformation, a stable and non-soluble state in water or biological fluids. The fibers showed a high degree of transparency to visible and infrared radiation. Using a red laser (λ = 650 nm) as source, the light was efficiently diffused along the fiber wall, promoting a significant increment in the cell metabolism 5 h after the irradiation. SGFs have shown their excellent properties as light-diffusing optical fibers with a stimulatory effect on cells. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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10 pages, 2474 KiB

Open AccessArticle

A Δ-9 Fatty Acid Desaturase Gene in the Microalga Myrmecia incisa Reisigl: Cloning and Functional Analysis

by Wen-Bin Xue, Fan Liu, Zheng Sun^*

and Zhi-Gang Zhou^*

College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China

Int. J. Mol. Sci. 2016, 17(7), 1143; https://doi.org/10.3390/ijms17071143 - 16 Jul 2016

Cited by 15 | Viewed by 5138

Abstract

The green alga Myrmecia incisa is one of the richest natural sources of arachidonic acid (ArA). To better understand the regulation of ArA biosynthesis in M. incisa, a novel gene putatively encoding the Δ9 fatty acid desaturase (FAD) was cloned and characterized [...] Read more.

The green alga Myrmecia incisa is one of the richest natural sources of arachidonic acid (ArA). To better understand the regulation of ArA biosynthesis in M. incisa, a novel gene putatively encoding the Δ9 fatty acid desaturase (FAD) was cloned and characterized for the first time. Rapid-amplification of cDNA ends (RACE) was employed to yield a full length cDNA designated as MiΔ9FAD, which is 2442 bp long in sequence. Comparing cDNA open reading frame (ORF) sequence to genomic sequence indicated that there are 8 introns interrupting the coding region. The deduced MiΔ9FAD protein is composed of 432 amino acids. It is soluble and localized in the chloroplast, as evidenced by the absence of transmembrane domains as well as the presence of a 61-amino acid chloroplast transit peptide. Multiple sequence alignment of amino acids revealed two conserved histidine-rich motifs, typical for Δ9 acyl-acyl carrier protein (ACP) desaturases. To determine the function of MiΔ9FAD, the gene was heterologously expressed in a Saccharomyces cerevisiae mutant strain with impaired desaturase activity. Results of GC-MS analysis indicated that MiΔ9FAD was able to restore the synthesis of monounsaturated fatty acids, generating palmitoleic acid and oleic acid through the addition of a double bond in the Δ9 position of palmitic acid and stearic acid, respectively. Full article

(This article belongs to the Section Molecular Plant Sciences)

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18 pages, 2313 KiB

Open AccessReview

Signaling Pathways in Melanogenesis

by Stacey A. N. D’Mello¹, Graeme J. Finlay^1,2, Bruce C. Baguley² and Marjan E. Askarian-Amiri^1,2,*

¹ Department of Molecular Medicine and Pathology, University of Auckland, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd. Grafton, Auckland 1023, New Zealand

² Auckland Cancer Society Research Centre, University of Auckland, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd. Grafton, Auckland 1023, New Zealand

Int. J. Mol. Sci. 2016, 17(7), 1144; https://doi.org/10.3390/ijms17071144 - 15 Jul 2016

Cited by 768 | Viewed by 44810

Abstract

Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are [...] Read more.

Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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12 pages, 7643 KiB

Open AccessArticle

Expression and Distribution Pattern of Aquaporin 4, 5 and 11 in Retinas of 15 Different Species

by Barbara Amann¹, Kristina J. H. Kleinwort¹

, Sieglinde Hirmer¹, Walter Sekundo², Elisabeth Kremmer³, Stefanie M. Hauck⁴

and Cornelia A. Deeg^1,5,*

¹ Institute for Animal Physiology, Department of Veterinary Sciences, Ludwig-Maximilians-University, Veterinärstraße 13, D-80539 Munich, Germany

² Clinic for Ophthalmology, University Clinic Gießen und Marburg GmbH, Marburg, Baldingerstrasse, D-35033 Marburg, Germany

³ Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Marchioninistraße 25, D-81377 München, Germany

⁴ Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Heidemannstr. 1, D-80939 München, Germany

⁵ Experimental Ophthalmology, Philipps University of Marburg, Baldingerstrasse, D-35033 Marburg, Germany

Int. J. Mol. Sci. 2016, 17(7), 1145; https://doi.org/10.3390/ijms17071145 - 16 Jul 2016

Cited by 22 | Viewed by 7490

Abstract

Aquaporins (AQPs) are small integral membrane proteins with 13 members in mammals and are essential for water transport across membranes. They are found in many different tissues and cells. Currently, there are conflicting results regarding retinal aquaporin expression and subcellular localization between genome [...] Read more.

Aquaporins (AQPs) are small integral membrane proteins with 13 members in mammals and are essential for water transport across membranes. They are found in many different tissues and cells. Currently, there are conflicting results regarding retinal aquaporin expression and subcellular localization between genome and protein analyses and among various species. AQP4, 7, 9 and 11 were described in the retina of men; whereas AQP6, 8 and 10 were earlier identified in rat retinas and AQP4, 5 and 11 in horses. Since there is a lack of knowledge regarding AQP expression on protein level in retinas of different animal models, we decided to analyze retinal cellular expression of AQP4, 5 and 11 in situ with immunohistochemistry. AQP4 was detected in all 15 explored species, AQP5 and AQP11 in 14 out of 15. Interestingly, AQP4 was unambiguously expressed in Muller glial cells, whereas AQP5 was differentially allocated among the species analyzed. AQP11 expression was Muller glial cell-specific in 50% of the animals, whereas in the others, AQP11 was detected in ganglion cell layer and at photoreceptor outer segments. Our data indicate a disparity in aquaporin distribution in retinas of various animals, especially for AQP5 and 11. Full article

(This article belongs to the Special Issue Aquaporin)

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16 pages, 923 KiB

Open AccessReview

Progress in AQP Research and New Developments in Therapeutic Approaches to Ischemic and Hemorrhagic Stroke

by Lauren E. Previch^1,†, Linlin Ma^2,†, Joshua C. Wright¹, Sunpreet Singh¹, Xiaokun Geng^1,2,3,* and Yuchuan Ding^1,3,*

¹ Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA

² Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing 101199, China

³ China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing 101199, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1146; https://doi.org/10.3390/ijms17071146 - 18 Jul 2016

Cited by 28 | Viewed by 6273

Abstract

Cerebral edema often manifests after the development of cerebrovascular disease, particularly in the case of stroke, both ischemic and hemorrhagic. Without clinical intervention, the influx of water into brain tissues leads to increased intracranial pressure, cerebral herniation, and ultimately death. Strategies to manage [...] Read more.

Cerebral edema often manifests after the development of cerebrovascular disease, particularly in the case of stroke, both ischemic and hemorrhagic. Without clinical intervention, the influx of water into brain tissues leads to increased intracranial pressure, cerebral herniation, and ultimately death. Strategies to manage the development of edema constitute a major unmet therapeutic need. However, despite its major clinical significance, the mechanisms underlying cerebral water transport and edema formation remain elusive. Aquaporins (AQPs) are a class of water channel proteins which have been implicated in the regulation of water homeostasis and cerebral edema formation, and thus represent a promising target for alleviating stroke-induced cerebral edema. This review examines the significance of relevant AQPs in stroke injury and subsequently explores neuroprotective strategies aimed at modulating AQP expression, with a particular focus on AQP4, the most abundant AQP in the central nervous system. Full article

(This article belongs to the Special Issue Aquaporin)

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14 pages, 511 KiB

Open AccessReview

Environmental Factors Associated with Altered Gut Microbiota in Children with Eczema: A Systematic Review

by Carmen W. H. Chan^1,*

, Rosa S. Wong¹, Patrick T. W. Law¹, Cho Lee Wong¹

, Stephen K. W. Tsui², Winnie P. Y. Tang¹ and Janet W. H. Sit¹

¹ Nethersole School of Nursing, The Chinese University of Hong Kong, Hong Kong, China

² School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2016, 17(7), 1147; https://doi.org/10.3390/ijms17071147 - 16 Jul 2016

Cited by 20 | Viewed by 9068

Abstract

Eczema is a common skin condition that impairs children’s daily life activities and quality of life. Previous research shows that gut microbiome composition plays an important role in the development of eczema. The present review summarizes evidence on environmental factors related to altered [...] Read more.

Eczema is a common skin condition that impairs children’s daily life activities and quality of life. Previous research shows that gut microbiome composition plays an important role in the development of eczema. The present review summarizes evidence on environmental factors related to altered gut microbiota in children with eczema. We searched Medline, PubMed, Embase, and the Cochrane database of Systematic Reviews through October 2015. The search strategy focused on articles published in peer-reviewed, English-language journals with no publication year limit. Only original studies and review articles that reported environmental factors on gut microbiome specific to eczema were included in this review. We selected six studies (total 1990 participants) for full review and identified that the composition of gut microbiota specific to eczema could be influenced by the following environmental factors: length of gestation, mode of delivery, type of feeding, method of treatment, number of older siblings, and other lifestyle factors. There has been inconsistent empirical evidence as to the modulatory effects of gut microbiota on immunological functions in children with eczema. Further research on the environmental-host-microbial interaction is needed to develop a strong base of knowledge for the development and implementation of prevention strategies and policies for eczema. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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14 pages, 2518 KiB

Open AccessArticle

Potential Metabolic Biomarkers to Identify Interstitial Lung Abnormalities

by Yong Tan^1,†, Dongmei Jia^2,†, Zhang Lin³, Baosheng Guo⁴, Bing He⁴, Cheng Lu¹, Cheng Xiao⁵, Zhongdi Liu⁴, Ning Zhao¹, Zhaoxiang Bian⁴, Ge Zhang⁴

, Weidong Zhang³, Xinru Liu^3,* and Aiping Lu^1,4,6,*

¹ Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China

² Traditional Chinese Medicine Division, Science Press, Beijing 100717, China

³ School of Pharmacy, Second Military Medical University, Shanghai 200433, China

⁴ Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China

⁵ Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China

⁶ E-Institutes of Shanghai Municipal Education Commission, Shanghai 201203, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1148; https://doi.org/10.3390/ijms17071148 - 16 Jul 2016

Cited by 12 | Viewed by 5578

Abstract

Determining sensitive biomarkers in the peripheral blood to identify interstitial lung abnormalities (ILAs) is essential for the simple early diagnosis of ILAs. This study aimed to determine serum metabolic biomarkers of ILAs and the corresponding pathogenesis. Three groups of subjects undergoing health screening, [...] Read more.

Determining sensitive biomarkers in the peripheral blood to identify interstitial lung abnormalities (ILAs) is essential for the simple early diagnosis of ILAs. This study aimed to determine serum metabolic biomarkers of ILAs and the corresponding pathogenesis. Three groups of subjects undergoing health screening, including healthy subjects, subjects with ILAs, and subjects who were healthy initially and with ILAs one year later (Healthy→ILAs), were recruited for this study. The metabolic profiles of all of the subjects’ serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry. The metabolic characteristics of the ILAs subjects were discovered, and the corresponding biomarkers were predicted. The metabolomic data from the Healthy→ILAs subjects were collected for further verification. The results indicated that five serum metabolite alterations (up-regulated phosphatidylcholine, phosphatidic acid, betaine aldehyde and phosphatidylethanolamine, as well as down-regulated 1-acylglycerophosphocholine) were sensitive and reliable biomarkers for identifying ILAs. Perturbation of the corresponding biological pathways (RhoA signaling, mTOR/P70S6K signaling and phospholipase C signaling) might be at least partially responsible for the pathogenesis of ILAs. This study may provide a good template for determining the early diagnostic markers of subclinical disease status and for obtaining a better understanding of their pathogenesis. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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10 pages, 485 KiB

Open AccessReview

Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model

by Atsushi Takeda^*

, Haruna Tamano, Ryusuke Nishio and Taku Murakami

Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan

Int. J. Mol. Sci. 2016, 17(7), 1149; https://doi.org/10.3390/ijms17071149 - 16 Jul 2016

Cited by 17 | Viewed by 5339

Abstract

Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after [...] Read more.

Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer’s disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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13 pages, 8404 KiB

Open AccessReview

Non-Classical Inhibition of Carbonic Anhydrase

by Carrie L. Lomelino¹, Claudiu T. Supuran²

and Robert McKenna^1,*

¹ Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611, USA

² Neurofarba Department, University of Florence, Piazza di San Marco, Firenze 50019, Italy

Int. J. Mol. Sci. 2016, 17(7), 1150; https://doi.org/10.3390/ijms17071150 - 16 Jul 2016

Cited by 106 | Viewed by 7741

Abstract

Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, [...] Read more.

Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, are examined as antiglaucoma, antiepileptic, antiobesity, antineuropathic pain and anticancer compounds. However, many sulfonamide compounds inhibit all CA isoforms nonspecifically, diluting drug effectiveness and causing undesired side effects due to off-target inhibition. In addition, a small but significant percentage of the general population cannot be treated with sulfonamide-based compounds due to a sulfa allergy. Therefore, CAIs must be developed that are not only isoform specific, but also non-classical, i.e. not based on sulfonamides, sulfamates, or sulfamides. This review covers the classes of non-classical CAIs and the recent advances in the development of isoform-specific inhibitors based on phenols, polyamines, coumarins and their derivatives. Full article

(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)

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22 pages, 903 KiB

Open AccessReview

A Mini-Review for Cancer Immunotherapy: Molecular Understanding of PD-1/PD-L1 Pathway & Translational Blockade of Immune Checkpoints

by Yongshu Li^1,2,3,†, Fangfei Li^2,3,4,†, Feng Jiang^1,2,3,4,5, Xiaoqing Lv^1,2,3,6, Rongjiang Zhang^1,2,3, Aiping Lu^1,2,3,4,* and Ge Zhang^1,2,3,4,*

¹ Institute of Precision Medicine and Innovative Drug Discovery, Institute of Science and Technology, Hong Kong Baptist University, Haimen 226133, China

² Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University, Hong Kong, China

³ Institute of Research and Continuing Education, Hong Kong Baptist University, Hong Kong, China

⁴ Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

⁵ Faculty of Materials Science and Chemical Engineering, The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Ningbo University, Ningbo 315211, China

⁶ College of Medicine, Jiaxing University, Jiaxing 314001, China

^† These authors contributed equally to this work

Int. J. Mol. Sci. 2016, 17(7), 1151; https://doi.org/10.3390/ijms17071151 - 18 Jul 2016

Cited by 133 | Viewed by 16406

Abstract

Interference of the binding of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has become a new inspiring immunotherapy for resisting cancers. To date, the FDA has approved two PD-1 monoclonal antibody drugs against cancer as well as a monoclonal [...] Read more.

Interference of the binding of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has become a new inspiring immunotherapy for resisting cancers. To date, the FDA has approved two PD-1 monoclonal antibody drugs against cancer as well as a monoclonal antibody for PD-L1. More PD-1 and PD-L1 monoclonal antibody drugs are on their way in clinical trials. In this review, we focused on the mechanism of the PD-1/PD-L1 signaling pathway and the monoclonal antibodies (mAbs) against PD-1 and PD-L1, which were approved by the FDA or are still in clinical trials. And also presented is the prospect of the PD-1/PD-L1 immune checkpoint blockade in the next generation of immunotherapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 4674 KiB

Open AccessArticle

The Conserved Arginine Cluster in the Insert of the Third Cytoplasmic Loop of the Long Form of the D₂ Dopamine Receptor (D_2L-R) Acts as an Intracellular Retention Signal

by Valentina Kubale^1,†, Kaja Blagotinšek^1,†,‡

, Jane Nøhr², Karin A. Eidne³ and Milka Vrecl^1,*

¹ Institute of Anatomy, Histology & Embryology, Veterinary Faculty, University of Ljubljana, Gerbičeva 60, SI-1000 Ljubljana, Slovenia

² Department of Incretin & Islet Biology, Novo Nordisk A/S, DK-2760 Måløv, Denmark

³ Laboratory for Molecular Endocrinology-G Protein-Coupled Receptors, Western Australian Institute for Medical Research (WAIMR) and Centre for Medical Research, The University of Western Australia, WA 6009 Perth, Australia

^† These authors contributed equally to this work.

^‡ Present address: Institute of Biochemistry, Center for Functional Genomics and Bio-Chips, Medical Faculty, University of Ljubljana, SI-1000 Ljubljana, Slovenia

Int. J. Mol. Sci. 2016, 17(7), 1152; https://doi.org/10.3390/ijms17071152 - 19 Jul 2016

Cited by 8 | Viewed by 6220

Abstract

This study examined whether the conserved arginine cluster present within the 29-amino acid insert of the long form of the D₂ dopamine receptor (D_2L-R) confers its predominant intracellular localization. We hypothesized that the conserved arginine cluster (RRR) located within the [...] Read more.

This study examined whether the conserved arginine cluster present within the 29-amino acid insert of the long form of the D₂ dopamine receptor (D_2L-R) confers its predominant intracellular localization. We hypothesized that the conserved arginine cluster (RRR) located within the insert could act as an RXR-type endoplasmic reticulum (ER) retention signal. Arginine residues (R) within the cluster at positions 267, 268, and 269 were charge-reserved to glutamic acids (E), either individually or in clusters, thus generating single, double, and triple D_2L-R mutants. Through analyses of cellular localization by confocal microscopy and enzyme-linked immunosorbent assay (ELISA), radioligand binding assay, bioluminescence resonance energy transfer (BRET²) β-arrestin 2 (βarr2) recruitment assay, and cAMP signaling, it was revealed that charge reversal of the R residues at all three positions within the motif impaired their colocalization with ER marker calnexin and led to significantly improved cell surface expression. Additionally, these data demonstrate that an R to glutamic acid (E) substitution at position 2 within the RXR motif is not functionally permissible. Furthermore, all generated D_2L-R mutants preserved their functional integrity regarding ligand binding, agonist-induced βarr2 recruitment and Gα_i-mediated signaling. In summary, our results show that the conserved arginine cluster within the 29-amino acid insert of third cytoplasmic loop (IC3) of the D_2L-R appears to be the ER retention signal. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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11 pages, 2444 KiB

Open AccessArticle

The OsCYP19-4 Gene Is Expressed as Multiple Alternatively Spliced Transcripts Encoding Isoforms with Distinct Cellular Localizations and PPIase Activities under Cold Stress

by Areum Lee^1,2, Sang Sook Lee², Won Yong Jung², Hyun Ji Park², Bo Ra Lim², Hyun-Soon Kim², Jun Cheul Ahn³ and Hye Sun Cho^1,2,*

¹ Biosystems and Bioengineering Program, University of Science and Technology (UST), Daejeon 34113, Korea

² Molecular Biofarming Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea

³ Department of Pharmacology, College of Medicine, Seonam University, Namwon 55724, Korea

Int. J. Mol. Sci. 2016, 17(7), 1154; https://doi.org/10.3390/ijms17071154 - 19 Jul 2016

Cited by 16 | Viewed by 5557

Abstract

Alternative splicing (AS) is an important molecular mechanism by which single genes can generate multiple mRNA isoforms. We reported previously that, in Oryza sativa, the cyclophilin 19-4 (OsCYP19-4.1) transcript was significantly upregulated in response to cold stress, and that transgenic [...] Read more.

Alternative splicing (AS) is an important molecular mechanism by which single genes can generate multiple mRNA isoforms. We reported previously that, in Oryza sativa, the cyclophilin 19-4 (OsCYP19-4.1) transcript was significantly upregulated in response to cold stress, and that transgenic plants were cold tolerant. Here we show that, under cold stress, OsCYP19-4 produces eight transcript variants by intron retention and exon skipping, resulting in production of four distinct protein isoforms. The OsCYP19-4 AS isoforms exhibited different cellular localizations in the epidermal cells: in contrast to OsCYP19-4.1, the OsCYP19-4.2 and OsCYP19-4.3 proteins were primarily targeted to guard and subsidiary cells, whereas OsCYP19-4.5, which consists largely of an endoplasmic reticulum (ER) targeting signal, was co-localized with the RFP-BiP marker in the ER. In OsCYP19-4.2, the key residues of the PPIase domain are altered; consistent with this, recombinant OsCYP19-4.2 had significantly lower PPIase activity than OsCYP19-4.1 in vitro. Specific protein-protein interactions between OsCYP19-4.2/3 and AtRCN1 were verified in yeast two-hybrid (Y2H) and bimolecular fluoresence complementation (BiFC assays), although the OsCYP19-4 isoforms could not bind each other. Based on these results, we propose that two OsCYP19-4 AS isoforms, OsCYP19-4.2 and OsCYP19-4.3, play roles linking auxin transport and cold stress via interactions with RCN1. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing 2016)

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13 pages, 724 KiB

Open AccessReview

Cellular and Molecular Mechanisms of 3,3′-Diindolylmethane in Gastrointestinal Cancer

by Soo Mi Kim

Department of Physiology, Chonbuk National University Medical School, Jeonju 561-180, Korea

Int. J. Mol. Sci. 2016, 17(7), 1155; https://doi.org/10.3390/ijms17071155 - 19 Jul 2016

Cited by 47 | Viewed by 7787

Abstract

Studies in humans have shown that 3,3′-diindolylmethane (DIM), which is found in cruciferous vegetables, such as cabbage and broccoli, is effective in the attenuation of gastrointestinal cancers. This review presents the latest findings on the use, targets, and modes of action of DIM [...] Read more.

Studies in humans have shown that 3,3′-diindolylmethane (DIM), which is found in cruciferous vegetables, such as cabbage and broccoli, is effective in the attenuation of gastrointestinal cancers. This review presents the latest findings on the use, targets, and modes of action of DIM for the treatment of human gastrointestinal cancers. DIM acts upon several cellular and molecular processes in gastrointestinal cancer cells, including apoptosis, autophagy, invasion, cell cycle regulation, metastasis, angiogenesis, and endoplasmic reticulum (ER) stress. In addition, DIM increases the efficacy of other drugs or therapeutic chemicals when used in combinatorial treatment for gastrointestinal cancer. The studies to date offer strong evidence to support the use of DIM as an anticancer and therapeutic agent for gastrointestinal cancer. Therefore, this review provides a comprehensive understanding of the preventive and therapeutic properties of DIM in addition to its different perspective on the safety of DIM in clinical applications for the treatment of gastrointestinal cancers. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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15 pages, 1091 KiB

Open AccessArticle

Evaluation of the Anti-Inflammatory Activity of Raisins (Vitis vinifera L.) in Human Gastric Epithelial Cells: A Comparative Study

by Chiara Di Lorenzo¹

, Enrico Sangiovanni¹

, Marco Fumagalli¹, Elisa Colombo¹, Gianfranco Frigerio¹

, Francesca Colombo¹

, Luis Peres de Sousa², Ahmet Altindişli³, Patrizia Restani¹ and Mario Dell’Agli^1,*

¹ Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan 20133, Italy

² Instituto Politecnico de Beja, Beja 7800-295, Portugal

³ Fakulty of Agriculture, Ege University, Bornova, Izmir 35100, Turkey

Int. J. Mol. Sci. 2016, 17(7), 1156; https://doi.org/10.3390/ijms17071156 - 19 Jul 2016

Cited by 32 | Viewed by 7516

Abstract

Raisins (Vitis vinifera L.) are dried grapes largely consumed as important source of nutrients and polyphenols. Several studies report health benefits of raisins, including anti-inflammatory and antioxidant properties, whereas the anti-inflammatory activity at gastric level of the hydro-alcoholic extracts, which are mostly [...] Read more.

Raisins (Vitis vinifera L.) are dried grapes largely consumed as important source of nutrients and polyphenols. Several studies report health benefits of raisins, including anti-inflammatory and antioxidant properties, whereas the anti-inflammatory activity at gastric level of the hydro-alcoholic extracts, which are mostly used for food supplements preparation, was not reported until now. The aim of this study was to compare the anti-inflammatory activity of five raisin extracts focusing on Interleukin (IL)-8 and Nuclear Factor (NF)-κB pathway. Raisin extracts were characterized by High Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD) analysis and screened for their ability to inhibit Tumor necrosis factor (TNF)α-induced IL-8 release and promoter activity in human gastric epithelial cells. Turkish variety significantly inhibited TNFα-induced IL-8 release, and the effect was due to the impairment of the corresponding promoter activity. Macroscopic evaluation showed the presence of seeds, absent in the other varieties; thus, hydro-alcoholic extracts from fruits and seeds were individually tested on IL-8 and NF-κB pathway. Seed extract inhibited IL-8 and NF-κB pathway, showing higher potency with respect to the fruit. Although the main effect was due to the presence of seeds, the fruit showed significant activity as well. Our data suggest that consumption of selected varieties of raisins could confer a beneficial effect against gastric inflammatory diseases. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food)

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21 pages, 1571 KiB

Open AccessReview

Carbon Sources for Polyhydroxyalkanoates and an Integrated Biorefinery

by Guozhan Jiang¹, David J. Hill¹, Marek Kowalczuk^1,2, Brian Johnston¹, Grazyna Adamus²

, Victor Irorere¹ and Iza Radecka^1,*

¹ School of Biology Chemistry and Forensic Science, University of Wolverhampton, Wolverhampton WV1 1LY, UK

² Polish Academy of Sciences, Centre of Polymer and Carbon Materials, Zabrze 41-819, Poland

Int. J. Mol. Sci. 2016, 17(7), 1157; https://doi.org/10.3390/ijms17071157 - 19 Jul 2016

Cited by 198 | Viewed by 13594

Abstract

Polyhydroxyalkanoates (PHAs) are a group of bioplastics that have a wide range of applications. Extensive progress has been made in our understanding of PHAs’ biosynthesis, and currently, it is possible to engineer bacterial strains to produce PHAs with desired properties. The substrates for [...] Read more.

Polyhydroxyalkanoates (PHAs) are a group of bioplastics that have a wide range of applications. Extensive progress has been made in our understanding of PHAs’ biosynthesis, and currently, it is possible to engineer bacterial strains to produce PHAs with desired properties. The substrates for the fermentative production of PHAs are primarily derived from food-based carbon sources, raising concerns over the sustainability of their production in terms of their impact on food prices. This paper gives an overview of the current carbon sources used for PHA production and the methods used to transform these sources into fermentable forms. This allows us to identify the opportunities and restraints linked to future sustainable PHA production. Hemicellulose hydrolysates and crude glycerol are identified as two promising carbon sources for a sustainable production of PHAs. Hemicellulose hydrolysates and crude glycerol can be produced on a large scale during various second generation biofuels’ production. An integration of PHA production within a modern biorefinery is therefore proposed to produce biofuels and bioplastics simultaneously. This will create the potential to offset the production cost of biofuels and reduce the overall production cost of PHAs. Full article

(This article belongs to the Special Issue Biodegradable Materials 2017)

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17 pages, 1101 KiB

Open AccessArticle

Immunomodulation Induced by Stem Cell Mobilization and Harvesting in Healthy Donors: Increased Systemic Osteopontin Levels after Treatment with Granulocyte Colony-Stimulating Factor

by Guro Kristin Melve^1,2, Elisabeth Ersvaer³, Çiğdem Akalın Akkök⁴, Aymen Bushra Ahmed⁵, Einar K. Kristoffersen^1,2, Tor Hervig^1,2 and Øystein Bruserud^2,5,*

¹ Department of Immunology and Transfusion Medicine, Haukeland University Hospital, N-5021 Bergen, Norway

² Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway

³ Department of Biomedical Laboratory Sciences and Chemical Engineering, Faculty of Engineering and Business Administration, Bergen University College, N-5020 Bergen, Norway

⁴ Department of Immunology and Transfusion Medicine, Oslo University Hospital, Ullevål, N-0424 Oslo, Norway

⁵ Division for Hematology, Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway

Int. J. Mol. Sci. 2016, 17(7), 1158; https://doi.org/10.3390/ijms17071158 - 19 Jul 2016

Cited by 3 | Viewed by 4977

Abstract

Peripheral blood stem cells from healthy donors mobilized by granulocyte colony-stimulating factor (G-CSF) and harvested by leukapheresis are commonly used for allogeneic stem cell transplantation. The frequency of severe graft versus host disease is similar for patients receiving peripheral blood and bone marrow [...] Read more.

Peripheral blood stem cells from healthy donors mobilized by granulocyte colony-stimulating factor (G-CSF) and harvested by leukapheresis are commonly used for allogeneic stem cell transplantation. The frequency of severe graft versus host disease is similar for patients receiving peripheral blood and bone marrow allografts, even though the blood grafts contain more T cells, indicating mobilization-related immunoregulatory effects. The regulatory phosphoprotein osteopontin was quantified in plasma samples from healthy donors before G-CSF treatment, after four days of treatment immediately before and after leukapheresis, and 18–24 h after apheresis. Myeloma patients received chemotherapy, combined with G-CSF, for stem cell mobilization and plasma samples were prepared immediately before, immediately after, and 18–24 h after leukapheresis. G-CSF treatment of healthy stem cell donors increased plasma osteopontin levels, and a further increase was seen immediately after leukapheresis. The pre-apheresis levels were also increased in myeloma patients compared to healthy individuals. Finally, in vivo G-CSF exposure did not alter T cell expression of osteopontin ligand CD44, and in vitro osteopontin exposure induced only small increases in anti-CD3- and anti-CD28-stimulated T cell proliferation. G-CSF treatment, followed by leukapheresis, can increase systemic osteopontin levels, and this effect may contribute to the immunomodulatory effects of G-CSF treatment. Full article

(This article belongs to the Special Issue Advances in Cell Transplantation)

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15 pages, 5153 KiB

Open AccessArticle

Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning

by Britta Mayer^1,†, Josefin Soppert^1,†, Sandra Kraemer¹

, Sabrina Schemmel¹, Christian Beckers¹, Christian Bleilevens², Rolf Rossaint², Mark Coburn², Andreas Goetzenich^1,* and Christian Stoppe^2,3,*

¹ Department of Thoracic & Cardiovascular Surgery, University Hospital RWTH, 52074 Aachen, Germany

² Department of Anesthesiology, University Hospital RWTH, 52074 Aachen, Germany

³ Department of Intensive Care Medicine, University Hospital RWTH, 52074 Aachen, Germany

^† These authors contributed equally in this manuscript.

Int. J. Mol. Sci. 2016, 17(7), 1159; https://doi.org/10.3390/ijms17071159 - 19 Jul 2016

Cited by 20 | Viewed by 5148

Abstract

Increasing evidence indicates that argon has organoprotective properties. So far, the underlying mechanisms remain poorly understood. Therefore, we investigated the effect of argon preconditioning in cardiomyocytes within the first and second window of preconditioning. Primary isolated cardiomyocytes from neonatal rats were subjected to [...] Read more.

Increasing evidence indicates that argon has organoprotective properties. So far, the underlying mechanisms remain poorly understood. Therefore, we investigated the effect of argon preconditioning in cardiomyocytes within the first and second window of preconditioning. Primary isolated cardiomyocytes from neonatal rats were subjected to 50% argon for 1 h, and subsequently exposed to a sublethal dosage of hypoxia (<1% O₂) for 5 h either within the first (0–3 h) or second window (24–48 h) of preconditioning. Subsequently, the cell viability and proliferation was measured. The argon-induced effects were assessed by evaluation of mRNA and protein expression after preconditioning. Argon preconditioning did not show any cardioprotective effects in the early window of preconditioning, whereas it leads to a significant increase of cell viability 24 h after preconditioning compared to untreated cells (p = 0.015) independent of proliferation. Argon-preconditioning significantly increased the mRNA expression of heat shock protein (HSP) B1 (HSP27) (p = 0.048), superoxide dismutase 2 (SOD2) (p = 0.001), vascular endothelial growth factor (VEGF) (p < 0.001) and inducible nitric oxide synthase (iNOS) (p = 0.001). No difference was found with respect to activation of pro-survival kinases in the early and late window of preconditioning. The findings provide the first evidence of argon-induced effects on the survival of cardiomyocytes during the second window of preconditioning, which may be mediated through the induction of HSP27, SOD2, VEGF and iNOS. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 9951 KiB

Open AccessArticle

Leptin Receptor Metabolism Disorder in Primary Chondrocytes from Adolescent Idiopathic Scoliosis Girls

by Yun-Jia Wang

, Hong-Gui Yu, Zhen-Hai Zhou, Qiang Guo, Long-Jie Wang and Hong-Qi Zhang^*

Department of Spine Surgery, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha 410008, China

Int. J. Mol. Sci. 2016, 17(7), 1160; https://doi.org/10.3390/ijms17071160 - 20 Jul 2016

Cited by 30 | Viewed by 5648

Abstract

To investigate the underlying mechanisms of low metabolic activity of primary chondrocytes obtained from girls with adolescent idiopathic scoliosis (AIS); AIS is a spine-deforming disease that often occurs in girls. AIS is associated with a lower bone mass than that of healthy individuals [...] Read more.

To investigate the underlying mechanisms of low metabolic activity of primary chondrocytes obtained from girls with adolescent idiopathic scoliosis (AIS); AIS is a spine-deforming disease that often occurs in girls. AIS is associated with a lower bone mass than that of healthy individuals and osteopenia. Leptin was shown to play an important role in bone growth. It can also regulate the function of chondrocytes. Changes in leptin and Ob-R levels in AIS patients have been reported in several studies. The underlying mechanisms between the dysfunction of peripheral leptin signaling and abnormal chondrocytes remain unclear; The following parameters were evaluated in AIS patients and the control groups: total serum leptin levels; Ob-R expression in the plasma membrane of primary chondrocytes; JAK2 and STAT3 phosphorylation status. Then, we inhibited the lysosome and proteasome and knocked down clathrin heavy chain (CHC) expression in primary chondrocytes isolated from girls with AIS and evaluated Ob-R expression. We investigated the effects of leptin combined with a lysosome inhibitor or CHC knockdown in primary chondrocytes obtained from AIS patients; Compared with the controls, AIS patients showed similar total serum leptin levels, reduced JAK2 and STAT3 phosphorylation, and decreased cartilage matrix synthesis in the facet joint. Lower metabolic activity and lower membrane expression of Ob-R were observed in primary chondrocytes from the AIS group than in the controls. Lysosome inhibition increased the total Ob-R content but had no effect on the membrane expression of Ob-R or leptin’s effects on AIS primary chondrocytes. CHC knockdown upregulated the membrane Ob-R levels and enhanced leptin’s effects on AIS primary chondrocytes; The underlying mechanism of chondrocytes that are hyposensitive to leptin in some girls with AIS is low plasma membrane Ob-R expression that results from an imbalance between the rate of receptor endocytosis and the insertion of newly synthesized receptors into the membrane. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)

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12 pages, 12569 KiB

Open AccessArticle

Effectiveness of Hypochlorous Acid to Reduce the Biofilms on Titanium Alloy Surfaces in Vitro

by Chun-Ju Chen¹, Chun-Cheng Chen^2,3,* and Shinn-Jyh Ding^1,2,3,*

¹ Institute of Oral Science, Chung Shan Medical University, Taichung City 402, Taiwan

² School of Dentistry, Chung Shan Medical University, Taichung City 402, Taiwan

³ Department of Dentistry, Chung Shan Medical University Hospital, Taichung City 402, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1161; https://doi.org/10.3390/ijms17071161 - 19 Jul 2016

Cited by 48 | Viewed by 15122

Abstract

Chemotherapeutic agents have been used as an adjunct to mechanical debridement for peri-implantitis treatment. The present in vitro study evaluated and compared the effectiveness of hypochlorous acid (HOCl), sodium hypochlorite (NaOCl), and chlorhexidine (CHX) at eliminating Gram-negative (E. coli and P. gingivalis [...] Read more.

Chemotherapeutic agents have been used as an adjunct to mechanical debridement for peri-implantitis treatment. The present in vitro study evaluated and compared the effectiveness of hypochlorous acid (HOCl), sodium hypochlorite (NaOCl), and chlorhexidine (CHX) at eliminating Gram-negative (E. coli and P. gingivalis) and Gram-positive (E. faecalis and S. sanguinis) bacteria. The effect of irrigating volume and exposure time on the antimicrobial efficacy of HOCl was evaluated, and a durability analysis was completed. Live/dead staining, morphology observation, alamarBlue assay, and lipopolysaccharide (LPS) detection were examined on grit-blasted and biofilm-contaminated titanium alloy discs after treatment with the three chemotherapeutic agents. The results indicated that HOCl exhibited better antibacterial efficacy with increasing irrigating volumes. HOCl achieved greater antibacterial efficacy as treatment time was increased. A decrease in antimicrobial effectiveness was observed when HOCl was unsealed and left in contact with the air. All the irrigants showed antibacterial activity and killed the majority of bacteria on the titanium alloy surfaces of biofilm-contaminated implants. Moreover, HOCl significantly lowered the LPS concentration of P. gingivalis when compared with NaOCl and CHX. Thus, a HOCl antiseptic may be effective for cleaning biofilm-contaminated implant surfaces. Full article

(This article belongs to the Special Issue Molecular Research on Dental Materials and Biomaterials)

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13 pages, 701 KiB

Open AccessReview

Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis

by Xiaojuan Ma^1,2 and Yingmei Feng^1,2,*

¹ Beijing Key Laboratory of Diabetes Prevention and Research, Lu He Hospital, Capital Medical University, Beijing 101149, China

² Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing 101149, China

Int. J. Mol. Sci. 2016, 17(7), 1162; https://doi.org/10.3390/ijms17071162 - 19 Jul 2016

Cited by 24 | Viewed by 6823

Abstract

As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens [...] Read more.

As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression. Hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) expresses a panel of lipoprotein receptors to control cholesterol homeostasis. Deficiency of these receptors abrogates cellular cholesterol efflux, resulting in HSPC proliferation and differentiation in hypercholesterolemic mice. Reduction of the cholesterol level in the lipid rafts by infusion of reconstituted high-density lipoprotein (HDL) or its major apolipoprotein, apoA-I, reverses hypercholesterolemia-induced HSPC expansion. Apart from impaired cholesterol metabolism, inhibition of reactive oxygen species production suppresses HSPC activation and leukocytosis. These data indicate that the mechanisms underlying the effects of hypercholesterolemia on HSPC proliferation and differentiation could be multifaceted. Furthermore, dyslipidemia also regulates HSPC-neighboring cells, resulting in HSPC mobilization. In the article, we review how hypercholesterolemia evokes HSPC activation and mobilization directly or via its modification of BM microenvironment. We hope this review will bring light to finding key molecules to control HSPC expansion, inflammation, and atherosclerosis for the treatment of CVD. Full article

(This article belongs to the Special Issue Vascular Biology and Therapeutics)

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14 pages, 2017 KiB

Open AccessReview

Current Stem Cell Biomarkers and Their Functional Mechanisms in Prostate Cancer

by Kaile Zhang^1,2,†, Shukui Zhou^1,†, Leilei Wang³, Jianlong Wang⁴, Qingsong Zou¹, Weixin Zhao², Qiang Fu^1,* and Xiaolan Fang^5,*,‡

¹ The Department of Urology, Affiliated Sixth People’s Hospital, Shanghai JiaoTong University, Shanghai 200233, China

² Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, USA

³ VIP Department of Beijing Hospital, Beijing 100730, China

⁴ Urology Department of Beijing Hospital, Beijing 100730, China

⁵ Department of Cancer Biology, Wake Forest University School of Medicine, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, USA

^† These authors contributed equally to this work.

^‡ Current address: New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA

Int. J. Mol. Sci. 2016, 17(7), 1163; https://doi.org/10.3390/ijms17071163 - 19 Jul 2016

Cited by 27 | Viewed by 7317

Abstract

Currently there is little effective treatment available for castration resistant prostate cancer, which is responsible for the majority of prostate cancer related deaths. Emerging evidence suggested that cancer stem cells might play an important role in resistance to traditional cancer therapies, and the [...] Read more.

Currently there is little effective treatment available for castration resistant prostate cancer, which is responsible for the majority of prostate cancer related deaths. Emerging evidence suggested that cancer stem cells might play an important role in resistance to traditional cancer therapies, and the studies of cancer stem cells (including specific isolation and targeting on those cells) might benefit the discovery of novel treatment of prostate cancer, especially castration resistant disease. In this review, we summarized major biomarkers for prostate cancer stem cells, as well as their functional mechanisms and potential application in clinical diagnosis and treatment of patients. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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18 pages, 816 KiB

Open AccessReview

Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy

by Valentina Turinetto^*

, Emanuela Vitale and Claudia Giachino

Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy

Int. J. Mol. Sci. 2016, 17(7), 1164; https://doi.org/10.3390/ijms17071164 - 19 Jul 2016

Cited by 388 | Viewed by 21255

Abstract

Regenerative medicine is extensively interested in developing cell therapies using mesenchymal stem cells (MSCs), with applications to several aging-associated diseases. For successful therapies, a substantial number of cells are needed, requiring extensive ex vivo cell expansion. However, MSC proliferation is limited and it [...] Read more.

Regenerative medicine is extensively interested in developing cell therapies using mesenchymal stem cells (MSCs), with applications to several aging-associated diseases. For successful therapies, a substantial number of cells are needed, requiring extensive ex vivo cell expansion. However, MSC proliferation is limited and it is quite likely that long-term culture evokes continuous changes in MSCs. Therefore, a substantial proportion of cells may undergo senescence. In the present review, we will first present the phenotypic characterization of senescent human MSCs (hMSCs) and their possible consequent functional alterations. The accumulation of oxidative stress and dysregulation of key differentiation regulatory factors determine decreased differentiation potential of senescent hMSCs. Senescent hMSCs also show a marked impairment in their migratory and homing ability. Finally, many factors present in the secretome of senescent hMSCs are able to exacerbate the inflammatory response at a systemic level, decreasing the immune modulation activity of hMSCs and promoting either proliferation or migration of cancer cells. Considering the deleterious effects that these changes could evoke, it would appear of primary importance to monitor the occurrence of senescent phenotype in clinically expanded hMSCs and to evaluate possible ways to prevent in vitro MSC senescence. An updated critical presentation of the possible strategies for in vitro senescence monitoring and prevention constitutes the second part of this review. Understanding the mechanisms that drive toward hMSC growth arrest and evaluating how to counteract these for preserving a functional stem cell pool is of fundamental importance for the development of efficient cell-based therapeutic approaches. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)

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9 pages, 1642 KiB

Open AccessArticle

Tissue-Specific Effects of Vitamin E Supplementation

by Eugene Jansen^1,*, Dale Viezeliene², Piet Beekhof¹, Eric Gremmer¹ and Leonid Ivanov²

¹ Centre for Health Protection, National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands

² Biochemistry Department, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 4, LT-50009 Kaunas, Lithuania

Int. J. Mol. Sci. 2016, 17(7), 1166; https://doi.org/10.3390/ijms17071166 - 19 Jul 2016

Cited by 10 | Viewed by 6206

Abstract

A multivitamin and mineral supplementation study of 6 weeks was conducted with male and female mice. The control group received a standard dose of vitamins and minerals of 1× the Recommended Daily Intake (RDI), whereas a second group received 3× RDI. A third [...] Read more.

A multivitamin and mineral supplementation study of 6 weeks was conducted with male and female mice. The control group received a standard dose of vitamins and minerals of 1× the Recommended Daily Intake (RDI), whereas a second group received 3× RDI. A third group received a high dose of vitamin E (25× RDI), close to the upper limit of toxicity (UL), but still recommended and considered to be harmless and beneficial. The high dose of vitamin E caused a number of beneficial, but also adverse effects. Different biomarkers of tissue toxicity, oxidative stress related processes and inflammation were determined. These biomarkers did not change in plasma and erythrocytes to a large extent. In the liver of male mice, some beneficial effects were observed by a lower concentration of several biomarkers of inflammation. However, in the kidney of male mice, a number of biomarkers increased substantially with the higher dose of vitamin E, indicating tissue toxicity and an increased level of inflammation. Since this dose of vitamin E, which is lower than the UL, cause some adverse effects, even after a short exposure period, further studies are required to reconsider the UL for vitamin E. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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25 pages, 1893 KiB

Open AccessReview

Clinical Metabolomics: The New Metabolic Window for Inborn Errors of Metabolism Investigations in the Post-Genomic Era

by Abdellah Tebani^1,2,3

, Lenaig Abily-Donval^2,4, Carlos Afonso³, Stéphane Marret^2,4 and Soumeya Bekri^1,2,*

¹ Department of Metabolic Biochemistry, Rouen University Hospital, Rouen 76031, France

² Normandie Univ, UNIROUEN, INSERM, CHU Rouen, IRIB, Laboratoire NeoVasc ERI28, Rouen 76000, France

³ Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, Rouen 76000, France

⁴ Department of Neonatal Pediatrics and Intensive Care, Rouen University Hospital, Rouen 76031, France

Int. J. Mol. Sci. 2016, 17(7), 1167; https://doi.org/10.3390/ijms17071167 - 20 Jul 2016

Cited by 100 | Viewed by 13417

Abstract

Inborn errors of metabolism (IEM) represent a group of about 500 rare genetic diseases with an overall estimated incidence of 1/2500. The diversity of metabolic pathways involved explains the difficulties in establishing their diagnosis. However, early diagnosis is usually mandatory for successful treatment. [...] Read more.

Inborn errors of metabolism (IEM) represent a group of about 500 rare genetic diseases with an overall estimated incidence of 1/2500. The diversity of metabolic pathways involved explains the difficulties in establishing their diagnosis. However, early diagnosis is usually mandatory for successful treatment. Given the considerable clinical overlap between some inborn errors, biochemical and molecular tests are crucial in making a diagnosis. Conventional biological diagnosis procedures are based on a time-consuming series of sequential and segmented biochemical tests. The rise of “omic” technologies offers holistic views of the basic molecules that build a biological system at different levels. Metabolomics is the most recent “omic” technology based on biochemical characterization of metabolites and their changes related to genetic and environmental factors. This review addresses the principles underlying metabolomics technologies that allow them to comprehensively assess an individual biochemical profile and their reported applications for IEM investigations in the precision medicine era. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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7 pages, 959 KiB

Open AccessCommunication

Inflammaging and Frailty Status Do Not Result in an Increased Extracellular Vesicle Concentration in Circulation

by Ainhoa Alberro¹

, Matías Sáenz-Cuesta^1,2, Maider Muñoz-Culla^1,2, Maider Mateo-Abad³, Esperanza Gonzalez⁴, Estefania Carrasco-Garcia⁵, Marcos J. Araúzo-Bravo^6,7

, Ander Matheu^5,7, Itziar Vergara^3,8 and David Otaegui^1,2,*

¹ Multiple Sclerosis Unit, Biodonostia Health Research Institute—Donostia University Hospital, San Sebastian 20014, Spain

² Spanish Network of Multiple Sclerosis, Barcelona 08028, Spain

³ Primary Care Research Unit-Gipuzkoa, Osakidetza, Biodonostia Health Research Institute, San Sebastian 20014, Spain

⁴ Metabolomics Unit, CIC bioGUNE, CIBERehd, Technology Park of Bizkaia, Derio, Bizkaia 48980, Spain

⁵ Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian 20014, Spain

⁶ Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, San Sebastian 20014, Spain

⁷ IKERBASQUE, Basque Foundation for Science, Bilbao 48015, Spain

⁸ Health Services Research on Chronic Patients Network (REDISSEC), Bilbao 48013, Spain

Int. J. Mol. Sci. 2016, 17(7), 1168; https://doi.org/10.3390/ijms17071168 - 20 Jul 2016

Cited by 25 | Viewed by 5925

Abstract

In the last decades extracellular vesicles (EVs) have emerged as key players for intercellular communication. In the case of inflammation, several studies have reported that EV levels are increased in circulation during inflammatory episodes. Based on this, we investigated whether aging results in [...] Read more.

In the last decades extracellular vesicles (EVs) have emerged as key players for intercellular communication. In the case of inflammation, several studies have reported that EV levels are increased in circulation during inflammatory episodes. Based on this, we investigated whether aging results in elevated EV number, as a basal proinflammatory status termed “inflammaging” has been described in aged individuals. Moreover, we also hypothesized that frailty and dependence conditions of the elderly could affect EV concentration in plasma. Results showed that inflammaging, frailty or dependence status do not result in EV increase, at least in the total number of EVs in circulation. These results open a new perspective for investigating the role of EVs in human aging and in the inflammaging process. Full article

(This article belongs to the Special Issue Focus on Extracellular Vesicles)

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13 pages, 400 KiB

Open AccessReview

Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?

by Gloria Mittica^1,2,†, Sofia Genta^1,2,†, Massimo Aglietta^1,2 and Giorgio Valabrega^1,2,*

¹ Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy

² Department of Oncology, University of Torino, Turin 10060, Italy

^† These authors contributed equally to the work.

Int. J. Mol. Sci. 2016, 17(7), 1169; https://doi.org/10.3390/ijms17071169 - 20 Jul 2016

Cited by 52 | Viewed by 8834

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents [...] Read more.

Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the “turn off” signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC. Full article

(This article belongs to the Special Issue Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy)

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13 pages, 3029 KiB

Open AccessArticle

Structural Analysis of Hand Drawn Bumblebee Bombus terrestris Silk

by Andrea L. Woodhead¹, Tara D. Sutherland²

and Jeffrey S. Church^1,*

¹ CSIRO Manufacturing, Pigdons Road, Waurn Ponds, VIC 3216, Australia

² CSIRO Food and Nutrition, Clunies Ross Street, Black Mountain, ACT 2601, Australia

Int. J. Mol. Sci. 2016, 17(7), 1170; https://doi.org/10.3390/ijms17071170 - 20 Jul 2016

Cited by 5 | Viewed by 6091

Abstract

Bombus terrestris, commonly known as the buff-tailed bumblebee, is native to Europe, parts of Africa and Asia. It is commercially bred for use as a pollinator of greenhouse crops. Larvae pupate within a silken cocoon that they construct from proteins produced in [...] Read more.

Bombus terrestris, commonly known as the buff-tailed bumblebee, is native to Europe, parts of Africa and Asia. It is commercially bred for use as a pollinator of greenhouse crops. Larvae pupate within a silken cocoon that they construct from proteins produced in modified salivary glands. The amino acid composition and protein structure of hand drawn B. terrestris, silk fibres was investigated through the use of micro-Raman spectroscopy. Spectra were obtained from single fibres drawn from the larvae salivary gland at a rate of 0.14 cm/s. Raman spectroscopy enabled the identification of poly(alanine), poly(alanine-glycine), phenylalanine, tryptophan, and methionine, which is consistent with the results of amino acid analysis. The dominant protein conformation was found to be coiled coil (73%) while the β-sheet content of 10% is, as expected, lower than those reported for hornets and ants. Polarized Raman spectra revealed that the coiled coils were highly aligned along the fibre axis while the β-sheet and random coil components had their peptide carbonyl groups roughly perpendicular to the fibre axis. The protein orientation distribution is compared to those of other natural and recombinant silks. A structural model for the B. terrestris silk fibre is proposed based on these results. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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20 pages, 2205 KiB

Open AccessReview

Developments in Methods for Measuring the Intestinal Absorption of Nanoparticle-Bound Drugs

by Wei Liu^1,2,†, Hao Pan^3,†, Caiyun Zhang²

, Liling Zhao², Ruixia Zhao², Yongtao Zhu² and Weisan Pan^1,*

¹ Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

² Department of Pharmaceutics, School of Pharmacy, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China

³ School of Pharmacy, Queen’s University Belfast, Belfast BT7 1NN, UK

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1171; https://doi.org/10.3390/ijms17071171 - 21 Jul 2016

Cited by 57 | Viewed by 13333

Abstract

With the rapid development of nanotechnology, novel drug delivery systems comprising orally administered nanoparticles (NPs) have been paid increasing attention in recent years. The bioavailability of orally administered drugs has significant influence on drug efficacy and therapeutic dosage, and it is therefore imperative [...] Read more.

With the rapid development of nanotechnology, novel drug delivery systems comprising orally administered nanoparticles (NPs) have been paid increasing attention in recent years. The bioavailability of orally administered drugs has significant influence on drug efficacy and therapeutic dosage, and it is therefore imperative that the intestinal absorption of oral NPs be investigated. This review examines the various literature on the oral absorption of polymeric NPs, and provides an overview of the intestinal absorption models that have been developed for the study of oral nanoparticles. Three major categories of models including a total of eight measurement methods are described in detail (in vitro: dialysis bag, rat gut sac, Ussing chamber, cell culture model; in situ: intestinal perfusion, intestinal loops, intestinal vascular cannulation; in vivo: the blood/urine drug concentration method), and the advantages and disadvantages of each method are contrasted and elucidated. In general, in vitro and in situ methods are relatively convenient but lack accuracy, while the in vivo method is troublesome but can provide a true reflection of drug absorption in vivo. This review summarizes the development of intestinal absorption experiments in recent years and provides a reference for the systematic study of the intestinal absorption of nanoparticle-bound drugs. Full article

(This article belongs to the Section Materials Science)

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10 pages, 3299 KiB

Open AccessReview

Aquaporins in the Colon as a New Therapeutic Target in Diarrhea and Constipation

by Nobutomo Ikarashi^*,†, Risako Kon^† and Kiyoshi Sugiyama

¹ Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1172; https://doi.org/10.3390/ijms17071172 - 20 Jul 2016

Cited by 122 | Viewed by 10985

Abstract

Aquaporins (AQPs) play important roles in the water transport system in the human body. There are currently 13 types of AQP, AQP0 through AQP12, which are expressed in various organs. Many members of the AQP family are expressed in the intestinal tract. AQP3 [...] Read more.

Aquaporins (AQPs) play important roles in the water transport system in the human body. There are currently 13 types of AQP, AQP0 through AQP12, which are expressed in various organs. Many members of the AQP family are expressed in the intestinal tract. AQP3 is predominantly expressed in the colon, ultimately controlling the water transport. Recently, it was clarified that several laxatives exhibit a laxative effect by changing the AQP3 expression level in the colon. In addition, it was revealed that morphine causes severe constipation by increasing the AQP3 expression level in the colon. These findings have shown that AQP3 is one of the most important functional molecules in water transport in the colon. This review will focus on the physiological and pathological roles of AQP3 in the colon, and discuss clinical applications of colon AQP3. Full article

(This article belongs to the Special Issue Aquaporin)

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13 pages, 1839 KiB

Open AccessArticle

Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease

by Jian Guo¹

, Yang Li¹, Yi-Hong Ren², Zhijun Sun², Jie Dong¹, Han Yan¹, Yujun Xu³, Dao Wen Wang³, Gu-Yan Zheng¹, Jie Du⁴ and Xiao-Li Tian^1,5,*

¹ Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China

² Department of Cardiovascular, PLA General Hospital, Beijing 100853, China

³ The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China

⁴ Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China

⁵ Department of Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, Nanchang 330031, China

Int. J. Mol. Sci. 2016, 17(7), 1173; https://doi.org/10.3390/ijms17071173 - 22 Jul 2016

Cited by 13 | Viewed by 5792

Abstract

Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic [...] Read more.

Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6_Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging 2016)

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16 pages, 3811 KiB

Open AccessArticle

La Autoantigen Induces Ribosome Binding Protein 1 (RRBP1) Expression through Internal Ribosome Entry Site (IRES)-Mediated Translation during Cellular Stress Condition

by Wenqing Gao^†, Qi Li^†, Ruiyu Zhu^* and Jian Jin^*

¹ Laboratory of Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1174; https://doi.org/10.3390/ijms17071174 - 20 Jul 2016

Cited by 18 | Viewed by 7017

Abstract

The function of ribosome binding protein 1 (RRBP1) is regulating the transportation and secretion of some intracellular proteins in mammalian cells. Transcription of RRBP1 is induced by various cytokines. However, few studies focused on the process of RRPB1 mRNA translation. The RRBP1 mRNA [...] Read more.

The function of ribosome binding protein 1 (RRBP1) is regulating the transportation and secretion of some intracellular proteins in mammalian cells. Transcription of RRBP1 is induced by various cytokines. However, few studies focused on the process of RRPB1 mRNA translation. The RRBP1 mRNA has a long 5′ untranslated region that potentially formed a stable secondary structure. In this study, we show that the 5′ UTR of RRBP1 mRNA contains an internal ribosome entry site (IRES). Moreover, the RRBP1 expression is induced by chemotherapeutic drug paclitaxel or adriamycin in human hepatocellular carcinoma cells and accompanied with the increased expression of La autoantigen (La), which binds to RRBP1 IRES element and facilitates translation initiation. Interestingly, we found IRES-mediated RRBP1 translation is also activated during serum-starvation condition which can induce cytoplasmic localization of La. After mapping the entire RRBP1 5′ UTR, we determine the core IRES activity is located between nt-237 and -58. Furthermore, two apical GARR loops within the functional RRBP1 IRES elements may be important for La binding. These results strongly suggest an important role for IRES-dependent translation of RRBP1 mRNA in hepatocellular carcinoma cells during cellular stress conditions. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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12 pages, 5042 KiB

Open AccessArticle

Enhancement of Anti-Hypoxic Activity and Differentiation of Cardiac Stem Cells by Supernatant Fluids from Cultured Macrophages that Phagocytized Dead Mesenchymal Stem Cells

by Liang Liu^1,†

, Xian Jin^2,†, Zhong’e Zhou² and Chengxing Shen^1,*

¹ Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China

² Department of Cardiology, Central Hospital of Minhang District, 170 Xinsong Road, Shanghai 201199, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1175; https://doi.org/10.3390/ijms17071175 - 20 Jul 2016

Cited by 1 | Viewed by 5433

Abstract

Background: Most mesenchymal stem cells (MSCs) die shortly after transplantation into a myocardial infarcted area. Dead MSCs (dMSCs) are phagocytized by macrophages (pMΦ) in vivo and in vitro; however, the effects of pMΦ on cardiac stem cells (CSCs) remain unknown. Methods: MSCs, CSCs, [...] Read more.

Background: Most mesenchymal stem cells (MSCs) die shortly after transplantation into a myocardial infarcted area. Dead MSCs (dMSCs) are phagocytized by macrophages (pMΦ) in vivo and in vitro; however, the effects of pMΦ on cardiac stem cells (CSCs) remain unknown. Methods: MSCs, CSCs, and macrophages were obtained from bone marrow, hearts, and peritoneal cavity of mice, respectively. dMSCs were harvested after hypoxia for 24 h, and incubated with macrophages (2:1) for another 2 days with or without lipopolysaccharide (LPS, 50 ng/mL) and sorted by flow cytometry to obtain pMΦ. Viability and apoptosis of CSCs were respectively evaluated with the cell counting kit-8 (CCk-8) assay and Annexin V-PE/7-AAD staining at 0, 6, 12, and 24 h of culture with supernatant fluids from macrophages (MΦ), LPS-stimulated macrophages (LPS-pMΦ), pMΦ, and MSCs. GATA-4 and c-TnI expression was measured by flow cytometry on the seventh day. Expression of inflammation and growth factors was assessed by real-time polymerase chain reaction (RT-PCR) in MΦ, LPS-pMΦ, and pMΦ cells. Results: pMΦ expressed higher levels of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β)and lower levels of tumor necrosis factor-α(TNF-α)and IL-6 than LPS-pMΦ, higher levels of growth factors and of GATA-4 and c-TnI at the 7th day, which were similar to those in MSCs. CSCs cultured with supernatant fluids of pMΦ exhibited higher proliferative, anti-hypoxic, and differentiation activities. Conclusion: The supernatant fluids of macrophages that had phagocytized dead MSCs encouraged changes in phenotype and growth factor expression, enhanced proliferation, differentiation, and anti-hypoxic activity of CSCs, which is relevant to understanding the persistent therapeutic effect of MSCs after their massive demise upon transplantation in myocardial infarction. Furthermore, some miRNAs or proteins which were extracted from the supernatant fluids may give us a new insight into the treatment of myocardial infarction in the future. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 6795 KiB

Open AccessArticle

Protective Effect of Salicornia europaea Extracts on High Salt Intake-Induced Vascular Dysfunction and Hypertension

by Nisha Panth^1,†

, Sin-Hee Park^1,2,†, Hyun Jung Kim¹, Deuk-Hoi Kim³ and Min-Ho Oak^1,*

¹ College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam 58554, Korea

² UMR CNRS 7213, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch 67401, France

³ Research Center, Phyto Corporation, Seoul 08826, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1176; https://doi.org/10.3390/ijms17071176 - 21 Jul 2016

Cited by 35 | Viewed by 8825

Abstract

High salt intake causes and aggravates arterial hypertension and vascular dysfunction. We investigated the effect of Salicornia europaea extracts (SE) on vascular function and blood pressure. SE constituents were analyzed using high performance liquid chromatography, and SE’s effect on vascular function was evaluated [...] Read more.

High salt intake causes and aggravates arterial hypertension and vascular dysfunction. We investigated the effect of Salicornia europaea extracts (SE) on vascular function and blood pressure. SE constituents were analyzed using high performance liquid chromatography, and SE’s effect on vascular function was evaluated in isolated porcine coronary arteries. SE’s vascular protective effect was also evaluated in vivo using normotensive and spontaneous hypertensive rats (SHRs). SE mainly contained sodium chloride (55.6%), 5-(hydroxymethyl)furfural, p-coumaric acid, and trans-ferulic acid. High sodium (160 mmol/L) induced vascular dysfunction; however, SE containing the same quantity of sodium did not cause vascular dysfunction. Among the compounds in SE, trans-ferulic acid accounts for the vascular protective effect. Normotensive rats fed a high-salt diet showed significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which decreased significantly in the SE-treated groups. In SHRs, high edible salt intake significantly increased SBP, DBP, and MAP, but SE intake was associated with a significantly lower MAP. Thus, SE did not induce vascular dysfunction, and trans-ferulic acid might be at least partly responsible for the vasoprotective effect of SE. Taken together, SE could be used as an alternative to purified salt to prevent and ameliorate hypertension. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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33 pages, 6466 KiB

Open AccessReview

Molecular Approaches to Genetically Improve the Accumulation of Health-Promoting Secondary Metabolites in Staple Crops—A Case Study: The Lipoxygenase-B1 Genes and Regulation of the Carotenoid Content in Pasta Products

by Grazia M. Borrelli

and Daniela Trono^*

Consiglio per la Ricerca in Agricoltura e l’Analisi dell’Economia Agraria, Centro di Ricerca per la Cerealicoltura, S.S. 673 Km 25,200, 71122 Foggia, Italy

Int. J. Mol. Sci. 2016, 17(7), 1177; https://doi.org/10.3390/ijms17071177 - 21 Jul 2016

Cited by 27 | Viewed by 8729

Abstract

Secondary metabolites, also known as phytochemicals, represent a large subset of plant molecules that include compounds with health-promoting effects. Indeed, a number of epidemiological studies have shown that, when taken regularly and in adequate amounts, these molecules can have long-term beneficial effects on [...] Read more.

Secondary metabolites, also known as phytochemicals, represent a large subset of plant molecules that include compounds with health-promoting effects. Indeed, a number of epidemiological studies have shown that, when taken regularly and in adequate amounts, these molecules can have long-term beneficial effects on human health, through reduction of the incidence of degenerative diseases, such as cardiovascular diseases, obesity, diabetes, and cancer. As the dietary intake of these phytochemicals is often inadequate, various strategies are in use to improve their content in staple crops, and the end-products thereof. One of the most effective strategies is crop improvement through genetic approaches, as this is the only way to generate new cultivars in which the high accumulation of a given phytochemical is stably fixed. Efforts to genetically improve quality traits are rapidly evolving, from classical breeding to molecular-assisted approaches; these require sound understanding of the molecular bases underlying the traits, to identify the genes/alleles that control them. This can be achieved through global analysis of the metabolic pathway responsible for phytochemical accumulation, to identify the link between phytochemical content and the activities of key enzymes that regulate the metabolic pathway, and between the key enzymes and their encoding genes/alleles. Once these have been identified, they can be used as markers for selection of new improved genotypes through biotechnological approaches. This review provides an overview of the major health-promoting properties shown to be associated with the dietary intake of phytochemicals, and describes how molecular approaches provide means for improving the health quality of edible crops. Finally, a case study is illustrated, of the identification in durum wheat of the Lipoxygenase-B1 genes that control the final carotenoid content in semolina-based foods, such as pasta products. Full article

(This article belongs to the Section Molecular Plant Sciences)

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29 pages, 991 KiB

Open AccessReview

Matrix Metalloproteinases in Non-Neoplastic Disorders

by Akinori Tokito and Michihisa Jougasaki^*

Institute for Clinical Research, National Hospital Organization Kagoshima Medical Center, 8-1 Shiroyama-cho, Kagoshima 892-0853, Japan

Int. J. Mol. Sci. 2016, 17(7), 1178; https://doi.org/10.3390/ijms17071178 - 21 Jul 2016

Cited by 71 | Viewed by 13292

Abstract

The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not [...] Read more.

The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action. Full article

(This article belongs to the Special Issue Metalloproteins)

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19 pages, 573 KiB

Open AccessArticle

Aluminum Toxicity-Induced Alterations of Leaf Proteome in Two Citrus Species Differing in Aluminum Tolerance

by Huan Li^1,2, Lin-Tong Yang^1,2, Yi-Ping Qi³, Peng Guo^1,2, Yi-Bin Lu^1,2 and Li-Song Chen^1,2,4,*

¹ Institute of Plant Nutritional Physiology and Molecular Biology, College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, China

² Fujian Provincial Key Laboratory of Soil Environmental Health and Regulation, College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, China

³ Institute of Materia Medica, Fujian Academy of Medical Sciences, Fuzhou 350001, China

⁴ The Higher Educational Key Laboratory of Fujian Province for Soil Ecosystem Health and Regulation, Fujian Agriculture and Forestry University, Fuzhou 350002, China

Int. J. Mol. Sci. 2016, 17(7), 1180; https://doi.org/10.3390/ijms17071180 - 21 Jul 2016

Cited by 44 | Viewed by 7619

Abstract

Seedlings of aluminum-tolerant ‘Xuegan’ (Citrus sinensis) and Al-intolerant ‘sour pummelo’ (Citrus grandis) were fertigated for 18 weeks with nutrient solution containing 0 and 1.2 mM AlCl₃·6H₂O. Al toxicity-induced inhibition of photosynthesis and the decrease of [...] Read more.

Seedlings of aluminum-tolerant ‘Xuegan’ (Citrus sinensis) and Al-intolerant ‘sour pummelo’ (Citrus grandis) were fertigated for 18 weeks with nutrient solution containing 0 and 1.2 mM AlCl₃·6H₂O. Al toxicity-induced inhibition of photosynthesis and the decrease of total soluble protein only occurred in C. grandis leaves, demonstrating that C. sinensis had higher Al tolerance than C. grandis. Using isobaric tags for relative and absolute quantification (iTRAQ), we obtained more Al toxicity-responsive proteins from C. sinensis than from C. grandis leaves, which might be responsible for the higher Al tolerance of C. sinensis. The following aspects might contribute to the Al tolerance of C. sinensis: (a) better maintenance of photosynthesis and energy balance via inducing photosynthesis and energy-related proteins; (b) less increased requirement for the detoxification of reactive oxygen species and other toxic compounds, such as aldehydes, and great improvement of the total ability of detoxification; and (c) upregulation of low-phosphorus-responsive proteins. Al toxicity-responsive proteins related to RNA regulation, protein metabolism, cellular transport and signal transduction might also play key roles in the higher Al tolerance of C. sinensis. We present the global picture of Al toxicity-induced alterations of protein profiles in citrus leaves, and identify some new Al toxicity-responsive proteins related to various biological processes. Our results provide some novel clues about plant Al tolerance. Full article

(This article belongs to the Special Issue Plant Proteomic Research)

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13 pages, 8410 KiB

Open AccessArticle

High Morphologic Plasticity of Microglia/Macrophages Following Experimental Intracerebral Hemorrhage in Rats

by Shu-Sheng Yang^1,2,†, Li Lin^1,3,†, Yue Liu^4,5, Jie Wang⁵, Jiang Chu¹, Teng Zhang¹, Lin-Na Ning¹, Yan Shi¹, Ying-Yan Fang¹, Peng Zeng¹, Jian-Zhi Wang¹, Ming-Yi Qiu^2,* and Qing Tian^1,*

¹ Department of Pathology and Pathophysiology, School of Basic Medicine; Institute for Brain Research, Huazhong University of Science and Technology, Hangkong Road 13#, Wuhan 430030, China

² Department of Shang-Han, Clinical College of Traditional Chinese Medicine, Hubei University of Traditional Chinese Medicine, Tan-Hua-Lin Road 1, Wuhan 430061, China

³ Laboratory of Medical Molecular and Cellular Biology, School of Basic Medicine, Hubei University of Traditional Chinese Medicine, Wuhan 430065, China

⁴ Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China

⁵ Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1181; https://doi.org/10.3390/ijms17071181 - 21 Jul 2016

Cited by 18 | Viewed by 7183

Abstract

As current efforts have limited effects on the clinical outcome of intracerebral hemorrhage (ICH), the mechanisms including microglia/macrophages that involved inflammation need further investigation. Here, 0.4 units of collagenase VII were injected into the left caudate putamen (CPu) to duplicate ICH rat models. [...] Read more.

As current efforts have limited effects on the clinical outcome of intracerebral hemorrhage (ICH), the mechanisms including microglia/macrophages that involved inflammation need further investigation. Here, 0.4 units of collagenase VII were injected into the left caudate putamen (CPu) to duplicate ICH rat models. In the brains of ICH rats, microglia/macrophages, the nearest cells to the hemorrhagic center, were observed as ameboid and Prussian-blue positive. Furthermore, the ameboid microglia/macrophages were differentiation (CD) 68 and interleukin-1β (IL-1β) positive, and neither CD206 nor chitinase3-like 3 (Ym1) positive, suggesting their strong abilities of phagocytosis and secretion of IL-1β. According to the distance to the hemorrhagic center, we selected four areas—I, II, III, and IV—to analyze the morphology of microglia/macrophages. The processes decreased successively from region I to region IV. Microglia/macrophages in region IV had no processes. The processes in region I were radially distributed, however, they showed obvious directivity towards the hemorrhagic center in regions II and III. Region III had the largest density of compactly arrayed microglia/macrophages. All these in vivo results present the high morphologic plasticity of microglia/macrophages and their functions in the pathogenesis of ICHs. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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11 pages, 3220 KiB

Open AccessArticle

The Effects of Aquaporin-1 in Pulmonary Edema Induced by Fat Embolism Syndrome

by Yiwei Zhang^†, Kun Tian^†, Yan Wang, Rong Zhang, Jiawei Shang, Wei Jiang and Aizhong Wang^*

¹ Department of Anesthesiology, the Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1183; https://doi.org/10.3390/ijms17071183 - 21 Jul 2016

Cited by 19 | Viewed by 6613

Abstract

This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs). [...] Read more.

This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs). In vivo, edema was more serious in FES mice compared with the control group. The expression of AQP1 and the wet-to-dry lung weight ratio (W/D) in the FES group were significantly increased compared with the control group. At the same time, inhibition of AQP1 decreased the pathological damage resulting from pulmonary edema. Then we performed a study in vitro to investigate whether AQP1 was induced by FFA release in FES. The mRNA and protein level of AQP1 were increased by FFAs in a dose- and time-dependent manner in PMVECs. In addition, the up-regulation of AQP1 was blocked by the inhibitor of p38 kinase, implicating the p38 MAPK pathway as involved in the FFA-induced AQP1 up-regulation in PMVECs. Our results demonstrate that AQP1 may play important roles in pulmonary edema induced by FES and can be regarded as a new therapy target for treatment of pulmonary edema induced by FES. Full article

(This article belongs to the Special Issue Aquaporin)

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10 pages, 408 KiB

Open AccessArticle

Psychopathological Variables and Sleep Quality in Psoriatic Patients

by Maria Luca¹

, Antonina Luca²

, Maria Letizia Musumeci³, Federica Fiorentini³, Giuseppe Micali³ and Carmela Calandra^1,*

¹ Psychiatry Unit, Department of Medical and Surgical Sciences and Advanced Technologies, University Hospital Policlinico-Vittorio Emanuele, Santa Sofia Street 78, Catania, 95100 Sicily, Italy

² Department of Medical and Surgical Sciences and Advanced Technologies, University Hospital Policlinico-Vittorio Emanuele, Santa Sofia Street 78, Catania, 95100 Sicily, Italy

³ Dermatology Clinic, University of Catania, University Hospital Policlinico-Vittorio Emanuele, Santa Sofia Street 78, Catania, 95100 Sicily, Italy

Int. J. Mol. Sci. 2016, 17(7), 1184; https://doi.org/10.3390/ijms17071184 - 21 Jul 2016

Cited by 18 | Viewed by 6019

Abstract

Psoriasis is an inflammatory disease frequently associated with psychiatric disturbances and sleep disorders. The aim of the study was to assess the prevalence of depression, interaction anxiety, audience anxiety, and sleep quality in psoriatic patients. One hundred and two psoriatic patients were enrolled [...] Read more.

Psoriasis is an inflammatory disease frequently associated with psychiatric disturbances and sleep disorders. The aim of the study was to assess the prevalence of depression, interaction anxiety, audience anxiety, and sleep quality in psoriatic patients. One hundred and two psoriatic patients were enrolled and underwent the following questionnaires: Zung Self-Rating Depression Scale (SDS), Interaction Anxiousness Scale (IAS), Audience Anxiousness Scale (AAS), Pittsburgh Sleep Quality Index (PSQI). The severity of skin lesions was assessed by Psoriasis Area Severity Index (PASI). The presence of a link between clinical variables and with demographic data has been investigated. Psoriasis was linked to depression, interaction and audience anxiety, as well as to poor sleep quality; 37.5% of patients were depressed, 46.1% scored above 37 at the IAS, 47.1% scored above 33 at the AAS. Thirty-nine subjects (38.2%) presented a PSQI ≥ 5. An association between interaction anxiety and lower limbs psoriasis-related erythema as well as between PSQI and head psoriasis-related erythema was found, particularly among male patients. Hence, psoriatic patients should be assessed from a holistic point of view, in order to identify associated disorders that could benefit from targeted treatments. Full article

(This article belongs to the Special Issue Sleep, Circadian Rhythm and Skin)

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10 pages, 701 KiB

Open AccessArticle

Assessment of Dextran Antigenicity of Intravenous Iron Preparations with Enzyme-Linked Immunosorbent Assay (ELISA)

by Susann Neiser¹, Taija S. Koskenkorva², Katrin Schwarz¹, Maria Wilhelm¹ and Susanna Burckhardt^2,*

¹ Chemical and Preclinical Research and Development, Vifor International Ltd., 9014 St. Gallen, Switzerland

² Global Medical Affairs, Vifor Pharma Ltd., 8152 Glattbrugg, Switzerland

Int. J. Mol. Sci. 2016, 17(7), 1185; https://doi.org/10.3390/ijms17071185 - 21 Jul 2016

Cited by 21 | Viewed by 8909

Abstract

Intravenous iron preparations are typically classified as non-dextran-based or dextran/dextran-based complexes. The carbohydrate shell for each of these preparations is unique and is key in determining the various physicochemical properties, the metabolic pathway, and the immunogenicity of the iron-carbohydrate complex. As intravenous dextran [...] Read more.

Intravenous iron preparations are typically classified as non-dextran-based or dextran/dextran-based complexes. The carbohydrate shell for each of these preparations is unique and is key in determining the various physicochemical properties, the metabolic pathway, and the immunogenicity of the iron-carbohydrate complex. As intravenous dextran can cause severe, antibody-mediated dextran-induced anaphylactic reactions (DIAR), the purpose of this study was to explore the potential of various intravenous iron preparations, non-dextran-based or dextran/dextran-based, to induce these reactions. An IgG-isotype mouse monoclonal anti-dextran antibody (5E7H3) and an enzyme-linked immunosorbent assay (ELISA) were developed to investigate the dextran antigenicity of low molecular weight iron dextran, ferumoxytol, iron isomaltoside 1000, ferric gluconate, iron sucrose and ferric carboxymaltose, as well as isomaltoside 1000, the isolated carbohydrate component of iron isomaltoside 1000. Low molecular weight iron dextran, as well as dextran-based ferumoxytol and iron isomaltoside 1000, reacted with 5E7H3, whereas ferric carboxymaltose, iron sucrose, sodium ferric gluconate, and isolated isomaltoside 1000 did not. Consistent results were obtained with reverse single radial immunodiffusion assay. The results strongly support the hypothesis that, while the carbohydrate alone (isomaltoside 1000) does not form immune complexes with anti-dextran antibodies, iron isomaltoside 1000 complex reacts with anti-dextran antibodies by forming multivalent immune complexes. Moreover, non-dextran based preparations, such as iron sucrose and ferric carboxymaltose, do not react with anti-dextran antibodies. This assay allows to assess the theoretical possibility of a substance to induce antibody-mediated DIARs. Nevertheless, as this is only one possible mechanism that may cause a hypersensitivity reaction, a broader set of assays will be required to get an understanding of the mechanisms that may lead to intravenous iron-induced hypersensitivity reactions. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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15 pages, 1627 KiB

Open AccessReview

Non-Invasive Methods to Monitor Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer: Where Do We Stand?

by Paola Ulivi

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy

Int. J. Mol. Sci. 2016, 17(7), 1186; https://doi.org/10.3390/ijms17071186 - 22 Jul 2016

Cited by 20 | Viewed by 6616

Abstract

The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific [...] Read more.

The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific drugs are have been developed. However, other molecular alterations have also been reported as induced resistance mechanisms to EGFR-TKIs. Similarly, there is growing evidence of acquired resistance mechanisms to anaplastic lymphoma kinase (ALK)-TKI treatment. A better understanding of these acquired resistance mechanisms is essential in clinical practice as patients could be treated with specific drugs that are active against the induced alterations. The use of free circulating tumor nucleic acids or circulating tumor cells (CTCs) enables resistance mechanisms to be characterized in a non-invasive manner and reduces the need for tumor re-biopsy. This review discusses the main resistance mechanisms to TKIs and provides a comprehensive overview of innovative strategies to evaluate known resistance mechanisms in free circulating nucleic acids or CTCs and potential future orientations for these non-invasive approaches. Full article

(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)

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10 pages, 991 KiB

Open AccessReview

The Clinical Value of High-Intensity Signals on the Coronary Atherosclerotic Plaques: Noncontrast T1-Weighted Magnetic Resonance Imaging

by Shoichi Ehara^*, Kenji Matsumoto and Kenei Shimada

Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan

Int. J. Mol. Sci. 2016, 17(7), 1187; https://doi.org/10.3390/ijms17071187 - 21 Jul 2016

Cited by 6 | Viewed by 5460

Abstract

Over the past several decades, significant progress has been made in the pathohistological assessment of vulnerable plaques and in invasive intravascular imaging techniques. However, the assessment of plaque morphology by invasive modalities is of limited value for the detection of subclinical coronary atherosclerosis [...] Read more.

Over the past several decades, significant progress has been made in the pathohistological assessment of vulnerable plaques and in invasive intravascular imaging techniques. However, the assessment of plaque morphology by invasive modalities is of limited value for the detection of subclinical coronary atherosclerosis and the subsequent prediction or prevention of acute cardiovascular events. Recently, magnetic resonance (MR) imaging technology has reached a sufficient level of spatial resolution, which allowed the plaque visualization of large and static arteries such as the carotids and aorta. However, coronary wall imaging by MR is still challenging due to the small size of coronary arteries, cardiac and respiratory motion, and the low contrast-to-noise ratio between the coronary artery wall and the surrounding structures. Following the introduction of carotid plaque imaging with noncontrast T1-weighted imaging (T1WI), some investigators have reported that coronary artery high-intensity signals on T1WI are associated with vulnerable plaque morphology and an increased risk of future cardiac events. Although there are several limitations and issues that need to be resolved, this novel MR technique for coronary plaque imaging could influence treatment strategies for atherothrombotic disease and may be useful for understanding the pathophysiological mechanisms of atherothrombotic plaque formation. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging 2016)

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12 pages, 3762 KiB

Open AccessArticle

High Expression of XRCC6 Promotes Human Osteosarcoma Cell Proliferation through the β-Catenin/Wnt Signaling Pathway and Is Associated with Poor Prognosis

by Bin Zhu^1,†, Dongdong Cheng^1,†, Shijie Li¹, Shumin Zhou²

and Qingcheng Yang^1,*

¹ Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600, Yishan Road, Shanghai 200233, China

² Institute of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600, Yishan Road, Shanghai 200233, China

^† These authors contribute equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1188; https://doi.org/10.3390/ijms17071188 - 22 Jul 2016

Cited by 18 | Viewed by 7913

Abstract

Increasing evidences show that XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6) was upregulated and involved in tumor growth in several tumor types. However, the correlation of XRCC6 and human osteosarcoma (OS) is still unknown. This study was conducted with [...] Read more.

Increasing evidences show that XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6) was upregulated and involved in tumor growth in several tumor types. However, the correlation of XRCC6 and human osteosarcoma (OS) is still unknown. This study was conducted with the aim to reveal the expression and biological function of XRCC6 in OS and elucidate the potential mechanism. The mRNA expression level of XRCC6 was measured in osteosarcoma cells and OS samples by quantitative transcription-PCR (qRT-PCR). The expression of XRCC6 protein was measured using Western blot and immunohistochemical staining in osteosarcoma cell lines and patient samples. Cell Counting Kit 8 (CCK8), colony-forming and cell cycle assays were used to test cell survival capacity. We found that XRCC6 was overexpressed in OS cells and OS samples compared with the adjacent non-tumorous samples. High expression of XRCC6 was correlated with clinical stage and tumor size in OS. Reduced expression of XRCC6 inhibits OS cell proliferation through G2/M phase arrest. Most importantly, further experiments demonstrated that XRCC6 might regulate OS growth through the β-catenin/Wnt signaling pathway. In conclusion, these findings indicate that XRCC6 exerts tumor-promoting effects for OS through β-catenin/Wnt signaling pathway. XRCC6 may serve as a novel therapeutic target for OS patients. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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13 pages, 2051 KiB

Open AccessArticle

Orofacial Manifestations and Temporomandibular Disorders of Systemic Scleroderma: An Observational Study

by Vito Crincoli^1,*

, Laura Fatone¹, Margherita Fanelli²

, Rossana Patricia Rotolo¹, Angela Chialà³, Gianfranco Favia¹ and Giovanni Lapadula³

¹ Complex Operating Unit of Odontostomatology, Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari., Piazza Giulio Cesare 11, 70124 Bari, Italy

² Complex Operating Unit of Nuclear Medicine—Medical Statistics, Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari., Piazza Giulio Cesare 11, 70124 Bari, Italy

³ Complex Operating Unit of Rheumatology, Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari., Piazza Giulio Cesare 11, 70124 Bari, Italy

Int. J. Mol. Sci. 2016, 17(7), 1189; https://doi.org/10.3390/ijms17071189 - 22 Jul 2016

Cited by 74 | Viewed by 17162

Abstract

Scleroderma is a disorder involving oral and facial tissues, with skin hardening, thin lips, deep wrinkles, xerostomia, tongue rigidity, and microstomia. The aim of this study was to investigate the prevalence of oral manifestations and temporomandibular disorders (TMD) in Systemic Sclerosis (SSc) patients [...] Read more.

Scleroderma is a disorder involving oral and facial tissues, with skin hardening, thin lips, deep wrinkles, xerostomia, tongue rigidity, and microstomia. The aim of this study was to investigate the prevalence of oral manifestations and temporomandibular disorders (TMD) in Systemic Sclerosis (SSc) patients compared with healthy people. Eighty patients (6 men, 74 women) fulfilling ACR/EULAR SSc Criteria were enrolled. A randomly selected group of 80 patients, matched by sex and age served as control group. The examination for TMD signs and symptoms was based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) through a questionnaire and clinical examination. SSc patients complained more frequently (78.8%) of oral symptoms (Xerostomia, dysgeusia, dysphagia and stomatodynia) than controls (28.7%) (χ² = 40.23 p = 0.001). TMD symptoms (muscle pain on chewing, difficulty in mouth opening, headaches) were complained by 92.5% of SSc patients and by 76.2% of controls (χ² = 8.012 p = 0.005). At the clinical examination, 85% of SSc patients showed restricted opening versus 20.0% of controls (χ² = 67.77 p = 0.001), 81.2% of SSc showed reduced right lateral excursion versus 50% of controls (χ² = 17.316 p = 0.001); 73.8% of SSc showed limited left lateral excursion versus 53.8% of controls (χ² = 6.924 p = 0.009); and 73.8% of SSc had narrow protrusion versus 56.2% of controls (χ² = 5.385 p = 0.02). Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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10 pages, 1738 KiB

Open AccessArticle

Neuroprotective Effect of Salvianolic Acids against Cerebral Ischemia/Reperfusion Injury

by Shuai Hou¹

, Ming-Ming Zhao¹, Ping-Ping Shen¹, Xiu-Ping Liu², Yuan Sun³ and Jia-Chun Feng^1,*

¹ Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, China

² Department of Neurology, the Center Hospital of Jilin City, Jilin 132000, China

³ Department of Neurology, Xuzhou Center Hospital, Xuzhou 221000, China

Int. J. Mol. Sci. 2016, 17(7), 1190; https://doi.org/10.3390/ijms17071190 - 22 Jul 2016

Cited by 64 | Viewed by 7004

Abstract

This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and [...] Read more.

This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and also evaluated the morphology of astrocyte mitochondria with transmission electron microscopy. In vivo, we determined the cerebral infarction volume and measured superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Additionally, mtCx43, p-mtCx43, AKT, and p-AKT levels were determined. In vitro, we found that I/R injury induced apoptosis, decreased cell mitochondrial membrane potential (MMP), and damaged mitochondrial morphology in astrocytes. In vivo, we found that I/R injury resulted in a large cerebral infarction, decreased SOD activity, and increased MDA expression. Additionally, I/R injury reduced both the p-mtCx43/mtCx43 and p-AKT/AKT ratios. We reported that both in vivo and in vitro, SA ameliorated the detrimental outcomes of the I/R. Interestingly, co-administering an inhibitor of the PI3K/AKT pathway blunted the effects of SA. SA represents a potential treatment option for cerebral infarction by up-regulating mtCx43 through the PI3K/AKT pathway. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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14 pages, 2057 KiB

Open AccessArticle

Revisiting the Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission

by Yu-Yin Huang^1,2, Yu-Chao Liu², Cheng-Ta Lee³, Yen-Chu Lin³, Mong-Lien Wang⁴

, Yi-Ping Yang^1,5,6, Kaung-Yi Chang⁷ and Shih-Hwa Chiou^1,4,5,*

¹ Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan

² Department of Anesthesiology, Cheng Hsin General Hospital, Taipei 112, Taiwan

³ Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan

⁴ Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan

⁵ Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan

⁶ Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan

⁷ Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1191; https://doi.org/10.3390/ijms17071191 - 22 Jul 2016

Cited by 14 | Viewed by 6213

Abstract

Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Na_v) channel blocker. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, [...] Read more.

Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Na_v) channel blocker. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, predominantly fast-spiking basket cells (BCs), powerfully inhibit granule cells (GCs) in the hippocampal dentate gyrus. Notably, BCs express abundant Na_v channels and HCN channels, both of which are able to support sustained action potential generation. Using whole-cell recording in rat hippocampal slices, we investigated the net LTG effect on BC output. We showed that bath application of LTG significantly decreased the amplitude of evoked compound inhibitory postsynaptic currents (IPSCs) in GCs. In contrast, simultaneous paired recordings from BCs to GCs showed that LTG had no effect on both the amplitude and the paired-pulse ratio of the unitary IPSCs, suggesting that LTG did not affect GABA release, though it suppressed cell excitability. In line with this, LTG decreased spontaneous IPSC (sIPSC) frequency, but not miniature IPSC frequency. When re-examining the LTG effect on GABAergic transmission in the cornus ammonis region 1 (CA1) area, we found that LTG markedly inhibits both the excitability of dendrite-targeting INs in the stratum oriens and the concurrent sIPSCs recorded on their targeting pyramidal cells (PCs) without significant hyperpolarization-activated current (I_h) enhancement. In summary, LTG has no effect on augmenting I_h in GABAergic INs and does not promote GABAergic inhibitory output. The antiepileptic effect of LTG is likely through Na_v channel inhibition and the suppression of global neuronal network activity. Full article

(This article belongs to the Section Biochemistry)

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