International Journal of Molecular Sciences

Research

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Open AccessArticle

MicroRNA-944 Affects Cell Growth by Targeting EPHA7 in Non-Small Cell Lung Cancer

by Minxia Liu^1,†, Kecheng Zhou^1,2,† and Yi Cao^1,*

¹ Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China

² Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650223, China

Int. J. Mol. Sci. 2016, 17(10), 1493; https://doi.org/10.3390/ijms17101493 - 26 Sep 2016

Cited by 41 | Viewed by 5934

Abstract

MicroRNAs (miRNAs) have critical roles in lung tumorigenesis and development. To determine aberrantly expressed miRNAs involved in non-small cell lung cancer (NSCLC) and investigate pathophysiological functions and mechanisms, we firstly carried out small RNA deep sequencing in NSCLC cell lines (EPLC-32M1, A549 and [...] Read more.

MicroRNAs (miRNAs) have critical roles in lung tumorigenesis and development. To determine aberrantly expressed miRNAs involved in non-small cell lung cancer (NSCLC) and investigate pathophysiological functions and mechanisms, we firstly carried out small RNA deep sequencing in NSCLC cell lines (EPLC-32M1, A549 and 801D) and a human immortalized cell line 16HBE, we then studied miRNA function by cell proliferation and apoptosis. cDNA microarray, luciferase reporter assay and miRNA transfection were used to investigate interaction between the miRNA and target gene. miR-944 was significantly down-regulated in NSCLC and had many putative targets. Moreover, the forced expression of miR-944 significantly inhibited the proliferation of NSCLC cells in vitro. By integrating mRNA expression data and miR-944-target prediction, we disclosed that EPHA7 was a potential target of miR-944, which was further verified by luciferase reporter assay and microRNA transfection. Our data indicated that miR-944 targets EPHA7 in NSCLC and regulates NSCLC cell proliferation, which may offer a new mechanism underlying the development and progression of NSCLC. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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Open AccessArticle

CXCL12/CXCR4 Axis Regulates Aggrecanase Activation and Cartilage Degradation in a Post-Traumatic Osteoarthritis Rat Model

by Weiwei Lu, Jia Shi, Jinming Zhang, Zhengtao Lv, Fengjing Guo, Hui Huang, Wentao Zhu^* and Anmin Chen^*

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Int. J. Mol. Sci. 2016, 17(10), 1522; https://doi.org/10.3390/ijms17101522 - 29 Sep 2016

Cited by 36 | Viewed by 6616

Abstract

We evaluated the role of the CXCL12/CXCR4 (C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4) axis in aggrecanase-mediated cartilage degradation, and explored the underlying mechanism in a post-traumatic osteoarthritis rat model. Expression of CXCL12/CXCR4 and ADAMTS-5 was analyzed in the knees of [...] Read more.

We evaluated the role of the CXCL12/CXCR4 (C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4) axis in aggrecanase-mediated cartilage degradation, and explored the underlying mechanism in a post-traumatic osteoarthritis rat model. Expression of CXCL12/CXCR4 and ADAMTS-5 was analyzed in the knees of osteoarthritic and non-arthritic rats using Western blot, ELISA, immunohistochemistry and immunofluorescence. Rodent studies were performed using Sprague-Dawley rats, with animals divided into three groups: Destabilization of the medial meniscus/AMD3100-treated (DMM/AMD3100-treated), DMM/PBS-treated, and sham controls. Rats were sacrificed after eight weeks, and samples were collected for histology and immunohistochemistry analyses. IL-1-pretreated primary chondrocytes were cultured with untreated control, CXCL12a, siNC + CXCL12a, or siRNA CXCR4 + CXCL12a, and analyzed for expression of relevant markers and cellular pathways. Higher levels of CXCL12 were detected in the knee fluid of osteoarthritic subjects, with strong staining for CXCR4 in chondrocytes and CXCL12 in synoviocytes together with enhanced expression of ADAMTS-5. DMM/AMD3100-treated rats showed a significantly reduced immunological response, with minimal evidence of pathology in both histological and immunohistochemical analyses. Treatment with CXCL12a increased the expression of ACAN, RUNX-2, and ADAMTS-4/5 in IL-1-pretreated primary chondrocytes, together with a decrease in the expression of SOX-9. Molecular analyses revealed strong induction of NF-κB activation, along with phosphorylation of MAPKs, and activation of canonical Wnt/β-catenin signaling. In conclusion, inhibition of SDF-1α/CXCR4 signaling axis was able to inhibit aggrecanase expression and lessen cartilage degeneration in post-traumatic osteoarthritis rats. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

by Chao Zhang¹, Chendan Wang², Jianbo Ren¹, Xiangjie Guo¹ and Keming Yun^1,*

¹ Department of Forensic Medicine, Shanxi Medical University, 56 South Xinjian Road, Taiyuan 030001, China

² Department of Nephrology, People’s Hospital of Shanxi Province, 29 Shuang-ta Street, Taiyuan 030012, China

Int. J. Mol. Sci. 2016, 17(10), 1523; https://doi.org/10.3390/ijms17101523 - 24 Oct 2016

Cited by 21 | Viewed by 6048

Abstract

Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated [...] Read more.

Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca²⁺ release, thereby inducing endoplasmic reticulum (ER) stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of κ-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca²⁺ release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca²⁺ overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca²⁺ release and ER stress. Full article

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

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Open AccessArticle

α6β4 Integrin Genetic Variations (A380T and R1281W) and Breast Cancer Risk in an Argentinian Population

by Karina Beatriz Acosta^1,*, Melina Noelia Lorenzini Campos¹, Susana Beatriz Etcheverry^2,3 and Pedro Dario Zapata¹

¹ Instituto de Biotecnología Misiones “Dra. Maria EbeReca” (InBioMis), Facultad de Ciencias Exactas, Químicas y Naturales, Universidad Nacional de Misiones, Ruta Nacional Nº12 km 7 ½, Posadas 3300, Argentina

² Cátedra de Bioquímica Patológica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, La Plata 1900, Argentina

³ Centro de Química Inorgánica (CEQUINOR, CONICET), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, La Plata 1900, Argentina

Int. J. Mol. Sci. 2016, 17(10), 1540; https://doi.org/10.3390/ijms17101540 - 18 Oct 2016

Cited by 2 | Viewed by 4050

Abstract

The α6β4 integrin is composed of the α6 and β4 subunits that are encoded by the ITGα6 and the ITGβ4 genes, respectively. The α6β4 main function is to intervene in lamination and epithelia integrity maintenance by cell-matrix interactions. This integrin appears to have [...] Read more.

The α6β4 integrin is composed of the α6 and β4 subunits that are encoded by the ITGα6 and the ITGβ4 genes, respectively. The α6β4 main function is to intervene in lamination and epithelia integrity maintenance by cell-matrix interactions. This integrin appears to have importance in breast cancer malignancy, as well as other epithelial carcinomas. The aim of this work was to investigate the potential role of ITGα6 (A380T) and ITGβ4 (R1281W) genetic variations in breast cancer susceptibility, in a female population from the northeast region of Argentina (Misiones). We performed a case-control study of 85 breast cancer patients and 113 cancer-free controls. Genotyping was performed by RFLP-PCR. For ITGα6 (A380T) single nucleotide polymorphism, a high frequency of heterozygous genotype GA in cases compared to controls was observed, achieving values of 48% and 49%, respectively. No association between the A380T SNP and breast cancer development was found (Odds Ratio = 0.92; 95% Confidence Interval = 0.52–1.63; p = 0.884). In conclusion, we did not find evidence of an association between A380T (ITGα6) and the risk of developing breast cancer. The results represent the first report of these genetic variations in breast cancer; therefore, they are an important contribution to the literature. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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Open AccessCommunication

Virus-Induced Gene Silencing Identifies an Important Role of the TaRSR1 Transcription Factor in Starch Synthesis in Bread Wheat

by Guoyu Liu¹, Yufang Wu^1,2, Mengjun Xu^2,3, Tian Gao^2,3, Pengfei Wang^1,2, Lina Wang^1,3, Tiancai Guo^1,3,* and Guozhang Kang^1,2,3,*

¹ The Collaborative Innovation Center of Henan Food Crops, Henan Agricultural University, Zhengzhou 450002, China

² The National Key Laboratory of Wheat and Maize Crop Science, Henan Agricultural University, Zhengzhou 450002, China

³ The National Engineering Research Centre for Wheat, Henan Agricultural University, Zhengzhou 450002, China

Int. J. Mol. Sci. 2016, 17(10), 1557; https://doi.org/10.3390/ijms17101557 - 23 Sep 2016

Cited by 32 | Viewed by 5366

Abstract

The function of a wheat starch regulator 1 (TaRSR1) in regulating the synthesis of grain storage starch was determined using the barley stripe mosaic virus—virus induced gene-silencing (BSMV-VIGS) method in field experiments. Chlorotic stripes appeared on the wheat spikes infected with [...] Read more.

The function of a wheat starch regulator 1 (TaRSR1) in regulating the synthesis of grain storage starch was determined using the barley stripe mosaic virus—virus induced gene-silencing (BSMV-VIGS) method in field experiments. Chlorotic stripes appeared on the wheat spikes infected with barley stripe mosaic virus-virus induced gene-silencing- wheat starch regulator 1 (BSMV-VIGS-TaRSR1) at 15 days after anthesis, at which time the transcription levels of the TaRSR1 gene significantly decreased. Quantitative real-time PCR was also used to measure the transcription levels of 26 starch synthesis-related enzyme genes in the grains of BSMV-VIGS-TaRSR1-silenced wheat plants at 20, 27, and 31 days after anthesis. The results showed that the transcription levels of some starch synthesis-related enzyme genes were markedly induced at different sampling time points: TaSSI, TaSSIV, TaBEIII, TaISA1, TaISA3, TaPHOL, and TaDPE1 genes were induced at each of the three sampling time points and TaAGPS1-b, TaAGPL1, TaAGPL2, TaSSIIb, TaSSIIc, TaSSIIIb, TaBEI, TaBEIIa, TaBEIIb, TaISA2, TaPHOH, and TaDPE2 genes were induced at one sampling time point. Moreover, both the grain starch contents, one thousand kernel weights, grain length and width of BSMV-VIGS-TaRSR1-infected wheat plants significantly increased. These results suggest that TaRSR1 acts as a negative regulator and plays an important role in starch synthesis in wheat grains by temporally regulating the expression of specific starch synthesis-related enzyme genes. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessArticle

Preparation, Characterization and in Vivo Antimycobacterial Studies of Panchovillin-Chitosan Nanocomposites

by Edward Rwegasila¹, Egid B. Mubofu¹, Stephen S. Nyandoro¹, Paul Erasto² and Joan J. E. Munissi^1,*

¹ Chemistry Department, College of Natural and Applied Sciences, University of Dar es Salaam, P.O. Box 35061, 14115 Dar es Salaam, Tanzania

² National Institute for Medical Research (NIMR), P.O. Box 9653, 14115 Dar es Salaam, Tanzania

Int. J. Mol. Sci. 2016, 17(10), 1559; https://doi.org/10.3390/ijms17101559 - 27 Sep 2016

Cited by 14 | Viewed by 5466

Abstract

Chitosan (CS, molecular weight 20.2 kDa, degree of deacylation (DD) 73.31%) was successfully obtained by deacetylation of chitin extracted from shrimp (Litopenaeus vannamei) shell wastes. The encapsulation of the bioactive natural product, panchovillin (PANV), isolated from Erythrina schliebenii, on a [...] Read more.

Chitosan (CS, molecular weight 20.2 kDa, degree of deacylation (DD) 73.31%) was successfully obtained by deacetylation of chitin extracted from shrimp (Litopenaeus vannamei) shell wastes. The encapsulation of the bioactive natural product, panchovillin (PANV), isolated from Erythrina schliebenii, on a chitosan-tripolyphosphate (CS/TPP) nano-framework was achieved by ionotropic gelation. Characterization of pure CS, CS/TPP and PANV-CS/TPP nanocomposites was performed by FTIR, SEM and XRD. The molecular weight of chitosan and the thermal stability of the materials were determined by MALDI-TOF-MS and simultaneous thermal analyzer (STA)/DTG, respectively. The respective encapsulation efficiency and loading capacity of the PANV were found to be 70% and 0.36%. The in vitro release studies showed an initial burst of 42% of PANV in the first six hours. This was followed by a slow and sustained release up to 72 h. The in vivo antimycobacterial activities of both PANV and PANV-CS/TPP nanocomposite against Mycobacterium indicus pranii (MIP) using Galleria mellonella larvae as an in vivo infection model are reported in this paper. Full article

(This article belongs to the Special Issue Drug Delivery and Antimicrobial Agents)

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Open AccessArticle

Sodium Copper Chlorophyllin Immobilization onto Hippospongia communis Marine Demosponge Skeleton and Its Antibacterial Activity

by Małgorzata Norman¹, Przemysław Bartczak¹, Jakub Zdarta¹, Wiktor Tomala¹, Barbara Żurańska¹, Anna Dobrowolska², Adam Piasecki³

, Katarzyna Czaczyk², Hermann Ehrlich⁴ and Teofil Jesionowski^1,*

¹ Institute of Chemical Technology and Engineering, Faculty of Chemical Technology, Poznan University of Technology, Berdychowo 4, 60965 Poznan, Poland

² Department of Biotechnology and Food Microbiology, Poznan University of Life Sciences, 60627 Poznan, Poland

³ Institute of Materials Science and Engineering, Faculty of Mechanical Engineering and Management, Poznan University of Technology, Jana Pawla II 24, 60965 Poznan, Poland

⁴ Institute of Experimental Physics, TU Bergakademie Freiberg, Leipziger 23, 09599 Freiberg, Germany

Int. J. Mol. Sci. 2016, 17(10), 1564; https://doi.org/10.3390/ijms17101564 - 27 Sep 2016

Cited by 22 | Viewed by 8073

Abstract

In this study, Hippospongia communis marine demosponge skeleton was used as an adsorbent for sodium copper chlorophyllin (SCC). Obtained results indicate the high sorption capacity of this biomaterial with respect to SCC. Batch experiments were performed under different conditions and kinetic and isotherms [...] Read more.

In this study, Hippospongia communis marine demosponge skeleton was used as an adsorbent for sodium copper chlorophyllin (SCC). Obtained results indicate the high sorption capacity of this biomaterial with respect to SCC. Batch experiments were performed under different conditions and kinetic and isotherms properties were investigated. Acidic pH and the addition of sodium chloride increased SCC adsorption. The experimental data were well described by a pseudo-second order kinetic model. Equilibrium adsorption isotherms were determined and the experimental data were analyzed using both Langmuir and Freundlich isotherms. The effectiveness of the process was confirmed by ¹³C Cross Polarization Magic Angle Spinning Nuclear Magnetic Resonance (¹³C CP/MAS NMR), Fourier transform infrared spectroscopy (FTIR), energy-dispersive X-ray spectroscopy (EDS) and thermogravimetric analysis (TG). This novel SCC-sponge-based functional hybrid material was found to exhibit antimicrobial activity against the gram-positive bacterium Staphylococcus aureus. Full article

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

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Open AccessArticle

Identification of Resistance to Wet Bubble Disease and Genetic Diversity in Wild and Cultivated Strains of Agaricus bisporus

by Yongping Fu^1,†, Xinxin Wang^1,†, Dan Li¹, Yuan Liu¹, Bing Song¹, Chunlan Zhang¹, Qi Wang¹, Meiyuan Chen², Zhiwu Zhang^3,* and Yu Li^1,*

¹ Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, College of Agriculture, Jilin Agricultural University, Changchun 130118, China

² The Institute of Edible Fungi, Fujian Academy of Agricultural Sciences, Fuzhou 350014, China

³ Department of Crop and Soil Sciences, Washington State University, Pullman, Washington, DC 99163, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1568; https://doi.org/10.3390/ijms17101568 - 22 Sep 2016

Cited by 38 | Viewed by 5890

Abstract

Outbreaks of wet bubble disease (WBD) caused by Mycogone perniciosa are increasing across the world and seriously affecting the yield of Agaricus bisporus. However, highly WBD-resistant strains are rare. Here, we tested 28 A. bisporus strains for WBD resistance by inoculating M. [...] Read more.

Outbreaks of wet bubble disease (WBD) caused by Mycogone perniciosa are increasing across the world and seriously affecting the yield of Agaricus bisporus. However, highly WBD-resistant strains are rare. Here, we tested 28 A. bisporus strains for WBD resistance by inoculating M. perniciosa spore suspension on casing soil, and assessed genetic diversity of these strains using 17 new simple sequence repeat (SSR) markers developed in this study. We found that 10 wild strains originating from the Tibetan Plateau in China were highly WBD-resistant strains, and 13 cultivated strains from six countries were highly susceptible strains. A total of 88 alleles were detected in these 28 strains, and the observed number of alleles per locus ranged from 2 to 8. Cluster and genetic structure analysis results revealed the wild resources from China have a relatively high level of genetic diversity and occur at low level of gene flow and introgression with cultivated strains. Moreover, the wild strains from China potentially have the consensus ancestral genotypes different from the cultivated strains and evolved independently. Therefore, the highly WBD-resistant wild strains from China and newly developed SSR markers could be used as novel sources for WBD-resistant breeding and quantitative trait locus (QTL) mapping of WBD-resistant gene of A. bisporus. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessArticle

Serum 25(OH) Vitamin D Levels in Polish Women during Pregnancies Complicated by Hypertensive Disorders and Gestational Diabetes

by Piotr Domaracki¹

, Pawel Sadlecki¹, Grazyna Odrowaz-Sypniewska², Ewa Dzikowska¹, Pawel Walentowicz¹, Joanna Siodmiak², Marek Grabiec¹ and Malgorzata Walentowicz-Sadlecka^1,*

¹ Department of Obstetrics and Gynecology, L. Rydygier Collegium in Bydgoszcz, Nicolaus Copernicus University, ul. Ujejskiego 75, Bydgoszcz 85-168, Poland

² Department of Laboratory Medicine, L. Rydygier Collegium in Bydgoszcz, Nicolaus Copernicus University, M. Curie Skłodowskiej 9, Bydgoszcz 85-094, Poland

Int. J. Mol. Sci. 2016, 17(10), 1574; https://doi.org/10.3390/ijms17101574 - 27 Sep 2016

Cited by 13 | Viewed by 7121

Abstract

Background: An association between the level of vitamin D and the risk of pregnancy-related complications remains unclear. The aim of this study was to examine concentrations of 25(OH) vitamin D in Polish women with normal pregnancies and pregnancies complicated by gestational hypertension, preeclampsia [...] Read more.

Background: An association between the level of vitamin D and the risk of pregnancy-related complications remains unclear. The aim of this study was to examine concentrations of 25(OH) vitamin D in Polish women with normal pregnancies and pregnancies complicated by gestational hypertension, preeclampsia or gestational diabetes mellitus (GDM). Moreover, we analyzed an association between maternal serum 25(OH)D and the risk of gestational hypertension, preeclampsia and GDM. Material and Methods: The study included 207 pregnant women, among them 171 with pregnancy-related complications: gestational hypertension (n = 45), preeclampsia (n = 23) or GDM (n = 103). The control group consisted of 36 women with normal pregnancies. Concentrations of serum 25(OH)D were measured at admission to the hospital prior to delivery Results: Patients with hypertension did not differ significantly from the controls in terms of their serum 25(OH)D concentrations (18.20 vs. 22.10 ng/mL, p = 0.15). Highly significant differences were found in 25(OH)D concentrations of women with preeclampsia and the controls (14.75 vs. 22.10 ng/mL, p = 0.0021). GDM was not associated with significant differences in 25(OH)D concentration. A low level of 25(OH)D turned out to be associated with an increased risk of preeclampsia during pregnancy on both univariate and multivariate regression analysis, and was a significant predictor of this condition on ROC (receiver operating characteristic) analysis (AUC = 0.70, p < 0.01). Conclusions: 25(OH)D deficiency is common among pregnant Polish women. Low concentrations of 25(OH)D may play a role in the etiopathogenesis of preeclampsia. Routine assessment of the 25(OH)D level during pregnancy may be crucial for the identification of women at increased risk of preeclampsia. Full article

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

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Open AccessArticle

Characterization of a β-Adrenergic-Like Octopamine Receptor in the Oriental Fruit Fly, Bactrocera dorsalis (Hendel)

by Hui-Min Li¹, Hong-Bo Jiang¹

, Shun-Hua Gui¹, Xiao-Qiang Liu¹, Hong Liu¹, Xue-Ping Lu¹, Guy Smagghe^1,2

and Jin-Jun Wang^1,*

¹ Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China

² Department of Crop Protection, Ghent University, Ghent 9000, Belgium

Int. J. Mol. Sci. 2016, 17(10), 1577; https://doi.org/10.3390/ijms17101577 - 22 Sep 2016

Cited by 13 | Viewed by 5057

Abstract

The biogenic amine octopamine plays a critical role in the regulation of many physiological processes in insects. Octopamine transmits its action through a set of specific G-protein coupled receptors (GPCRs), namely octopamine receptors. Here, we report on a β-adrenergic-like octopamine receptor gene ( [...] Read more.

The biogenic amine octopamine plays a critical role in the regulation of many physiological processes in insects. Octopamine transmits its action through a set of specific G-protein coupled receptors (GPCRs), namely octopamine receptors. Here, we report on a β-adrenergic-like octopamine receptor gene (BdOctβR1) from the oriental fruit fly, Bactrocera dorsalis (Hendel), a destructive agricultural pest that occurs in North America and the Asia-Pacific region. As indicated by RT-qPCR, BdOctβR1 was highly expressed in the central nervous system (CNS) and Malpighian tubules (MT) in the adult flies, suggesting it may undertake important roles in neural signaling in the CNS as well as physiological functions in the MT of this fly. Furthermore, its ligand specificities were tested in a heterologous expression system where BdOctβR1 was expressed in HEK-293 cells. Based on cyclic AMP response assays, we found that BdOctβR1 could be activated by octopamine in a concentration-dependent manner, confirming that this receptor was functional, while tyramine and dopamine had much less potency than octopamine. Naphazoline possessed the highest agonistic activity among the tested agonists. In antagonistic assays, mianserin had the strongest activity and was followed by phentolamine and chlorpromazine. Furthermore, when the flies were kept under starvation, there was a corresponding increase in the transcript level of BdOctβR1, while high or low temperature stress could not induce significant expression changes. The above results suggest that BdOctβR1 may be involved in the regulation of feeding processes in Bactrocera dorsalis and may provide new potential insecticide leads targeting octopamine receptors. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer

by Xingyun Su¹, Weibin Wang¹, Guodong Ruan², Min Liang³, Jing Zheng³, Ye Chen³, Huiling Wu⁴, Thomas J. Fahey III⁵, Minxin Guan^3,* and Lisong Teng^1,*

¹ Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China

² Department of Oncology, the Second Hospital of Shaoxing, Shaoxing 312000, China

³ Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, China

⁴ Department of Plastic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China

⁵ Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY 10021, USA

Int. J. Mol. Sci. 2016, 17(10), 1594; https://doi.org/10.3390/ijms17101594 - 10 Oct 2016

Cited by 19 | Viewed by 5780

Abstract

Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were [...] Read more.

Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were 2508 variations (543 sites) detected in PTCs, among which 33 variations were novel. Nearly half of the PTCs (31/66) had heteroplasmic variations. Among the 31 PTCs, 28 specimens harbored a total of 52 somatic mutations distributed in 44 sites. Thirty-three variations including seven nonsense, 11 frameshift and 15 non-synonymous variations selected by bioinformatic software were regarded as pathogenic. These 33 pathogenic mutations were associated with older age (p = 0.0176) and advanced tumor stage (p = 0.0218). In addition, they tended to be novel (p = 0.0003), heteroplasmic (p = 0.0343) and somatic (p = 0.0018). The mtDNA copy number increased in more than two-third (46/66) of PTCs, and the average content in tumors was nearly four times higher than that in adjacent normal tissues (p < 0.0001). Three sub-haplogroups of N (A4, B4a and B4g) and eight single-nucleotide polymorphisms (mtSNPs) (A16164G, C16266T, G5460A, T6680C, G9123A, A14587G, T16362C, and G709A) were associated with the occurrence of PTC. Here we report a comprehensive characterization of the mitochondrial genome and demonstrate its significance in pathogenesis and progression of PTC. This can help to clarify the molecular mechanisms underlying PTC and offer potential biomarkers or therapeutic targets for future clinical practice. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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Open AccessArticle

Selenomethionine Ameliorates Neuropathology in the Olfactory Bulb of a Triple Transgenic Mouse Model of Alzheimer’s Disease

by Zhong-Hao Zhang¹, Chen Chen², Qiu-Yan Wu², Rui Zheng², Yao Chen², Qiong Liu², Jia-Zuan Ni^1,2 and Guo-Li Song^2,*

¹ Changchun Institute of Applied Chemistry, University of Chinese Academy of Sciences, Changchun 130022, China

² Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China

Int. J. Mol. Sci. 2016, 17(10), 1595; https://doi.org/10.3390/ijms17101595 - 27 Sep 2016

Cited by 13 | Viewed by 6251

Abstract

Olfactory dysfunction is an early and common symptom in Alzheimer′s disease (AD) and is reported to be related to several pathologic changes, including the deposition of Aβ and hyperphosphorylated tau protein as well as synaptic impairment. Selenomethionine (Se-Met), the major form of selenium [...] Read more.

Olfactory dysfunction is an early and common symptom in Alzheimer′s disease (AD) and is reported to be related to several pathologic changes, including the deposition of Aβ and hyperphosphorylated tau protein as well as synaptic impairment. Selenomethionine (Se-Met), the major form of selenium in animals and humans, may be a promising therapeutic option for AD as it decreases the deposition of Aβ and tau hyperphosphorylation in a triple transgenic mouse model of AD (3× Tg-AD). In this study, 4-month-old AD mice were treated with 6 µg/mL Se-Met in drinking water for 12 weeks and the effect of Se-Met on neuropathological deficits in olfactory bulb (OB) of 3× Tg-AD mice was investigated. The administration of Se-Met effectively decreased the production and deposition of Aβ by inhibiting β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-regulated amyloid precursor protein (APP) processing and reduced the level of total tau and phosphorylated tau, which depended on depressing the activity and expression of glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5). Meanwhile, Se-Met reduced glial activation, relieved neuroinflammation and attenuated neuronal cell death in the OB of AD mice. So Se-Met could improve pathologic changes of AD in the OB, which further demonstrated the potential therapeutic effect of Se-Met in AD. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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Open AccessArticle

Ocular Albinism Type 1 Regulates Melanogenesis in Mouse Melanocytes

by Tianzhi Chen^1,†, Haidong Wang^1,†, Yu Liu², Bingling Zhao¹, Yuanyuan Zhao³, Ruiwen Fan¹, Pengchao Wang¹ and Changsheng Dong^1,*

¹ College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030600, China

² College of Animal Science and Technology, Northeast Agricultural University, Harbin 150000, China

³ Wujiang River Institute of Agricultural & Forestry Economic, Tongren University, Tongren 554300, China

Int. J. Mol. Sci. 2016, 17(10), 1596; https://doi.org/10.3390/ijms17101596 - 27 Sep 2016

Cited by 7 | Viewed by 7551

Abstract

To investigate whether ocular albinism type 1 (OA1) is differentially expressed in the skin of mice with different coat colors and to determine its correlation with coat color establishment in mouse, the expression patterns and tissue distribution characterization of OA1 in [...] Read more.

To investigate whether ocular albinism type 1 (OA1) is differentially expressed in the skin of mice with different coat colors and to determine its correlation with coat color establishment in mouse, the expression patterns and tissue distribution characterization of OA1 in the skin of mice with different coat colors were qualitatively and quantitatively analyzed by real-time quantitative PCR (qRT-PCR), immunofluorescence staining and Western blot. The qRT-PCR analysis revealed that OA1 mRNA was expressed in all mice skin samples tested, with the highest expression level in brown skin, a moderate expression level in black skin and the lowest expression level in gray skin. Positive OA1 protein bands were also detected in all skin samples by Western blot analysis. The relative expression levels of OA1 protein in both black and brown skin were significantly higher than that in gray skin, but there was no significant difference between black and brown mice. Immunofluorescence assays revealed that OA1 was mainly expressed in the hair follicle matrix, the inner and outer root sheath in the skin tissues with different coat colors. To get further insight into the important role of OA1 in the melanocytes’ pigmentation, we transfected the OA1 into mouse melanocytes and then detected the relative expression levels of pigmentation-related gene. Simultaneously, we tested the melanin content of melanocytes. As a result, the overexpression of OA1 significantly increased the expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein 1 (TRP1) and premelanosome protein (PMEL). However, the tyrosinase-related protein 2 (TRP2) level was attenuated. By contrast, the level of glycoprotein non-metastatic melanoma protein b (GPNMB) was unaffected by OA1 overexpression. Furthermore, we observed a significant increase in melanin content in mouse melanocyte transfected OA1. Therefore, we propose that OA1 may participate in the formation of coat color by regulating the level of MITF and the number, size, motility and maturation of melanosome. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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by Xiayu Wu^1,*

, Jiaoni Cheng² and Kaiyun Yang³

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, China

² Yunnan Key laboratory for Basic Research on Bone and Joint Diseases, Yunnan Stem Cell Translational Research Center, Kunming University, Kunming 650500, China

³ Hospital of Kunming Medical College, Kunming 650101, China

Int. J. Mol. Sci. 2016, 17(10), 1597; https://doi.org/10.3390/ijms17101597 - 22 Sep 2016

Cited by 45 | Viewed by 6286

Abstract

Epidemiological studies regarding the relationship between vitamin D, genetic polymorphisms in the vitamin D metabolism, cigarette smoke and non-small cell lung cancer (NSCLC) risk have not been investigated comprehensively. To search for additional evidence, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique [...] Read more.

Epidemiological studies regarding the relationship between vitamin D, genetic polymorphisms in the vitamin D metabolism, cigarette smoke and non-small cell lung cancer (NSCLC) risk have not been investigated comprehensively. To search for additional evidence, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique and radioimmunoassay method were utilized to evaluate 5 single-nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR), 6 SNPs in 24-hydroxylase (CYP24A1), 2 SNPs in 1α-hydroxylase (CYP27B1) and 2 SNPs in vitamin D-binding protein (group-specific component, GC) and plasma vitamin D levels in 426 NSCLC cases and 445 controls from China. Exposure to cigarette smoke was ascertained through questionnaire information. Multivariable linear regressions and mixed effects models were used in statistical analysis. The results showed that Reference SNP rs6068816 in CYP24A1, rs1544410 and rs731236 in VDR and rs7041 in GC were statistically significant in relation to reduction in NSCLC risk (p < 0.001–0.05). No significant connection was seen between NSCLC risk and overall plasma 25-hydroxyvitamin D [25(OH)D] concentrations, regardless of smoking status. However, the mutation genotype of CYP24A1 rs6068816 and VDR rs1544410 were also significantly associated with increased 25(OH)D levels only in both the smoker and non-smoker cases (p < 0.01–0.05). Meanwhile, smokers and non-smokers with mutated homozygous rs2181874 in CYP24A1 had significantly increased NSCLC risk (odds ratio (OR) = 2.14, 95% confidence interval (CI) 1.47–3.43; p = 0.031; OR = 3.57, 95% CI 2.66–4.74; p = 0.019, respectively). Smokers with mutated homozygous rs10735810 in VDR had significantly increased NSCLC risk (OR = 1.93, 95% CI 1.41–2.76; p = 0.015). However, smokers with mutated homozygous rs6068816 in CYP24A1 had significantly decreased NSCLC risk (OR = 0.43, 95% CI 0.27–1.02; p = 0.006); and smokers and non-smokers with mutated homozygous rs1544410 in VDR had significantly decreased NSCLC risk (OR = 0.51, 95% CI 0.34–1.17; p = 0.002; OR = 0.26, 95% CI 0.20–0.69; p = 0.001, respectively). There are significant joint effects between smoking and CYP24A1 rs2181874, CYP24A1 rs6068816, VDR rs10735810, and VDR rs1544410 (p < 0.01–0.05). Smokers with mutated homozygous rs10735810 in VDR had significantly increased NSCLC risk (OR = 1.93, 95% CI 1.41–2.76; p = 0.015). In summary, the results suggested that the lower the distribution of vitamin D concentration, the more the genetic variations in CYP24A1, VDR and GC genes may be associated with NSCLC risk. In addition, there are significant joint associations of cigarette smoking and vitamin D deficiency on NSCLC risk. Full article

(This article belongs to the Special Issue Nutrigenomics of Risk Factors for Disease)

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Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer

by Hanna Kędzierska¹, Piotr Popławski¹, Grażyna Hoser², Beata Rybicka¹, Katarzyna Rodzik¹, Elżbieta Sokół¹, Joanna Bogusławska¹, Zbigniew Tański³, Anna Fogtman⁴, Marta Koblowska^4,5 and Agnieszka Piekiełko-Witkowska^1,*

¹ Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland

² Laboratory of Flow Cytometry, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland

³ Department of Urology, Regional Hospital, 07-410 Ostrołęka, Poland

⁴ Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland

⁵ Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland

Int. J. Mol. Sci. 2016, 17(10), 1598; https://doi.org/10.3390/ijms17101598 - 28 Sep 2016

Cited by 30 | Viewed by 7884 | Correction

Abstract

Serine and arginine rich splicing factor 2(SRSF2) belongs to the serine/arginine (SR)-rich family of proteins that regulate alternative splicing. Previous studies suggested that SRSF2 can contribute to carcinogenic processes. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, [...] Read more.

Serine and arginine rich splicing factor 2(SRSF2) belongs to the serine/arginine (SR)-rich family of proteins that regulate alternative splicing. Previous studies suggested that SRSF2 can contribute to carcinogenic processes. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, highly aggressive and difficult to treat, mainly due to resistance to apoptosis. In this study we hypothesized that SRSF2 contributes to the regulation of apoptosis in ccRCC. Using tissue samples obtained from ccRCC patients, as well as independent validation on The Cancer Genome Atlas (TCGA) data, we demonstrate for the first time that expression of SRSF2 is decreased in ccRCC tumours when compared to non-tumorous control tissues. Furthermore, by employing a panel of ccRCC-derived cell lines with silenced SRSF2 expression and qPCR arrays we show that SRSF2 contributes not only to splicing patterns but also to expression of multiple apoptotic genes, including new SRSF2 targets: DIABLO, BIRC5/survivin, TRAIL, BIM, MCL1, TNFRSF9, TNFRSF1B, CRADD, BCL2L2, BCL2A1, and TP53. We also identified a new splice variant of CFLAR, an inhibitor of caspase activity. These changes culminate in diminished caspase-9 activity and inhibition of apoptosis. In summary, we show for the first time that decreased expression of SRSF2 in ccRCC contributes to protection of cancer cells viability. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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Inducible Expression of both ermB and ermT Conferred High Macrolide Resistance in Streptococcus gallolyticus subsp. pasteurianus Isolates in China

by Meixia Li

, Chao Cai, Juan Chen, Changwei Cheng, Guofu Cheng

, Xueying Hu and Cuiping Liu^*

College of Veterinary Medicine, Huazhong Agricultural University, 1st Shizishan Street, Wuhan 430070, China

Int. J. Mol. Sci. 2016, 17(10), 1599; https://doi.org/10.3390/ijms17101599 - 22 Sep 2016

Cited by 11 | Viewed by 6596

Abstract

Streptococcus gallolyticus subsp. pasteurianus is an under-recognized pathogen and zoonotic agent causing opportunistic infections in humans. Despite increasing recognition of this subspecies as a cause for human infectious diseases, limited information is known about its antibiotic resistance mechanism. In this study, we aim [...] Read more.

Streptococcus gallolyticus subsp. pasteurianus is an under-recognized pathogen and zoonotic agent causing opportunistic infections in humans. Despite increasing recognition of this subspecies as a cause for human infectious diseases, limited information is known about its antibiotic resistance mechanism. In this study, we aim to identify the molecular mechanism underlying the high macrolide resistance of six S. gallolyticus subsp. pasteurianus isolates from dead ducklings collected in several natural outbreaks in China during 2010–2013. All isolates exhibited multi-drug resistance including high macrolide resistance (MIC ≥ 1024 mg/L for erythromycin, and 512 mg/L for clarithromycin). Efflux-encoding mefA and mefE genes were not detectable in these isolates. The presence of 23S rRNA mutations in specific isolates did not significantly change macrolide MICs. No nucleotide substitutions were found in genes encoding ribosomal proteins L4 or L22. The ermB and ermT genes were found in the genomes of all isolates. These two genes were acquired independently in one highly virulent isolate AL101002, and clustered with Tn916 and IS1216, respectively. The expression of both ermB and ermT in all isolates was erythromycin inducible and yielded comparable macrolide MICs in all six isolates. Taken together, inducible expression of both ermB and ermT conferred high macrolide resistance in these S. gallolyticus subsp. pasterianus isolates. Our findings reveal new macrolide resistance features in S. gallolyticus subsp. pasteurianus by both ermB and ermT. Full article

(This article belongs to the Section Biochemistry)

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Protein/CaCO₃/Chitin Nanofiber Complex Prepared from Crab Shells by Simple Mechanical Treatment and Its Effect on Plant Growth

by Yihun Fantahun Aklog¹, Mayumi Egusa², Hironori Kaminaka²

, Hironori Izawa¹, Minoru Morimoto¹, Hiroyuki Saimoto¹ and Shinsuke Ifuku^1,*

¹ Graduate School of Engineering, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8552, Japan

² Faculty of Agriculture, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8553, Japan

Int. J. Mol. Sci. 2016, 17(10), 1600; https://doi.org/10.3390/ijms17101600 - 22 Sep 2016

Cited by 43 | Viewed by 7530

Abstract

A protein/CaCO₃/chitin nanofiber complex was prepared from crab shells by a simple mechanical treatment with a high-pressure water-jet (HPWJ) system. The preparation process did not involve chemical treatments, such as removal of protein and calcium carbonate with sodium hydroxide and hydrochloric [...] Read more.

A protein/CaCO₃/chitin nanofiber complex was prepared from crab shells by a simple mechanical treatment with a high-pressure water-jet (HPWJ) system. The preparation process did not involve chemical treatments, such as removal of protein and calcium carbonate with sodium hydroxide and hydrochloric acid, respectively. Thus, it was economically and environmentally friendly. The nanofibers obtained had uniform width and dispersed homogeneously in water. Nanofibers were characterized in morphology, transparency, and viscosity. Results indicated that the shell was mostly disintegrated into nanofibers at above five cycles of the HPWJ system. The chemical structure of the nanofiber was maintained even after extensive mechanical treatments. Subsequently, the nanofiber complex was found to improve the growth of tomatoes in a hydroponics system, suggesting the mechanical treatments efficiently released minerals into the system. The homogeneous dispersion of the nanofiber complex enabled easier application as a fertilizer compared to the crab shell flakes. Full article

(This article belongs to the Special Issue Chitins 2016)

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MicroRNA Transcriptome of Poly I:C-Stimulated Peripheral Blood Mononuclear Cells Reveals Evidence for MicroRNAs in Regulating Host Response to RNA Viruses in Pigs

by Jiying Wang^1,2, Yanping Wang¹, Haifei Wang², Jianfeng Guo¹, Huaizhong Wang¹, Ying Wu¹ and Jianfeng Liu^2,*

¹ Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan 250100, China

² Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China

Int. J. Mol. Sci. 2016, 17(10), 1601; https://doi.org/10.3390/ijms17101601 - 22 Sep 2016

Cited by 13 | Viewed by 5278

Abstract

MicroRNAs (miRNAs) are one family of small noncoding RNAs that function to modulate the activity of specific mRNA targets in animals. To understand the role of miRNAs in regulating genes involved in the host immune response to RNA viruses, we profiled and characterized [...] Read more.

MicroRNAs (miRNAs) are one family of small noncoding RNAs that function to modulate the activity of specific mRNA targets in animals. To understand the role of miRNAs in regulating genes involved in the host immune response to RNA viruses, we profiled and characterized the miRNAs of swine peripheral blood mononuclear cells (PBMC) stimulated with poly I:C, a synthetic dsRNA analog, by miRNA-sequencing (miRNA-seq). We identified a total of 905 miRNAs, of which 503 miRNAs were firstly exploited herein with no annotation in the latest miRBase 21.0. Expression analysis demonstrated that poly I:C stimulation can elicit significantly differentially expressed (DE) miRNAs in Dapulian (n = 20), one Chinese indigenous breed, as well as Landrace (n = 23). By integrating the mRNA expression profiles of the same sample with miRNA profiles, we carried out function analyses of the target genes of these DE miRNAs, with the results indicating that target genes were most enriched in some immune-related pathways and gene ontology (GO) terms, suggesting that DE miRNAs play an important role in the regulation of host to poly I:C stimulation. Furthermore, we also detected 43 and 61 significantly DE miRNAs between the two breeds in the control sample groups and poly I:C stimulation groups, respectively, which may be involved in regulation of the different characteristics of the two breeds. This study describes for the first time the PBMC miRNA transcriptomic response to poly I:C stimulation in pigs, which not only contributes to a broad view of the pig miRNAome but improves our understanding of miRNA function in regulating host immune response to RNA viruses. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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Fine Mapping of Virescent Leaf Gene v-1 in Cucumber (Cucumis sativus L.)

by Han Miao^1,2,†, Shengping Zhang^1,†, Min Wang¹, Ye Wang¹, Yiqun Weng^2,* and Xingfang Gu^1,*

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

² USDA-ARS Vegetable Crops Research Unit, Horticulture Department, University of Wisconsin, Madison, WI 53706, USA

Int. J. Mol. Sci. 2016, 17(10), 1602; https://doi.org/10.3390/ijms17101602 - 22 Sep 2016

Cited by 24 | Viewed by 5958

Abstract

Leaf color mutants are common in higher plants that can be used as markers in crop breeding or as an important tool in understanding regulatory mechanisms in chlorophyll biosynthesis and chloroplast development. In virescent leaf mutants, young leaves are yellow in color, which [...] Read more.

Leaf color mutants are common in higher plants that can be used as markers in crop breeding or as an important tool in understanding regulatory mechanisms in chlorophyll biosynthesis and chloroplast development. In virescent leaf mutants, young leaves are yellow in color, which gradually return to normal green when the seedlings grow large. In the present study, we conducted phenotypic characterization and genetic mapping of the cucumber virescent leaf mutant 9110Gt conferred by the v-1 locus. Total chlorophyll and carotenoid content in 9110Gt was reduced by 44% and 21%, respectively, as compared with its wild type parental line 9110G. Electron microscopic investigation revealed fewer chloroplasts per cell and thylakoids per chloroplast in 9110Gt than in 9110G. Fine genetic mapping allowed for the assignment of the v-1 locus to a 50.4 kb genomic DNA region in chromosome 6 with two flanking markers that were 0.14 and 0.16 cM away from v-1, respectively. Multiple lines of evidence supported CsaCNGCs as the only candidate gene for the v-1 locus, which encoded a cyclic-nucleotide-gated ion channel protein. A single nucleotide change in the promoter region of v-1 seemed to be associated with the virescent color change in 9110Gt. Real-time PCR revealed significantly lower expression of CsaCNGCs in the true leaves of 9110Gt than in 9110G. This was the first report that connected the CsaCNGCs gene to virescent leaf color change, which provided a useful tool to establish linkages among virescent leaf color change, chloroplast development, chlorophyll biosynthesis, and the functions of the CsaCNGCs gene. Full article

(This article belongs to the Section Molecular Plant Sciences)

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A Novel Tetraenoic Fatty Acid Isolated from Amaranthus spinosus Inhibits Proliferation and Induces Apoptosis of Human Liver Cancer Cells

by Arijit Mondal^1,*, Tanmoy Guria²

, Tapan Kumar Maity² and Anupam Bishayee^3,*

¹ Department of Pharmaceutical Chemistry, Bengal College of Pharmaceutical Sciences and Research, Durgapur 713 212, West Bengal, India

² Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, West Bengal, India

³ Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, Miami, FL 33169, USA

Int. J. Mol. Sci. 2016, 17(10), 1604; https://doi.org/10.3390/ijms17101604 - 22 Sep 2016

Cited by 18 | Viewed by 5380

Abstract

Amaranthus spinosus Linn. (Family: Amaranthaceae) has been shown to be useful in preventing and mitigating adverse pathophysiological conditions and complex diseases. However, only limited information is available on the anticancer potential of this plant. In this study, we examined the antiproliferative and pro-apoptotic [...] Read more.

Amaranthus spinosus Linn. (Family: Amaranthaceae) has been shown to be useful in preventing and mitigating adverse pathophysiological conditions and complex diseases. However, only limited information is available on the anticancer potential of this plant. In this study, we examined the antiproliferative and pro-apoptotic effects of a novel fatty acid isolated from A. spinosus—(14E,18E,22E,26E)-methyl nonacosa-14,18,22,26 tetraenoate—against HepG2 human liver cancer cells. We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to determine cell viability, flow cytometry assay for cell cycle analysis, and Western blot analysis to measure protein expression of Cdc2), cyclin B1, Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2). The MTT assay showed that the fatty acid markedly inhibited the proliferation of HepG2 cells in a dosage-dependent fashion, with a half maximal inhibitory concentration (IC₅₀) value of 25.52 µmol/L. This antiproliferative result was superior to that of another known fatty acid, linoleic acid (IC₅₀ 38.65 µmol/L), but comparable to that of standard anticancer drug doxorubicin (IC₅₀ 24.68 µmol/L). The novel fatty acid also induced apoptosis mediated by downregulation of cyclin B1, upregulation of Bax, and downregulation of Bcl-2, resulting in the G₂/M transition arrest. Our results provide the first experimental evidence that a novel fatty acid isolated from A. spinosus exhibits significant antiproliferative activity mediated through the induction of apoptosis in HepG2 cells. These encouraging results may facilitate the development of A. spinosus fatty acid for the prevention and intervention of hepatocellular carcinoma. Full article

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

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Proteomic Analysis of Hylocereus polyrhizus Reveals Metabolic Pathway Changes

by Qingzhu Hua¹, Qianjun Zhou², Susheng Gan³, Jingyu Wu¹, Canbin Chen¹, Jiaqiang Li⁴, Yaoxiong Ye⁴, Jietang Zhao¹, Guibing Hu^1,* and Yonghua Qin^1,*

¹ State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources/Key Laboratory of Biology and Genetic Improvement of Horticultural Crops-South China, Ministry of Agriculture, College of Horticulture, South China Agricultural University, Guangzhou 510642, China

² General Station of the Administration of Seeds Guangdong Province, Guangzhou 510500, China

³ Plant Biology Section, School of Integrative Plant Science, Cornell University, Ithaca, NY 14853, USA

⁴ Dongguan Institute of Forest Science, Dongguan 523106, China

Int. J. Mol. Sci. 2016, 17(10), 1606; https://doi.org/10.3390/ijms17101606 - 28 Sep 2016

Cited by 17 | Viewed by 7111

Abstract

Red dragon fruit or red pitaya (Hylocereus polyrhizus) is the only edible fruit that contains betalains. The color of betalains ranges from red and violet to yellow in plants. Betalains may also serve as an important component of health-promoting and disease-preventing [...] Read more.

Red dragon fruit or red pitaya (Hylocereus polyrhizus) is the only edible fruit that contains betalains. The color of betalains ranges from red and violet to yellow in plants. Betalains may also serve as an important component of health-promoting and disease-preventing functional food. Currently, the biosynthetic and regulatory pathways for betalain production remain to be fully deciphered. In this study, isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analyses were used to reveal the molecular mechanism of betalain biosynthesis in H. polyrhizus fruits at white and red pulp stages, respectively. A total of 1946 proteins were identified as the differentially expressed between the two samples, and 936 of them were significantly highly expressed at the red pulp stage of H. polyrhizus. RNA-seq and iTRAQ analyses showed that some transcripts and proteins were positively correlated; they belonged to “phenylpropanoid biosynthesis”, “tyrosine metabolism”, “flavonoid biosynthesis”, “ascorbate and aldarate metabolism”, “betalains biosynthesis” and “anthocyanin biosynthesis”. In betalains biosynthesis pathway, several proteins/enzymes such as polyphenol oxidase, CYP76AD3 and 4,5-dihydroxy-phenylalanine (DOPA) dioxygenase extradiol-like protein were identified. The present study provides a new insight into the molecular mechanism of the betalain biosynthesis at the posttranscriptional level. Full article

(This article belongs to the Special Issue Plant Proteomic Research)

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Isobaric Tags for Relative and Absolute Quantitation (iTRAQ)-Based Comparative Proteome Analysis of the Response of Ramie under Drought Stress

by Xia An^1,2, Jingyu Zhang¹, Lunjin Dai¹, Gang Deng³, Yiwen Liao¹, Lijun Liu¹, Bo Wang^1,* and Dingxiang Peng^1,*

¹ Key Laboratory of Crop Ecophysiology and Farming Systems in the Middle Reaches of the Yangtze River, Ministry of Agriculture, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China

² Flower Research and Development Centre, Zhejiang Academy of Agricultural Sciences, Hangzhou 311202, China

³ School of Agricultural Science, Yunnan University, Kunming 650091, China

Int. J. Mol. Sci. 2016, 17(10), 1607; https://doi.org/10.3390/ijms17101607 - 27 Sep 2016

Cited by 17 | Viewed by 6049

Abstract

In this study, we conducted the first isobaric tags for relative and absolute quantitation (isobaric tags for relative and absolute quantitation (iTRAQ))-based comparative proteomic analysis of ramie plantlets after 0 (minor drought stress), 24 (moderate drought stress), and 72 h (severe drought [...] Read more.

In this study, we conducted the first isobaric tags for relative and absolute quantitation (isobaric tags for relative and absolute quantitation (iTRAQ))-based comparative proteomic analysis of ramie plantlets after 0 (minor drought stress), 24 (moderate drought stress), and 72 h (severe drought stress) of treatment with 15% (w/v) poly (ethylene glycol)6000 (PEG6000) to simulate drought stress. In our study, the association analysis of proteins and transcript expression revealed 1244 and 968 associated proteins identified in leaves and roots, respectively. L1, L2, and L3 are leaf samples which were harvested at 0, 24, and 72 h after being treated with 15% PEG6000, respectively. Among those treatment groups, a total of 118, 216, and 433 unique proteins were identified as differentially expressed during L1 vs. L2, L2 vs. L3, and L1 vs. L3, respectively. R1, R2, and R3 are root samples which were harvested at 0, 24, and 72 h after being treated with 15% PEG6000, respectively. Among those treatment groups，a total of 124, 27, and 240 unique proteins were identified as differentially expressed during R1 vs. R2, R2 vs. R3, and R1 vs. R3, respectively. Bioinformatics analysis indicated that glycolysis/gluconeogenesis was significantly upregulated in roots in response to drought stress. This enhancement may result in more glycolytically generated adenosine triphosphate (ATP) in roots to adapt to adverse environmental conditions. To obtain complementary information related to iTRAQ data, the mRNA levels of 12 proteins related to glycolysis/gluconeogenesis in leaves and 7 in roots were further analyzed by qPCR. Most of their expression levels were higher in R3 than R1 and R2, suggesting that these compounds may promote drought tolerance by modulating the production of available energy. Full article

(This article belongs to the Special Issue Plant Proteomic Research)

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Waste Soybean Oil and Corn Steep Liquor as Economic Substrates for Bioemulsifier and Biodiesel Production by Candida lipolytica UCP 0998

by Adriana Ferreira Souza^1,2, Dayana M. Rodriguez^2,3, Daylin R. Ribeaux^2,3, Marcos A. C. Luna^2,4, Thayse A. Lima e Silva^2,5, Rosileide F. Silva Andrade^2,5, Norma B. Gusmão⁶ and Galba M. Campos-Takaki^2,*

¹ Fungal Biology Post-graduation Program, Federal University of Pernambuco, 50670-901 Recife-PE, Brazil

² Nucleus of Research in Environmental Sciences and Biotechnology, Catholic University of Pernambuco, 50050-590 Recife-PE, Brazil

³ Biological Sciences Post-graduation Program, Federal University of Pernambuco, 50670-420 Recife-PE, Brazil

⁴ Northeast Network for Biotechnology Post-graduation Program, Federal Rural University of Pernambuco, 52171-900 Recife-PE, Brazil

⁵ National Post-Doctorate Program-CAPES, Catholic University of Pernambuco, 50050-900 Recife-PE, Brazil

⁶ Department of Antibiotics, Federal University of Pernambuco, 50670-901 Recife-PE, Brazil

Int. J. Mol. Sci. 2016, 17(10), 1608; https://doi.org/10.3390/ijms17101608 - 23 Sep 2016

Cited by 28 | Viewed by 6375

Abstract

Almost all oleaginous microorganisms are available for biodiesel production, and for the mechanism of oil accumulation, which is what makes a microbial approach economically competitive. This study investigated the potential that the yeast Candida lipolytica UCP0988, in an anamorphous state, has to produce [...] Read more.

Almost all oleaginous microorganisms are available for biodiesel production, and for the mechanism of oil accumulation, which is what makes a microbial approach economically competitive. This study investigated the potential that the yeast Candida lipolytica UCP0988, in an anamorphous state, has to produce simultaneously a bioemulsifier and to accumulate lipids using inexpensive and alternative substrates. Cultivation was carried out using waste soybean oil and corn steep liquor in accordance with 2² experimental designs with 1% inoculums (10⁷ cells/mL). The bioemulsifier was produced in the cell-free metabolic liquid in the late exponential phase (96 h), at Assay 4 (corn steep liquor 5% and waste soybean oil 8%), with 6.704 UEA, IE₂₄ of 96.66%, and showed an anionic profile. The emulsion formed consisted of compact small and stable droplets (size 0.2–5 µm), stable at all temperatures, at pH 2 and 4, and 2% salinity, and showed an ability to remove 93.74% of diesel oil from sand. The displacement oil (ODA) showed 45.34 cm² of dispersion (central point of the factorial design). The biomass obtained from Assay 4 was able to accumulate lipids of 0.425 g/g biomass (corresponding to 42.5%), which consisted of Palmitic acid (28.4%), Stearic acid (7.7%), Oleic acid (42.8%), Linoleic acid (19.0%), and γ-Linolenic acid (2.1%). The results showed the ability of C. lipopytica to produce both bioemulsifier and biodiesel using the metabolic conversion of waste soybean oil and corn steep liquor, which are economic renewable sources. Full article

(This article belongs to the Special Issue Biodegradable Materials 2017)

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Designing Efficient Double RNA trans-Splicing Molecules for Targeted RNA Repair

by Clemens Hüttner^1,*, Eva M. Murauer¹, Stefan Hainzl¹, Thomas Kocher¹, Anna Neumayer¹, Julia Reichelt¹

, Johann W. Bauer^2,† and Ulrich Koller^1,*,†

¹ EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria

² Department of Dermatology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria

Int. J. Mol. Sci. 2016, 17(10), 1609; https://doi.org/10.3390/ijms17101609 - 22 Sep 2016

Cited by 7 | Viewed by 5898

Abstract

RNA trans-splicing is a promising tool for mRNA modification in a diversity of genetic disorders. In particular, the substitution of internal exons of a gene by combining 3′ and 5′ RNA trans-splicing seems to be an elegant way to modify especially [...] Read more.

RNA trans-splicing is a promising tool for mRNA modification in a diversity of genetic disorders. In particular, the substitution of internal exons of a gene by combining 3′ and 5′ RNA trans-splicing seems to be an elegant way to modify especially large pre-mRNAs. Here we discuss a robust method for designing double RNA trans-splicing molecules (dRTM). We demonstrate how the technique can be implemented in an endogenous setting, using COL7A1, the gene encoding type VII collagen, as a target. An RTM screening system was developed with the aim of testing the replacement of two internal COL7A1 exons, harbouring a homozygous mutation, with the wild-type version. The most efficient RTMs from a pool of randomly generated variants were selected via our fluorescence-based screening system and adapted for use in an in vitro disease model system. Transduction of type VII collagen-deficient keratinocytes with the selected dRTM led to accurate replacement of two internal COL7A1 exons resulting in a restored wild-type RNA sequence. This is the first study demonstrating specific exon replacement by double RNA trans-splicing within an endogenous transcript in cultured cells, corroborating the utility of this technology for mRNA repair in a variety of genetic disorders. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing 2016)

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Prenatal Dexamethasone and Postnatal High-Fat Diet Decrease Interferon Gamma Production through an Age-Dependent Histone Modification in Male Sprague-Dawley Rats

by Hong-Ren Yu

, You-Lin Tain

, Jiunn-Ming Sheen, Mao-Meng Tiao

, Chih-Cheng Chen, Ho-Chang Kuo

, Pi-Lien Hung, Kai-Sheng Hsieh and Li-Tung Huang^*

Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

Int. J. Mol. Sci. 2016, 17(10), 1610; https://doi.org/10.3390/ijms17101610 - 22 Sep 2016

Cited by 17 | Viewed by 5400

Abstract

Overexposure to prenatal glucocorticoid (GC) disturbs hypothalamic-pituitary-adrenocortical axis-associated neuroendocrine metabolism and susceptibility to metabolic syndrome. A high-fat (HF) diet is a major environmental factor that can cause metabolic syndrome. We aimed to investigate whether prenatal GC plus a postnatal HF diet could alter [...] Read more.

Overexposure to prenatal glucocorticoid (GC) disturbs hypothalamic-pituitary-adrenocortical axis-associated neuroendocrine metabolism and susceptibility to metabolic syndrome. A high-fat (HF) diet is a major environmental factor that can cause metabolic syndrome. We aimed to investigate whether prenatal GC plus a postnatal HF diet could alter immune programming in rat offspring. Pregnant Sprague-Dawley rats were given intraperitoneal injections of dexamethasone or saline at 14–21 days of gestation. Male offspring were then divided into four groups: vehicle, prenatal dexamethasone exposure, postnatal HF diet (VHF), and prenatal dexamethasone exposure plus a postnatal HF diet (DHF). The rats were sacrificed and adaptive immune function was evaluated. Compared to the vehicle, the DHF group had lower interferon gamma (IFN-γ) production by splenocytes at postnatal day 120. Decreases in H3K9 acetylation and H3K36me3 levels at the IFN-γ promoter correlated with decreased IFN-γ production. The impaired IFN-γ production and aberrant site-specific histone modification at the IFN-γ promoter by prenatal dexamethasone treatment plus a postnatal HF diet resulted in resilience at postnatal day 180. Prenatal dexamethasone and a postnatal HF diet decreased IFN-γ production through a site-specific and an age-dependent histone modification. These findings suggest a mechanism by which prenatal exposure to GC and a postnatal environment exert effects on fetal immunity programming. Full article

(This article belongs to the Section Biochemistry)

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Keratinocyte Growth Factor Combined with a Sodium Hyaluronate Gel Inhibits Postoperative Intra-Abdominal Adhesions

by Guangbing Wei¹, Cancan Zhou², Guanghui Wang¹, Lin Fan¹, Kang Wang¹ and Xuqi Li^1,*

¹ Department of General Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China

² Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China

Int. J. Mol. Sci. 2016, 17(10), 1611; https://doi.org/10.3390/ijms17101611 - 22 Sep 2016

Cited by 22 | Viewed by 9148

Abstract

Postoperative intra-abdominal adhesion is a very common complication after abdominal surgery. One clinical problem that remains to be solved is to identify an ideal strategy to prevent abdominal adhesions. Keratinocyte growth factor (KGF) has been proven to improve the proliferation of mesothelial cells, [...] Read more.

Postoperative intra-abdominal adhesion is a very common complication after abdominal surgery. One clinical problem that remains to be solved is to identify an ideal strategy to prevent abdominal adhesions. Keratinocyte growth factor (KGF) has been proven to improve the proliferation of mesothelial cells, which may enhance fibrinolytic activity to suppress postoperative adhesions. This study investigated whether the combined administration of KGF and a sodium hyaluronate (HA) gel can prevent intra-abdominal adhesions by improving the orderly repair of the peritoneal mesothelial cells. The possible prevention mechanism was also explored. The cecum wall and its opposite parietal peritoneum were abraded after laparotomy to induce intra-abdominal adhesion formation. Animals were randomly allocated to receive topical application of HA, KGF, KGF + HA, or normal saline (Control). On postoperative day 7, the adhesion score was assessed with a visual scoring system. Masson’s trichrome staining, picrosirius red staining and hydroxyproline assays were used to assess the magnitude of adhesion and tissue fibrosis. Cytokeratin, a marker of the mesothelial cells, was detected by immunohistochemistry. The levels of tissue plasminogen activator (tPA), interleukin-6 (IL-6), and transforming growth factor β1 (TGF-β1) in the abdominal fluid were determined using enzyme-linked immunosorbent assays (ELISAs). Western blotting was performed to examine the expression of the TGF-β1, fibrinogen and α-smooth muscle actin (α-SMA) proteins in the rat peritoneal adhesion tissue. The combined administration of KGF and HA significantly reduced intra-abdominal adhesion formation and fibrin deposition and improved the orderly repair of the peritoneal mesothelial cells in the rat model. Furthermore, the combined administration of KGF and HA significantly increased the tPA levels but reduced the levels of IL-6, tumor necrosis factor α (TNF-α) and TGF-β1 in the abdominal fluid. The expression levels of TGF-β1, fibrinogen and α-SMA protein and mRNA in the rat peritoneum or adhesion tissues were also down-regulated following the combined administration of KGF and HA. The combined administration of KGF and HA can significantly prevent postoperative intra-abdominal adhesion formation by maintaining the separation of the injured peritoneum and promoting mesothelial cell regeneration. The potential mechanism may be associated with rapid mesothelial cell repair in the injured peritoneum. This study suggests that combined administration of KGF and HA may be a promising pharmacotherapeutic strategy for preventing abdominal adhesions, which is worth further study, and has potential value in clinical applications. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration)

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Elevated Expression of Calpain-4 Predicts Poor Prognosis in Patients with Gastric Cancer after Gastrectomy

by Peike Peng^1,†, Lingqiang Min^2,†, Shushu Song^1,†, Junjie Zhao², Lili Li¹, Caiting Yang¹, Miaomiao Shao¹, Mingming Zhang¹, Hao Wu¹, Jie Zhang³, Can Li¹, Xuefei Wang², Hongshan Wang^2,*, Jing Qin^2,*, Yuanyuan Ruan^1,* and Jianxin Gu^1,3

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

² Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China

³ Institute of Biomedical Science, Fudan University, Shanghai 200032, China

Int. J. Mol. Sci. 2016, 17(10), 1612; https://doi.org/10.3390/ijms17101612 - 27 Sep 2016

Cited by 6 | Viewed by 5109

Abstract

Calpain-4 belongs to the calpain family of calcium-dependent cysteine proteases, and functions as a small regulatory subunit of the calpains. Recent evidence indicates that calpain-4 plays critical roles in tumor migration and invasion. However, the roles of calpain-4 in gastric tumorigenesis remain poorly [...] Read more.

Calpain-4 belongs to the calpain family of calcium-dependent cysteine proteases, and functions as a small regulatory subunit of the calpains. Recent evidence indicates that calpain-4 plays critical roles in tumor migration and invasion. However, the roles of calpain-4 in gastric tumorigenesis remain poorly understood. Herein, we examined calpain-4 expression by immunohistochemical staining on tissue microarrays containing tumor samples of 174 gastric cancer patients between 2004 and 2008 at a single center. The Kaplan-Meier method was used to compare survival curves, and expression levels were correlated to clinicopathological factors and overall survival. Our data demonstrated that calpain-4 was generally increased in gastric cancer cell lines and primary tumor tissues. High expression of calpain-4 was positively associated with vessel invasion, lymph node metastasis, and advanced TNM (Tumor Node Metastasis) stage. Multivariate analysis identified calpain-4 as an independent prognostic factor for poor prognosis. A predictive nomogram integrating calpain-4 expression with other independent prognosticators was constructed, which generated a better prognostic value for overall survival of gastric cancer patients than a TNM staging system. In conclusion, calpain-4 could be regarded as a potential prognosis indicator for clinical outcomes in gastric cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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PlGF and VEGF-A Regulate Growth of High-Risk MYCN-Single Copy Neuroblastoma Xenografts via Different Mechanisms

by Karin Zins¹

, Daniel Kovatchki¹, Trevor Lucas¹ and Dietmar Abraham^1,2,*

¹ Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, A-1090 Vienna, Austria

² Comprehensive Cancer Center (CCC), Medical University of Vienna, A-1090 Vienna, Austria

Int. J. Mol. Sci. 2016, 17(10), 1613; https://doi.org/10.3390/ijms17101613 - 23 Sep 2016

Cited by 5 | Viewed by 5050

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and is a rapidly growing, highly-vascularized cancer. NBs frequently express angiogenic factors and high tumor angiogenesis has been associated with poor outcomes. Placental growth factor (PlGF) is an angiogenic protein belonging to [...] Read more.

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and is a rapidly growing, highly-vascularized cancer. NBs frequently express angiogenic factors and high tumor angiogenesis has been associated with poor outcomes. Placental growth factor (PlGF) is an angiogenic protein belonging to the vascular endothelial growth factor (VEGF) family and is up-regulated mainly in pathologic conditions. Recently, PlGF was identified as a member of a gene expression signature characterizing highly malignant NB stem cells drawing attention as a potential therapeutic target in NB. In the present study, we sought to investigate the expression of PlGF in NB patients and the effect of PlGF inhibition on high-risk MYCN-non-amplified SK-N-AS NB xenografts. Human SK-N-AS cells, which are poorly differentiated and express PlGF and VEGF-A, were implanted subcutaneously in athymic nude mice. Treatment was done by intratumoral injection of replication-incompetent adenoviruses (Ad) expressing PlGF- or VEGF-specific short hairpin (sh)RNA, or soluble (s)VEGF receptor 2 (VEGFR2). The effect on tumor growth and angiogenesis was analyzed. High PlGF expression levels were observed in human advanced-stage NBs. Down-regulating PlGF significantly reduced NB growth in established NB xenografts by reducing cancer cell proliferation but did not suppress angiogenesis. In contrast, blocking VEGF by administration of Ad(sh)VEGF and Ad(s)VEGFR2 reduced tumor growth associated with decreased tumor vasculature. These findings suggest that PlGF and VEGF-A modulate MYCN-non-amplified NB tumors by different mechanisms and support a role for PlGF in NB biology. Full article

(This article belongs to the Special Issue Vascular Biology and Therapeutics)

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APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome

by Rosanna Palumbo^1,†, Marta Gogliettino^2,*,†, Ennio Cocca²

, Roberta Iannitti¹, Annamaria Sandomenico¹

, Menotti Ruvo¹, Marco Balestrieri², Mosè Rossi² and Gianna Palmieri^2,*

¹ Institute of Biostructure and Bioimaging, National Research Council (CNR-IBB), Napoli 80134, Italy

² Institute of Biosciences and BioResources, National Research Council (CNR-IBBR), Napoli 80131, Italy

Int. J. Mol. Sci. 2016, 17(10), 1614; https://doi.org/10.3390/ijms17101614 - 23 Sep 2016

Cited by 15 | Viewed by 4620

Abstract

The proteasome is a multienzymatic complex that controls the half-life of the majority of intracellular proteins, including those involved in apoptosis and cell-cycle progression. Recently, proteasome inhibition has been shown to be an effective anticancer strategy, although its downregulation is often accompanied by [...] Read more.

The proteasome is a multienzymatic complex that controls the half-life of the majority of intracellular proteins, including those involved in apoptosis and cell-cycle progression. Recently, proteasome inhibition has been shown to be an effective anticancer strategy, although its downregulation is often accompanied by severe undesired side effects. We previously reported that the inhibition of acylpeptide hydrolase (APEH) by the peptide SsCEI 4 can significantly affect the proteasome activity in A375 melanoma or Caco-2 adenocarcinoma cell lines, thus shedding new light on therapeutic strategies based on downstream regulation of proteasome functions. In this work, we investigated the functional correlation between APEH and proteasome in a panel of cancer cell lines, and evaluated the cell proliferation upon SsCEI 4-treatments. Results revealed that SsCEI 4 triggered a proliferative arrest specifically in osteosarcoma U2OS cells via downregulation of the APEH–proteasome system, with the accumulation of the typical hallmarks of proteasome: NF-κB, p21^Waf1, and polyubiquitinylated proteins. We found that the SsCEI 4 anti-proliferative effect involved a senescence-like growth arrest without noticeable cytotoxicity. These findings represent an important step toward understanding the mechanism(s) underlying the APEH-mediated downregulation of proteasome in order to design new molecules able to efficiently regulate the proteasome system for alternative therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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Radiological Patterns of Brain Metastases in Breast Cancer Patients: A Subproject of the German Brain Metastases in Breast Cancer (BMBC) Registry

by Elena Laakmann^1,†, Isabell Witzel^1,†

, Verena Scriba¹, Ulrich Grzyska², Christine Zu Eulenburg^3,4, Nicole Burchardi⁵, Tobias Hesse⁶, Florian Würschmidt⁷, Tanja Fehm⁸, Volker Möbus⁹, Gunter Von Minckwitz⁵, Sibylle Loibl⁵, Tjoung-Won Park-Simon¹⁰

and Volkmar Mueller^1,*

¹ Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany

² Department of Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany

³ Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany

⁴ Department for Epidemiology, University Medical Center Groningen, Groningen 9700, The Netherlands

⁵ German Breast Group GmbH, Neu-Isenburg 63263, Germany

⁶ Department of Gynecology, Agaplesion Diakonie-Clinic Rotenburg, Rotenburg 27356, Germany

⁷ Department of Radiotherapy, Radiology Allianz, Hamburg 22767, Germany

⁸ Translational Research Board of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO-Trafo), Duesseldorf 40225, Germany

⁹ Breast Study Group of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO-B), Frankfurt 65929, Germany

¹⁰ Department of Gynecology, Hannover Medical School, Hannover 30625, Germany

Int. J. Mol. Sci. 2016, 17(10), 1615; https://doi.org/10.3390/ijms17101615 - 23 Sep 2016

Cited by 21 | Viewed by 5795

Abstract

Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases [...] Read more.

Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment. Full article

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

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The Effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on Alcohol-Induced Liver Injury

by Yu-Jie Zhang^1,†, Tong Zhou^1,†, Fang Wang¹

, Yue Zhou¹, Ya Li¹

, Jiao-Jiao Zhang¹, Jie Zheng¹, Dong-Ping Xu¹ and Hua-Bin Li^1,2,*

¹ Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China

² South China Sea Bioresource Exploitation and Utilization Collaborative Innovation Center, Sun Yat-sen University, Guangzhou 510006, China

Int. J. Mol. Sci. 2016, 17(10), 1616; https://doi.org/10.3390/ijms17101616 - 26 Sep 2016

Cited by 34 | Viewed by 5898

Abstract

Previous studies have shown that fruits have different effects on alcohol metabolism and alcohol-induced liver injury. The present work selected three fruits and aimed at studying the effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on alcohol-induced liver injury in mice. [...] Read more.

Previous studies have shown that fruits have different effects on alcohol metabolism and alcohol-induced liver injury. The present work selected three fruits and aimed at studying the effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on alcohol-induced liver injury in mice. The animals were treated daily with alcohol and fruit juices for fifteen days. Chronic treatment with alcohol increased the levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin (TBIL), triglyceride (TG), malondialdehyde (MDA), and decreased total protein (TP). Histopathological evaluation also showed that ethanol induced extensive fat droplets in hepatocyte cytoplasm. Syzygium samarangense and Passiflora edulis normalized various biochemical parameters. Solanum muricatum increased the level of ALT and induced infiltration of inflammatory cells in the liver. These results strongly suggest that treatment with Syzygium samarangense and Passiflora edulis could protect liver from the injury of alcohol, while Solanum muricatum could aggravate the damage. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Long Noncoding RNA lncCAMTA1 Promotes Proliferation and Cancer Stem Cell-Like Properties of Liver Cancer by Inhibiting CAMTA1

by Li-Juan Ding¹, Yan Li², Shu-Dong Wang³, Xin-Sen Wang⁴, Fang Fang², Wei-Yao Wang⁵, Peng Lv⁵, Dong-Hai Zhao⁵, Feng Wei^6,* and Ling Qi^5,*

¹ Department of Radio-Oncology, First Hospital of Jilin University, No. 71 Xinmin Street, Changchun 130021, China

² Academy of Laboratory, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China

³ Center of Cardiovascular Diseases, First Hospital of Jilin University, No. 71 Xinmin Street, Changchun 130021, China

⁴ Department of Interventional Therapy, First Hospital of Jilin University, No. 71 Xinmin Street, Changchun 130021, China

⁵ Department of Pathology, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China

⁶ Department of Hepatobiliary and Pancreas Surgery, First Hospital of Jilin University, No. 71 Xinmin Street, Changchun 130021, China

Int. J. Mol. Sci. 2016, 17(10), 1617; https://doi.org/10.3390/ijms17101617 - 23 Sep 2016

Cited by 63 | Viewed by 6908

Abstract

Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC [...] Read more.

Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC therapy. Here, using long noncoding RNA (lncRNA) microarray analysis, we identified a novel lncRNA termed lncCAMTA1 that is increased in both liver CSCs and HCC. High lncCAMTA1 expression in HCC indicates poor clinical outcome. In vitro and in vivo functional experiments showed that overexpression of lncCAMTA1 promotes HCC cell proliferation, CSC-like properties, and tumorigenesis. Conversely, depletion of lncCAMTA1 inhibits HCC cell proliferation, CSC-like properties, and tumorigenesis. Mechanistically, we demonstrated that lncCAMTA1 physically associates with the calmodulin binding transcription activator 1 (CAMTA1) promoter, induces a repressive chromatin structure, and inhibits CAMTA1 transcription. Furthermore, CAMTA1 is required for the effects of lncCAMTA1 on HCC cell proliferation and CSC-like properties, and the expression of lncCAMTA1 and CAMTA1 is significantly negatively correlated in HCC tissues. Collectively, our study revealed the important roles and underlying molecular mechanisms of lncCAMTA1 on HCC, and suggested that lncCAMTA1 could be an effective prognostic factor and a potential therapeutic target for HCC. Full article

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

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The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models

by Silvia Ribback^1,*, Verena Sailer^1,2, Enrico Böhning¹, Julia Günther¹, Jaqueline Merz¹, Frauke Steinmüller^1,3, Kirsten Utpatel^1,4, Antonio Cigliano¹, Kristin Peters¹, Maria G. Pilo¹, Matthias Evert^1,4, Diego F. Calvisi¹ and Frank Dombrowski¹

¹ Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany

² Englander Institut for Precision Medicine, Weill Cornell University of Medicine, New York, NY 10065, USA

³ Pathologisches Institut Diakonie-Krankenhaus, 27356 Rotenburg (Wümme), Germany

⁴ Institut für Pathologie, Universitätsklinikum Regensburg, 93053 Regensburg, Germany

Int. J. Mol. Sci. 2016, 17(10), 1618; https://doi.org/10.3390/ijms17101618 - 23 Sep 2016

Cited by 4 | Viewed by 4965

Abstract

Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions [...] Read more.

Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)

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by Piotr Donizy^1,*, Maciej Kaczorowski¹, Przemyslaw Biecek²

, Agnieszka Halon¹, Teresa Szkudlarek¹ and Rafal Matkowski^3,4

¹ Department of Pathomorphology and Oncological Cytology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland

² Faculty of Mathematics and Information Science, Warsaw University of Technology, Koszykowa 75, 00-662 Warsaw, Poland

³ Department of Oncology, Wroclaw Medical University; pl. Hirszfelda 12, 53-413 Wroclaw, Poland

⁴ Lower Silesian Cancer Center, Hirszfelda 12, 53-413 Wroclaw, Poland

Int. J. Mol. Sci. 2016, 17(10), 1619; https://doi.org/10.3390/ijms17101619 - 1 Oct 2016

Cited by 30 | Viewed by 5500

Abstract

GOLPH2 and GOLPH3 are Golgi-related proteins associated with aggressiveness and progression of a number of cancers. Their prognostic significance in melanoma has not yet been analyzed. We performed immunohistochemical analysis for GOLPH2 and GOLPH3 in 20 normal skin, 30 benign nevi and 100 [...] Read more.

GOLPH2 and GOLPH3 are Golgi-related proteins associated with aggressiveness and progression of a number of cancers. Their prognostic significance in melanoma has not yet been analyzed. We performed immunohistochemical analysis for GOLPH2 and GOLPH3 in 20 normal skin, 30 benign nevi and 100 primary melanoma tissue samples and evaluated their expression in three compartments: cancer cells, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). High levels of both proteins in melanoma cells were associated with characteristics of aggressive disease, and shorter disease-free survival (DFS) and cancer-specific overall survival (CSOS). On the contrary, increased numbers of GOLPH2-positive and GOLPH3-positive TAMs were observed in thinner, non-ulcerated tumors, with brisk lymphocytic reaction and absent lymphangioinvasion. Distant metastases were not observed among patients with high numbers of GOLPH2-positive TAMs. Increased expression of either protein in TAMs was related to prolonged CSOS and DFS. Similarly, GOLPH3-expressing CAFs were more frequent in thin melanomas with low mitotic rate, without ulceration and lymphangioinvasion. Moreover, increased GOLPH3-positive CAFs correlated with the absence of regional or distant metastases, and with longer CSOS and DFS. GOLPH2 expression was not observed in CAFs. Our results suggest that GOLPH2 and GOLPH3 play a role in melanoma progression and are potential targets for molecular-based therapies. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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miR33a/miR33b* and miR122 as Possible Contributors to Hepatic Lipid Metabolism in Obese Women with Nonalcoholic Fatty Liver Disease

by Teresa Auguet^1,2,*, Gemma Aragonès¹, Alba Berlanga¹, Esther Guiu-Jurado¹, Andreu Martí², Salomé Martínez³, Fàtima Sabench⁴, Mercé Hernández⁴, Carmen Aguilar¹, Joan Josep Sirvent³, Daniel Del Castillo⁴ and Cristóbal Richart^1,2,*

¹ Group de Recerca GEMMAIR (AGAUR)-Medicina Aplicada, Institut Investigació Sanitària Pere Virgili (IISPV), Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Tarragona 43007, Spain

² Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, Tarragona 43007, Spain

³ Servei Anatomia Patològica, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, Tarragona 43007, Spain

⁴ Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, Avinguda Doctor Josep Laporte, 2, 43204 Reus, Tarragona 43204, Spain

Int. J. Mol. Sci. 2016, 17(10), 1620; https://doi.org/10.3390/ijms17101620 - 24 Sep 2016

Cited by 46 | Viewed by 5851

Abstract

Specific miRNA expression profiles have been shown to be associated with nonalcoholic fatty liver disease (NAFLD). We examined the correlation between the circulating levels and hepatic expression of miR122 and miR33a/b*, the key lipid metabolism-related gene expression and the clinicopathological factors of obese [...] Read more.

Specific miRNA expression profiles have been shown to be associated with nonalcoholic fatty liver disease (NAFLD). We examined the correlation between the circulating levels and hepatic expression of miR122 and miR33a/b*, the key lipid metabolism-related gene expression and the clinicopathological factors of obese women with NAFLD. We measured miR122 and miR33a/b* expression in liver samples from 62 morbidly obese (MO), 30 moderately obese (ModO), and eight normal-weight controls. MiR122 and miR33a/b* expression was analyzed by qRT-PCR. Additionally, miR122 and miR33b* circulating levels were analyzed in 122 women. Hepatic miR33b* expression was increased in MO compared to ModO and controls, whereas miR122 expression was decreased in the MO group compared to ModO. In obese cohorts, miR33b* expression was increased in nonalcoholic steatohepatitis (NASH). Regarding circulating levels, MO patients with NASH showed higher miR122 levels than MO with simple steatosis (SS). These circulating levels are good predictors of histological features associated with disease severity. MO is associated with altered hepatic miRNA expression. In obese women, higher miR33b* liver expression is associated with NASH. Moreover, multiple correlations between miRNAs and the expression of genes related to lipid metabolism were found, that would suggest a miRNA-host gene circuit. Finally, miR122 circulating levels could be included in a panel of different biomarkers to improve accuracy in the non-invasive diagnosis of NASH. Full article

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

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Genome-Wide Characterization and Expression Analysis of the Germin-Like Protein Family in Rice and Arabidopsis

by Lu Li, Xihui Xu, Chen Chen^* and Zhenguo Shen

College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China

Int. J. Mol. Sci. 2016, 17(10), 1622; https://doi.org/10.3390/ijms17101622 - 23 Sep 2016

Cited by 42 | Viewed by 6658

Abstract

Previous studies have shown that germin-like proteins (GLPs) are present ubiquitously in rice and Arabidopsis. However, the understanding regarding their role in development and abiotic/biotic stress resistance remains limited. In the present study, we report genome-wide identification, characterisation, subcellular localization, enzyme activity, and [...] Read more.

Previous studies have shown that germin-like proteins (GLPs) are present ubiquitously in rice and Arabidopsis. However, the understanding regarding their role in development and abiotic/biotic stress resistance remains limited. In the present study, we report genome-wide identification, characterisation, subcellular localization, enzyme activity, and expression analysis of the GLP gene family in rice and Arabidopsis to study their functions. In total, 43 and 32 GLPs in the rice and Arabidopsis genome were identified based on a systematic analysis, respectively. The GLP genes were clustered into six clades based on phylogenetic analysis, and many stress and developmental-related cis-elements were detected in promoters of GLP genes. In addition, subcellular location and superoxide dismutase (SOD) analysis demonstrated that the random selected OsGLP genes on chromosomes 8 and 4 of rice were expressed in the cell wall with SOD activity. Overall, our results showed that tandem duplication events, especially the clusters of tandem duplication genes on chromosome 8 in rice, play a major role in expansion of the GLP family and thus increase our understanding of the role of the GLP family in abiotic/biotic stress and development. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessArticle

Identification of Protein–Protein Interactions via a Novel Matrix-Based Sequence Representation Model with Amino Acid Contact Information

by Yijie Ding¹

, Jijun Tang^1,2 and Fei Guo^1,*

¹ School of Computer Science and Technology, Tianjin University, Tianjin 300350, China

² Department of Computer Science and Engineering, University of South Carolina, Columbia, SC 29208, USA

Int. J. Mol. Sci. 2016, 17(10), 1623; https://doi.org/10.3390/ijms17101623 - 24 Sep 2016

Cited by 86 | Viewed by 6206

Abstract

Identification of protein–protein interactions (PPIs) is a difficult and important problem in biology. Since experimental methods for predicting PPIs are both expensive and time-consuming, many computational methods have been developed to predict PPIs and interaction networks, which can be used to complement experimental [...] Read more.

Identification of protein–protein interactions (PPIs) is a difficult and important problem in biology. Since experimental methods for predicting PPIs are both expensive and time-consuming, many computational methods have been developed to predict PPIs and interaction networks, which can be used to complement experimental approaches. However, these methods have limitations to overcome. They need a large number of homology proteins or literature to be applied in their method. In this paper, we propose a novel matrix-based protein sequence representation approach to predict PPIs, using an ensemble learning method for classification. We construct the matrix of Amino Acid Contact (AAC), based on the statistical analysis of residue-pairing frequencies in a database of 6323 protein–protein complexes. We first represent the protein sequence as a Substitution Matrix Representation (SMR) matrix. Then, the feature vector is extracted by applying algorithms of Histogram of Oriented Gradient (HOG) and Singular Value Decomposition (SVD) on the SMR matrix. Finally, we feed the feature vector into a Random Forest (RF) for judging interaction pairs and non-interaction pairs. Our method is applied to several PPI datasets to evaluate its performance. On the

S . c e r e v i s i a e

dataset, our method achieves

94.83 %

accuracy and

92.40 %

sensitivity. Compared with existing methods, and the accuracy of our method is increased by

0.11

percentage points. On the

H . p y l o r i

dataset, our method achieves

89.06 %

accuracy and

88.15 %

sensitivity, the accuracy of our method is increased by

0.76 %

. On the

H u m a n

PPI dataset, our method achieves

97.60 %

accuracy and

96.37 %

sensitivity, and the accuracy of our method is increased by

1.30 %

. In addition, we test our method on a very important PPI network, and it achieves

92.71 %

accuracy. In the Wnt-related network, the accuracy of our method is increased by

16.67 %

. The source code and all datasets are available at https://figshare.com/s/580c11dce13e63cb9a53. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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Open AccessArticle

Hepatic Fasting-Induced PPARα Activity Does Not Depend on Essential Fatty Acids

by Arnaud Polizzi¹, Edwin Fouché¹, Simon Ducheix¹, Frédéric Lasserre¹, Alice P. Marmugi¹, Laila Mselli-Lakhal¹, Nicolas Loiseau¹, Walter Wahli^1,2,3

, Hervé Guillou^1,* and Alexandra Montagner^1,*

¹ INRA ToxAlim, 180, Chemin de Tournefeuille, 31027 Toulouse Cedex 3, France

² Lee Kong Chian School of Medicine, Nanyang Technological University, 637553 Singapore, Singapore

³ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland

Int. J. Mol. Sci. 2016, 17(10), 1624; https://doi.org/10.3390/ijms17101624 - 24 Sep 2016

Cited by 6 | Viewed by 4720

Abstract

The liver plays a central role in the regulation of fatty acid metabolism, which is highly sensitive to transcriptional responses to nutrients and hormones. Transcription factors involved in this process include nuclear hormone receptors. One such receptor, PPARα, which is highly expressed in [...] Read more.

The liver plays a central role in the regulation of fatty acid metabolism, which is highly sensitive to transcriptional responses to nutrients and hormones. Transcription factors involved in this process include nuclear hormone receptors. One such receptor, PPARα, which is highly expressed in the liver and activated by a variety of fatty acids, is a critical regulator of hepatic fatty acid catabolism during fasting. The present study compared the influence of dietary fatty acids and fasting on hepatic PPARα-dependent responses. Pparα^−/− male mice and their wild-type controls were fed diets containing different fatty acids for 10 weeks prior to being subjected to fasting or normal feeding. In line with the role of PPARα in sensing dietary fatty acids, changes in chronic dietary fat consumption influenced liver damage during fasting. The changes were particularly marked in mice fed diets lacking essential fatty acids. However, fasting, rather than specific dietary fatty acids, induced acute PPARα activity in the liver. Taken together, the data imply that the potent signalling involved in triggering PPARα activity during fasting does not rely on essential fatty acid-derived ligand. 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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Open AccessArticle

Autoimmunity and Cytokine Imbalance in Inherited Epidermolysis Bullosa

by Susanna Esposito^1,*

, Sophie Guez¹, Annalisa Orenti¹

, Gianluca Tadini^1,2, Giulietta Scuvera¹, Laura Corti²

, Alessia Scala¹, Elia Biganzoli³, Emilio Berti² and Nicola Principi¹

¹ Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy

² Dermatology Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy

³ Unit of Medical Statistics, Biometry and Bioinformatics “G.A. Maccacaro”, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan 20122, Italy

Int. J. Mol. Sci. 2016, 17(10), 1625; https://doi.org/10.3390/ijms17101625 - 24 Sep 2016

Cited by 39 | Viewed by 5353

Abstract

In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB) types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls ( [...] Read more.

In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB) types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls (p = 0.008, p < 0.001, p < 0.001, p < 0.001 and p < 0.001 for desmoglein 1 (DSG1) desmoglein 3 (DSG3), bullous pemphigoid 180 (BP180), BP230 and type VII collagen (COL7), respectively). The same trend was observed for interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-β, and interferon-γ (p < 0.001, p < 0.001, p < 0.001, p = 0.008, p < 0.001 and p = 0.002, respectively). Increases in anti-skin antibodies and cytokine concentrations were higher in patients with recessive dystrophic EB than in those with different types of EB, in generalized cases than in localized ones, and in patients with higher Birmingham Epidermolysis Bullosa Severity (BEBS) scores than in those with a lower score. The BEBS score was directly correlated with BP180, BP230, COL7 (p = 0.015, p = 0.008 and p < 0.001, respectively) and IL-6 (p = 0.03), whereas IL-6 appeared significantly associated with DSG1, DSG3, BP180, BP230 and COL7 (p = 0.015, p = 0.023, p = 0.023, p = 0.015 and p = 0.005, respectively). This study showed that autoimmunity and inflammatory responses are frequently activated in EB, mainly in severe forms, suggesting the use of immunosuppressive drugs or biologicals that are active against pro-inflammatory cytokines to reduce clinical signs and symptoms of disease. Full article

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

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Open AccessArticle

CAPS1 Negatively Regulates Hepatocellular Carcinoma Development through Alteration of Exocytosis-Associated Tumor Microenvironment

by Ruyi Xue^1,*,†, Wenqing Tang^1,†, Pingping Dong^1,†, Shuqiang Weng¹, Lijie Ma², She Chen³, Taotao Liu¹, Xizhong Shen¹, Xiaowu Huang², Si Zhang³ and Ling Dong^1,*

¹ Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China

² Department of Hepatic Surgery of Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China

³ Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Int. J. Mol. Sci. 2016, 17(10), 1626; https://doi.org/10.3390/ijms17101626 - 27 Sep 2016

Cited by 6 | Viewed by 4892

Abstract

The calcium-dependent activator protein for secretion 1 (CAPS1) regulates exocytosis of dense-core vesicles (DCVs) in neurons and neuroendocrine cells. The role of CAPS1 in cancer biology remains unknown. The purpose of this study was to investigate the role of CAPS1 in hepatocellular carcinoma [...] Read more.

The calcium-dependent activator protein for secretion 1 (CAPS1) regulates exocytosis of dense-core vesicles (DCVs) in neurons and neuroendocrine cells. The role of CAPS1 in cancer biology remains unknown. The purpose of this study was to investigate the role of CAPS1 in hepatocellular carcinoma (HCC). We determined the levels of CAPS1 in eight hepatoma cell lines and 141 HCC specimens. We evaluated the prognostic value of CAPS1 expression and its association with clinical parameters. We investigated the biological consequences of CAPS1 overexpression in two hepatoma cell lines in vitro and in vivo. The results showed that loss of CAPS1 expression in HCC tissues was markedly correlated with aggressive tumor phenotypes, such as high-grade tumor node metastasis (TNM) stage (p = 0.003) and absence of tumor encapsulation (p = 0.016), and was associated with poor overall survival (p = 0.008) and high recurrence (p = 0.015). CAPS1 overexpression inhibited cell proliferation and migration by changing the exocytosis-associated tumor microenvironment in hepatoma cells in vitro. The in vivo study showed that CAPS1 overexpression inhibited xenograft tumor growth. Together, these results identified a previously unrecognized tumor suppressor role for CAPS1 in HCC development. Full article

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

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Open AccessArticle

Potential of LC Coupled to Fluorescence Detection in Food Metabolomics: Determination of Phenolic Compounds in Virgin Olive Oil

by Romina P. Monasterio¹

, Lucía Olmo-García²

, Aadil Bajoub², Alberto Fernández-Gutiérrez² and Alegría Carrasco-Pancorbo^2,*

¹ Instituto de Biología Agrícola de Mendoza (IBAM), CONICET, Alt. Brown 500, Chacras de Coria, 5505 Mendoza, Argentina

² Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Ave. Fuentenueva s/n, E-18071 Granada, Spain

Int. J. Mol. Sci. 2016, 17(10), 1627; https://doi.org/10.3390/ijms17101627 - 24 Sep 2016

Cited by 9 | Viewed by 5311

Abstract

A powerful chromatographic method coupled to a fluorescence detector was developed to determine the phenolic compounds present in virgin olive oil (VOO), with the aim to propose an appropriate alternative to liquid chromatography-mass spectrometry. An excitation wavelength of 285 nm was selected and [...] Read more.

A powerful chromatographic method coupled to a fluorescence detector was developed to determine the phenolic compounds present in virgin olive oil (VOO), with the aim to propose an appropriate alternative to liquid chromatography-mass spectrometry. An excitation wavelength of 285 nm was selected and four different emission wavelengths (316, 328, 350 and 450 nm) were simultaneously recorded, working therefore on “multi-emission” detection mode. With the use of commercially available standards and other standards obtained by semipreparative high performance liquid chromatography, it was possible to identify simple phenols, lignans, several complex phenols, and other phenolic compounds present in the matrix under study. A total of 26 phenolic compounds belonging to different chemical families were identified (23 of them were susceptible of being quantified). The proposed methodology provided detection and quantification limits within the ranges of 0.004–7.143 μg·mL⁻¹ and 0.013–23.810 μg·mL⁻¹, respectively. As far as the repeatability is concerned, the relative standard deviation values were below 0.43% for retention time, and 9.05% for peak area. The developed methodology was applied for the determination of phenolic compounds in ten VOOs, both monovarietals and blends. Secoiridoids were the most abundant fraction in all the samples, followed by simple phenolic alcohols, lignans, flavonoids, and phenolic acids (being the abundance order of the latter chemical classes logically depending on the variety and origin of the VOOs). Full article

(This article belongs to the Special Issue New Foodomics Approaches in Food Science)

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Open AccessArticle

New Potential Biomarker for Methasterone Misuse in Human Urine by Liquid Chromatography Quadrupole Time of Flight Mass Spectrometry

by Jianli Zhang^1,2, Jianghai Lu^2,*, Yun Wu², Xiaobing Wang², Youxuan Xu², Yinong Zhang² and Yan Wang^1,*

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

² China Anti-Doping Agency, Beijing 100029, China

Int. J. Mol. Sci. 2016, 17(10), 1628; https://doi.org/10.3390/ijms17101628 - 24 Sep 2016

Cited by 5 | Viewed by 5219

Abstract

In this study, methasterone urinary metabolic profiles were investigated by liquid chromatography quadrupole time of flight mass spectrometry (LC-QTOF-MS) in full scan and targeted MS/MS modes with accurate mass measurement. A healthy male volunteer was asked to take the drug and liquid–liquid extraction [...] Read more.

In this study, methasterone urinary metabolic profiles were investigated by liquid chromatography quadrupole time of flight mass spectrometry (LC-QTOF-MS) in full scan and targeted MS/MS modes with accurate mass measurement. A healthy male volunteer was asked to take the drug and liquid–liquid extraction was employed to process urine samples. Chromatographic peaks for potential metabolites were hunted out with the theoretical [M − H]⁻ as a target ion in a full scan experiment and actual deprotonated ions were studied in targeted MS/MS experiment. Fifteen metabolites including two new sulfates (S1 and S2), three glucuronide conjugates (G2, G6 and G7), and three free metabolites (M2, M4 and M6) were detected for methasterone. Three metabolites involving G4, G5 and M5 were obtained for the first time in human urine samples. Owing to the absence of helpful fragments to elucidate the steroid ring structure of methasterone phase II metabolites, gas chromatography mass spectrometry (GC-MS) was employed to obtain structural information of the trimethylsilylated phase I metabolite released after enzymatic hydrolysis and the potential structure was inferred using a combined MS method. Metabolite detection times were also analyzed and G2 (18-nor-17β-hydroxymethyl-2α, 17α-dimethyl-androst-13-en-3α-ol-ξ-O-glucuronide) was thought to be new potential biomarker for methasterone misuse which can be detected up to 10 days. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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Open AccessArticle

Direct LAMP Assay without Prior DNA Purification for Sex Determination of Papaya

by Chi-Chu Tsai^1,2,†, Huei-Chuan Shih^3,†, Ya-Zhu Ko^4,†, Ren-Huang Wang^1,†, Shu-Ju Li¹ and Yu-Chung Chiang^4,5,*

¹ Kaohsiung District Agricultural Research and Extension Station, Pingtung 908, Taiwan

² Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 912, Taiwan

³ Department of Nursing, Meiho University, Pingtung 912, Taiwan

⁴ Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan

⁵ Department of Biomedical Science and Environment Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan

Int. J. Mol. Sci. 2016, 17(10), 1630; https://doi.org/10.3390/ijms17101630 - 24 Sep 2016

Cited by 9 | Viewed by 6839

Abstract

Papaya (Carica papaya L.) is an economically important tropical fruit tree with hermaphrodite, male and female sex types. Hermaphroditic plants are the major type used for papaya production because their fruits have more commercial advantages than those of female plants. Sex determination [...] Read more.

Papaya (Carica papaya L.) is an economically important tropical fruit tree with hermaphrodite, male and female sex types. Hermaphroditic plants are the major type used for papaya production because their fruits have more commercial advantages than those of female plants. Sex determination of the seedlings, or during the early growth stages, is very important for the papaya seedling industry. Thus far, the only method for determining the sex type of a papaya at the seedling stage has been DNA analysis. In this study, a molecular technique—based on DNA analysis—was developed for detecting male-hermaphrodite-specific markers to examine the papaya’s sex type. This method is based on the loop-mediated isothermal amplification (LAMP) and does not require prior DNA purification. The results show that the method is an easy, efficient, and inexpensive way to determine a papaya’s sex. This is the first report on the LAMP assay, using intact plant materials-without DNA purification-as samples for the analysis of sex determination of papaya. We found that using high-efficiency DNA polymerase was essential for successful DNA amplification, using trace intact plant material as a template DNA source. Full article

(This article belongs to the Special Issue Plant-Derived Pharmaceuticals by Molecular Farming 2016)

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Open AccessArticle

Fabrication and Mechanical Characterization of Hydrogel Infused Network Silk Scaffolds

by Lakshminath Kundanati^1,*, Saket K. Singh², Biman B. Mandal², Tejas G. Murthy³, Namrata Gundiah⁴ and Nicola M. Pugno^1,5,6,*

¹ Laboratory of Bio-Inspired & Graphene Nanomechanics, Department of Civil, Environmental and Mechanical Engineering, University of Trento, Via Mesiano 77, 38123 Trento, Italy

² Biomaterial and Tissue Engineering Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati 781039, Assam, India

³ Departments of Civil Engineering, Indian Institute of Science, Bangalore 560012, Karnataka, India

⁴ Departments of Mechanical Engineering, Indian Institute of Science, Bangalore 560012, Karnataka, India

⁵ Center for Materials and Microsystems, Fondazione Bruno Kessler, Via Sommarive 18, Povo, I-38123 Trento, Italy

⁶ School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, UK

Int. J. Mol. Sci. 2016, 17(10), 1631; https://doi.org/10.3390/ijms17101631 - 26 Sep 2016

Cited by 14 | Viewed by 5364

Abstract

Development and characterization of porous scaffolds for tissue engineering and regenerative medicine is of great importance. In recent times, silk scaffolds were developed and successfully tested in tissue engineering and drug release applications. We developed a novel composite scaffold by mechanical infusion of [...] Read more.

Development and characterization of porous scaffolds for tissue engineering and regenerative medicine is of great importance. In recent times, silk scaffolds were developed and successfully tested in tissue engineering and drug release applications. We developed a novel composite scaffold by mechanical infusion of silk hydrogel matrix into a highly porous network silk scaffold. The mechanical behaviour of these scaffolds was thoroughly examined for their possible use in load bearing applications. Firstly, unconfined compression experiments show that the denser composite scaffolds displayed significant enhancement in the elastic modulus as compared to either of the components. This effect was examined and further explained with the help of foam mechanics principles. Secondly, results from confined compression experiments that resemble loading of cartilage in confinement, showed nonlinear material responses for all scaffolds. Finally, the confined creep experiments were performed to calculate the hydraulic permeability of the scaffolds using soil mechanics principles. Our results show that composite scaffolds with some modifications can be a potential candidate for use of cartilage like applications. We hope such approaches help in developing novel scaffolds for tissue engineering by providing an understanding of the mechanics and can further be used to develop graded scaffolds by targeted infusion in specific regions. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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Open AccessArticle

Global Transcriptomic Analysis of Targeted Silencing of Two Paralogous ACC Oxidase Genes in Banana

by Yan Xia¹

, Chi Kuan², Chien-Hsiang Chiu², Xiao-Jing Chen¹, Yi-Yin Do^2,* and Pung-Ling Huang^1,2,3,*

¹ College of Horticulture, Fujian Agriculture and Forestry University, Fuzhou 350002, China

² Department of Horticulture and Landscape Architecture, National Taiwan University, Taipei 10617, Taiwan

³ Graduate Institute of Biotechnology, Chinese Culture University, Taipei 11114, Taiwan

Int. J. Mol. Sci. 2016, 17(10), 1632; https://doi.org/10.3390/ijms17101632 - 26 Sep 2016

Cited by 5 | Viewed by 5766

Abstract

Among 18 1-aminocyclopropane-1-carboxylic acid (ACC) oxidase homologous genes existing in the banana genome there are two genes, Mh-ACO1 and Mh-ACO2, that participate in banana fruit ripening. To better understand the physiological functions of Mh-ACO1 and Mh-ACO2, two hairpin-type siRNA expression vectors [...] Read more.

Among 18 1-aminocyclopropane-1-carboxylic acid (ACC) oxidase homologous genes existing in the banana genome there are two genes, Mh-ACO1 and Mh-ACO2, that participate in banana fruit ripening. To better understand the physiological functions of Mh-ACO1 and Mh-ACO2, two hairpin-type siRNA expression vectors targeting both the Mh-ACO1 and Mh-ACO2 were constructed and incorporated into the banana genome by Agrobacterium-mediated transformation. The generation of Mh-ACO1 and Mh-ACO2 RNAi transgenic banana plants was confirmed by Southern blot analysis. To gain insights into the functional diversity and complexity between Mh-ACO1 and Mh-ACO2, transcriptome sequencing of banana fruits using the Illumina next-generation sequencer was performed. A total of 32,093,976 reads, assembled into 88,031 unigenes for 123,617 transcripts were obtained. Significantly enriched Gene Oncology (GO) terms and the number of differentially expressed genes (DEGs) with GO annotation were ‘catalytic activity’ (1327, 56.4%), ‘heme binding’ (65, 2.76%), ‘tetrapyrrole binding’ (66, 2.81%), and ‘oxidoreductase activity’ (287, 12.21%). Real-time RT-PCR was further performed with mRNAs from both peel and pulp of banana fruits in Mh-ACO1 and Mh-ACO2 RNAi transgenic plants. The results showed that expression levels of genes related to ethylene signaling in ripening banana fruits were strongly influenced by the expression of genes associated with ethylene biosynthesis. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessArticle

MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais

by Sen Lian^1,†, Jung Sun Park^1,†, Yong Xia¹, Thi Thinh Nguyen¹, Young Eun Joo¹, Kyung Keun Kim¹, Hark Kyun Kim² and Young Do Jung^1,3,*

¹ Research Institute of Medical Sciences, Chonnam National University Medical School, 501-190 Gwangju, Korea

² Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics, National Cancer Center, 410-769 Goyang, Korea

³ Department of Biochemistry, Chonnam National University Medical School, 5 Hakdong, 501-190 Gwangju, Korea

Int. J. Mol. Sci. 2016, 17(10), 1633; https://doi.org/10.3390/ijms17101633 - 27 Sep 2016

Cited by 22 | Viewed by 5746

Abstract

Emerging evidence supports a fundamental role for microRNAs (miRNA) in regulating cancer metastasis. Recently, microRNA-375 (miR-375) was reported to be downregulated in many types of cancers, including gastric cancer. Increase in the expression of Recepteur d’Origine Nantais (RON), a receptor tyrosine [...] Read more.

Emerging evidence supports a fundamental role for microRNAs (miRNA) in regulating cancer metastasis. Recently, microRNA-375 (miR-375) was reported to be downregulated in many types of cancers, including gastric cancer. Increase in the expression of Recepteur d’Origine Nantais (RON), a receptor tyrosine kinase, has been reported in tumors. However, the function of miR-375 and RON expression in gastric cancer metastasis has not been sufficiently studied. In silico analysis identified miR-375 binding sites in the 3′-untranslated regions (3′-UTR) of the RON-encoding gene. Expression of miR-375 resulted in reduced activity of a luciferase reporter containing the 3′-UTR fragments of RON-encoding mRNA, confirming that miR-375 directly targets the 3′-UTR of RON mRNA. Moreover, we found that overexpression of miR-375 inhibited mRNA and protein expression of RON, which was accompanied by the suppression of cell proliferation, migration, and invasion in gastric cancer AGS and MKN-28 cells. Ectopic miR-375 expression also induced G1 cell cycle arrest through a decrease in the expression of cyclin D1, cyclin D3, and in the phosphorylation of retinoblastoma (Rb). Knockdown of RON by RNAi, similar to miR-375 overexpression, suppressed tumorigenic properties and induced G1 arrest through a decrease in the expression of cyclin D1, cyclin D3, and in the phosphorylation of Rb. Thus, our study provides evidence that miR-375 acts as a suppressor of metastasis in gastric cancer by targeting RON, and might represent a new potential therapeutic target for gastric cancer. Full article

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

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Open AccessCommunication

Disruption of Membranes of Extracellular Vesicles Is Necessary for ELISA Determination of Urine AQP2: Proof of Disruption and Epitopes of AQP2 Antibodies

by Masaaki Nameta^1,†, Yoko Saijo^2,†

, Yasukazu Ohmoto³, Kiyonori Katsuragi², Keiko Yamamoto⁴, Tadashi Yamamoto⁴, Kenichi Ishibashi⁵ and Sei Sasaki^5,6,*

¹ Electron Microscope Core Facility, Niigata University, Niigata 951-851, Japan

² Department of Research and Development, Diagnostic Division, Otsuka Pharmaceutical Co., Ltd., Tokusima 771-0182, Japan

³ Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokusima 771-0192, Japan

⁴ Biofluid Biomarker Center, Institute of Social Innovation and Promotion, Niigata University, Niigata 950-2181, Japan

⁵ Department of Pathophysiology, Meiji Pharmaceutical University, Tokyo 204-8588, Japan

⁶ Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan

Int. J. Mol. Sci. 2016, 17(10), 1634; https://doi.org/10.3390/ijms17101634 - 26 Sep 2016

Cited by 8 | Viewed by 5196

Abstract

Aquaporin-2 (AQP2) is present in urine extracellular vesicles (EVs) and is a useful biomarker for water balance disorders. We previously found that pre-treatment of urine with alkali/detergent or storage at −25 °C is required for enzyme-linked immunosorbent assay (ELISA) measurement. We speculated that [...] Read more.

Aquaporin-2 (AQP2) is present in urine extracellular vesicles (EVs) and is a useful biomarker for water balance disorders. We previously found that pre-treatment of urine with alkali/detergent or storage at −25 °C is required for enzyme-linked immunosorbent assay (ELISA) measurement. We speculated that disruptions of EVs membranes are necessary to allow for the direct contact of antibodies with their epitopes. Human urine EVs were prepared using an ultracentrifugation method. Urine EV samples were stored at different temperatures for a week. Electron microscopy showed abundant EVs with diameters of 20–100 nm, consistent with those of exosomes, in normal urine, whereas samples from alkali/detergent pre-treated urine showed fewer EVs with large swollen shapes and frequent membrane disruptions. The abundance and structures of EVs were maintained during storage at −80 °C, but were severely damaged at −25 °C. Binding and competitive inhibition assays showed that epitopes of monoclonal antibody and polyclonal antibody were the hydrophilic Loop D and C-terminus of AQP2, respectively, both of which are present on the inner surface of EVs. Thus, urine storage at −25 °C or pre-treatment with alkali/detergent disrupt EVs membranes and allow AQP2 antibodies to bind to their epitopes located inside EVs. Full article

(This article belongs to the Special Issue Aquaporin)

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Open AccessArticle

Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients

by Haorile Chagan-Yasutan^1,2,*

, Yue Chen², Talitha Lea Lacuesta³, Prisca Susan A. Leano⁴, Hiroko Iwasaki¹, Firmanto Hanan^2,5, Delsi Taurustiati^2,5, Yasukazu Ohmoto⁶, Yugo Ashino^1,2, Hiroki Saitoh², Hideyasu Kiyomoto⁷

, Yasuhiko Suzuki^8,9, Freda O. Elizabeth Telan⁴ and Toshio Hattori^1,2,10

¹ Disaster-Related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, 980-8575 Sendai, Japan

² Emerging Infectious Diseases, Department of Internal Medicine, Graduate School of Medicine, Tohoku University, 980-8575 Sendai, Japan

³ Adult Infectious Disease and Tropical Medicine Department, San Lazaro Hospital, 1003 Manila, Philippines

⁴ National Reference Laboratory for HIV/AIDS, Hepatitis, and other STDs, STD/AIDS Cooperative Central Laboratory, 1003 Manila, Philippines

⁵ Faculty of Medicine, Universitas Padjadjaran, 40161 Bandung, Indonesia

⁶ Research Institute of Pharmacological Therapeutical Development, Otsuka Pharmaceutical Co., Ltd., 771-0192 Tokushima, Japan

⁷ Division of Integrated Nephrology and Telemedicine, Tohoku Medical Megabank Organization, Tohoku University, 980-8573 Sendai, Japan

⁸ Research Center for Zoonosis Control, Hokkaido University, 001-0020 Sapporo, Japan

⁹ GI-CoRE Global Station for Zoonosis Control, Hokkaido University, 001-0020 Sapporo, Japan

¹⁰ Department of Occupational Therapy, Graduate School of Health Science Studies, Kibi International University, 716-8508 Takahashi, Japan

Int. J. Mol. Sci. 2016, 17(10), 1637; https://doi.org/10.3390/ijms17101637 - 27 Sep 2016

Cited by 7 | Viewed by 4885

Abstract

Leptospirosis is a zoonotic disease whose severe forms are often accompanied by kidney dysfunction. In the present study, urinary markers were studied for potential prediction of disease severity. Urine samples from 135 patients with or without leptospirosis at San Lazaro Hospital, the Philippines, [...] Read more.

Leptospirosis is a zoonotic disease whose severe forms are often accompanied by kidney dysfunction. In the present study, urinary markers were studied for potential prediction of disease severity. Urine samples from 135 patients with or without leptospirosis at San Lazaro Hospital, the Philippines, were analyzed. Urine levels of defensin α1 (uDA1) were compared with those of neutrophil gelatinase-associated lipocalin (uNGAL) and N-acetyl-β-d-glucosidase (uNAG). Serum creatinine (Cr) was used as a marker of kidney injury. The levels of uDA1/Cr, uNGAL/Cr, and uNAG/Cr were positive in 46%, 90%, and 80% of leptospirosis patients, and 69%, 70%, and 70% of non-leptospirosis patients, respectively. In leptospirosis patients, the correlation of uDA1/Cr, uNGAL/Cr and uNAG/Cr levels with serum Cr were r = 0.3 (p < 0.01), r = 0.29 (p < 0.01), and r = 0.02 (p = 0.81), respectively. uDA1/Cr levels were correlated with uNGAL/Cr levels (r = 0.49, p < 0.01) and uNAG/Cr levels (r = 0.47, p < 0.0001) in leptospirosis patients. These findings suggest that uDA1, uNGAL, and uNAG were elevated in leptospirosis patients and reflected various types of kidney damage. uDA1 and uNGAL can be used to track kidney injury in leptospirosis patients because of their correlation with the serum Cr level. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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Probiotics Differently Affect Gut-Associated Lymphoid Tissue Indolamine-2,3-Dioxygenase mRNA and Cerebrospinal Fluid Neopterin Levels in Antiretroviral-Treated HIV-1 Infected Patients: A Pilot Study

by Carolina Scagnolari^1,2, Giuseppe Corano Scheri³, Carla Selvaggi², Ivan Schietroma³, Saeid Najafi Fard³, Andrea Mastrangelo³, Noemi Giustini³, Sara Serafino³, Claudia Pinacchio¹, Paolo Pavone³, Gianfranco Fanello⁴, Giancarlo Ceccarelli³

, Vincenzo Vullo³ and Gabriella D’Ettorre^3,*

¹ Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy

² Department of Molecular Medicine, Laboratory of Virology, Sapienza University of Rome, Viale di Porta Tiburtina 28, 00185 Rome, Italy

³ Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy

⁴ Department of Emergency Surgery, Emergency Endoscopic Unit, Policlinico Umberto I, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy

Int. J. Mol. Sci. 2016, 17(10), 1639; https://doi.org/10.3390/ijms17101639 - 27 Sep 2016

Cited by 19 | Viewed by 7493

Abstract

Recently the tryptophan pathway has been considered an important determinant of HIV-1 infected patients’ quality of life, due to the toxic effects of its metabolites on the central nervous system (CNS). Since the dysbiosis described in HIV-1 patients might be responsible for the [...] Read more.

Recently the tryptophan pathway has been considered an important determinant of HIV-1 infected patients’ quality of life, due to the toxic effects of its metabolites on the central nervous system (CNS). Since the dysbiosis described in HIV-1 patients might be responsible for the microbial translocation, the chronic immune activation, and the altered utilization of tryptophan observed in these individuals, we speculated a correlation between high levels of immune activation markers in the cerebrospinal fluid (CSF) of HIV-1 infected patients and the over-expression of indolamine-2,3-dioxygenase (IDO) at the gut mucosal surface. In order to evaluate this issue, we measured the levels of neopterin in CSF, and the expression of IDO mRNA in gut-associated lymphoid tissue (GALT), in HIV-1-infected patients on effective combined antiretroviral therapy (cART), at baseline and after six months of probiotic dietary management. We found a significant reduction of neopterin and IDO mRNA levels after the supplementation with probiotic. Since the results for the use of adjunctive therapies to reduce the levels of immune activation markers in CSF have been disappointing so far, our pilot study showing the efficacy of this specific probiotic product should be followed by a larger confirmatory trial. Full article

(This article belongs to the Special Issue Immuno- and Neuropathogenesis of HIV Disease: Mechanisms, Prevention, Treatment, and Cure)

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An Inflammatory Nucleus Pulposus Tissue Culture Model to Test Molecular Regenerative Therapies: Validation with Epigallocatechin 3-Gallate

by Olga Krupkova^1,*

, Marian Hlavna¹, Julie Amir Tahmasseb¹, Joel Zvick¹, Dominik Kunz^1,2, Keita Ito³

, Stephen J. Ferguson^1,4 and Karin Wuertz-Kozak^1,4

¹ Institute for Biomechanics, ETH Zurich, Hoenggerbergring 64, CH-8093 Zurich, Switzerland

² Health Department, ZHAW—Zurich University of Applied Sciences, Technikumstrasse 71, CH-8401 Winterthur, Switzerland

³ Department of Biomedical Engineering, Eindhoven University of Technology, Postbus 513, 5600 MB Eindhoven, The Netherlands

⁴ Competence Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland

Int. J. Mol. Sci. 2016, 17(10), 1640; https://doi.org/10.3390/ijms17101640 - 27 Sep 2016

Cited by 23 | Viewed by 6539

Abstract

Organ cultures are practical tools to investigate regenerative strategies for the intervertebral disc. However, most existing organ culture systems induce severe tissue degradation with only limited representation of the in vivo processes. The objective of this study was to develop a space- and [...] Read more.

Organ cultures are practical tools to investigate regenerative strategies for the intervertebral disc. However, most existing organ culture systems induce severe tissue degradation with only limited representation of the in vivo processes. The objective of this study was to develop a space- and cost-efficient tissue culture model, which represents degenerative processes of the nucleus pulposus (NP). Intact bovine NPs were cultured in a previously developed system using Dyneema jackets. Degenerative changes in the NP tissue were induced either by the direct injection of chondroitinase ABC (1–20 U/mL) or by the diffusion of interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) (both 100 ng/mL) from the culture media. Extracellular matrix composition (collagens, proteoglycans, water, and DNA) and the expression of inflammatory and catabolic genes were analyzed. The anti-inflammatory and anti-catabolic compound epigallocatechin 3-gallate (EGCG, 10 µM) was employed to assess the relevance of the degenerative NP model. Although a single injection of chondroitinase ABC reduced the proteoglycan content in the NPs, it did not activate cellular responses. On the other hand, IL-1β and TNF-α significantly increased the mRNA expression of inflammatory mediators IL-6, IL-8, inducible nitric oxide synthase (iNOS), prostaglandin-endoperoxide synthase 2 (PTGS2) and matrix metalloproteinases (MMP1, MMP3, and MMP13). The cytokine-induced gene expression in the NPs was ameliorated with EGCG. This study provides a proof of concept that inflammatory NP cultures, with appropriate containment, can be useful for the discovery and evaluation of molecular therapeutic strategies against early degenerative disc disease. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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Next-Generation Sequencing of Two Mitochondrial Genomes from Family Pompilidae (Hymenoptera: Vespoidea) Reveal Novel Patterns of Gene Arrangement

by Peng-Yan Chen^1,2, Bo-Ying Zheng¹, Jing-Xian Liu^2,* and Shu-Jun Wei^1,*

¹ Institute of Plant and Environmental Protection, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China

² Department of Entomology, South China Agricultural University, Guangzhou 510640, China

Int. J. Mol. Sci. 2016, 17(10), 1641; https://doi.org/10.3390/ijms17101641 - 11 Oct 2016

Cited by 19 | Viewed by 5338

Abstract

Animal mitochondrial genomes have provided large and diverse datasets for evolutionary studies. Here, the first two representative mitochondrial genomes from the family Pompilidae (Hymenoptera: Vespoidea) were determined using next-generation sequencing. The sequenced region of these two mitochondrial genomes from the species Auplopus sp. [...] Read more.

Animal mitochondrial genomes have provided large and diverse datasets for evolutionary studies. Here, the first two representative mitochondrial genomes from the family Pompilidae (Hymenoptera: Vespoidea) were determined using next-generation sequencing. The sequenced region of these two mitochondrial genomes from the species Auplopus sp. and Agenioideus sp. was 16,746 bp long with an A + T content of 83.12% and 16,596 bp long with an A + T content of 78.64%, respectively. In both species, all of the 37 typical mitochondrial genes were determined. The secondary structure of tRNA genes and rRNA genes were predicted and compared with those of other insects. Atypical trnS1 using abnormal anticodons TCT and lacking D-stem pairings was identified. There were 49 helices belonging to six domains in rrnL and 30 helices belonging to three domains in rrns present. Compared with the ancestral organization, four and two tRNA genes were rearranged in mitochondrial genomes of Auplopus and Agenioideus, respectively. In both species, trnM was shuffled upstream of the trnI-trnQ-trnM cluster, and trnA was translocated from the cluster trnA-trnR-trnN-trnS1-trnE-trnF to the region between nad1 and trnL1, which is novel to the Vespoidea. In Auplopus, the tRNA cluster trnW-trnC-trnY was shuffled to trnW-trnY-trnC. Phylogenetic analysis within Vespoidea revealed that Pompilidae and Mutillidae formed a sister lineage, and then sistered Formicidae. The genomes presented in this study have enriched the knowledge base of molecular markers, which is valuable in respect to studies about the gene rearrangement mechanism, genomic evolutionary processes and phylogeny of Hymenoptera. Full article

(This article belongs to the Section Biochemistry)

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Oral Supplementation with a Special Additive of Retinyl Palmitate and Alpha Tocopherol Reduces Growth Retardation in Young Pancreatic Duct Ligated Pigs Used as a Model for Children Suffering from Exocrine Pancreatic Insufficiency

by Anne Mößeler^1,*

, Marion Schmicke²

, Martin Höltershinken², Martin Beyerbach³ and Josef Kamphues¹

¹ Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, D-30173 Hanover, Germany

² Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, D-30173 Hanover, Germany

³ Department for Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover, Foundation, Bünteweg 2, D-30559 Hanover, Germany

Int. J. Mol. Sci. 2016, 17(10), 1642; https://doi.org/10.3390/ijms17101642 - 28 Sep 2016

Cited by 1 | Viewed by 5803

Abstract

Pancreatic exocrine insufficiency (PEI) is a disease of diverse aetiology—e.g., majority of patients suffering from cystic fibrosis (CF) show PEI congenitally. Malnutrition and malabsorption of nutrients impair growth and nutritional status. As reduced fat digestion leads to a deficiency of fat-soluble vitamins the [...] Read more.

Pancreatic exocrine insufficiency (PEI) is a disease of diverse aetiology—e.g., majority of patients suffering from cystic fibrosis (CF) show PEI congenitally. Malnutrition and malabsorption of nutrients impair growth and nutritional status. As reduced fat digestion leads to a deficiency of fat-soluble vitamins the supplementation is standard, but absorption is a critical point in PEI-patients. The pancreatic duct ligated (PL) pig is an established model for PEI in humans and has been proven to be a suitable model to compare different vitamin additives for supplementation. In a former study, PEI caused distinct growth retardation in young piglets, but did not affect growth in older ones. Our study hypothesised that this age-dependent effect is caused by exhausted body reserves of fat-soluble vitamins and, therefore, extra supply reduces growth retardation. PEI was induced by PL at the age of seven (PL-7) or 16 weeks (PL-16). Controls (C) underwent a sham surgery. Some PL-7 pigs (PL-7 + Vit) were fed a special vitamin additive. PEI reduced the mean final body weight (kg) at 26 weeks of age significantly with lower effect in PL-16-pigs (C:117; PL-7:49.5; PL-7 + Vit:77.1; PL-16:96.4). Extra vitamin supply resulted in an increased growth and normalised serum concentration of alpha-tocopherol, underlining the importance of special supplementation in PEI-patients. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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iTRAQ-Based Proteomics Analysis of Serum Proteins in Wistar Rats Treated with Sodium Fluoride: Insight into the Potential Mechanism and Candidate Biomarkers of Fluorosis

by Yan Wei^1,3, Beibei Zeng¹, Hua Zhang^1,3, Cheng Chen², Yanli Wu¹, Nanlan Wang¹, Yanqiu Wu¹ and Liming Shen^2,*

¹ Department of Environmental Hygiene, School of Public Health, Guizhou Medical University, Guiyang 550025, China

² College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, China

³ Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, China

Int. J. Mol. Sci. 2016, 17(10), 1644; https://doi.org/10.3390/ijms17101644 - 28 Sep 2016

Cited by 21 | Viewed by 6919

Abstract

Fluorosis induced by exposure to high level fluoride is quite widespread in the world. The manifestations of fluorosis include dental mottling, bone damage, and impaired malfunction of soft tissues. However, the molecular mechanism of fluorosis has not been clarified until now. To explore [...] Read more.

Fluorosis induced by exposure to high level fluoride is quite widespread in the world. The manifestations of fluorosis include dental mottling, bone damage, and impaired malfunction of soft tissues. However, the molecular mechanism of fluorosis has not been clarified until now. To explore the underlying mechanisms of fluorosis and screen out serum biomarkers, we carried out a quantitative proteomics study to identify differentially expressed serum proteins in Wistar rats treated with sodium fluoride (NaF) by using a proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ). We fed Wistar rats drinking water that had 50, 150, and 250 mg/L of dissolved NaF for 24 weeks. For the experimental duration, each rat was given an examination of the lower incisors to check for the condition of dental fluorosis (DF). By the end of the treatment, fluoride ion concentration in serum and lower incisors were detected. The results showed that NaF treatment can induce rat fluorosis. By iTRAQ analysis, a total of 37 differentially expressed serum proteins were identified between NaF-treated and control rats. These proteins were further analyzed by bioinformatics, out of which two proteins were validated by enzyme-linked immunoadsorbent assays (ELISA). The major proteins were involved in complement and coagulation cascade, inflammatory response, complement activation, defense response, and wound response, suggesting that inflammation and immune reactions may play a key role in fluorosis pathogenesis. These proteins may contribute to the understanding of the mechanism of fluoride toxicity, and may serve as potential biomarkers for fluorosis. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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Diatom Valve Three-Dimensional Representation: A New Imaging Method Based on Combined Microscopies

by Maria Antonietta Ferrara^*

, Edoardo De Tommasi

, Giuseppe Coppola

, Luca De Stefano

, Ilaria Rea and Principia Dardano^*

Institute for Microelectronics and Microsystems, Department of Naples, National Research Council, Naples 80131, Italy

Int. J. Mol. Sci. 2016, 17(10), 1645; https://doi.org/10.3390/ijms17101645 - 28 Sep 2016

Cited by 10 | Viewed by 5207

Abstract

The frustule of diatoms, unicellular microalgae, shows very interesting photonic features, generally related to its complicated and quasi-periodic micro- and nano-structure. In order to simulate light propagation inside and through this natural structure, it is important to develop three-dimensional (3D) models for synthetic [...] Read more.

The frustule of diatoms, unicellular microalgae, shows very interesting photonic features, generally related to its complicated and quasi-periodic micro- and nano-structure. In order to simulate light propagation inside and through this natural structure, it is important to develop three-dimensional (3D) models for synthetic replica with high spatial resolution. In this paper, we present a new method that generates images of microscopic diatoms with high definition, by merging scanning electron microscopy and digital holography microscopy or atomic force microscopy data. Starting from two digital images, both acquired separately with standard characterization procedures, a high spatial resolution (Δz = λ/20, Δx = Δy ≅ 100 nm, at least) 3D model of the object has been generated. Then, the two sets of data have been processed by matrix formalism, using an original mathematical algorithm implemented on a commercially available software. The developed methodology could be also of broad interest in the design and fabrication of micro-opto-electro-mechanical systems. Full article

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

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Construction and Characterization of a Cellulolytic Consortium Enriched from the Hindgut of Holotrichia parallela Larvae

by Ping Sheng^*

, Jiangli Huang, Zhihong Zhang, Dongsheng Wang, Xiaojuan Tian and Jiannan Ding

Institute of Biological Resources, Jiangxi Academy of Sciences, Nanchang 330096, China

Int. J. Mol. Sci. 2016, 17(10), 1646; https://doi.org/10.3390/ijms17101646 - 30 Sep 2016

Cited by 19 | Viewed by 4247

Abstract

Degradation of rice straw by cooperative microbial activities is at present the most attractive alternative to fuels and provides a basis for biomass conversion. The use of microbial consortia in the biodegradation of lignocelluloses could reduce problems such as incomplete synergistic enzymes, end-product [...] Read more.

Degradation of rice straw by cooperative microbial activities is at present the most attractive alternative to fuels and provides a basis for biomass conversion. The use of microbial consortia in the biodegradation of lignocelluloses could reduce problems such as incomplete synergistic enzymes, end-product inhibition, and so on. In this study, a cellulolytic microbial consortium was enriched from the hindgut of Holotrichia parallela larvae via continuous subcultivation (20 subcultures in total) under static conditions. The degradation ratio for rice straw was about 83.1% after three days of cultivation, indicating its strong cellulolytic activity. The diversity analysis results showed that the bacterial diversity and richness decreased during the consortium enrichment process, and the consortium enrichment process could lead to a significant enrichment of phyla Proteobacteria and Spirochaetes, classes Clostridia, Epsilonproteobacteria, and Betaproteobacteria, and genera Arcobacter, Treponema, Comamonas, and Clostridium. Some of these are well known as typical cellulolytic and hemicellulolytic microorganisms. Our results revealed that the microbial consortium identified herein is a potential candidate for use in the degradation of waste lignocellulosic biomass and further highlights the hindgut of the larvae as a reservoir of extensive and specific cellulolytic and hemicellulolytic microbes. Full article

(This article belongs to the Section Biochemistry)

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GSPE Inhibits HMGB1 Release, Attenuating Renal IR-Induced Acute Renal Injury and Chronic Renal Fibrosis

by Juan Zhan, Kun Wang, Conghui Zhang, Chunxiu Zhang, Yueqiang Li, Ying Zhang, Xiaoyan Chang, Qiaodan Zhou, Ying Yao, Yanyan Liu^* and Gang Xu^*

Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China

Int. J. Mol. Sci. 2016, 17(10), 1647; https://doi.org/10.3390/ijms17101647 - 29 Sep 2016

Cited by 19 | Viewed by 6352

Abstract

Grape seed proanthocyanindin extract (GSPE) is a polyphenolic bioflavonoid derived from grape seeds and has been widely studied for its potent antioxidant, anti-inflammatory and antitumor activities. HMGB1 is a newly discovered danger-associated molecular pattern (DAMP) that has potent proinflammatory effects once released by [...] Read more.

Grape seed proanthocyanindin extract (GSPE) is a polyphenolic bioflavonoid derived from grape seeds and has been widely studied for its potent antioxidant, anti-inflammatory and antitumor activities. HMGB1 is a newly discovered danger-associated molecular pattern (DAMP) that has potent proinflammatory effects once released by necrotic cells. However, the effect of GSPE on the HMGB1, and the relationship of those two with acute kidney injury and chronic kidney fibrosis are unknown. This study aimed to investigate the impact of GSPE on acute kidney injury and chronic fibrosis. C57bl/6 mice were subjected to bilateral ischemia/reperfusion (I/R) and unilateral I/R with or without GSPE administration. After bilateral I/R, mice administered GSPE had a marked improvement in renal function (BUN and Cr), decreased pathological damage and reduced inflammation. In unilateral I/R, mice subjected GSPE showed reduced tubulointerstitial fibrosis and decreased inflammatory reaction. The renoprotection of GSPE on both models was associated with the inhibition of HMGB1 nucleocytoplasmic shuttling and release, which can amplify the inflammation through binding to its downstream receptor TLR4 and facilitated P65 transcription. Thus, we have reason to believe that GSPE could be a good alternative therapy for the prevention and treatment of IR-induced renal injury and fibrosis in clinical practice. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

by Meng Yan^1,†, Pan Fan^2,†, Yanhui Shi¹, Lifang Feng¹, Junnan Wang¹, Ge Zhan¹ and Baoxin Li^1,*

¹ Department of Pharmacology, Harbin Medical University, No. 194 Xuefu Road, Nangang District, Harbin 150081, China

² Department of Ophthalmology, the Second Affiliated Hospital, Harbin Medical University, No. 148 Baojian Road, Nangang District, Harbin 150081, China

Int. J. Mol. Sci. 2016, 17(10), 1648; https://doi.org/10.3390/ijms17101648 - 28 Sep 2016

Cited by 14 | Viewed by 6304

Abstract

Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The [...] Read more.

Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics. The results imply their stereospecific block effect on the hERG channel. However, F656C-hERG reversed this stereoselectivity. The mutation decreases affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. These data suggest that F656 residue contributes to the stereoselective pocket for quinidine and quinine. Further study demonstrates that both drugs do not change hERG protein levels. In rescue experiments, we found that they exert no reverse effect on pentamidine- or desipramine-induced hERG trafficking defect, although quinidine has been reported to rescue trafficking-deficient pore mutation hERG G601S based on the interaction with F656. Our research demonstrated stereoselective effects of quinidine and quinine on the hERG channel, and this is the first study to explore their reversal potency on drug-induced hERG deficiency. Full article

(This article belongs to the Section Biochemistry)

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EpCAM Expression in Lymph Node and Bone Metastases of Prostate Carcinoma: A Pilot Study

by Anna K. Campos¹, Hilde D. Hoving^2,*, Stefano Rosati³, Geert J. L. H. Van Leenders⁴ and Igle J. De Jong²

¹ Laboratory of Neuroimmunology, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Avenida Insurgentes Sur 3877, La Fama, Tlalpan, 14269 Mexico City, Mexico

² Department of Urology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, Groningen 9700 RB, The Netherlands

³ Department of Pathology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, Groningen 9700 RB, The Netherlands

⁴ Department of Pathology, Josephine Nefkens Institute, Erasmus MC, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands

Int. J. Mol. Sci. 2016, 17(10), 1650; https://doi.org/10.3390/ijms17101650 - 29 Sep 2016

Cited by 7 | Viewed by 3986

Abstract

There is an urgent need for new imaging modalities in prostate carcinoma staging. A non-invasive modality that can assess lymph node and bone metastases simultaneously is preferred. Epithelial cell adhesion molecule (EpCAM) is a membranous protein of interest as an imaging target since [...] Read more.

There is an urgent need for new imaging modalities in prostate carcinoma staging. A non-invasive modality that can assess lymph node and bone metastases simultaneously is preferred. Epithelial cell adhesion molecule (EpCAM) is a membranous protein of interest as an imaging target since it is overexpressed in prostatic carcinoma compared with benign prostate epithelium and compared with stroma. However, EpCAM expression in lymph node metastases is sparsely available in the literature and EpCAM expression in bone metastases is yet unknown. The current study evaluates the expression of EpCAM in prostate carcinoma lymph nodes, in matched normal lymph nodes, in prostate carcinoma bone metastases, and in normal bone by immunohistochemistry. EpCAM was expressed in 100% of lymph node metastases (21 out of 21), in 0% of normal lymph nodes (0 out of 21), in 95% of bone metastases (19 out of 20), and in 0% of normal bone (0 out of 14). Based on these results, EpCAM may be a feasible imaging target in prostate carcinoma lymph node and bone metastases. Prospective clinical trials are needed to confirm current results. Preoperative visualization of prostate carcinoma metastases will improve disease staging and will prevent unnecessary invasive surgery. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)

by Al-Abboodi Shakir Ashwaq^1,*, Mothanna Sadiq Al-Qubaisi¹, Abdullah Rasedee², Ahmad Bustamam Abdul^1,3, Yun Hin Taufiq-Yap⁴ and Swee Keong Yeap⁵

¹ MAKNA-UPM, Cancer Research Laboratory, Institute of Bioscience, University Putra Malaysia, 43400 Selangor, Malaysia

² Department of Veterinary Laboratory Diagnosis, Faculty of Veterinary Medicine, University Putra Malaysia, 43400 Selangor, Malaysia

³ Department of Biomedical Science, Faculty of Medicine & Health Science, University Putra Malaysia, 43400 Selangor, Malaysia

⁴ Department of Chemistry, Faculty of Science, University Putra Malaysia, 43400 Selangor, Malaysia

⁵ LIVES, Institute of Bioscience, University Putra Malaysia, 43400 Selangor, Malaysia

Int. J. Mol. Sci. 2016, 17(10), 1653; https://doi.org/10.3390/ijms17101653 - 18 Oct 2016

Cited by 15 | Viewed by 6761

Abstract

Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPβCD (hydroxypropyl-β-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line [...] Read more.

Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPβCD (hydroxypropyl-β-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line and compare with a crystal DEN in dimethyl sulfoxide (DMSO). The exposure of the cancer cells to DEN or DEN-HPβCD complex leads to cell growth inhibition as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. To analyze the mechanism, in which DEN or DEN-HPβCD complex causes the death in human colon HT29 cancer cells, was evaluated by the enzyme-linked immunosorbent assay (ELIZA)-based assays for caspase-3, 8, 9, and reactive oxygen species (ROS). The findings showed that an anti-proliferative effect of DEN or DEN-HPβCD complex were via cell cycle arrest at the G2/M phase and eventually induced apoptosis through both mitochondrial and extrinsic pathways. The down-regulation of poly(ADP-ribose) polymerase (PARP) which leaded to apoptosis upon treatment, was investigated by Western-blotting. Hence, complexation between DEN and HPβCD did not diminish or eliminate the effective properties of DEN as anticancer agent. Therefore, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents in the future. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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Phenotype-Genotype Association Analysis of ACTH-Secreting Pituitary Adenoma and Its Molecular Link to Patient Osteoporosis

by Renzhi Wang^1,2,3,*,†, Yakun Yang^1,2,†, Miaomiao Sheng^4,†, Dechao Bu^5,†, Fengming Huang⁴, Xiaohai Liu^1,2, Cuiqi Zhou^3,6, Congxin Dai^1,2, Bowen Sun^1,2, Jindong Zhu⁴, Yi Qiao¹, Yong Yao¹, Huijuan Zhu⁷, Lin Lu⁷, Hui Pan⁷, Ming Feng¹, Kan Deng¹, Bing Xing¹, Wei Lian¹, Yi Zhao^5,* and Chengyu Jiang^2,4,* Show full author list Hide full author list

¹ Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China

² Center for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China

³ Joint Pituitary Research Center of Cedars-Sinai Medical Center & Peking Union Medical College Hospital, Beijing 100730, China

⁴ State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; Department of Biochemistry and Molecular Biology, Peking Union Medical College, Tsinghua University; Beijing 100005, China

⁵ Key Lab of Intelligent Information Processing of Chinese Academy of Sciences (CAS), Institute of Computing Technology, CAS, Beijing 100190, China

⁶ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA

⁷ Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China

Int. J. Mol. Sci. 2016, 17(10), 1654; https://doi.org/10.3390/ijms17101654 - 29 Sep 2016

Cited by 5 | Viewed by 5905

Abstract

Adrenocorticotrophin (ACTH)-secreting pituitary adenoma, also known as Cushing disease (CD), is rare and causes metabolic syndrome, cardiovascular disease and osteoporosis due to hypercortisolism. However, the molecular pathogenesis of CD is still unclear because of a lack of human cell lines and animal models. [...] Read more.

Adrenocorticotrophin (ACTH)-secreting pituitary adenoma, also known as Cushing disease (CD), is rare and causes metabolic syndrome, cardiovascular disease and osteoporosis due to hypercortisolism. However, the molecular pathogenesis of CD is still unclear because of a lack of human cell lines and animal models. Here, we study 106 clinical characteristics and gene expression changes from 118 patients, the largest cohort of CD in a single-center. RNA deep sequencing is used to examine genotypic changes in nine paired female ACTH-secreting pituitary adenomas and adjacent nontumorous pituitary tissues (ANPT). We develop a novel analysis linking disease clinical characteristics and whole transcriptomic changes, using Pearson Correlation Coefficient to discover a molecular network mechanism. We report that osteoporosis is distinguished from the phenotype and genotype analysis. A cluster of genes involved in osteoporosis is identified using Pearson correlation coefficient analysis. Most of the genes are reported in the bone related literature, confirming the feasibility of phenotype-genotype association analysis, which could be used in the analysis of almost all diseases. Secreted phosphoprotein 1 (SPP1), collagen type I α 1 chain (COL1A1), 5′-nucleotidase ecto (NT5E), HtrA serine peptidase 1 (HTRA1) and angiopoietin 1 (ANGPT1) and their signalling pathways are shown to be involved in osteoporosis in CD patients. Our discoveries provide a molecular link for osteoporosis in CD patients, and may open new potential avenues for osteoporosis intervention and treatment. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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Longitudinal Claudin Gene Expression Analyses in Canine Mammary Tissues and Thereof Derived Primary Cultures and Cell Lines

by Susanne C. Hammer^1,2, Annegret Becker³, Katja Rateitschak⁴, Annika Mohr^1,2, Florenza Lüder Ripoli^1,2, Silvia Hennecke⁵, Johannes Junginger⁶, Marion Hewicker-Trautwein⁶, Bertram Brenig⁵, Anaclet Ngezahayo^3,7, Ingo Nolte^1,* and Hugo Murua Escobar^1,2

¹ Small Animal Clinic, University of Veterinary Medicine Hannover, Bünteweg 9, 30559 Hannover, Germany

² Division of Medicine, Haematology, Oncology and Palliative Medicine, University of Rostock, Ernst-Heydemann-Str. 6, 18055 Rostock, Germany

³ Institute of Biophysics, Leibniz University Hannover, Herrenhäuser Straße 2, 30419 Hannover, Germany

⁴ Institute for Bioinformatics, University Medicine Greifswald, Walther-Rathenau-Str. 48, 17475 Greifswald, Germany

⁵ Institute of Veterinary Medicine, Georg-August-University Göttingen, Burckhardtweg 2, 37077 Göttingen, Germany

⁶ Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany

⁷ Center for Systems Neuroscience (ZSN) Hannover, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany

Int. J. Mol. Sci. 2016, 17(10), 1655; https://doi.org/10.3390/ijms17101655 - 29 Sep 2016

Cited by 7 | Viewed by 6138

Abstract

Human and canine mammary tumours show partial claudin expression deregulations. Further, claudins have been used for directed therapeutic approaches. However, the development of claudin targeting approaches requires stable claudin expressing cell lines. This study reports the establishment and characterisation of canine mammary tissue [...] Read more.

Human and canine mammary tumours show partial claudin expression deregulations. Further, claudins have been used for directed therapeutic approaches. However, the development of claudin targeting approaches requires stable claudin expressing cell lines. This study reports the establishment and characterisation of canine mammary tissue derived cell lines, analysing longitudinally the claudin-1, -3, -4 and -7 expressions in original tissue samples, primary cultures and developed cell lines. Primary cultures were derived from 17 canine mammary tissues: healthy, lobular hyperplasia, simple adenoma, complex adenoma, simple tubular carcinoma, complex carcinoma, carcinoma arising in a benign mixed tumour and benign mixed tissue. Cultivation was performed, if possible, until passage 30. Claudin mRNA and protein expressions were analysed by PCR, QuantiGene Plex Assay, immunocytochemistry and immunofluorescence. Further, cytokeratin expression was analysed immunocytochemically. Cultivation resulted in 11 established cell lines, eight showing epithelial character. In five of the early passages the claudin expressions decreased compared to the original tissues. In general, claudin expressions were diminished during cultivation. Three cell lines kept longitudinally claudin, as well as epithelial marker expressions, representing valuable tools for the development of claudin targeted anti-tumour therapies. Full article

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

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Cinnamide Derivatives as Mammalian Arginase Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

by Thanh-Nhat Pham¹, Simon Bordage^1,2, Marc Pudlo¹, Céline Demougeot¹, Khac-Minh Thai³ and Corine Girard-Thernier^1,*

¹ PEPITE EA4267, University Bourgogne Franche-Comté, F-25000 Besançon, France

² University Lille, EA 7394-ICV-Institut Charles Viollette, F-59000 Lille, France

³ Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, 41 Dinh Tien Hoang, Dist 1, Ho Chi Minh City 700000, Vietnam

Int. J. Mol. Sci. 2016, 17(10), 1656; https://doi.org/10.3390/ijms17101656 - 29 Sep 2016

Cited by 26 | Viewed by 6875

Abstract

Arginases are enzymes that are involved in many human diseases and have been targeted for new treatments. Here a series of cinnamides was designed, synthesized and evaluated in vitro and in silico for their inhibitory activity against mammalian arginase. Using a microassay on [...] Read more.

Arginases are enzymes that are involved in many human diseases and have been targeted for new treatments. Here a series of cinnamides was designed, synthesized and evaluated in vitro and in silico for their inhibitory activity against mammalian arginase. Using a microassay on purified liver bovine arginase (b-ARG I), (E)-N-(2-phenylethyl)-3,4-dihydroxycinnamide, also named caffeic acid phenylamide (CAPA), was shown to be slightly more active than our natural reference inhibitor, chlorogenic acid (IC₅₀ = 6.9 ± 1.3 and 10.6 ± 1.6 µM, respectively) but it remained less active that the synthetic reference inhibitor N^ω-hydroxy-nor-l-arginine nor-NOHA (IC₅₀ = 1.7 ± 0.2 µM). Enzyme kinetic studies showed that CAPA was a competitive inhibitor of arginase with Ki = 5.5 ± 1 µM. Whereas the activity of nor-NOHA was retained (IC₅₀ = 5.7 ± 0.6 µM) using a human recombinant arginase I (h-ARG I), CAPA showed poorer activity (IC₅₀ = 60.3 ± 7.8 µM). However, our study revealed that the cinnamoyl moiety and catechol function were important for inhibitory activity. Docking results on h-ARG I demonstrated that the caffeoyl moiety could penetrate into the active-site pocket of the enzyme, and the catechol function might interact with the cofactor Mn²⁺ and several crucial amino acid residues involved in the hydrolysis mechanism of arginase. The results of this study suggest that 3,4-dihydroxycinnamides are worth being considered as potential mammalian arginase inhibitors, and could be useful for further research on the development of new arginase inhibitors. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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ns-μs Time-Resolved Step-Scan FTIR of ba₃ Oxidoreductase from Thermus thermophilus: Protonic Connectivity of w941-w946-w927

by Antonis Nicolaides¹, Tewfik Soulimane² and Constantinos Varotsis^1,*

¹ Department of Environmental Science and Technology, Cyprus University of Technology, P.O. Box 50329, 3603 Lemesos, Cyprus

² Chemical and Environmental Science Department and Materials & Surface Science Institute, University of Limerick, V94 T9PX Limerick, Ireland

Int. J. Mol. Sci. 2016, 17(10), 1657; https://doi.org/10.3390/ijms17101657 - 29 Sep 2016

Cited by 7 | Viewed by 5390

Abstract

Time-resolved step-scan FTIR spectroscopy has been employed to probe the dynamics of the ba₃ oxidoreductase from Thermus thermophilus in the ns-μs time range and in the pH/pD 6–9 range. The data revealed a pH/pD sensitivity of the D372 residue and of the [...] Read more.

Time-resolved step-scan FTIR spectroscopy has been employed to probe the dynamics of the ba₃ oxidoreductase from Thermus thermophilus in the ns-μs time range and in the pH/pD 6–9 range. The data revealed a pH/pD sensitivity of the D372 residue and of the ring-A propionate of heme a₃. Based on the observed transient changes a model in which the protonic connectivity of w941-w946-927 to the D372 and the ring-A propionate of heme a₃ is described. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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Fruit Antioxidants during Vinegar Processing: Changes in Content and in Vitro Bio-Accessibility

by Sena Bakir^1,2

, Gamze Toydemir³, Dilek Boyacioglu¹, Jules Beekwilder⁴ and Esra Capanoglu^1,*

¹ Department of Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical University, Maslak, 34469 Istanbul, Turkey

² Department of Food Engineering, Faculty of Engineering, Recep Tayyip Erdogan University, Merkez, 53100 Rize, Turkey

³ Department of Food Engineering, Faculty of Engineering and Architecture, Okan University, Akfirat-Tuzla, 34959 Istanbul, Turkey

⁴ Plant Research International, Wageningen UR, 6700 AA Wageningen, The Netherlands

Int. J. Mol. Sci. 2016, 17(10), 1658; https://doi.org/10.3390/ijms17101658 - 29 Sep 2016

Cited by 48 | Viewed by 7740

Abstract

Background: Vinegars based on fruit juices could conserve part of the health-associated compounds present in the fruits. However, in general very limited knowledge exists on the consequences of vinegar-making on different antioxidant compounds from fruit. In this study vinegars derived from apple and [...] Read more.

Background: Vinegars based on fruit juices could conserve part of the health-associated compounds present in the fruits. However, in general very limited knowledge exists on the consequences of vinegar-making on different antioxidant compounds from fruit. In this study vinegars derived from apple and grape are studied. Methods: A number of steps, starting from the fermentation of the fruit juices to the formation of the final vinegars, were studied from an industrial vinegar process. The effect of each of the vinegar processing steps on content of antioxidants, phenolic compounds and flavonoids was studied, by spectroscopic methods and by high-performance liquid chromatography (HPLC). Results: The major observation was that spectrophotometric methods indicate a strong loss of antioxidant phenolic compounds during the transition from fruit wine to fruit vinegar. A targeted HPLC analysis indicates that metabolites such as gallic acid are lost in later stages of the vinegar process. Conclusion: The major conclusion of this work is that major changes occur in phenolic compounds during vinegar making. An untargeted metabolite analysis should be used to reveal these changes in more detail. In addition, the effect of vinegar processing on bio-accessibility of phenolic compounds was investigated by mimicking the digestive tract in an in vitro set up. This study is meant to provide insight into the potential of vinegar as a source of health-related compounds from fruit. Full article

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

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Extracellular Self-DNA (esDNA), but Not Heterologous Plant or Insect DNA (etDNA), Induces Plasma Membrane Depolarization and Calcium Signaling in Lima Bean (Phaseolus lunatus) and Maize (Zea mays)

by Francesca Barbero¹

, Michela Guglielmotto², Andrea Capuzzo³ and Massimo E. Maffei^1,*

¹ Department of Life Sciences and Systems Biology, University of Turin, Via Quarello 15/a, 10135 Turin, Italy

² Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Turin, Regione Gonzole 10, Orbassano, 10043 Turin, Italy

³ Biosfered Srl, Academic Spin-Off of the University of Turin, Via Quarello 15/a, 10135 Turin, Italy

Int. J. Mol. Sci. 2016, 17(10), 1659; https://doi.org/10.3390/ijms17101659 - 29 Sep 2016

Cited by 56 | Viewed by 7220

Abstract

Extracellular self-DNA (esDNA) is produced during cell and tissue damage or degradation and has been shown to induce significant responses in several organisms, including plants. While the inhibitory effects of esDNA have been shown in conspecific individuals, little is known on the early [...] Read more.

Extracellular self-DNA (esDNA) is produced during cell and tissue damage or degradation and has been shown to induce significant responses in several organisms, including plants. While the inhibitory effects of esDNA have been shown in conspecific individuals, little is known on the early events involved upon plant esDNA perception. We used electrophysiology and confocal laser scanning microscopy calcium localization to evaluate the plasma membrane potential (Vm) variations and the intracellular calcium fluxes, respectively, in Lima bean (Phaseolus lunatus) and maize (Zea mays) plants exposed to esDNA and extracellular heterologous DNA (etDNA) and to etDNA from Spodoptera littoralis larvae and oral secretions. In both species, esDNA induced a significant Vm depolarization and an increased flux of calcium, whereas etDNA was unable to exert any of these early signaling events. These findings confirm the specificity of esDNA to induce plant cell responses and to trigger early signaling events that eventually lead to plant response to damage. Full article

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

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Modified Aloe Polysaccharide Restores Chronic Stress-Induced Immunosuppression in Mice

by Youngjoo Lee¹, Sun-A Im², Jiyeon Kim¹, Sungwon Lee¹, Junghak Kwon¹, Heetae Lee¹, Hyunseok Kong¹, Youngcheon Song¹, Eunju Shin³, Seon-Gil Do³, Chong-Kil Lee^2,* and Kyungjae Kim^1,*

¹ College of Pharmacy, Sahmyook University, Seoul 01795, Korea

² College of Pharmacy, Chungbuk National University, Cheongju 28644, Korea

³ Wellness R&D Center, Univera, Inc., Seoul 04782, Korea

Int. J. Mol. Sci. 2016, 17(10), 1660; https://doi.org/10.3390/ijms17101660 - 30 Sep 2016

Cited by 6 | Viewed by 4280

Abstract

Chronic stress generally experienced in our daily lives; is known to augment disease vulnerability by suppressing the host immune system. In the present study; the effect of modified Aloe polysaccharide (MAP) on chronic stress-induced immunosuppression was studied; this Aloe compound was characterized in [...] Read more.

Chronic stress generally experienced in our daily lives; is known to augment disease vulnerability by suppressing the host immune system. In the present study; the effect of modified Aloe polysaccharide (MAP) on chronic stress-induced immunosuppression was studied; this Aloe compound was characterized in our earlier study. Mice were orally administered with MAP for 24 days and exposed to electric foot shock (EFS; duration; 3 min; interval; 10 s; intensity; 2 mA) for 17 days. The stress-related immunosuppression and restorative effect of MAP were then analyzed by measuring various immunological parameters. MAP treatment alleviated lymphoid atrophy and body weight loss. The numbers of lymphocyte subsets were significantly normalized in MAP-treated mice. Oral administration of MAP also restored the proliferative activities of lymphocytes; ovalbumin (OVA)-specific T cell proliferation; antibody production; and the cell killing activity of cytotoxic T lymphocytes. In summary; oral administration of MAP ameliorated chronic EFS stress-induced immunosuppression. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Dimerization of the Vacuolar Receptors AtRMR1 and -2 from Arabidopsis thaliana Contributes to Their Localization in the trans-Golgi Network

by Alessandro Occhialini^1,2,*, Guillaume Gouzerh², Gian-Pietro Di Sansebastiano³

and Jean-Marc Neuhaus^2,*

¹ Plant Biology and Crop Science, Rothamsted Research, Harpenden, AL5 2JQ Herts, UK

² Laboratory of Cell and Molecular Biology, Institute of Biology, University of Neuchâtel, Rue Emile-Argand 11, CH-2009 Neuchâtel, Switzerland

³ DISTEBA, Department of Biological and Environmental Sciences and Technologies, University of Salento, Campus Ecotekne, 73100 Lecce, Italy

Int. J. Mol. Sci. 2016, 17(10), 1661; https://doi.org/10.3390/ijms17101661 - 30 Sep 2016

Cited by 16 | Viewed by 7849

Abstract

In Arabidopsis thaliana, different types of vacuolar receptors were discovered. The AtVSR (Vacuolar Sorting Receptor) receptors are well known to be involved in the traffic to lytic vacuole (LV), while few evidences demonstrate the involvement of the receptors from AtRMR family (Receptor [...] Read more.

In Arabidopsis thaliana, different types of vacuolar receptors were discovered. The AtVSR (Vacuolar Sorting Receptor) receptors are well known to be involved in the traffic to lytic vacuole (LV), while few evidences demonstrate the involvement of the receptors from AtRMR family (Receptor Membrane RING-H2) in the traffic to the protein storage vacuole (PSV). In this study we focused on the localization of two members of AtRMR family, AtRMR1 and -2, and on the possible interaction between these two receptors in the plant secretory pathway. Our experiments with agroinfiltrated Nicotiana benthamiana leaves demonstrated that AtRMR1 was localized in the endoplasmic reticulum (ER), while AtRMR2 was targeted to the trans-Golgi network (TGN) due to the presence of a cytosolic 23-amino acid sequence linker. The fusion of this linker to an equivalent position in AtRMR1 targeted this receptor to the TGN, instead of the ER. By using a Bimolecular Fluorescent Complementation (BiFC) technique and experiments of co-localization, we demonstrated that AtRMR2 can make homodimers, and can also interact with AtRMR1 forming heterodimers that locate to the TGN. Such interaction studies strongly suggest that the transmembrane domain and the few amino acids surrounding it, including the sequence linker, are essential for dimerization. These results suggest a new model of AtRMR trafficking and dimerization in the plant secretory pathway. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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Dexmedetomidine-Induced Contraction Involves CPI-17 Phosphorylation in Isolated Rat Aortas

by Seong-Ho Ok^1,†, Seong-Chun Kwon^2,†, Jiseok Baik³, Jeong-Min Hong³, Jiah Oh⁴, Jeong Yeol Han⁵ and Ju-Tae Sohn^1,6,*

¹ Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si 52727, Korea

² Department of Physiology, Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 25601, Korea

³ Department of Anesthesiology and Pain Medicine, Pusan National University Hospital, Biomed Research Institute, Pusan National University School of Medicine, Busan 49241, Korea

⁴ Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju-si 52727, Korea

⁵ Department of Anesthesiology and Pain Medicine, Gyeongsang National University Changwon Hospital, Changwon 51472, Korea

⁶ Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1663; https://doi.org/10.3390/ijms17101663 - 30 Sep 2016

Cited by 10 | Viewed by 4492

Abstract

Dexmedetomidine, a highly selective α-2 adrenoceptor agonist, produces vasoconstriction, which leads to transiently increased blood pressure. The goal of this study was to investigate specific protein kinases and the associated cellular signal pathways responsible for the increased calcium sensitization induced by dexmedetomidine in [...] Read more.

Dexmedetomidine, a highly selective α-2 adrenoceptor agonist, produces vasoconstriction, which leads to transiently increased blood pressure. The goal of this study was to investigate specific protein kinases and the associated cellular signal pathways responsible for the increased calcium sensitization induced by dexmedetomidine in isolated rat aortas, with a particular focus on phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17). The effect of Y-27632 and chelerythrine on the dexmedetomidine-induced intracellular calcium concentration ([Ca²⁺]_i) and tension were assessed using fura-2-loaded aortic strips. The effects of rauwolscine, Y-27632, chelerythrine, and ML-7 hydrochloride on the dexmedetomidine-induced phosphorylation of CPI-17 or of the 20-kDa regulatory light chain of myosin (MLC₂₀) were investigated in rat aortic vascular smooth muscle cells. The effects of rauwolscine, Y-27632, and chelerythrine on the membrane translocation of Rho-kinase and protein kinase C (PKC) phosphorylation induced by dexmedetomidine were assessed. Y-27632 and chelerythrine each reduced the slopes of the [Ca²⁺]_i-tension curves of dexmedetomidine-induced contraction, and Y-27632 more strongly reduced these slopes than did chelerythrine. Rauwolscine, Y-27632, chelerythrine, and ML-7 hydrochloride attenuated the dexmedetomidine-induced phosphorylation of CPI-17 and MLC₂₀. Taken together, these results suggest that dexmedetomidine-induced contraction involves calcium sensitization, which appears to be mediated by CPI-17 phosphorylation via Rho-kinase or PKC. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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Extraction of Natural Antioxidants from the Thelephora ganbajun Mushroom by an Ultrasound-Assisted Extraction Technique and Evaluation of Antiproliferative Activity of the Extract against Human Cancer Cells

by Dong-Ping Xu^1,†, Jie Zheng^1,†, Yue Zhou¹, Ya Li¹

, Sha Li² and Hua-Bin Li^1,3,*

¹ Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China

² School of Chinese Medicine, The University of Hong Kong, Hong Kong 999077, China

³ South China Sea Bioresource Exploitation and Utilization Collaborative Innovation Center, Sun Yat-sen University, Guangzhou 510006, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1664; https://doi.org/10.3390/ijms17101664 - 1 Oct 2016

Cited by 52 | Viewed by 5802

Abstract

The Thelephora ganbajun mushroom has been found to be a potential rich source of natural antioxidants. In this study, an ultrasound-assisted extraction (UAE) technique together with GRAS (generally recognized as safe) solvents (ethanol and water) was used to maximize the extraction of antioxidants [...] Read more.

The Thelephora ganbajun mushroom has been found to be a potential rich source of natural antioxidants. In this study, an ultrasound-assisted extraction (UAE) technique together with GRAS (generally recognized as safe) solvents (ethanol and water) was used to maximize the extraction of antioxidants from Thelephora ganbajun. Five extraction parameters (ethanol concentration, solvent to solid ratio, extraction time, temperature and ultrasound power) were investigated by single-factor experiments, and then a central composite rotatable design was employed to study interaction of three key extraction parameters. The optimum conditions were as follows: 57.38% ethanol, 70.15 mL/g solvent to solid ratio, 10.58 min extraction time, 40 °C extraction temperature and 500 W ultrasound power. Under the optimum conditions, the antioxidant activity obtained was 346.98 ± 12.19 µmol Trolox/g DW, in accordance with the predicted value of 344.67 µmol Trolox/g DW. Comparison of UAE with conventional maceration and Soxhlet extraction, the UAE method showed stronger extract efficiency in a shorter extraction time. These results showed that UAE was an effective technique to extract antioxidants from Thelephora ganbajun. Furthermore, the extracts obtained under the optimized conditions exhibited antiproliferative activities toward human lung (A549), breast (MCF-7), liver (HepG2) and colon (HT-29) cancer cells, especially for liver and lung cancer cells. In addition, rutin, 2-hydrocinnamic acid and epicatechin were identified in the extract, which might contribute to antioxidant and antiproliferative activities. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Detection and Characterization of Circulating Tumor Associated Cells in Metastatic Breast Cancer

by Zhaomei Mu^1,*, Naoual Benali-Furet², Georges Uzan², Anaëlle Znaty², Zhong Ye³, Carmela Paolillo⁴, Chun Wang³, Laura Austin³, Giovanna Rossi¹, Paolo Fortina^4,5, Hushan Yang³ and Massimo Cristofanilli^1,*

¹ Department of Medicine-Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA

² ScreenCell SA, Sarcelles 95200, France

³ Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA

⁴ Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA

⁵ Department of Molecular Medicine, University of Rome “Sapienza”, Rome 00185, Italy

Int. J. Mol. Sci. 2016, 17(10), 1665; https://doi.org/10.3390/ijms17101665 - 30 Sep 2016

Cited by 61 | Viewed by 8541

Abstract

The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs [...] Read more.

The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs. In this pilot study, we evaluated circulating tumor associated cells in one blood draw by size exclusion technology and cytological analysis. Among 30 prospectively enrolled MBC patients, CTCs, circulating tumor cell clusters (CTC clusters), CTCs of epithelial–mesenchymal transition (EMT) and cancer associated macrophage-like cells (CAMLs) were detected and analyzed. For molecular characterization of CTCs, size-exclusion method for CTC enrichment was tested in combination with DEPArray™ technology, which allows the recovery of single CTCs or pools of CTCs as a pure CTC sample for mutation analysis. Genomic mutations of TP53 and ESR1 were analyzed by targeted sequencing on isolated 7 CTCs from a patient with MBC. The results of genomic analysis showed heterozygous TP53 R248W mutation from one single CTC and pools of three CTCs, and homozygous TP53 R248W mutation from one single CTC and pools of two CTCs. Wild-type ESR1 was detected in the same isolated CTCs. The results of this study reveal that size-exclusion method can be used to enrich and identify circulating tumor associated cells, and enriched CTCs were characterized for genetic alterations in MBC patients, respectively. Full article

(This article belongs to the Special Issue Circulating Tumor Cells)

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Disease Activity and Conversion into Multiple Sclerosis after Optic Neuritis Is Treated with Erythropoietin

by Kurt-Wolfram Sühs^1,*

, Panagiotis Papanagiotou², Katharina Hein³, Refik Pul¹, Kerstin Scholz⁴, Christoph Heesen⁵ and Ricarda Diem⁶

¹ Department of Neurology, Medical School Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany

² Department of Neuroradiology, Hospital Bremen Mitte, St. Jürgen Str. 1, 28177 Bremen, Germany

³ Department of Neurology, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, Germany

⁴ Department of Radiology, Lüneburg Hospital, Bögelstr. 1, 21339 Lüneburg, Germany

⁵ Department of Neurology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

⁶ Department of Neurooncology, University Clinic Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

Int. J. Mol. Sci. 2016, 17(10), 1666; https://doi.org/10.3390/ijms17101666 - 30 Sep 2016

Cited by 6 | Viewed by 5558

Abstract

Changes in cerebral lesion load by magnetic resonance imaging (MRI) in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095) were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU [...] Read more.

Changes in cerebral lesion load by magnetic resonance imaging (MRI) in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095) were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU of recombinant human erythropoietin (IV) daily for three days, or a placebo, as an add-on to methylprednisolone. Of 35 patients, we investigated changes in cerebral lesion load in MRIs obtained at baseline and at weeks 4, 8, and 16. In 5 of the 35 patients, we found conversion into multiple sclerosis (MS) based on MRI progression only. These five patients had received the placebo. Another five patients showed MRI progression together with relapses. Three of these patients had received erythropoietin, and two the placebo. Yet, analyzing the change in absolute numbers of periventricular, juxtacortical, and infratentorial lesions including gadolinium-enhancing lesions, there were no significant differences between the groups. Although effective in terms of retinal nerve fiber layer protection, erythropoietin treatment of acute isolated optic neuritis did not influence further evolution of MRI lesions in the brain when comparing absolute numbers. However, early conversion from clinically isolated syndrome to MS assessed by MRI activity seemed to occur more frequently in the placebo-treated group. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Internet-Supported Physical Exercise Training for Persons with Multiple Sclerosis—A Randomised, Controlled Study

by Alexander Tallner¹, René Streber¹, Christian Hentschke¹, Marc Morgott¹, Wolfgang Geidl¹, Mathias Mäurer^2,* and Klaus Pfeifer¹

¹ Division Exercise and Health, Institute of Sport Science and Sport, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany

² Department of Neurology, Stiftung Juliusspital, 97070 Würzburg, Germany

Int. J. Mol. Sci. 2016, 17(10), 1667; https://doi.org/10.3390/ijms17101667 - 30 Sep 2016

Cited by 50 | Viewed by 8108

Abstract

Physical exercise is effective in improving functional outcomes in persons with multiple sclerosis (pwMS). We evaluated the feasibility and effectiveness of internet-based exercise training (e-training) for pwMS on health-related quality of life (HrQoL). Secondary outcomes were muscle strength, aerobic capacity, lung function, physical [...] Read more.

Physical exercise is effective in improving functional outcomes in persons with multiple sclerosis (pwMS). We evaluated the feasibility and effectiveness of internet-based exercise training (e-training) for pwMS on health-related quality of life (HrQoL). Secondary outcomes were muscle strength, aerobic capacity, lung function, physical activity, and fatigue. This is a randomised, controlled trial with a wait-list control group. Data were collected at baseline, after three and six months, and analysed using a hybrid linear model. One-hundred twenty-six pwMS participated in the home-based aerobic (1×/week) and strength training (2×/week) intervention that was supervised and documented via an internet-platform. The intervention group received e-training for six months, and the control group received e-training after a three months waiting period. Significant differences between the groups were only observed for muscle strength (knee flexion (effect size ES = 0.3, p = 0.003), knee extension (ES = 0.24, p = 0.015)), peak expiratory flow (ES = 0.2, p = 0.039), and sports activity (ES = 0.33, p = 0.001) after three months. E-training had no effect on HrQoL but did on muscle strength, lung function, and physical activity. It is a promising and feasible approach to facilitate large-scale, yet individual, training support. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Porcine Zygote Injection with Cas9/sgRNA Results in DMD-Modified Pig with Muscle Dystrophy

by Hong-Hao Yu^1,2,3,4,†, Heng Zhao^2,3,†, Yu-Bo Qing^2,3, Wei-Rong Pan³, Bao-Yu Jia^2,3, Hong-Ye Zhao², Xing-Xu Huang^1,* and Hong-Jiang Wei^2,3,*

¹ School of Life Science and Technology, ShanghaiTech University, 100 Haike Rd., Pudong New Area, Shanghai 201210, China

² State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan Agricultural University, Kunming 650201, China

³ College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China

⁴ Research Center of Life Science, Yulin University, Yulin 719000, China

^† These authors contribute equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1668; https://doi.org/10.3390/ijms17101668 - 9 Oct 2016

Cited by 68 | Viewed by 8494

Abstract

Dystrophinopathy, including Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and [...] Read more.

Dystrophinopathy, including Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease. Here, we successfully achieved precise DMD targeting in Chinese Diannan miniature pigs by co-injecting zygotes with Cas9 mRNA and sgRNA targeting DMD. Two piglets were obtained after embryo transfer, one of piglets was identified as DMD-modified individual via traditional cloning, sequencing and T7EN1 cleavage assay. An examination of targeting rates in the DMD-modified piglet revealed that sgRNA:Cas9-mediated on-target mosaic mutations were 70% and 60% of dystrophin alleles in skeletal and smooth muscle, respectively. Meanwhile, no detectable off-target mutations were found, highlighting the high specificity of genetic modification using CRISPR/Cas9. The DMD-modified piglet exhibited degenerative and disordered phenotypes in skeletal and cardiac muscle, and declining thickness of smooth muscle in the stomach and intestine. In conclusion, we successfully generated myopathy animal model by modifying the DMD via CRISPR/Cas9 system in a miniature pig. Full article

(This article belongs to the Section Biochemistry)

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Identification, Molecular Cloning of IL-1β and Its Expression Profile during Nocardia seriolae Infection in Largemouth Bass, Micropterus salmoides

by Ping-Yueh Ho^1,†, Omkar Byadgi^1,†, Pei-Chyi Wang^1,*, Ming-An Tsai¹, Li-Ling Liaw² and Shih-Chu Chen^1,*

¹ Department of Veterinary Medicine, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan

² Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu 300, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1670; https://doi.org/10.3390/ijms17101670 - 1 Oct 2016

Cited by 30 | Viewed by 5016

Abstract

In the present study, IL-1β cDNA was identified and analyzed from largemouth bass (Micropterus salmoides). Full length IL-1β mRNA was obtained using Rapid Amplification of cDNA Ends (RACE), which contains 78 bp 3′-UTR, a 455 bp 5′-UTR, and an open reading [...] Read more.

In the present study, IL-1β cDNA was identified and analyzed from largemouth bass (Micropterus salmoides). Full length IL-1β mRNA was obtained using Rapid Amplification of cDNA Ends (RACE), which contains 78 bp 3′-UTR, a 455 bp 5′-UTR, and an open reading frame (ORF) of 702 bp coding for 233 amino acid residues. The molecular weight and theoretical isoelectric point of largemouth bass IL-1β protein was predicted to be 26.7 kDa and 6.08 respectively. A largemouth bass IL-1β phylogenetic analysis showed a close relation to the IL-1βs of striped trumpeter (Latris lineata), Chinese perch (Siniperca chuatsi), and Japanese sea bass (Lateolabrax japonicus). Peptidoglycan upregulated IL-1β in the spleen and head kidney, while lipopolysaccharide upregulated detectable levels of IL-1β in the spleen only. Largemouth bass, challenged with Nocardia seriolae (1.0 × 10⁶ cfu/mL), showed a significant increase in IL-1β at 3 and 5 days post infection (dpi) in the spleen, while in the head kidney significant expression was found at 2 and 3 dpi, peaking at 3 dpi. Furthermore, tumor necrosis factor α (TNF-α) showed significantly higher expression in the spleen at 3 and 5 dpi, and in the head kidney at 1 and 3 dpi, with expression decreasing at 5 dpi in both tissues. Full article

(This article belongs to the Section Biochemistry)

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Interactions of β-Conglycinin (7S) with Different Phenolic Acids—Impact on Structural Characteristics and Proteolytic Degradation of Proteins

by Jing Gan¹, Hao Chen¹, Jiyuan Liu¹, Yongquan Wang¹, Satoru Nirasawa² and Yongqiang Cheng^1,*

¹ Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China

² Japan International Research Center for Agricultural Sciences, Enzyme Laboratory, Tsukuba 305-8686, Japan

Int. J. Mol. Sci. 2016, 17(10), 1671; https://doi.org/10.3390/ijms17101671 - 2 Oct 2016

Cited by 17 | Viewed by 6822

Abstract

p-Coumalic acid (PCA), caffeic acid (CA), gallic acid (GA) and chlorogenic acid (CGA) are the major phenolic acids that co-exist with soy protein components in foodstuffs. Surprisingly, there are only a handful of reports that describe their interaction with β-Conglycinin (7S), a [...] Read more.

p-Coumalic acid (PCA), caffeic acid (CA), gallic acid (GA) and chlorogenic acid (CGA) are the major phenolic acids that co-exist with soy protein components in foodstuffs. Surprisingly, there are only a handful of reports that describe their interaction with β-Conglycinin (7S), a major soy protein. In this report, we investigated the interaction between phenolic acids and soy protein 7S and observed an interaction between each of these phenolic acids and soy protein 7S, which was carried out by binding. Further analysis revealed that the binding activity of the phenolic acids was structure dependent. Here, the binding affinity of CA and GA towards 7S was found to be stronger than that of PCA, because CA and GA have one more hydroxyl group. Interestingly, the binding of phenolic acids with soy protein 7S did not affect protein digestion by pepsin and trypsin. These findings aid our understanding of the relationship between different phenolic acids and proteins in complex food systems. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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Genome-Wide Identification, Characterization and Expression Analysis of the Solute Carrier 6 Gene Family in Silkworm (Bombyx mori)

by Xin Tang¹

, Huawei Liu¹, Quanmei Chen², Xin Wang^1,3

, Ying Xiong¹ and Ping Zhao^1,3,*

¹ State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China

² Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China

³ Chongqing Engineering and Technology Research Center for Novel Silk Materials, Chongqing 400715, China

Int. J. Mol. Sci. 2016, 17(10), 1675; https://doi.org/10.3390/ijms17101675 - 3 Oct 2016

Cited by 6 | Viewed by 5288

Abstract

The solute carrier 6 (SLC6) gene family, initially known as the neurotransmitter transporters, plays vital roles in the regulation of neurotransmitter signaling, nutrient absorption and motor behavior. In this study, a total of 16 candidate genes were identified as SLC6 family gene homologs [...] Read more.

The solute carrier 6 (SLC6) gene family, initially known as the neurotransmitter transporters, plays vital roles in the regulation of neurotransmitter signaling, nutrient absorption and motor behavior. In this study, a total of 16 candidate genes were identified as SLC6 family gene homologs in the silkworm (Bombyx mori) genome. Spatio-temporal expression patterns of silkworm SLC6 gene transcripts indicated that these genes were highly and specifically expressed in midgut, brain and gonads; moreover, these genes were expressed primarily at the feeding stage or adult stage. Levels of expression for most midgut-specific and midgut-enriched gene transcripts were down-regulated after starvation but up-regulated after re-feeding. In addition, we observed that expression levels of these genes except for BmSLC6-15 and BmGT1 were markedly up-regulated by a juvenile hormone analog. Moreover, brain-enriched genes showed differential expression patterns during wandering and mating processes, suggesting that these genes may be involved in modulating wandering and mating behaviors. Our results improve our understanding of the expression patterns and potential physiological functions of the SLC6 gene family, and provide valuable information for the comprehensive functional analysis of the SLC6 gene family. Full article

(This article belongs to the Section Biochemistry)

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In Vitro Metabolic Studies of REV-ERB Agonists SR9009 and SR9011

by Lore Geldof^*

, Koen Deventer, Kris Roels, Eva Tudela and Peter Van Eeno

Department of Clinical Chemistry, Microbiology and Immunology, Doping Control Laboratory (DoCoLab), Ghent University, Technologiepark 30 B, B-9052 Zwijnaarde, 9000 Ghent, Belgium

Int. J. Mol. Sci. 2016, 17(10), 1676; https://doi.org/10.3390/ijms17101676 - 3 Oct 2016

Cited by 16 | Viewed by 10067

Abstract

SR9009 and SR9011 are attractive as performance-enhancing substances due to their REV-ERB agonist effects and thus circadian rhythm modulation activity. Although no pharmaceutical preparations are available yet, illicit use of SR9009 and SR9011 for doping purposes can be anticipated, especially since SR9009 is [...] Read more.

SR9009 and SR9011 are attractive as performance-enhancing substances due to their REV-ERB agonist effects and thus circadian rhythm modulation activity. Although no pharmaceutical preparations are available yet, illicit use of SR9009 and SR9011 for doping purposes can be anticipated, especially since SR9009 is marketed in illicit products. Therefore, the aim was to identify potential diagnostic metabolites via in vitro metabolic studies to ensure effective (doping) control. The presence of SR9009 could be demonstrated in a black market product purchased over the Internet. Via human liver microsomal metabolic assays, eight metabolites were detected for SR9009 and fourteen metabolites for SR9011 by liquid chromatography-high resolution mass spectrometry (LC–HRMS). Structure elucidation was performed for all metabolites by LC–HRMS product ion scans in both positive and negative ionization mode. Retrospective data analysis was applied to 1511 doping control samples previously analyzed by a full-scan LC–HRMS screening method to verify the presence of SR9009, SR9011 and their metabolites. So far, the presence of neither the parent compound nor the metabolites could be detected in routine urine samples. However, to further discourage use of these potentially harmful compounds, incorporation of SR9009 and SR9011 into screening methods is highly recommended. Full article

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

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Identification and Functional Analysis of microRNAs Involved in the Anther Development in Cotton Genic Male Sterile Line Yu98-8A

by Xiaojie Yang^1,†

, Yuanming Zhao^1,†, Deyi Xie^1,†, Yao Sun¹, Xunlu Zhu², Nardana Esmaeili²

, Zuoren Yang³, Ye Wang³, Guo Yin⁴, Shuping Lv¹, Lihong Nie¹, Zhongjie Tang¹, Fu’an Zhao¹, Wu Li¹, Neelam Mishra², Li Sun², Wei Zhu⁵ and Weiping Fang^1,*

¹ Economic Crop Research Institute, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China

² Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA

³ State Key Laboratory of Cotton Biology, Cotton Research Institute, CAAS, Anyang 455000, China

⁴ Handan Agronomy of Agricultural Sciences, Handan 056006, China

⁵ Agronomy College, Henan Agricultural University, Zhengzhou 450002, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1677; https://doi.org/10.3390/ijms17101677 - 7 Oct 2016

Cited by 13 | Viewed by 5611

Abstract

Hybrid vigor contributes in a large way to the yield and quality of cotton (Gossypium hirsutum) fiber. Although microRNAs play essential regulatory roles in flower induction and development, it is still unclear if microRNAs are involved in male sterility, as the regulatory molecular [...] Read more.

Hybrid vigor contributes in a large way to the yield and quality of cotton (Gossypium hirsutum) fiber. Although microRNAs play essential regulatory roles in flower induction and development, it is still unclear if microRNAs are involved in male sterility, as the regulatory molecular mechanisms of male sterility in cotton need to be better defined. In this study, two independent small RNA libraries were constructed and sequenced from the young buds collected from the sporogenous cell formation to the meiosis stage of the male sterile line Yu98-8A and the near-isogenic line. Sequencing revealed 1588 and 1536 known microRNAs and 347 and 351 novel miRNAs from male sterile and male fertile libraries, respectively. MicroRNA expression profiles revealed that 49 conserved and 51 novel miRNAs were differentially expressed. Bioinformatic and degradome analysis indicated the regulatory complexity of microRNAs during flower induction and development. Further RT-qPCR and physiological analysis indicated that, among the different Kyoto Encyclopedia Gene and Genomes pathways, indole-3-acetic acid and gibberellic acid signaling transduction pathways may play pivotal regulatory functions in male sterility. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Induction of Apoptosis in TNF-Treated L929 Cells in the Presence of Necrostatin-1

by Hirofumi Sawai

Department of Internal Medicine, Osaka Dental University, Hirakata 573-1121, Japan

Int. J. Mol. Sci. 2016, 17(10), 1678; https://doi.org/10.3390/ijms17101678 - 7 Oct 2016

Cited by 17 | Viewed by 9429

Abstract

It has been shown that necroptosis—caspase-independent programmed necrotic cell death—can be induced by treatment with tumor necrosis factor (TNF) in the L929 murine fibrosarcoma cell line, even in the absence of a caspase inhibitor. Although it was reported that necrostatin-1—a specific inhibitor of [...] Read more.

It has been shown that necroptosis—caspase-independent programmed necrotic cell death—can be induced by treatment with tumor necrosis factor (TNF) in the L929 murine fibrosarcoma cell line, even in the absence of a caspase inhibitor. Although it was reported that necrostatin-1—a specific inhibitor of necroptosis—inhibited TNF-induced necroptosis in L929 cells, it has not been elucidated whether the cells eventually die by apoptosis in the presence of necrostatin-1. In this paper, induction of apoptosis was demonstrated in TNF-treated L929 cells in the presence of necrostatin-1. Co-treatment with cycloheximide expedited apoptosis induction in necrostatin-1/TNF-treated L929 cells: typical apoptotic morphological changes, including membrane blebbing and nuclear fragmentation, induction of caspase-3 activity, proteolytic activation of caspases-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase (PARP) (a well-known substrate of caspase-3) were observed. Moreover, co-treatment with Z-VAD-fmk (a pan-caspase inhibitor) inhibited apoptosis by completely inhibiting caspases, resulting in a shift from apoptosis to necroptosis. In contrast, co-treatment with Z-Asp-CH2-DCB (a caspase inhibitor preferential to caspase-3) inhibited apoptosis without expediting necroptosis. These results indicate that apoptosis can be induced in TNF-treated L929 cells when the cells are protected from necroptosis, and support the notion that partial activation of caspase-8 in the presence of a caspase inhibitor preferential to caspase-3 suppresses both apoptosis and necroptosis. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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Ultra-Deep Sequencing Characterization of HCV Samples with Equivocal Typing Results Determined with a Commercial Assay

by Claudia Minosse, Emanuela Giombini

, Barbara Bartolini

, Maria R. Capobianchi and Anna R. Garbuglia^*

Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani”—IRCCS, Via Portuense 292, Rome 00149, Italy

Int. J. Mol. Sci. 2016, 17(10), 1679; https://doi.org/10.3390/ijms17101679 - 7 Oct 2016

Cited by 10 | Viewed by 3898

Abstract

Hepatitis C virus (HCV) is classified into seven phylogenetically distinct genotypes, which are further subdivided into related subtypes. Accurate assignment of genotype/subtype is mandatory in the era of directly acting antivirals. Several molecular methods are available for HCV genotyping; however, a relevant number [...] Read more.

Hepatitis C virus (HCV) is classified into seven phylogenetically distinct genotypes, which are further subdivided into related subtypes. Accurate assignment of genotype/subtype is mandatory in the era of directly acting antivirals. Several molecular methods are available for HCV genotyping; however, a relevant number of samples with indeterminate, mixed, or unspecified subtype results, or even with misclassified genotypes, may occur. Using NS5B direct (DS) and ultra-deep pyrosequencing (UDPS), we have tested 43 samples, which resulted in genotype 1 unsubtyped (n = 17), mixed infection (n = 17), or indeterminate (n = 9) with the Abbott RealTime HCV Genotype II assay. Genotype 1 was confirmed in 14/17 samples (82%): eight resulted in subtype 1b, and five resulted in subtype 1a with both DS and UDPS, while one was classified as subtype 1e by DS and mixed infection (1e + 1a) by UDPS. Three of seventeen genotype 1 samples resulted in genotype 3h with both sequencing approaches. Only one mixed infection was confirmed by UDPS (4d + 1a), while in 88% of cases a single component of the mixture was detected (five genotype 1a, four genotype 1b, two genotype 3a, two genotype 4m, and two genotype 4d); 44% of indeterminate samples resulted genotype 2c by both DS and UDPS, 22% resulted genotype 3a; one indeterminate sample by Abbott resulted in genotype 4d, one resulted in genotype 6n, and one was classified as subtype 3a by DS, and resulted mixed infection (3a + 3h) by UDPS. The concordance between DS and UDPS was 94%, 88%, and 89% for genotype 1, co-infection, and indeterminate results, respectively. UDPS should be considered very useful to resolve ambiguous HCV genotyping results. Full article

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

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Doxorubicin Regulates Autophagy Signals via Accumulation of Cytosolic Ca²⁺ in Human Cardiac Progenitor Cells

by Ji Hye Park^1,†, Sung Hyun Choi^2,†, Hyungtae Kim³, Seung Taek Ji¹, Woong Bi Jang¹, Jae Ho Kim⁴, Sang Hong Baek^5,* and Sang Mo Kwon^1,4,*

¹ Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Korea

² Cellular Therapeutics Team, Bio Reseach and Development Center, Daewoong Pham. Co., Ltd., Seoul 06170, Korea

³ Department of Thoracic and Cardiovascular Surgery; Pusan National University Yangsan Hospital, Yangsan 50612, Korea

⁴ Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, Yangsan 50612, Korea

⁵ Division of Cardiology, Seoul St. Mary’s Hospital, School of Medicine, The Catholic University of Korea, Seoul 06591, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1680; https://doi.org/10.3390/ijms17101680 - 9 Oct 2016

Cited by 28 | Viewed by 6494

Abstract

Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. Resident cardiac progenitor cells (hCPCs) act as key regulators of homeostasis in myocardial cells. However, little is known [...] Read more.

Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. Resident cardiac progenitor cells (hCPCs) act as key regulators of homeostasis in myocardial cells. However, little is known about the function of hCPCs in DOXO-induced cardiotoxicity. In this study, we found that DOXO-mediated hCPC toxicity is closely related to calcium-related autophagy signaling and was significantly attenuated by blocking mTOR signaling in human hCPCs. DOXO induced hCPC apoptosis with reduction of SMP30 (regucalcin) and autophagosome marker LC3, as well as remarkable induction of the autophagy-related markers, Beclin-1, APG7, and P62/SQSTM1 and induction of calcium-related molecules, CaM (Calmodulin) and CaMKII (Calmodulin kinase II). The results of an LC3 puncta assay further indicated that DOXO reduced autophagosome formation via accumulation of cytosolic Ca²⁺. Additionally, DOXO significantly induced mTOR expression in hCPCs, and inhibition of mTOR signaling by rapamycin, a specific inhibitor, rescued DOXO-mediated autophagosome depletion in hCPCs with significant reduction of DOXO-mediated cytosolic Ca²⁺ accumulation in hCPCs, and restored SMP30 and mTOR expression. Thus, DOXO-mediated hCPC toxicity is linked to Ca²⁺-related autophagy signaling, and inhibition of mTOR signaling may provide a cardio-protective effect against DOXO-mediated hCPC toxicity. Full article

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

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Amyloid β Peptide Enhances RANKL-Induced Osteoclast Activation through NF-κB, ERK, and Calcium Oscillation Signaling

by Shangfu Li^1,†, Bu Yang^1,†, Dian Teguh², Lin Zhou², Jiake Xu² and Limin Rong^1,*

¹ Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, TianHe Road 600, TianHe District, Guangzhou 510630, China

² Molecular Lab, School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, WA, Australia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1683; https://doi.org/10.3390/ijms17101683 - 10 Oct 2016

Cited by 38 | Viewed by 7563

Abstract

Osteoporosis and Alzheimer’s disease (AD) are common chronic degenerative disorders which are strongly associated with advanced age. We have previously demonstrated that amyloid beta peptide (Aβ), one of the pathological hallmarks of AD, accumulated abnormally in osteoporotic bone specimens in addition to having [...] Read more.

Osteoporosis and Alzheimer’s disease (AD) are common chronic degenerative disorders which are strongly associated with advanced age. We have previously demonstrated that amyloid beta peptide (Aβ), one of the pathological hallmarks of AD, accumulated abnormally in osteoporotic bone specimens in addition to having an activation effect on osteoclast (Bone 2014,61:164-75). However, the underlying molecular mechanisms remain unclear. Activation of NF-κB, extracellular signal-regulated kinase (ERK) phosphorylates, and calcium oscillation signaling pathways by receptor activator NF-κB ligand (RANKL) plays a pivotal role in osteoclast activation. Targeting this signaling to modulate osteoclast function has been a promising strategy for osteoclast-related diseases. In this study, we investigated the effects of Aβ on RANKL-induced osteoclast signaling pathways in vitro. In mouse bone marrow monocytes (BMMs), Aβ exerted no effect on RANKL-induced osteoclastogenesis but promoted osteoclastic bone resorption. In molecular levels, Aβ enhanced NF-κB activity and IκB-α degradation, activated ERK phosphorylation and stimulated calcium oscillation, thus leading to upregulation of NFAT-c1 expression during osteoclast activation. Taken together, our data demonstrate that Aβ enhances RANKL-induced osteoclast activation through IκB-α degradation, ERK phosphorylation, and calcium oscillation signaling pathways and that Aβ may be a promising agent in the treatment of osteoclast-related disease such as osteoporosis. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca²⁺-ERK1/2 Signal Transduction Process in C2C12 Cells

by Yuanfei Zhou^1,2, Jiao Ren¹, Tongxing Song¹, Jian Peng^1,2 and Hongkui Wei^1,2,*

¹ Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agriculture University, Wuhan 430070, Hubei, China

² The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, Hubei, China

Int. J. Mol. Sci. 2016, 17(10), 1684; https://doi.org/10.3390/ijms17101684 - 11 Oct 2016

Cited by 40 | Viewed by 6780

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) integrates amino acid (AA) availability to support protein synthesis and cell growth. Taste receptor type 1 member (T1R) is a G protein-coupled receptor that functions as a direct sensor of extracellular AA availability to regulate [...] Read more.

The mammalian target of rapamycin complex 1 (mTORC1) integrates amino acid (AA) availability to support protein synthesis and cell growth. Taste receptor type 1 member (T1R) is a G protein-coupled receptor that functions as a direct sensor of extracellular AA availability to regulate mTORC1 through Ca²⁺ stimulation and extracellular signal–regulated kinases 1 and 2 (ERK1/2) activation. However, the roles of specific AAs in T1R1/T1R3-regulated mTORC1 are poorly defined. In this study, T1R1 and T1R3 subunits were expressed in C2C12 myotubes, and l-AA sensing was accomplished by T1R1/T1R3 to activate mTORC1. In response to l-AAs, such as serine (Ser), arginine (Arg), threonine (Thr), alanine (Ala), methionine (Met), glutamine (Gln), and glycine (Gly), Met induced mTORC1 activation and promoted protein synthesis. Met also regulated mTORC1 via T1R1/T1R3-PLCβ-Ca²⁺-ERK1/2 signal transduction. Results revealed a new role for Met-regulated mTORC1 via an AA receptor. Further studies should be performed to determine the role of T1R1/T1R3 in mediating extracellular AA to regulate mTOR signaling and to reveal its mechanism. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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Preparation of Low Molecular Weight Chondroitin Sulfates, Screening of a High Anti-Complement Capacity of Low Molecular Weight Chondroitin Sulfate and Its Biological Activity Studies in Attenuating Osteoarthritis

by Lian Li¹, Yan Li¹, Danyang Feng¹, Linghua Xu¹, Fengxin Yin¹, Hengchang Zang^1,2, Chunhui Liu¹ and Fengshan Wang^1,2,*

¹ Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China

² National Glycoengineering Research Center, Shandong University, Jinan 250012, China

Int. J. Mol. Sci. 2016, 17(10), 1685; https://doi.org/10.3390/ijms17101685 - 11 Oct 2016

Cited by 35 | Viewed by 5678

Abstract

Chondroitin sulfate (CS) plays important roles in the complement system. However, the CS structure is complicated due to different sources and the number and positions of sulfate groups. The objective of this study was to prepare different low molecular weight chondroitin sulfates (LMWCSs) [...] Read more.

Chondroitin sulfate (CS) plays important roles in the complement system. However, the CS structure is complicated due to different sources and the number and positions of sulfate groups. The objective of this study was to prepare different low molecular weight chondroitin sulfates (LMWCSs) and to investigate the biological activity in anti-complement capacity. A series of LMWCSs was prepared from different sources and characterized by ultraviolet-visible (UV) spectroscopy, high-performance liquid chromatography (HPLC), size exclusion chromatography-multiangle laser light scattering (SEC-MALLS) and nuclear magnetic resonance (NMR) spectroscopy. Hemolytic, anti-complement 3 deposition capacity and cell viability assays were carried out to investigate the biological activities in vitro. The results showed that LMWCS prepared from shark cartilage with the oxidative degradation method (LMWCS-S-O) had the best anti-complement capacity. LMWCS-S-O could inhibit the alternative pathway of the complement system and protect chondrocytes from cell death. The attenuating effect of LMWCS-S-O on Osteoarthritis (OA) was investigated by destabilization of the medial meniscus (DMM) model in vivo. Functional wind-up, histological and C5b-9 analyses were used to evaluate the treatment effect on the OA model. In vivo results showed that LMWCS-S-O could attenuate OA. LMWCS-S-O with a high content of ΔDi-2,6diS and ΔDi-6S could be used for attenuating OA through regulating the complement system. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Construction of Metabolism Prediction Models for CYP450 3A4, 2D6, and 2C9 Based on Microsomal Metabolic Reaction System

by Shuai-Bing He¹, Man-Man Li¹, Bai-Xia Zhang², Xiao-Tong Ye¹, Ran-Feng Du¹, Yun Wang^1,* and Yan-Jiang Qiao^1,*

¹ Key Laboratory of Traditional Chinese Medicine-Information Engineer of State Administration of Traditional Chinese Medicine, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China

² College of Chinese Medicine, Hebei University, Baoding 071002, China

Int. J. Mol. Sci. 2016, 17(10), 1686; https://doi.org/10.3390/ijms17101686 - 9 Oct 2016

Cited by 8 | Viewed by 6311

Abstract

During the past decades, there have been continuous attempts in the prediction of metabolism mediated by cytochrome P450s (CYP450s) 3A4, 2D6, and 2C9. However, it has indeed remained a huge challenge to accurately predict the metabolism of xenobiotics mediated by these enzymes. To [...] Read more.

During the past decades, there have been continuous attempts in the prediction of metabolism mediated by cytochrome P450s (CYP450s) 3A4, 2D6, and 2C9. However, it has indeed remained a huge challenge to accurately predict the metabolism of xenobiotics mediated by these enzymes. To address this issue, microsomal metabolic reaction system (MMRS)—a novel concept, which integrates information about site of metabolism (SOM) and enzyme—was introduced. By incorporating the use of multiple feature selection (FS) techniques (ChiSquared (CHI), InfoGain (IG), GainRatio (GR), Relief) and hybrid classification procedures (Kstar, Bayes (BN), K-nearest neighbours (IBK), C4.5 decision tree (J48), RandomForest (RF), Support vector machines (SVM), AdaBoostM1, Bagging), metabolism prediction models were established based on metabolism data released by Sheridan et al. Four major biotransformations, including aliphatic C-hydroxylation, aromatic C-hydroxylation, N-dealkylation and O-dealkylation, were involved. For validation, the overall accuracies of all four biotransformations exceeded 0.95. For receiver operating characteristic (ROC) analysis, each of these models gave a significant area under curve (AUC) value >0.98. In addition, an external test was performed based on dataset published previously. As a result, 87.7% of the potential SOMs were correctly identified by our four models. In summary, four MMRS-based models were established, which can be used to predict the metabolism mediated by CYP3A4, 2D6, and 2C9 with high accuracy. Full article

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

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Low-Tech, Pilot Scale Purification of a Recombinant Spider Silk Protein Analog from Tobacco Leaves

by René Heppner¹, Nicola Weichert², Angelika Schierhorn³, Udo Conrad² and Markus Pietzsch^1,*

¹ Department of Downstream Processing, Institute of Pharmacy, Faculty of Sciences I—Biosciences, Martin Luther University Halle-Wittenberg, Weinbergweg 22, Halle 06120, Germany

² Institute of Plant Genetics and Crop Plant Research—IPK, Corrensstrasse 3, Seeland OT Gatersleben 06466, Germany

³ Institute of Biochemistry and Biotechnology, Faculty of Sciences I—Biosciences, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, Halle 06120, Germany

Int. J. Mol. Sci. 2016, 17(10), 1687; https://doi.org/10.3390/ijms17101687 - 9 Oct 2016

Cited by 9 | Viewed by 6508

Abstract

Spider dragline is used by many members of the Araneae family not only as a proteinogenic safety thread but also for web construction. Spider dragline has been shown to possess high tensile strength in combination with elastic behavior. This high tensile strength can [...] Read more.

Spider dragline is used by many members of the Araneae family not only as a proteinogenic safety thread but also for web construction. Spider dragline has been shown to possess high tensile strength in combination with elastic behavior. This high tensile strength can be attributed to the presence of antiparallel β-sheets within the thread; these antiparallel β-sheets are why the protein is classified as a silk. Due to the properties of spider silk and its technical and medical uses, including its use as a suture material and as a scaffold for tissue regeneration, spider dragline is a focus of the biotechnology industry. The production of sufficient amounts of spider silk is challenging, as it is difficult to produce large quantities of fibers because of the cannibalistic behavior of spiders and their large spatial requirements. In recent years, the heterologous expression of genes coding for spider silk analogs in various hosts, including plants such as Nicotiana tabacum, has been established. We developed a simple and scalable method for the purification of a recombinant spider silk protein elastin-like peptide fusion protein (Q-/K-MaSp1-100× ELP) after heterologous production in tobacco leaves involving heat and acetone precipitation. Further purification was performed using centrifugal Inverse Transition Cycling (cITC). Up to 400 mg of highly pure spider silk protein derivatives can be isolated from six kilograms of tobacco leaves, which is the highest amount of silk protein derivatives purified from plants thus far. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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Morphological, Genome and Gene Expression Changes in Newly Induced Autopolyploid Chrysanthemum lavandulifolium (Fisch. ex Trautv.) Makino

by Ri Gao^1,2, Haibin Wang¹, Bin Dong¹, Xiaodong Yang¹, Sumei Chen¹, Jiafu Jiang¹, Zhaohe Zhang¹, Chen Liu¹, Nan Zhao¹ and Fadi Chen^1,*

¹ College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China

² Department of Horticulture, Agricultural College Yanbian University, Park Road 977, Yanji 133002, China

Int. J. Mol. Sci. 2016, 17(10), 1690; https://doi.org/10.3390/ijms17101690 - 9 Oct 2016

Cited by 38 | Viewed by 5634

Abstract

Autopolyploidy is widespread in higher plants and plays an important role in the process of evolution. The present study successfully induced autotetraploidys from Chrysanthemum lavandulifolium by colchicine. The plant morphology, genomic, transcriptomic, and epigenetic changes between tetraploid and diploid plants were investigated. Ligulate [...] Read more.

Autopolyploidy is widespread in higher plants and plays an important role in the process of evolution. The present study successfully induced autotetraploidys from Chrysanthemum lavandulifolium by colchicine. The plant morphology, genomic, transcriptomic, and epigenetic changes between tetraploid and diploid plants were investigated. Ligulate flower, tubular flower and leaves of tetraploid plants were greater than those of the diploid plants. Compared with diploid plants, the genome changed as a consequence of polyploidization in tetraploid plants, namely, 1.1% lost fragments and 1.6% novel fragments occurred. In addition, DNA methylation increased after genome doubling in tetraploid plants. Among 485 common transcript-derived fragments (TDFs), which existed in tetraploid and diploid progenitors, 62 fragments were detected as differentially expressed TDFs, 6.8% of TDFs exhibited up-regulated gene expression in the tetraploid plants and 6.0% exhibited down-regulation. The present study provides a reference for further studying the autopolyploidization role in the evolution of C. lavandulifolium. In conclusion, the autopolyploid C. lavandulifolium showed a global change in morphology, genome and gene expression compared with corresponding diploid. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis

by Katalin Márta¹, Nelli Farkas^1,2, Imre Szabó³, Anita Illés³, Áron Vincze³, Gabriella Pár³, Patrícia Sarlós^1,3, Judit Bajor^1,3, Ákos Szűcs^1,4, József Czimmer³, Dóra Mosztbacher^1,5, Andrea Párniczky^1,6, Kata Szemes^1,3, Dániel Pécsi¹ and Péter Hegyi^1,7,8,*

¹ Institute for Translational Medicine, University of Pécs, Pécs H-7624, Hungary

² Institute of Bioanalysis, University of Pécs, Pécs H-7624, Hungary

³ Department of Gastroenterology, First Department of Medicine, University of Pécs, Pécs H-7624, Hungary

⁴ First Department of Surgery, Semmelweis University, Budapest H-1085, Hungary

⁵ First Department of Pediatrics, Semmelweis University, Budapest H-1083, Hungary

⁶ Heim Pál Children’s Hospital, Budapest H-1089, Hungary

⁷ Translational Gastroenterology Research Group, Hungarian Academy of Sciences, University of Szeged, Szeged H-6720, Hungary

⁸ First Department of Medicine, University of Szeged, Szeged H-6720, Hungary

Int. J. Mol. Sci. 2016, 17(10), 1691; https://doi.org/10.3390/ijms17101691 - 20 Oct 2016

Cited by 23 | Viewed by 9919

Abstract

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed [...] Read more.

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann–Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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Microalgae Cultivation on Anaerobic Digestate of Municipal Wastewater, Sewage Sludge and Agro-Waste

by Luca Zuliani, Nicola Frison, Aleksandra Jelic, Francesco Fatone, David Bolzonella

and Matteo Ballottari^*

Dipartimento di Biotecnologie, Università di Verona, Strada le Grazie 15, 37134 Verona, Italy

Int. J. Mol. Sci. 2016, 17(10), 1692; https://doi.org/10.3390/ijms17101692 - 10 Oct 2016

Cited by 79 | Viewed by 7700

Abstract

Microalgae are fast-growing photosynthetic organisms which have the potential to be exploited as an alternative source of liquid fuels to meet growing global energy demand. The cultivation of microalgae, however, still needs to be improved in order to reduce the cost of the [...] Read more.

Microalgae are fast-growing photosynthetic organisms which have the potential to be exploited as an alternative source of liquid fuels to meet growing global energy demand. The cultivation of microalgae, however, still needs to be improved in order to reduce the cost of the biomass produced. Among the major costs encountered for algal cultivation are the costs for nutrients such as CO₂, nitrogen and phosphorous. In this work, therefore, different microalgal strains were cultivated using as nutrient sources three different anaerobic digestates deriving from municipal wastewater, sewage sludge or agro-waste treatment plants. In particular, anaerobic digestates deriving from agro-waste or sewage sludge treatment induced a more than 300% increase in lipid production per volume in Chlorella vulgaris cultures grown in a closed photobioreactor, and a strong increase in carotenoid accumulation in different microalgae species. Conversely, a digestate originating from a pilot scale anaerobic upflow sludge blanket (UASB) was used to increase biomass production when added to an artificial nutrient-supplemented medium. The results herein demonstrate the possibility of improving biomass accumulation or lipid production using different anaerobic digestates. Full article

(This article belongs to the Special Issue Algae Based Bio-Renewable Energy for Sustainability)

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Molecular Characterization, Tissue Distribution and Expression, and Potential Antiviral Effects of TRIM32 in the Common Carp (Cyprinus carpio)

by Yeda Wang^1,2,3, Zeming Li^1,2,3, Yuanan Lu⁴, Guangfu Hu¹, Li Lin^1,2,3, Lingbing Zeng⁵, Yong Zhou⁵ and Xueqin Liu^1,2,3,*

¹ College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China

² Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Wuhan 430070, China

³ Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Wuhan 430070, China

⁴ Department of Public Health Sciences, University of Hawaii at Manoa, Honolulu, HI 96822, USA

⁵ Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430070, China

Int. J. Mol. Sci. 2016, 17(10), 1693; https://doi.org/10.3390/ijms17101693 - 9 Oct 2016

Cited by 13 | Viewed by 4719

Abstract

Tripartite motif-containing protein 32 (TRIM32) belongs to the tripartite motif (TRIM) family, which consists of a large number of proteins containing a RING (Really Interesting New Gene) domain, one or two B-box domains, and coiled coil motif followed by different C-terminal domains. The [...] Read more.

Tripartite motif-containing protein 32 (TRIM32) belongs to the tripartite motif (TRIM) family, which consists of a large number of proteins containing a RING (Really Interesting New Gene) domain, one or two B-box domains, and coiled coil motif followed by different C-terminal domains. The TRIM family is known to be implicated in multiple cellular functions, including antiviral activity. However, it is presently unknown whether TRIM32 of common carp (Cyprinus carpio) has the antiviral effect. In this study, the sequence, expression, and antiviral function of TRIM32 homolog from common carp were analyzed. The full-length coding sequence region of trim32 was cloned from common carp. The results showed that the expression of TRIM32 (mRNA) was highest in the brain, remained stably expressed during embryonic development, and significantly increased following spring viraemia of carp virus (SVCV) infection. Transient overexpression of TRIM32 in affected Epithelioma papulosum cyprinid cells led to significant decrease of SVCV production as compared to the control group. These results suggested a potentially important role of common carp TRIM32 in enhancing host immune response during SVCV infection both in vivo and in vitro. Full article

(This article belongs to the Section Biochemistry)

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NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer

by Chunhao Niu^1,†

, Xiaoying Sun^1,†

, Weijing Zhang¹, Han Li¹, Liqun Xu², Jun Li³, Benke Xu^4,* and Yanna Zhang^1,*

¹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gynecologic Oncology, Cancer Center, Sun Yat-sen University, No. 651, Dongfeng Road East, Guangzhou 510060, China

² Department of Gynecology, Women and Children Hospital of Guangdong Province, No. 13, Guang Yuan Road, Guangzhou 510060, China

³ Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China

⁴ Department of Anatomy, Medical School of Yangtzeu University, Jingzhou 434000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1694; https://doi.org/10.3390/ijms17101694 - 20 Oct 2016

Cited by 21 | Viewed by 5681

Abstract

Background: There is an abnormal expression of nuclear receptor subfamily 2 group F member 6 (NR2F6) in human cancers such as breast cancer, colon cancer, and acute myelogenous leukemia. However, its clinical significance in cervical cancer has not been established. We explored NR2F6 [...] Read more.

Background: There is an abnormal expression of nuclear receptor subfamily 2 group F member 6 (NR2F6) in human cancers such as breast cancer, colon cancer, and acute myelogenous leukemia. However, its clinical significance in cervical cancer has not been established. We explored NR2F6 expression and its clinicopathological significance in early-stage cervical cancer. Methods: NR2F6 expression in cervical cancer cell lines and cervical cancer tissues was determined by Western blotting, real-time PCR, and immunochemistry (IHC). NR2F6 expression in 189 human early-stage cervical cancer tissue samples was evaluated using IHC. The relevance between NR2F6 expression and early-stage cervical cancer prognosis and clinicopathological features was determined. Results: There was marked NR2F6 mRNA and protein overexpression in the cervical cancer cells and clinical tissues compared with an immortalized squamous cell line and adjacent noncancerous cervical tissues, respectively. In the 189 cervical cancer samples, NR2F6 expression was positively related to International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.006), squamous cell carcinoma antigen (p = 0.006), vital status (p < 0.001), tumor recurrence (p = 0.001), chemotherapy (p = 0.039), and lymph node metastasis (p < 0.001). Overall and disease-free survival was shorter in patients with early-stage cervical cancer and higher NR2F6 levels than in patients with lower levels of NR2F6. Univariate and multivariate analysis determined that NR2F6 was an independent prognostic factor of survival in early-stage cervical cancer. Conclusions: Taken together, our findings suggest that high NR2F6 expression predicts pelvic lymph node metastasis, tumor recurrence and poor prognosis in early-stage cervical cancer. NR2F6 might be a novel prognostic biomarker and potential therapeutic target of cervical cancer. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies)

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CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation

by Cheng Ye¹, Duo Zhang¹, Lei Zhao², Yan Li¹, Xiaohan Yao¹, Hui Wang¹, Shengjie Zhang¹, Wei Liu¹, Hongchao Cao¹, Shuxian Yu¹, Yucheng Wang³, Jingjing Jiang⁴, Hui Wang^1,5, Xihua Li² and Hao Ying^1,3,5,*

¹ Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China

² Department of Neuromuscular Disease, Children’s Hospital of Fudan University, Shanghai 201102, China

³ Shanghai Xuhui Central Hospital, Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai 200031, China

⁴ Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200031, China

⁵ Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China

Int. J. Mol. Sci. 2016, 17(10), 1695; https://doi.org/10.3390/ijms17101695 - 24 Oct 2016

Cited by 21 | Viewed by 7183

Abstract

Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; [...] Read more.

Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy. Overexpression of CaMKK2 suppressed C2C12 myoblast proliferation and differentiation, while inhibition of CaMKK2 had opposite effect. We also found that CaMKK2 is able to activate AMPK in C2C12 myocytes. Inhibition of AMPK could attenuate the effect of CaMKK2 overexpression, while AMPK agonist could abrogate the effect of CaMKK2 knockdown on C2C12 cell differentiation and proliferation. These results suggest that CaMKK2 functions as an AMPK kinase in muscle cells and AMPK mediates the effect of CaMKK2 on myoblast proliferation and differentiation. Our data also indicate that CaMKK2 might inhibit myoblast proliferation through AMPK-mediated cell cycle arrest by inducing cdc2-Tyr15 phosphorylation and repress differentiation through affecting PGC1α transcription. Lastly, we show that overexpressing CaMKK2 in the muscle of mice via electroporation impaired the muscle regeneration during freeze-induced injury, indicating that CaMKK2 could serve as a potential target to treat patients with muscle injury or myopathies. Together, our study reveals a new role for CaMKK2 as a negative regulator of myoblast differentiation and proliferation and sheds new light on the molecular regulation of muscle regeneration. Full article

(This article belongs to the Section Biochemistry)

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Sodium Butyrate Promotes Reassembly of Tight Junctions in Caco-2 Monolayers Involving Inhibition of MLCK/MLC2 Pathway and Phosphorylation of PKCβ2

by Wei Miao^1,2,3, Xiujuan Wu^1,2,3, Kang Wang^1,2,3, Wenjing Wang^1,2,3, Yumei Wang^1,2,3, Zhigang Li^1,2,3, Jingjing Liu^1,2,3, Li Li^1,2,3,* and Luying Peng^1,2,3,*

¹ Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai 200120, China

² Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China

³ Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China

Int. J. Mol. Sci. 2016, 17(10), 1696; https://doi.org/10.3390/ijms17101696 - 10 Oct 2016

Cited by 104 | Viewed by 8852

Abstract

As a physiological small molecular product from the microbial fermentation of dietary fibers, butyrate plays an important role in maintaining intestinal health. Our previous works have proved that the effect of sodium butyrate (NaB) on the intestinal barrier function is mediated by activation [...] Read more.

As a physiological small molecular product from the microbial fermentation of dietary fibers, butyrate plays an important role in maintaining intestinal health. Our previous works have proved that the effect of sodium butyrate (NaB) on the intestinal barrier function is mediated by activation of AMP-activated protein kinase (AMPK). However, the detailed pathway involved remains unknown. Using the calcium switch assay in the Caco-2 cell monolayer model, we found here that NaB activated AMPK mainly by increasing the calcium level, but not the ATP concentration, via promoting store-operated calcium entry (SOCE). Upon the activation of AMPK, NaB promoted the reassembly of tight junctions (TJs) based on reducing the phosphorylation of myosin II regulatory light chain (MLC2) at Ser19 and increasing phosphorylation of protein kinase C β2 (PKCβ2) at Ser660. Inhibiting (protein kinase C β) PKCβ blocked the reassembly of TJs induced by NaB in the barrier monolayer model. These results indicated that NaB could activate the calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) pathway to mediate AMPK phosphorylating, which then inhibited the phosphorylation of MLC2 and promoted the phosphorylation of PKCβ2, respectively, so that the downstream molecules of AMPK coordinately contributed to the reassembly of TJs in the Caco-2 barrier model. These results suggested a potential mechanism of butyrate for intestine homeostasis and protection. Full article

(This article belongs to the Section Biochemistry)

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Gelation Behaviors and Mechanism of Silk Fibroin According to the Addition of Nitrate Salts

by Dong Su Im, Min Hee Kim, Young Il Yoon^*

and Won Ho Park^*

Department of Advanced Organic Materials and Textile System Engineering, Chungnam National University, Daejeon 34134, Korea

Int. J. Mol. Sci. 2016, 17(10), 1697; https://doi.org/10.3390/ijms17101697 - 10 Oct 2016

Cited by 19 | Viewed by 7981

Abstract

Silk fibroin (SF) is a typical fibrous protein that is secreted by silkworms and spiders. It has been used in a variety of areas, and especially for tissue-engineering scaffolds, due to its sound processability, mechanical properties, biodegradability, and biocompatibility. With respect to gelation, [...] Read more.

Silk fibroin (SF) is a typical fibrous protein that is secreted by silkworms and spiders. It has been used in a variety of areas, and especially for tissue-engineering scaffolds, due to its sound processability, mechanical properties, biodegradability, and biocompatibility. With respect to gelation, the SF gelation time is long in aqueous solutions, so a novel approach is needed to shorten this time. The solubility of regenerated SF is sound in formic acid (FA), which is a carboxylic acid of the simplest structure. In this study, SF was dissolved in formic acid, and the addition of salts then induced a rapid gelation that accompanied a solution-color change. Based on the gelation behaviors of the SF solution according to different SF and salt concentrations, the gelation mechanism was investigated. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion

by Ohgi Takahashi^*, Ryota Kirikoshi and Noriyoshi Manabe

Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Int. J. Mol. Sci. 2016, 17(10), 1698; https://doi.org/10.3390/ijms17101698 - 10 Oct 2016

Cited by 22 | Viewed by 9615

Abstract

In proteins and peptides, d-aspartic acid (d-Asp) and d-β-Asp residues can be spontaneously formed via racemization of the succinimide intermediate formed from l-Asp and l-asparagine (l-Asn) residues. These biologically uncommon amino acid residues are known [...] Read more.

In proteins and peptides, d-aspartic acid (d-Asp) and d-β-Asp residues can be spontaneously formed via racemization of the succinimide intermediate formed from l-Asp and l-asparagine (l-Asn) residues. These biologically uncommon amino acid residues are known to have relevance to aging and pathologies. Although nonenzymatic, the succinimide racemization will not occur without a catalyst at room or biological temperature. In the present study, we computationally investigated the mechanism of succinimide racemization catalyzed by dihydrogen phosphate ion, H₂PO₄⁻, by B3LYP/6-31+G(d,p) density functional theory calculations, using a model compound in which an aminosuccinyl (Asu) residue is capped with acetyl (Ace) and NCH₃ (Nme) groups on the N- and C-termini, respectively (Ace–Asu–Nme). It was shown that an H₂PO₄⁻ ion can catalyze the enolization of the H_α–C_α–C=O portion of the Asu residue by acting as a proton-transfer mediator. The resulting complex between the enol form and H₂PO₄⁻ corresponds to a very flat intermediate region on the potential energy surface lying between the initial reactant complex and its mirror-image geometry. The calculated activation barrier (18.8 kcal·mol⁻¹ after corrections for the zero-point energy and the Gibbs energy of hydration) for the enolization was consistent with the experimental activation energies of Asp racemization. Full article

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

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Validated HPAEC-PAD Method for the Determination of Fully Deacetylated Chitooligosaccharides

by Lidong Cao¹

, Jinlong Wu², Xiuhuan Li¹, Li Zheng¹, Miaomiao Wu¹, Pingping Liu² and Qiliang Huang^1,*

¹ Key Laboratory of Pesticide Chemistry and Application, Ministry of Agriculture, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, No. 2 Yuanmingyuan West Road, Beijing 100193, China

² Institute for the Control of Agrochemicals, Ministry of Agriculture, No. 22 Maizidian Street, Beijing 110000, China

Int. J. Mol. Sci. 2016, 17(10), 1699; https://doi.org/10.3390/ijms17101699 - 10 Oct 2016

Cited by 23 | Viewed by 6963

Abstract

An efficient and sensitive analytical method based on high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) was established for the simultaneous separation and determination of glucosamine (GlcN)₁ and chitooligosaccharides (COS) ranging from (GlcN)₂ to (GlcN)₆ without prior derivatization. Detection [...] Read more.

An efficient and sensitive analytical method based on high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) was established for the simultaneous separation and determination of glucosamine (GlcN)₁ and chitooligosaccharides (COS) ranging from (GlcN)₂ to (GlcN)₆ without prior derivatization. Detection limits were 0.003 to 0.016 mg/L (corresponding to 0.4–0.6 pmol), and the linear range was 0.2 to 10 mg/L. The optimized analysis was carried out on a CarboPac-PA100 analytical column (4 × 250 mm) using isocratic elution with 0.2 M aqueous sodium hydroxide-water mixture (10:90, v/v) as the mobile phase at a 0.4 mL/min flow rate. Regression equations revealed a good linear relationship (R² = 0.9979–0.9995, n = 7) within the test ranges. Quality parameters, including precision and accuracy, were fully validated and found to be satisfactory. The fully validated HPAEC-PAD method was readily applied for the quantification of (GlcN)_1–6 in a commercial COS technical concentrate. The established method was also used to monitor the acid hydrolysis of a COS technical concentrate to ensure optimization of reaction conditions and minimization of (GlcN)₁ degradation. Full article

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

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Sulforaphane Prevents Testicular Damage in Kunming Mice Exposed to Cadmium via Activation of Nrf2/ARE Signaling Pathways

by Shu-Hua Yang^1,†, Miao Long^1,†

, Li-Hui Yu¹, Lin Li¹, Peng Li¹, Yi Zhang¹, Yang Guo¹, Feng Gao¹, Ming-Da Liu^2,* and Jian-Bin He^1,*

¹ Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China

² College of Land and Environmental Sciences, Shenyang Agricultural University, Shenyang 110866, China

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2016, 17(10), 1703; https://doi.org/10.3390/ijms17101703 - 11 Oct 2016

Cited by 39 | Viewed by 7025

Abstract

Sulforaphane (SFN) is a natural and highly effective antioxidant. Studies suggest that SFN protects cells and tissues against cadmium (Cd) toxicity. This study investigated the protective effect of SFN against oxidative damage in the testes of Kunming mice exposed to cadmium, and explored [...] Read more.

Sulforaphane (SFN) is a natural and highly effective antioxidant. Studies suggest that SFN protects cells and tissues against cadmium (Cd) toxicity. This study investigated the protective effect of SFN against oxidative damage in the testes of Kunming mice exposed to cadmium, and explored the possible molecular mechanisms involved. Cadmium greatly reduced the serum testosterone levels in mice, reduced sperm motility, total sperm count, and increased the sperm deformity rate. Cadmium also reduces superoxide dismutase (T-SOD) and glutathione (GSH) levels and increases malondialdehyde (MDA) concentrations. SFN intervention improved sperm quality, serum testosterone, and antioxidant levels. Both mRNA and protein expression of mouse testicular nuclear factor-erythroid 2-related factor 2 (Nrf2) was reduced in cadmium-treated group. Furthermore, the downstream genes of Nrf2, glutathione peroxidase (GSH-Px), γ-glutamyl cysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) were also decreased in cadmium-treated group. SFN intervention increases the expression of these genes. Sulforaphane prevents cadmium-induced testicular damage, probably via activation of Nrf2/ARE signaling. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using ¹⁸F-FDG-PET

by Xue-Yuan Li¹, Wei-Wei Men², Hua Zhu³, Jian-Feng Lei⁴, Fu-Xing Zuo¹, Zhan-Jing Wang³, Zhao-Hui Zhu⁵, Xin-Jie Bao^1,* and Ren-Zhi Wang^1,*

¹ Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

² Center for Magnetic Resonance Imaging, Peking University, Beijing 100871, China

³ Department of Pathology, Comparative Medical Center, Peking Union Medical College & Institute of Laboratory Animal Science, Chinese Academy of Medical Science, Beijing 100021, China

⁴ Center for Medical Experiments and Testing, Capital Medical University, Beijing 100069, China

⁵ Center for PET imaging, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

Int. J. Mol. Sci. 2016, 17(10), 1707; https://doi.org/10.3390/ijms17101707 - 18 Oct 2016

Cited by 57 | Viewed by 6931

Abstract

Alzheimer’s disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) [...] Read more.

Alzheimer’s disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using ¹⁸F-labed fluorodeoxyglucose (¹⁸F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer’s cognition after cognitive decline, at least in animals. Full article

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

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Potential Susceptibility Mutations in C Gene for Hepatitis B-Related Hepatocellular Carcinoma Identified by a Two-Stage Study in Qidong, China

by Lishuai Qu¹, Haifeng Zhang², Jinxia Liu¹, Taotao Liu³, Xizhong Shen³, Taoyang Chen⁴, Zhengpin Ni⁴ and Cuihua Lu^1,*

¹ Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, China

² Department of Infectious Disease, Affiliated Hospital of Nantong University, Nantong 226001, China

³ Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China

⁴ Qidong Liver Cancer Institute, Qidong 226200, China

Int. J. Mol. Sci. 2016, 17(10), 1708; https://doi.org/10.3390/ijms17101708 - 11 Oct 2016

Cited by 1 | Viewed by 3515

Abstract

A two stage study was conducted to explore new potential mutations in the full genome of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China. In stage 1, full genomes of HBV were compared between 30 HCC cases [...] Read more.

A two stage study was conducted to explore new potential mutations in the full genome of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China. In stage 1, full genomes of HBV were compared between 30 HCC cases and 30 controls. In stage 2, an independent case–control study including 100 HCC cases and 100 controls was enrolled to verify the relationship between hot-spot mutations and HCC development. Furthermore, a longitudinal study was conducted on 11 HCC cases with serial serum samples available before HCC diagnosis. A total of 10 mutations (including pre-S2 start codon mutation and pre-S deletion in pre-S gene, G1613A, C1653T, A1762T, and G1764A mutations in X gene, A2159G, A2189Y, G2203W, and C2288R mutations in C gene) showed an increased risk of HCC. In the validation study, pre-S deletion, C1653T, A1762T/G1764A, A2159G, A2189Y, G2203W, and C2288R mutations were associated with increased HCC risk in univariate analysis. Multivariate analysis indicated that pre-S deletion, A1762T/G1764A, A2159G, and A2189Y mutations were independently related with HCC development. Moreover, a significant biological gradient of HCC risk by number of mutations in the C gene was observed. Longitudinal observation demonstrated a gradual combination of the above mutations accumulated during the progression of HCC. Full article

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

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Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis

by Zygmunt Warzecha^1,*

, Paweł Sendur^1,2, Piotr Ceranowicz¹

, Marcin Dembiński³, Jakub Cieszkowski¹, Beata Kuśnierz-Cabala⁴, Rafał Olszanecki⁵, Romana Tomaszewska⁶, Tadeusz Ambroży⁷

and Artur Dembiński¹

¹ Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegórzecka St., 31-531 Cracow, Poland

² Department of Anesthesiology and Intensive Therapy, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Cracow, Poland

³ The Second Department of General Surgery, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Cracow, Poland

⁴ Department of Clinical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Cracow, Poland

⁵ Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

⁶ Department of Pathology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

⁷ Faculty of Physical Education and Sport, University of Physical Education, 31-571 Cracow, Poland

Int. J. Mol. Sci. 2016, 17(10), 1709; https://doi.org/10.3390/ijms17101709 - 12 Oct 2016

Cited by 25 | Viewed by 5081 | Correction

Abstract

Coagulation is recognized as a key player in inflammatory and autoimmune diseases. The aim of the current research was to examine the effect of pretreatment with acenocoumarol on the development of acute pancreatitis (AP) evoked by cerulein. Methods: AP was induced in rats [...] Read more.

Coagulation is recognized as a key player in inflammatory and autoimmune diseases. The aim of the current research was to examine the effect of pretreatment with acenocoumarol on the development of acute pancreatitis (AP) evoked by cerulein. Methods: AP was induced in rats by cerulein administered intraperitoneally. Acenocoumarol (50, 100 or 150 µg/kg/dose/day) or saline were given once daily for seven days before AP induction. Results: In rats with AP, pretreatment with acenocoumarol administered at the dose of 50 or 100 µg/kg/dose/day improved pancreatic histology, reducing the degree of edema and inflammatory infiltration, and vacuolization of acinar cells. Moreover, pretreatment with acenocoumarol given at the dose of 50 or 100 µg/kg/dose/day reduced the AP-evoked increase in pancreatic weight, serum activity of amylase and lipase, and serum concentration of pro-inflammatory interleukin-1β, as well as ameliorated pancreatic DNA synthesis and pancreatic blood flow. In contrast, acenocoumarol given at the dose of 150 μg/kg/dose did not exhibit any protective effect against cerulein-induced pancreatitis. Conclusion: Low doses of acenocoumarol, given before induction of AP by cerulein, inhibit the development of that inflammation. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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Learning the Relationship between the Primary Structure of HIV Envelope Glycoproteins and Neutralization Activity of Particular Antibodies by Using Artificial Neural Networks

by Cătălin Buiu^1,*

, Mihai V. Putz^2,3,* and Speranta Avram⁴

¹ Department of Automatic Control and Systems Engineering, Faculty of Automatic Control and Computers, Politehnica University of Bucharest, Bucharest 060042, Romania

² Laboratory of Structural and Computational Physical-Chemistry for Nanosciences and QSAR, Biology-Chemistry Department, Faculty of Chemistry-Biology-Geography, West University of Timisoara, Timisoara 300115, Romania

³ Laboratory of Renewable Energies-Photovoltaics, R&D National Institute for Electrochemistry and Condensed Matter, Timisoara 300569, Romania

⁴ Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest 050095, Romania

Int. J. Mol. Sci. 2016, 17(10), 1710; https://doi.org/10.3390/ijms17101710 - 11 Oct 2016

Cited by 15 | Viewed by 5817

Abstract

The dependency between the primary structure of HIV envelope glycoproteins (ENV) and the neutralization data for given antibodies is very complicated and depends on a large number of factors, such as the binding affinity of a given antibody for a given ENV protein, [...] Read more.

The dependency between the primary structure of HIV envelope glycoproteins (ENV) and the neutralization data for given antibodies is very complicated and depends on a large number of factors, such as the binding affinity of a given antibody for a given ENV protein, and the intrinsic infection kinetics of the viral strain. This paper presents a first approach to learning these dependencies using an artificial feedforward neural network which is trained to learn from experimental data. The results presented here demonstrate that the trained neural network is able to generalize on new viral strains and to predict reliable values of neutralizing activities of given antibodies against HIV-1. Full article

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

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Selection of Suitable Reference Genes for Analysis of Salivary Transcriptome in Non-Syndromic Autistic Male Children

by Yasin Panahi¹, Fahimeh Salasar Moghaddam², Zahra Ghasemi², Mandana Hadi Jafari¹, Reza Shervin Badv^3,4, Mohamad Reza Eskandari^5,6 and Mehrdad Pedram^1,*

¹ Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan 45139-56111, Iran

² Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan 45139-56111, Iran

³ Department of Pediatric Neurology, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran 14176-13151, Iran

⁴ Children’s Medical Center, Pediatric Center of Excellence, Tehran University of Medical Sciences (TUMS), Tehran 14176-13151, Iran

⁵ Metrowest CNS Research Center, Natick, MA 01760, USA

⁶ Department of Psychiatry, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan 45139-56111, Iran

Int. J. Mol. Sci. 2016, 17(10), 1711; https://doi.org/10.3390/ijms17101711 - 12 Oct 2016

Cited by 6 | Viewed by 5635

Abstract

Childhood autism is a severe form of complex genetically heterogeneous and behaviorally defined set of neurodevelopmental diseases, collectively termed as autism spectrum disorders (ASD). Reverse transcriptase quantitative real-time PCR (RT-qPCR) is a highly sensitive technique for transcriptome analysis, and it has been frequently [...] Read more.

Childhood autism is a severe form of complex genetically heterogeneous and behaviorally defined set of neurodevelopmental diseases, collectively termed as autism spectrum disorders (ASD). Reverse transcriptase quantitative real-time PCR (RT-qPCR) is a highly sensitive technique for transcriptome analysis, and it has been frequently used in ASD gene expression studies. However, normalization to stably expressed reference gene(s) is necessary to validate any alteration reported at the mRNA level for target genes. The main goal of the present study was to find the most stable reference genes in the salivary transcriptome for RT-qPCR analysis in non-syndromic male childhood autism. Saliva samples were obtained from nine drug naïve non-syndromic male children with autism and also sex-, age-, and location-matched healthy controls using the RNA-stabilizer kit from DNA Genotek. A systematic two-phased measurement of whole saliva mRNA levels for eight common housekeeping genes (HKGs) was carried out by RT-qPCR, and the stability of expression for each candidate gene was analyzed using two specialized algorithms, geNorm and NormFinder, in parallel. Our analysis shows that while the frequently used HKG ACTB is not a suitable reference gene, the combination of GAPDH and YWHAZ could be recommended for normalization of RT-qPCR analysis of salivary transcriptome in non-syndromic autistic male children. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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Auraptene and Other Prenyloxyphenylpropanoids Suppress Microglial Activation and Dopaminergic Neuronal Cell Death in a Lipopolysaccharide-Induced Model of Parkinson’s Disease

by Satoshi Okuyama^1,*, Tomoki Semba¹, Nobuki Toyoda¹, Francesco Epifano²

, Salvatore Genovese²

, Serena Fiorito²

, Vito Alessandro Taddeo²

, Atsushi Sawamoto¹, Mitsunari Nakajima¹ and Yoshiko Furukawa¹

¹ Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan

² Department of Pharmacy, University “G. D’Annunzio”, Chieti-Pescara Via dei Vestini 31, Chieti Scalo 66100, Italy

Int. J. Mol. Sci. 2016, 17(10), 1716; https://doi.org/10.3390/ijms17101716 - 17 Oct 2016

Cited by 38 | Viewed by 5754

Abstract

In patients with Parkinson’s disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that [...] Read more.

In patients with Parkinson’s disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that (1) auraptene (AUR), a natural prenyloxycoumain, suppressed inflammatory responses including the hyperactivation of microglia in the ischemic brain and inflamed brain, thereby inhibiting neuronal cell death; (2) 7-isopentenyloxycoumarin (7-IP), another natural prenyloxycoumain, exerted anti-inflammatory and neuroprotective effects against excitotoxicity; and (3) 4′-geranyloxyferulic acid (GOFA), a natural prenyloxycinnamic acid, also exerted anti-inflammatory effects. In the present study, using an intranigral lipopolysaccharide (LPS)-induced PD-like mouse model, we investigated whether AUR, 7-IP, and GOFA suppress microglial activation and protect against dopaminergic neuronal cell death in the SN. We successfully showed that these prenyloxyphenylpropanoids exhibited these prospective abilities, suggesting the potential of these compounds as neuroprotective agents for patients with PD. Full article

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

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Panax ginseng Fraction F3 Extracted by Supercritical Carbon Dioxide Protects against Oxidative Stress in ARPE-19 Cells

by Chao-Chin Yang¹, Chiu-Yuan Chen^2,3, Chun-Chi Wu^4,5, Malcolm Koo^6,7,*, Zer-Ran Yu⁸ and Be-Jen Wang^1,*

¹ Department of Food Science, National Chiayi University, 300 Syuefu Road, Chiayi City 60004, Taiwan

² Department of Natural Biotechnology, Nanhua University, Dalin, Chiayi 62249, Taiwan

³ Research and Extension Center of Natural Healing Sciences, Nanhua University, Dalin, Chiayi 62249, Taiwan

⁴ Institute of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan

⁵ Department of Medical Research, Chung-Shan Medical University Hospital, Taichung City 40201, Taiwan

⁶ Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chiayi 62247, Taiwan

⁷ Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada

⁸ Superwell Biotechnology Corporation, Taichung City 40876, Taiwan

Int. J. Mol. Sci. 2016, 17(10), 1717; https://doi.org/10.3390/ijms17101717 - 13 Oct 2016

Cited by 16 | Viewed by 3987

Abstract

In our previous work, the ethanolic extract of Panax ginseng C. A. Meyer was successively partitioned using supercritical carbon dioxide at pressures in series to yield residue (R), F1, F2, and F3 fractions. Among them, F3 contained the highest deglycosylated ginsenosides and exerted [...] Read more.

In our previous work, the ethanolic extract of Panax ginseng C. A. Meyer was successively partitioned using supercritical carbon dioxide at pressures in series to yield residue (R), F1, F2, and F3 fractions. Among them, F3 contained the highest deglycosylated ginsenosides and exerted the strongest antioxidant and anti-inflammatory activities. The aim of this study was to investigate the protective effects of P. ginseng fractions against cellular oxidative stress induced by hydrogen peroxide (H₂O₂). Viability of adult retinal pigment epithelium-19 (ARPE-19) cells was examined after treatments of different concentrations of fractions followed by exposure to H₂O₂. Oxidative levels (malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reactive oxygen species (ROS)) and levels of activity of antioxidant enzymes were assessed. Results showed that F3 could dose-dependently protected ARPE-19 cells against oxidative injury induced by H₂O₂. F3 at a level of 1 mg/mL could restore the cell death induced by H₂O₂ of up to 60% and could alleviate the increase in cellular oxidation (MDA, 8-OHdG, and ROS) induced by H₂O₂. Moreover, F3 could restore the activities of antioxidant enzymes suppressed by H₂O₂. In conclusion, F3 obtained using supercritical carbon dioxide fractionation could significantly increase the antioxidant capacity of P. ginseng extract. The antioxidant capacity was highly correlated with the concentration of F3. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells

by Yi Yang^1,2,3,4,†, Na Wu^2,3,5,6,†, Zhiyong Wang^1,2,3,4, Fei Zhang^1,2,3,4, Ran Tian^1,2,3,4, Wei Ji^1,2,3,4, Xiubao Ren^2,3,5,6,* and Ruifang Niu^1,2,3,4,*

¹ Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China

² Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China

³ Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China

⁴ Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China

⁵ Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China

⁶ Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1718; https://doi.org/10.3390/ijms17101718 - 13 Oct 2016

Cited by 25 | Viewed by 10095

Abstract

The emergence of multidrug resistance is always associated with more rapid tumor recurrence and metastasis. P-glycoprotein (P-gp), which is a well-known multidrug-efflux transporter, confers enhanced invasion ability in drug-resistant cells. Previous studies have shown that P-gp probably exerts its tumor-promoting function via protein-protein [...] Read more.

The emergence of multidrug resistance is always associated with more rapid tumor recurrence and metastasis. P-glycoprotein (P-gp), which is a well-known multidrug-efflux transporter, confers enhanced invasion ability in drug-resistant cells. Previous studies have shown that P-gp probably exerts its tumor-promoting function via protein-protein interaction. These interactions were implicated in the activation of intracellular signal transduction. We previously showed that P-gp binds to Anxa2 and promotes the invasiveness of multidrug-resistant (MDR) breast cancer cells through regulation of Anxa2 phosphorylation. However, the accurate mechanism remains unclear. In the present study, a co-immunoprecipitation coupled with liquid chromatography tandem mass spectrometry-based interactomic approach was performed to screen P-gp binding proteins. We identified Rack1 as a novel P-gp binding protein. Knockdown of Rack1 significantly inhibited proliferation and invasion of MDR cancer cells. Mechanistic studies demonstrated that Rack1 functioned as a scaffold protein that mediated the binding of P-gp to Anxa2 and Src. We showed that Rack1 regulated P-gp activity, which was necessary for adriamycin-induced P-gp-mediated phosphorylation of Anxa2 and Erk1/2. Overall, the findings in this study augment novel insights to the understanding of the mechanism employed by P-gp for promoting migration and invasion of MDR cancer cells. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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Development of an Advanced HPLC–MS/MS Method for the Determination of Carotenoids and Fat-Soluble Vitamins in Human Plasma

by Barbora Hrvolová¹, Miriam Martínez-Huélamo^2,3, Mariel Colmán-Martínez², Sara Hurtado-Barroso^2,3

, Rosa Maria Lamuela-Raventós^2,3,*

and Jiří Kalina¹

¹ Faculty of Science, University of Ostrava, Ostrava 70103, Czech Republic

² Department of Nutrition, Food Science and Gastronomy-XARTA-INSA, School of Pharmacy and Food Science, University of Barcelona, Barcelona 08028, Spain

³ CIBER CB06/03 Fisiopatología de la Obesidad y la Nutrición, CIBEROBN, Madrid 28049, Spain

Int. J. Mol. Sci. 2016, 17(10), 1719; https://doi.org/10.3390/ijms17101719 - 14 Oct 2016

Cited by 41 | Viewed by 9217

Abstract

The concentration of carotenoids and fat-soluble vitamins in human plasma may play a significant role in numerous chronic diseases such as age-related macular degeneration and some types of cancer. Although these compounds are of utmost interest for human health, methods for their simultaneous [...] Read more.

The concentration of carotenoids and fat-soluble vitamins in human plasma may play a significant role in numerous chronic diseases such as age-related macular degeneration and some types of cancer. Although these compounds are of utmost interest for human health, methods for their simultaneous determination are scarce. A new high pressure liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) method for the quantification of selected carotenoids and fat-soluble vitamins in human plasma was developed, validated, and then applied in a pilot dietary intervention study with healthy volunteers. In 50 min, 16 analytes were separated with an excellent resolution and suitable MS signal intensity. The proposed HPLC–MS/MS method led to improvements in the limits of detection (LOD) and quantification (LOQ) for all analyzed compounds compared to the most often used HPLC–DAD methods, in some cases being more than 100-fold lower. LOD values were between 0.001 and 0.422 µg/mL and LOQ values ranged from 0.003 to 1.406 µg/mL, according to the analyte. The accuracy, precision, and stability met with the acceptance criteria of the AOAC (Association of Official Analytical Chemists) International. According to these results, the described HPLC-MS/MS method is adequately sensitive, repeatable and suitable for the large-scale analysis of compounds in biological fluids. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessCommunication

Prokaryotic Expression, Purification and Immunogenicity in Rabbits of the Small Antigen of Hepatitis Delta Virus

by Vera L. Tunitskaya¹, Olesja V. Eliseeva², Vladimir T. Valuev-Elliston¹, Daria A. Tyurina¹, Natalia F. Zakirova¹, Olga A. Khomich¹, Martins Kalis³, Oleg E. Latyshev², Elizaveta S. Starodubova¹, Olga N. Ivanova¹

, Sergey N. Kochetkov¹, Maria G. Isaguliants^2,3,*

and Alexander V. Ivanov^1,*

¹ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia

² Gamaleya Research Center of Epidemiology and Microbiology, Gamaleja str. 16, Moscow 123098, Russia

³ A Kirchenstein Institute of Microbiology and Virology, Research Department, Riga Stradins University, Dzirciema iela 16, Riga LV-1007, Latvia

Int. J. Mol. Sci. 2016, 17(10), 1721; https://doi.org/10.3390/ijms17101721 - 20 Oct 2016

Cited by 4 | Viewed by 5284

Abstract

Hepatitis delta virus (HDV) is a viroid-like blood-borne human pathogen that accompanies hepatitis B virus infection in 5% patients. HDV has been studied for four decades; however, the knowledge on its life-cycle and pathogenesis is still sparse. The studies are hampered by the [...] Read more.

Hepatitis delta virus (HDV) is a viroid-like blood-borne human pathogen that accompanies hepatitis B virus infection in 5% patients. HDV has been studied for four decades; however, the knowledge on its life-cycle and pathogenesis is still sparse. The studies are hampered by the absence of the commercially-available HDV-specific antibodies. Here, we describe a set of reproducible methods for the expression in E. coli of His-tagged small antigen of HDV (S-HDAg), its purification, and production of polyclonal anti-S-HDAg antibodies in rabbits. S-HDAg was cloned into a commercial vector guiding expression of the recombinant proteins with the C-terminal His-tag. We optimized S-HDAg protein purification procedure circumventing a low affinity of the His-tagged S-HDAg to the Ni-nitrilotriacetyl agarose (Ni-NTA-agarose) resin. Optimization allowed us to obtain S-HDAg with >90% purity. S-HDAg was used to immunize Shinchilla grey rabbits which received 80 μg of S-HDAg in two subcutaneous primes in the complete, followed by four 40 μg boosts in incomplete Freunds adjuvant. Rabbits were bled two weeks post each boost. Antibody titers determined by indirect ELISA exceeded 10⁷. Anti-S-HDAg antibodies detected the antigen on Western blots in the amounts of up-to 100 pg. They were also successfully used to characterize the expression of S-HDAg in the eukaryotic cells by immunofluorescent staining/confocal microscopy. Full article

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

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Open AccessArticle

Endogenous Multiple Exon Skipping and Back-Splicing at the DMD Mutation Hotspot

by Hitoshi Suzuki^1,*, Yoshitsugu Aoki², Toshiki Kameyama³

, Takashi Saito², Satoru Masuda², Jun Tanihata², Tetsuya Nagata^2,4, Akila Mayeda³, Shin’ichi Takeda² and Toshifumi Tsukahara¹

¹ School of Materials Science, Japan Advanced Institute of Science and Technology, Nomi, Ishikawa 923-1292, Japan

² Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan

³ Division of Gene Expression Mechanism, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan

⁴ Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyoku, Tokyo 113-0034, Japan

Int. J. Mol. Sci. 2016, 17(10), 1722; https://doi.org/10.3390/ijms17101722 - 13 Oct 2016

Cited by 36 | Viewed by 8570

Abstract

Duchenne muscular dystrophy (DMD) is a severe muscular disorder. It was reported that multiple exon skipping (MES), targeting exon 45–55 of the DMD gene, might improve patients’ symptoms because patients who have a genomic deletion of all these exons showed very mild symptoms. [...] Read more.

Duchenne muscular dystrophy (DMD) is a severe muscular disorder. It was reported that multiple exon skipping (MES), targeting exon 45–55 of the DMD gene, might improve patients’ symptoms because patients who have a genomic deletion of all these exons showed very mild symptoms. Thus, exon 45–55 skipping treatments for DMD have been proposed as a potential clinical cure. Herein, we detected the expression of endogenous exons 44–56 connected mRNA transcript of the DMD using total RNAs derived from human normal skeletal muscle by reverse transcription polymerase chain reaction (RT-PCR), and identified a total of eight types of MES products around the hotspot. Surprisingly, the 5′ splice sites of recently reported post-transcriptional introns (remaining introns after co-transcriptional splicing) act as splicing donor sites for MESs. We also tested exon combinations to generate DMD circular RNAs (circRNAs) and determined the preferential splice sites of back-splicing, which are involved not only in circRNA generation, but also in MESs. Our results fit the current circRNA-generation model, suggesting that upstream post-transcriptional introns trigger MES and generate circRNA because its existence is critical for the intra-intronic interaction or for extremely distal splicing. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing 2016)

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Open AccessArticle

Effect of Genetic Polymorphisms and Long-Term Tobacco Exposure on the Risk of Breast Cancer

by Zoraida Verde^1,*, Catalina Santiago², Luis Miguel Chicharro³, Luis Reinoso-Barbero¹, Alejandro Tejerina⁴, Fernando Bandrés^3,5 and Félix Gómez-Gallego²

¹ Department of Biomedical Sciences, European University, Madrid 28670, Spain

² School of Doctoral Studies & Research, European University, Madrid 28670, Spain

³ Cátedra Complutense Diagnostic and Innovation, Universidad Complutense, Madrid 28040, Spain

⁴ Centro de Patología de la Mama-Fundación Tejerina, Madrid 28003, Spain

⁵ Department of Toxicology and Health Sanitary, Complutense University of Madrid, Madrid 28040, Spain

Int. J. Mol. Sci. 2016, 17(10), 1726; https://doi.org/10.3390/ijms17101726 - 14 Oct 2016

Cited by 7 | Viewed by 4799

Abstract

Introduction: Tobacco smoke contains many potentially harmful compounds that may act differently and at different stages in breast cancer development. The focus of this work was to assess the possible role of cigarette smoking (status, dose, duration or age at initiation) and polymorphisms [...] Read more.

Introduction: Tobacco smoke contains many potentially harmful compounds that may act differently and at different stages in breast cancer development. The focus of this work was to assess the possible role of cigarette smoking (status, dose, duration or age at initiation) and polymorphisms in genes coding for enzymes involved in tobacco carcinogen metabolism (CYP1A1, CYP2A6) or in DNA repair (XRCC1, APEX1, XRCC3 and XPD) in breast cancer development. Methods: We designed a case control study with 297 patients, 217 histologically verified breast cancers (141 smokers and 76 non-smokers) and 80 healthy smokers in a cohort of Spanish women. Results: We found an association between smoking status and early age at diagnosis of breast cancer. Among smokers, invasive carcinoma subtype incidence increased with intensity and duration of smoking (all P_trend < 0.05). When smokers were stratified by smoking duration, we only observed differences in long-term smokers, and the CYP1A1 Ile462Ile genotype was associated with increased risk of breast cancer (OR = 7.12 (1.98–25.59)). Conclusions: Our results support the main effect of CYP1A1 in estrogenic metabolism rather than in tobacco carcinogen activation in breast cancer patients and also confirmed the hypothesis that CYP1A1 Ile462Val, in association with long periods of active smoking, could be a breast cancer risk factor. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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Open AccessArticle

Effects of Mutations on Structure–Function Relationships of Matrix Metalloproteinase-1

by Warispreet Singh¹, Gregg B. Fields^2,3,*, Christo Z. Christov^1,* and Tatyana G. Karabencheva-Christova^1,*

¹ Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK

² Department of Chemistry & Biochemistry, Florida Atlantic University, Jupiter, FL 33458, USA

³ Department of Chemistry, The Scripps Research Institute/Scripps Florida, Jupiter, FL 33458, USA

Int. J. Mol. Sci. 2016, 17(10), 1727; https://doi.org/10.3390/ijms17101727 - 14 Oct 2016

Cited by 15 | Viewed by 6039

Abstract

Matrix metalloproteinase-1 (MMP-1) is one of the most widely studied enzymes involved in collagen degradation. Mutations of specific residues in the MMP-1 hemopexin-like (HPX) domain have been shown to modulate activity of the MMP-1 catalytic (CAT) domain. In order to reveal the structural [...] Read more.

Matrix metalloproteinase-1 (MMP-1) is one of the most widely studied enzymes involved in collagen degradation. Mutations of specific residues in the MMP-1 hemopexin-like (HPX) domain have been shown to modulate activity of the MMP-1 catalytic (CAT) domain. In order to reveal the structural and conformational effects of such mutations, a molecular dynamics (MD) study was performed of in silico mutated residues in the X-ray crystallographic structure of MMP-1 complexed with a collagen-model triple-helical peptide (THP). The results indicate an important role of the mutated residues in MMP-1 interactions with the THP and communication between the CAT and the HPX domains. Each mutation has a distinct impact on the correlated motions in the MMP-1•THP. An increased collagenase activity corresponded to the appearance of a unique anti-correlated motion and decreased correlated motions, while decreased collagenase activity corresponded both to increased and decreased anti-correlated motions. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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Open AccessCommunication

Ouabain Contributes to Kidney Damage in a Rat Model of Renal Ischemia-Reperfusion Injury

by Luca Villa^1,†, Roberta Buono^1,†, Mara Ferrandi², Isabella Molinari², Fabio Benigni¹, Arianna Bettiga¹, Giorgia Colciago¹, Masami Ikehata³, Elisabetta Messaggio⁴, Maria Pia Rastaldi³, Francesco Montorsi^1,5, Andrea Salonia^1,5 and Paolo Manunta^4,6,*

¹ Division of Experimental Oncology/Unit of Urology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy

² Prassis Sigma-Tau Research Institute, Settimo Milanese, 20019 Milan, Italy

³ Renal Research Laboratory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico & Fondazione D’Amico, 20122 Milan, Italy

⁴ Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy

⁵ Chair of Urology, Università Vita Salute San Raffaele, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy

⁶ Chair of Nephrology, Università Vita Salute San Raffaele, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2016, 17(10), 1728; https://doi.org/10.3390/ijms17101728 - 14 Oct 2016

Cited by 11 | Viewed by 4678

Abstract

Warm renal ischemia performed during partial nephrectomy has been found to be associated with kidney disease. Since endogenous ouabain (EO) is a neuro-endocrine hormone involved in renal damage, we evaluated the role of EO in renal ischemia-reperfusion injury (IRI). We measured plasma and [...] Read more.

Warm renal ischemia performed during partial nephrectomy has been found to be associated with kidney disease. Since endogenous ouabain (EO) is a neuro-endocrine hormone involved in renal damage, we evaluated the role of EO in renal ischemia-reperfusion injury (IRI). We measured plasma and renal EO variations and markers of glomerular and tubular damage (nephrin, KIM-1, Kidney-Injury-Molecule-1, α1 Na-K ATPase) and the protective effect of the ouabain inhibitor, rostafuroxin. We studied five groups of rats: (1) normal; (2) infused for eight weeks with ouabain (30 µg/kg/day, OHR) or (3) saline; (4) ouabain; or (5) saline-infused rats orally treated with 100 µg/kg/day rostafuroxin for four weeks. In group 1, 2–3 h after IRI, EO increased in ischemic kidneys while decreased in plasma. Nephrin progressively decreased and KIM-1 mRNA increased starting from 24 h. Ouabain infusion (group 2) increased blood pressure (from 111.7 to 153.4 mmHg) and ouabain levels in plasma and kidneys. In OHR ischemic kidneys at 120 h from IRI, nephrin, and KIM-1 changes were greater than those detected in the controls infused with saline (group 3). All these changes were blunted by rostafuroxin treatment (groups 4 and 5). These findings support the role of EO in IRI and suggest that rostafuroxin pre-treatment of patients before partial nephrectomy with warm ischemia may reduce IRI, particularly in those with high EO. Full article

(This article belongs to the Special Issue Nephrotoxicity)

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Open AccessArticle

Assessment of Amino Acid/Drug Transporters for Renal Transport of [¹⁸F]Fluciclovine (anti-[¹⁸F]FACBC) in Vitro

by Masahiro Ono^1,†, Atsumi Baden^1,†, Hiroyuki Okudaira¹, Masato Kobayashi²

, Keiichi Kawai³, Shuntaro Oka^1,* and Hirokatsu Yoshimura¹

¹ Research Center, Nihon Medi-Physics Co., Ltd., Chiba 299-0266, Japan

² Wellness Promotion Science Center, Institute of Medical, Pharmaceutical and Health Science, Kanazawa University, Ishikawa 920-0942, Japan

³ Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-0942, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1730; https://doi.org/10.3390/ijms17101730 - 14 Oct 2016

Cited by 3 | Viewed by 5122

Abstract

[¹⁸F]Fluciclovine (trans-1-amino-3-[¹⁸F]fluorocyclobutanecarboxylic acid; anti-[¹⁸F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (K_m: 97–230 μM). However, [...] Read more.

[¹⁸F]Fluciclovine (trans-1-amino-3-[¹⁸F]fluorocyclobutanecarboxylic acid; anti-[¹⁸F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (K_m: 97–230 μM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [¹⁸F]fluciclovine reuptake. [¹⁴C]Fluciclovine (trans-1-amino-3-fluoro[1-¹⁴C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [¹⁴C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) , organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporting polypeptide 1B3 (OATP1B3). The apical-to-basal transport of [¹⁴C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC) AATs. [¹⁴C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC₅₀ > 2.95 mM). Therefore, system ASC AATs may be partly involved in the renal reuptake of [¹⁸F]fluciclovine. Further, given that [¹⁸F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [¹⁸F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters. Full article

(This article belongs to the Special Issue Cancer Molecular Imaging in the Era of Precision Medicine)

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Open AccessArticle

Discovery of Potent Carbonic Anhydrase and Acetylcholinesterase Inhibitors: 2-Aminoindan β-Lactam Derivatives

by Hayriye Genç¹, Ramazan Kalin², Zeynep Köksal³

, Nastaran Sadeghian⁴

, Umit M. Kocyigit⁵

, Mustafa Zengin¹, İlhami Gülçin^4,6,*

and Hasan Özdemir⁴

¹ Department of Chemistry, Faculty of Arts and Sciences, Sakarya University, Sakarya 54050, Turkey

² Department of Basic Science, Faculty of Science, Erzurum Technical University, Erzurum 25700, Turkey

³ Department of Chemistry, Faculty of Sciences, İstanbul Medeniyet University, İstanbul 34730, Turkey

⁴ Department of Chemistry, Faculty of Science, Atatürk University, Erzurum 25240, Turkey

⁵ Vocational School of Health Services, Cumhuriyet University, Sivas 58140, Turkey

⁶ Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia

Int. J. Mol. Sci. 2016, 17(10), 1736; https://doi.org/10.3390/ijms17101736 - 20 Oct 2016

Cited by 69 | Viewed by 5033

Abstract

β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was examined for human carbonic anhydrase I and II (hCA I, and [...] Read more.

β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that β-lactams are inhibitors of hCA I, II and AChE. The K_i values of β-lactams (2a–k) were 0.44–6.29 nM against hCA I, 0.93–8.34 nM against hCA II, and 0.25–1.13 nM against AChE. Our findings indicate that β-lactams (2a–k) inhibit both carbonic anhydrases (CA) isoenzymes and AChE at low nanomolar concentrations. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Zinc Finger and X-Linked Factor (ZFX) Binds to Human SET Transcript 2 Promoter and Transactivates SET Expression

by Siliang Xu^1,2, Ping Duan³, Jinping Li², Tristan Senkowski², Fengbiao Guo^2,4, Haibin Chen⁴, Alberto Romero², Yugui Cui¹, Jiayin Liu^1,* and Shi-Wen Jiang^2,3,*

¹ The State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China

² Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA

³ Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China

⁴ Department of Histology and Embryology, Shantou University Medical College, Shantou 515000, China

Int. J. Mol. Sci. 2016, 17(10), 1737; https://doi.org/10.3390/ijms17101737 - 20 Oct 2016

Cited by 16 | Viewed by 5416

Abstract

SET (SE Translocation) protein carries out multiple functions including those for protein phosphatase 2A (PP2A) inhibition, histone modification, DNA repair, and gene regulation. SET overexpression has been detected in brain neurons of patients suffering Alzheimer’s disease, follicle theca cells of Polycystic Ovary Syndrome [...] Read more.

SET (SE Translocation) protein carries out multiple functions including those for protein phosphatase 2A (PP2A) inhibition, histone modification, DNA repair, and gene regulation. SET overexpression has been detected in brain neurons of patients suffering Alzheimer’s disease, follicle theca cells of Polycystic Ovary Syndrome (PCOS) patients, and ovarian cancer cells, indicating that SET may play a pathological role for these disorders. SET transcript 2, produced by a specific promoter, represents a major transcript variant in different cell types. In this study, we characterized the transcriptional activation of human SET transcript 2 promoter in HeLa cells. Promoter deletion experiments and co-transfection assays indicated that ZFX, the Zinc finger and X-linked transcription factor, was able to transactivate the SET promoter. A proximal promoter region containing four ZFX-binding sites was found to be critical for the ZFX-mediated transactivation. Mutagenesis study indicated that the ZFX-binding site located the closest to the transcription start site accounted for most of the ZFX-mediated transactivity. Manipulation of ZFX levels by overexpression or siRNA knockdown confirmed the significance and specificity of the ZFX-mediated SET promoter activation. Chromatin immunoprecipitation results verified the binding of ZFX to its cognate sites in the SET promoter. These findings have led to identification of ZFX as an upstream factor regulating SET gene expression. More studies are required to define the in vivo significance of this mechanism, and specifically, its implication for several benign and malignant diseases related to SET dysregulation. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Cloning and Expression of Ecdysone Receptor and Retinoid X Receptor from Procambarus clarkii: Induction by Eyestalk Ablation

by Tian-Hao Dai^1,2, Ali Sserwadda^1,2, Kun Song^1,2, Ya-Nan Zang^1,2 and Huai-Shun Shen^1,2,*

¹ Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China

² Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China

Int. J. Mol. Sci. 2016, 17(10), 1739; https://doi.org/10.3390/ijms17101739 - 18 Oct 2016

Cited by 19 | Viewed by 4186

Abstract

Ecdysone receptor and retinoid X receptor are key regulators in molting. Here, full length ecdysone receptor (PcEcR) and retinoid X receptor (PcRXR) cDNAs from Procambarus clarkii were cloned. Full length cDNA of PcEcR has 2500 bp, encoding 576 amino [...] Read more.

Ecdysone receptor and retinoid X receptor are key regulators in molting. Here, full length ecdysone receptor (PcEcR) and retinoid X receptor (PcRXR) cDNAs from Procambarus clarkii were cloned. Full length cDNA of PcEcR has 2500 bp, encoding 576 amino acid proteins, and full length cDNA of PcRXR has 2593 bp, in which a 15 bp and a 204 bp insert/deletion splice variant regions in DNA binding domain and hinge domain were identified. The two splice variant regions in PcRXR result four isoforms: PcRXR1-4, encoding 525, 520, 457 and 452 amino acids respectively. PcEcR was highly expressed in the hepatopancreas and eyestalk and PcRXR was highly expressed in the eyestalk among eight examined tissues. Both PcEcR and PcRXR had induced expression after eyestalk ablation (ESA) in the three examined tissues. In muscle, PcEcR and PcRXR were upregulated after ESA, PcEcR reached the highest level on day 3 after ESA and increased 33.5-fold relative to day 0, and PcRXR reached highest the level on day 1 after ESA and increased 2.7-fold relative to day 0. In the hepatopancreas, PcEcR and PcRXR dEcReased continuously after ESA, and the expression levels of PcEcR and PcRXR were only 0.7% and 1.7% on day 7 after ESA relative to day 0, respectively. In the ovaries, PcEcR was upregulated after ESA, reached the highest level on day 3 after ESA, increased 3.0-fold relative to day 0, and the expression level of PcRXR changed insignificantly after ESA (p > 0.05). The different responses of PcEcR and PcRXR after ESA indicates that different tissues play different roles (and coordinates their functions) in molting. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing 2016)

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Open AccessArticle

Brachycorynella asparagi (Mordv.) Induced—Oxidative Stress and Antioxidative Defenses of Asparagus officinalis L.

by Beata Borowiak-Sobkowiak¹, Agnieszka Woźniak², Waldemar Bednarski³, Magda Formela², Sławomir Samardakiewicz⁴ and Iwona Morkunas^2,*

¹ Department of Entomology and Environmental Protection, Poznań University of Life Sciences, Dąbrowskiego 159, Poznań 60-594, Poland

² Department of Plant Physiology, Poznań University of Life Sciences, Wołyńska 35, Poznań 60-637, Poland

³ Institute of Molecular Physics, Polish Academy of Sciences, Smoluchowskiego 17, Poznań 60-179, Poland

⁴ Laboratory of Electron and Confocal Microscopy, Faculty of Biology, Adam Mickiewicz University, Umultowska 89, Poznań 61-614, Poland

Int. J. Mol. Sci. 2016, 17(10), 1740; https://doi.org/10.3390/ijms17101740 - 20 Oct 2016

Cited by 10 | Viewed by 5165

Abstract

The aim of this study was to investigate whether and to what extent oxidative stress is induced in leaves of one- and two-month-old plants of Asparagus officinalis L. cv. Argenteuil infested by Brachycorynella asparagi (Mordvilko) at a varied population size. The pest B. [...] Read more.

The aim of this study was to investigate whether and to what extent oxidative stress is induced in leaves of one- and two-month-old plants of Asparagus officinalis L. cv. Argenteuil infested by Brachycorynella asparagi (Mordvilko) at a varied population size. The pest B. asparagi has been described as the most damaging species feeding on asparagus. Analyses using electron paramagnetic resonance (EPR) demonstrated generally higher concentrations of semiquinone radicals with g-values of 2.0045 ± 0.0005 and 2.0026 ± 0.0005 in Asparagus officinalis (A. officinalis) leaves after Brachycorynella asparagi (B. asparagi) infestation than in the control. Observations of leaves under a confocal microscope showed a post-infestation enhanced generation of the superoxide anion radical (O₂^•−) and hydrogen peroxide (H₂O₂) in comparison to the control. Strong fluctuations in Mn²⁺ ion levels detected by EPR spectroscopy versus time were detected in leaves infested by aphids, which may indicate the involvement of these ions in the control of O₂^•− production. An enhanced superoxide dismutase activity is an important element in leaf defense against oxidative stress. Visible symptoms were found in aphid-infested A. officinalis. Damage to leaves of one- and two-month-old A. officinalis plants by the aphid B. asparagi was dependent on the intensity, duration of infestation and plant age. Full article

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

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Open AccessArticle

Structural Interface Forms and Their Involvement in Stabilization of Multidomain Proteins or Protein Complexes

by Jacek Dygut¹, Barbara Kalinowska², Mateusz Banach³

, Monika Piwowar³, Leszek Konieczny⁴ and Irena Roterman^3,*

¹ Department of Rehabilitation, Hospital in Przemyśl, Monte Cassino 18, 37-700 Przemyśl, Poland

² Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Łojasiewicza 11, 30-348 Krakow, Poland

³ Department of Bioinformatics and Telemedicine, Jagiellonian University–Medical College, Łazarza 16, 31-530 Krakow, Poland

⁴ Chair of Medical Biochemistry, Jagiellonian University–Medical College, Kopernika 7, 31-034 Krakow, Poland

Int. J. Mol. Sci. 2016, 17(10), 1741; https://doi.org/10.3390/ijms17101741 - 18 Oct 2016

Cited by 31 | Viewed by 4559

Abstract

The presented analysis concerns the inter-domain and inter-protein interface in protein complexes. We propose extending the traditional understanding of the protein domain as a function of local compactness with an additional criterion which refers to the presence of a well-defined hydrophobic core. Interface [...] Read more.

The presented analysis concerns the inter-domain and inter-protein interface in protein complexes. We propose extending the traditional understanding of the protein domain as a function of local compactness with an additional criterion which refers to the presence of a well-defined hydrophobic core. Interface areas in selected homodimers vary with respect to their contribution to share as well as individual (domain-specific) hydrophobic cores. The basic definition of a protein domain, i.e., a structural unit characterized by tighter packing than its immediate environment, is extended in order to acknowledge the role of a structured hydrophobic core, which includes the interface area. The hydrophobic properties of interfaces vary depending on the status of interacting domains—In this context we can distinguish: (1) Shared hydrophobic cores (spanning the whole dimer); (2) Individual hydrophobic cores present in each monomer irrespective of whether the dimer contains a shared core. Analysis of interfaces in dystrophin and utrophin indicates the presence of an additional quasi-domain with a prominent hydrophobic core, consisting of fragments contributed by both monomers. In addition, we have also attempted to determine the relationship between the type of interface (as categorized above) and the biological function of each complex. This analysis is entirely based on the fuzzy oil drop model. Full article

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

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Involvement of JNK/NFκB Signaling Pathways in the Lipopolysaccharide-Induced Modulation of Aquaglyceroporin Expression in 3T3-L1 Cells Differentiated into Adipocytes

by Jeanne Durendale Chiadak^1,2, Tatjana Arsenijevic¹, Francoise Gregoire¹, Nargis Bolaky¹, Valerie Delforge¹, Jason Perret¹ and Christine Delporte^1,*

¹ Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium

² Department of Biochemistry, Faculty of Sciences, University of Dschang, 67 Dschang, Cameroon

Int. J. Mol. Sci. 2016, 17(10), 1742; https://doi.org/10.3390/ijms17101742 - 18 Oct 2016

Cited by 18 | Viewed by 5088

Abstract

Aquaglyceroporins, belonging to the family of aquaporins (AQPs), are integral plasma membrane proteins permeable to water and glycerol that have emerged as key players in obesity. The aim of this study was to investigate the expression profile of AQPs in undifferentiated and differentiated [...] Read more.

Aquaglyceroporins, belonging to the family of aquaporins (AQPs), are integral plasma membrane proteins permeable to water and glycerol that have emerged as key players in obesity. The aim of this study was to investigate the expression profile of AQPs in undifferentiated and differentiated 3T3-L1 cells and to investigate the changes in expression of aquaglyceroporins in 3T3-L1 cells differentiated into adipocytes and subjected to lipopolysaccharide (LPS) mimicking inflammation occurring during obesity. Furthermore, the study aimed at identifying the signaling cascade involved in the regulation of aquaglyceroporins expression upon LPS stimulation. 3T3-L1 cells were grown as undifferentiated cells (UDC; preadipocytes) or cells differentiated into adipocytes (DC, adipocytes). DC were incubated in the presence or absence of LPS with or without inhibitors of various protein kinases. AQPs mRNA expression levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR). AQP1, AQP2, AQP3, AQP9 and AQP11 mRNA were expressed in both UDC and DC, whereas AQP4, AQP7 and AQP8 mRNA were expressed only in DC. In DC, LPS up-regulated AQP3 mRNA levels (p < 0.05) compared to control; these effects were inhibited by CLI095, SP600125 and BAY11-7082 (p < 0.05). LPS decreased both AQP7 and AQP11 mRNA levels (p < 0.01) in DC as compared to control; this decrease was inhibited by CLI095 and BAY11-7082 (p < 0.05) and additionally by SP00125 for AQP7 (p < 0.05). SB203580 had no effect on LPS-induced AQP3, AQP7 and AQP11 mRNA levels modulations. In conclusion, our results clearly show that many AQPs are expressed in murine 3T3-L1 adipocytes. Moreover, in DCs, LPS led to decreased AQP7 and AQP11 mRNA levels but to increased AQP3 mRNA levels, resulting from the Toll-like receptor 4 (TLR4)-induced activation of JNK and/or NFκB pathway. Full article

(This article belongs to the Special Issue Aquaporin)

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Open AccessArticle

Transcriptome Sequencing and De Novo Assembly of Golden Cuttlefish Sepia esculenta Hoyle

by Changlin Liu, Fazhen Zhao, Jingping Yan, Chunsheng Liu, Siwei Liu and Siqing Chen^*

Key Laboratory of Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China

Int. J. Mol. Sci. 2016, 17(10), 1749; https://doi.org/10.3390/ijms17101749 - 22 Oct 2016

Cited by 16 | Viewed by 5405

Abstract

Golden cuttlefish Sepia esculenta Hoyle is an economically important cephalopod species. However, artificial hatching is currently challenged by low survival rate of larvae due to abnormal embryonic development. Dissecting the genetic foundation and regulatory mechanisms in embryonic development requires genomic background knowledge. Therefore, [...] Read more.

Golden cuttlefish Sepia esculenta Hoyle is an economically important cephalopod species. However, artificial hatching is currently challenged by low survival rate of larvae due to abnormal embryonic development. Dissecting the genetic foundation and regulatory mechanisms in embryonic development requires genomic background knowledge. Therefore, we carried out a transcriptome sequencing on Sepia embryos and larvae via mRNA-Seq. 32,597,241 raw reads were filtered and assembled into 98,615 unigenes (N50 length at 911 bp) which were annotated in NR database, GO and KEGG databases respectively. Digital gene expression analysis was carried out on cleavage stage embryos, healthy larvae and malformed larvae. Unigenes functioning in cell proliferation exhibited higher transcriptional levels at cleavage stage while those related to animal disease and organ development showed increased transcription in malformed larvae. Homologs of key genes in regulatory pathways related to early development of animals were identified in Sepia. Most of them exhibit higher transcriptional levels in cleavage stage than larvae, suggesting their potential roles in embryonic development of Sepia. The de novo assembly of Sepia transcriptome is fundamental genetic background for further exploration in Sepia research. Our demonstration on the transcriptional variations of genes in three developmental stages will provide new perspectives in understanding the molecular mechanisms in early embryonic development of cuttlefish. Full article

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

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Analogs of Natural 3-Deoxyanthocyanins: O-Glucosides of the 4′,7-Dihydroxyflavylium Ion and the Deep Influence of Glycosidation on Color

by Nuno Basílio¹

, Sheiraz Al Bittar², Nathalie Mora², Olivier Dangles^2,* and Fernando Pina^1,*

¹ LAQV-REQUIMTE, Department of Chemistry, Faculty of Science & Technology, Universidade NOVA de Lisboa, 2829-516 Monte de Caparica, Portugal

² Faculty of Sciences, Technology & Health, University of Avignon, INRA, UMR408, 84000 Avignon, France

Int. J. Mol. Sci. 2016, 17(10), 1751; https://doi.org/10.3390/ijms17101751 - 20 Oct 2016

Cited by 7 | Viewed by 4781

Abstract

3-Deoxyanthocyanidins and their O-β-d-glucosides are natural pigments abundant in black sorghum. O-glycosidation can perturb the acid-base properties of the chromophore and lower its electron density with a large impact on the distribution of colored and colorless forms in aqueous [...] Read more.

3-Deoxyanthocyanidins and their O-β-d-glucosides are natural pigments abundant in black sorghum. O-glycosidation can perturb the acid-base properties of the chromophore and lower its electron density with a large impact on the distribution of colored and colorless forms in aqueous solution. In this work, the influence of O-glycosidation on color is systematically studied from a series of 3-deoxyanthocyanin analogs. The pH- and light-dependent reversible reactions of 7-β-d-glucopyranosyloxy-4′-hydroxyflavylium (P3) and 4′-β-d-glucopyranosyloxy-7-hydroxyflavylium (P5) were completely characterized in mildly acidic solution and compared with the parent aglycone 4′,7-dihydroxyflavylium ion and the O-methylethers of P3 and P5. Except P5, the chalcone forms of the pigments exhibit a high cis-trans isomerization barrier that allows a pseudo-equilibrium involving all species except the trans-chalcone. At equilibrium, only the flavylium cation and trans-chalcone are observed. With all pigments, the colored flavylium ion can be generated by irradiation of the trans-chalcone (photochromism). Glycosidation of C7–OH accelerates hydration and strongly slows down cis-trans isomerization with the pH dependence of the apparent isomerization rate constant shifting from a bell-shaped curve to a sigmoid. The color of P5 is much more stable than that of its regioisomer P3 in near-neutral conditions. Full article

(This article belongs to the Special Issue Anthocyanins)

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MicroRNA-Mediated Down-Regulation of Apoptosis Signal-Regulating Kinase 1 (ASK1) Attenuates the Apoptosis of Human Mesenchymal Stem Cells (MSCs) Transplanted into Infarcted Heart

by Chang Youn Lee¹

, Sunhye Shin¹, Jiyun Lee², Hyang-Hee Seo², Kyu Hee Lim³, Hyemin Kim¹, Jung-Won Choi⁴, Sang Woo Kim⁴, Seahyung Lee^4,5, Soyeon Lim^4,5,* and Ki-Chul Hwang^4,5,*

¹ Department of Integrated Omics for Biomedical Sciences, Yonsei University, 03722 Seoul, Korea

² Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 03722 Seoul, Korea

³ Department of Veterinary Medicine, Chonbuk National University, 54896 Jeonju, Korea

⁴ Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, 25601 Gangwon-do, Korea

⁵ Catholic Kwandong University, International St. Mary’s Hospital, 22711 Incheon, Korea

Int. J. Mol. Sci. 2016, 17(10), 1752; https://doi.org/10.3390/ijms17101752 - 20 Oct 2016

Cited by 20 | Viewed by 5483

Abstract

Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs) has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic [...] Read more.

Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs) has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic effect of stem cells. In the damaged heart, oxidative stress due to reactive oxygen species (ROS) production can cause the death of transplanted MSCs. Apoptosis signal-regulating kinase 1 (ASK1) has been implicated in the development of oxidative stress-related pathologic conditions. Thus, we hypothesized that down-regulation of ASK1 in human MSCs (hMSCs) might attenuate the post-transplantation death of MSCs. To test this hypothesis, we screened microRNAs (miRNAs) based on a miRNA-target prediction database and empirical data and investigated the anti-apoptotic effect of selected miRNAs on human adipose-derived stem cells (hASCs) and on rat myocardial infarction (MI) models. Our data indicated that miRNA-301a most significantly suppressed ASK1 expression in hASCs. Apoptosis-related genes were significantly down-regulated in miRNA-301a-enriched hASCs exposed to hypoxic conditions. Taken together, these data show that miRNA-mediated down-regulation of ASK1 protects MSCs during post-transplantation, leading to an increase in the efficacy of MSC-based cell therapy. Full article

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

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A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival

by Mathieu Pecqueux^1,*,†

, Isabell Liebetrau^2,†, Wiebke Werft³, Hendrik Dienemann⁴, Thomas Muley⁴

, Joachim Pfannschmidt⁵

, Benjamin Müssle¹, Nuh Rahbari¹, Sebastian Schölch¹, Markus W. Büchler⁶, Jürgen Weitz¹, Christoph Reissfelder^1,† and Christoph Kahlert^1,†

¹ Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany

² ALB Fils clinic, Eybstr. 16, 73312 Geislingen, Germany

³ German Cancer Research Center, Division of Biostatistics, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

⁴ Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany

⁵ Department of Thoracic Surgery, Helios Clinic Emil von Behring, Walterhöferstraße 11, 14165 Berlin, Germany

⁶ Department of Surgery at Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany

^† These authors contributed equally to the manuscript.

Int. J. Mol. Sci. 2016, 17(10), 1755; https://doi.org/10.3390/ijms17101755 - 21 Oct 2016

Cited by 18 | Viewed by 6366

Abstract

MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent [...] Read more.

MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent tumor-associated stroma. Both of these compartments have a mutual influence on tumor progression. In the development of metastases, cancer cells initially interact with the host tissue. Therefore, compartment-specific expression signatures of these three locations—tumor, associated stroma, and host tissue—can provide new insights into the complex tumor biology of colorectal cancer. Frozen tissue samples of colorectal liver (n = 25) and lung metastases (n = 24) were laser microdissected to separate tumor cells and the adjacent tumor-associated stroma cells. Additionally, normal lung and liver tissue was collected from the same patients. We performed a microarray analysis in four randomly selected liver metastases and four randomly selected lung metastases, analyzing a total of 939 human miRNAs. miRNAs with a significant change >2-fold between the tumor, tumor stroma, and host tissue were analyzed in all samples using RT-qPCR (11 miRNAs) and correlated with the clinical data. We found a differential expression of several miRNAs between the tumor, the tumor-associated stroma, and the host tissue compartment. When comparing liver and lung metastases, miR-194 showed a 1.5-fold; miR-125, miR-127, and miR-192 showed a 2.5-fold; miR-19 and miR-215 a 3-fold; miR-145, miR-199-3, and miR-429 a 5-fold; miR-21 a 7-fold; and, finally, miR-199-5 a 12.5-fold downregulation in liver metastases compared to lung metastases. Furthermore miR-19, miR-125, miR-127, miR-192, miR-194, miR-199-5, and miR-215 showed a significant upregulation in the normal liver tissue compared to the normal lung tissue. Univariate analysis identified an association of poor survival with the expression of miR-125 (p = 0.05), miR-127 (p = 0.001), miR-145 (p = 0.005), miR-192 (p = 0.015), miR-194 (0.003), miR-199-5 (p = 0.008), miR-215 (p < 0.001), and miR-429 (p = 0.03) in the host liver tissue of the liver metastases. Colorectal liver and lung metastases have a unique miRNA expression profile. miRNA expression in the host tissue of colorectal liver metastases seems to be able to influence tumor progression and survival. These findings can be used in the development of tailored therapies. Full article

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

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Differential Amino Acid, Carbohydrate and Lipid Metabolism Perpetuations Involved in a Subtype of Rheumatoid Arthritis with Chinese Medicine Cold Pattern

by Hongtao Guo^1,†, Xuyan Niu^2,†, Yan Gu^3,4,†, Cheng Lu^2,5

, Cheng Xiao^6,7, Kevin Yue⁵, Ge Zhang⁵

, Xiaohua Pan⁸, Miao Jiang², Yong Tan^2,5, Hongwei Kong³, Zhenli Liu⁹, Guowang Xu^3,* and Aiping Lu^2,5,10,*

¹ Department of Rheumatology, First Affiliated Hospital of Henan University of TCM, Zhengzhou 450000, China

² Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China

³ CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China

⁴ School of Medicine, Shanxi Datong University, Datong 037009, China

⁵ Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong 00852, Hong Kong, China

⁶ Department of Scientific Research Administration, China-Japan Friendship Hospital, Beijing 100029, China

⁷ Department of Rheumatology, People Hospital of Yichun City, Yichun 336000, China

⁸ Jinan University & Hong Kong Baptist University Joint Laboratory of Innovative Drug Development, Institute of Biomedicine (Guangzhou), Jinan University, Guangzhou 510632, China

⁹ Institute of Basic Theory of TCM, China Academy of Chinese Medical Sciences, Beijing 100700, China

¹⁰ E-Institute of Chinese Traditional Internal Medicine, Shanghai Municipal Education Commission, Shanghai 201203, China

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2016, 17(10), 1757; https://doi.org/10.3390/ijms17101757 - 21 Oct 2016

Cited by 18 | Viewed by 5998

Abstract

Pattern classification is a key approach in Traditional Chinese Medicine (TCM), and it is used to classify the patients for intervention selection accordingly. TCM cold and heat patterns, two main patterns of rheumatoid arthritis (RA) had been explored with systems biology approaches. Different [...] Read more.

Pattern classification is a key approach in Traditional Chinese Medicine (TCM), and it is used to classify the patients for intervention selection accordingly. TCM cold and heat patterns, two main patterns of rheumatoid arthritis (RA) had been explored with systems biology approaches. Different regulations of apoptosis were found to be involved in cold and heat classification in our previous works. For this study, the metabolic profiling of plasma was explored in RA patients with typical TCM cold or heat patterns by integrating liquid chromatography/mass spectrometry (LC/MS) and gas chromatography/mass spectrometry (GC/MS) platforms in conjunction with the Ingenuity Pathway Analysis (IPA) software. Three main processes of metabolism, including amino acid, carbohydrate and lipid were focused on for function analysis. The results showed that 29 and 19 differential metabolites were found in cold and heat patterns respectively, compared with healthy controls. The perturbation of amino acid metabolism (increased essential amino acids), carbohydrate metabolism (galactose metabolism) and lipid metabolism, were found to be involved in both cold and heat pattern RA. In particular, more metabolic perturbations in protein and collagen breakdown, decreased glycolytic activity and aerobic oxidation, and increased energy utilization associated with RA cold pattern patients. These findings may be useful for obtaining a better understanding of RA pathogenesis and for achieving a better efficacy in RA clinical practice. Full article

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

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Stage-Wise Identification and Analysis of miRNA from Root-Knot Nematode Meloidogyne incognita

by Parthiban Subramanian^1,†, In-Chan Choi^1,†, Vimalraj Mani^1,2,†, Junhyung Park³, Sathiyamoorthy Subramaniyam³, Kang-Hyun Choi^1,2, Joon-Soo Sim¹, Chang-Muk Lee¹, Ja Choon Koo² and Bum-Soo Hahn^1,*

¹ Metabolic Engineering Division, Department of Agricultural Biotechnology, National Institute of Agricultural Sciences, Rural Development Administration, Jeonju 54874, Korea

² Division of Science Education and Institute of Fusion Science, Chonbuk National University, Jeonju 761-756, Korea

³ TheragenEtex Bio Institute, Gwanggyo-ro, Suwon 16229, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1758; https://doi.org/10.3390/ijms17101758 - 21 Oct 2016

Cited by 13 | Viewed by 5561

Abstract

In this study, we investigated global changes in miRNAs of Meloidogyne incognita throughout its life cycle. Small RNA sequencing resulted in approximately 62, 38, 38, 35, and 39 Mb reads in the egg, J2, J3, J4, and female stages, respectively. Overall, we identified [...] Read more.

In this study, we investigated global changes in miRNAs of Meloidogyne incognita throughout its life cycle. Small RNA sequencing resulted in approximately 62, 38, 38, 35, and 39 Mb reads in the egg, J2, J3, J4, and female stages, respectively. Overall, we identified 2724 known and 383 novel miRNAs (read count > 10) from all stages, of which 169 known and 13 novel miRNA were common to all the five stages. Among the stage-specific miRNAs, miR-286 was highly expressed in eggs, miR-2401 in J2, miR-8 and miR-187 in J3, miR-6736 in J4, and miR-17 in the female stages. These miRNAs are reported to be involved in embryo and neural development, muscular function, and control of apoptosis. Cluster analysis indicated the presence of 91 miRNA clusters, of which 36 clusters were novel and identified in this study. Comparison of miRNA families with other nematodes showed 17 families to be commonly absent in animal parasitic nematodes and M. incognita. Validation of 43 predicted common and stage-specific miRNA by quantitative PCR (qPCR) indicated their expression in the nematode. Stage-wise exploration of M. incognita miRNAs has not been carried out before and this work presents information on common and stage-specific miRNAs of the root-knot nematode. Full article

(This article belongs to the Section Biochemistry)

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Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma

by Paola Caria¹, Silvia Cantara²

, Daniela Virginia Frau¹, Furio Pacini^2,†, Roberta Vanni^1,*,† and Tinuccia Dettori¹

¹ Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato 09042, Italy

² Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena 53100, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1759; https://doi.org/10.3390/ijms17101759 - 21 Oct 2016

Cited by 7 | Viewed by 4876

Abstract

Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features [...] Read more.

Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features may be associated with chromosome instability. Here, we investigated the frequency of HER2 (Human Epidermal Growth Factor Receptor 2) amplification, and other recently reported genetic alterations in sporadic PTC (sPTC) and fPTC, and assessed correlations with RTL and BRAF mutational status. We analyzed HER2 gene amplification and the integrity of ALK, ETV6, RET, and BRAF genes by fluorescence in situ hybridization in isolated nuclei and paraffin-embedded formalin-fixed sections of 13 fPTC and 18 sPTC patients. We analyzed BRAF^V600E mutation and RTL by qRT-PCR. Significant HER2 amplification (p = 0.0076), which was restricted to scattered groups of cells, was found in fPTC samples. HER2 amplification in fPTCs was invariably associated with BRAF^V600E mutation. RTL was shorter in fPTCs than sPTCs (p < 0.001). No rearrangements of other tested genes were observed. These findings suggest that the association of HER2 amplification with BRAF^V600E mutation and telomere shortening may represent a marker of tumor aggressiveness, and, in refractory thyroid cancer, may warrant exploration as a site for targeted therapy. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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Role of Intracellular Lipid Logistics in the Preferential Usage of Very Long Chain-Ceramides in Glucosylceramide

by Toshiyuki Yamaji^1,*, Aya Horie^1,2, Yuriko Tachida¹, Chisato Sakuma¹, Yusuke Suzuki², Yasunori Kushi² and Kentaro Hanada¹

¹ Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan

² Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Chiyoda-ku, Tokyo 101-8308, Japan

Int. J. Mol. Sci. 2016, 17(10), 1761; https://doi.org/10.3390/ijms17101761 - 21 Oct 2016

Cited by 18 | Viewed by 5238

Abstract

Ceramide is a common precursor of sphingomyelin (SM) and glycosphingolipids (GSLs) in mammalian cells. Ceramide synthase 2 (CERS2), one of the six ceramide synthase isoforms, is responsible for the synthesis of very long chain fatty acid (C20–26 fatty acids) (VLC)-containing ceramides (VLC-Cer). It [...] Read more.

Ceramide is a common precursor of sphingomyelin (SM) and glycosphingolipids (GSLs) in mammalian cells. Ceramide synthase 2 (CERS2), one of the six ceramide synthase isoforms, is responsible for the synthesis of very long chain fatty acid (C20–26 fatty acids) (VLC)-containing ceramides (VLC-Cer). It is known that the proportion of VLC species in GSLs is higher than that in SM. To address the mechanism of the VLC-preference of GSLs, we used genome editing to establish three HeLa cell mutants that expressed different amounts of CERS2 and compared the acyl chain lengths of SM and GSLs by metabolic labeling experiments. VLC-sphingolipid expression was increased along with that of CERS2, and the proportion of VLC species in glucosylceramide (GlcCer) was higher than that in SM for all expression levels of CERS2. This higher proportion was still maintained even when the proportion of C16-Cer to the total ceramides was increased by disrupting the ceramide transport protein (CERT)-dependent C16-Cer delivery pathway for SM synthesis. On the other hand, merging the Golgi apparatus and the endoplasmic reticulum (ER) by Brefeldin A decreased the proportion of VLC species in GlcCer probably due to higher accessibility of UDP-glucose ceramide glucosyltransferase (UGCG) to C16-rich ceramides. These results suggest the existence of a yet-to-be-identified mechanism rendering VLC-Cer more accessible than C16-Cer to UGCG, which is independent of CERT. Full article

(This article belongs to the Section Biochemistry)

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Screening the Toxicity of Selected Personal Care Products Using Embryo Bioassays: 4-MBC, Propylparaben and Triclocarban

by Tiago Torres¹, Isabel Cunha¹

, Rosário Martins^1,2 and Miguel M. Santos^1,3,*

¹ CIMAR/CIIMAR, Laboratório Associado—Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Av. General Norton de Matos s/n, 4450-208 Porto, Portugal

² Escola Superior de Tecnologia de Saúde do Porto, Instituto Politécnico do Porto, 4200-072 Porto, Portugal

³ FCUP-Departamento de Biologia, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal

Int. J. Mol. Sci. 2016, 17(10), 1762; https://doi.org/10.3390/ijms17101762 - 21 Oct 2016

Cited by 50 | Viewed by 6943

Abstract

Recently, several emerging pollutants, including Personal Care Products (PCPs), have been detected in aquatic ecosystems, in the ng/L or µg/L range. Available toxicological data is limited, and, for certain PCPs, evidence indicates a potential risk for the environment. Hence, there is an urgent [...] Read more.

Recently, several emerging pollutants, including Personal Care Products (PCPs), have been detected in aquatic ecosystems, in the ng/L or µg/L range. Available toxicological data is limited, and, for certain PCPs, evidence indicates a potential risk for the environment. Hence, there is an urgent need to gather ecotoxicological data on PCPs as a proxy to improve risk assessment. Here, the toxicity of three different PCPs (4-Methylbenzylidene Camphor (4-MBC), propylparaben and triclocarban) was tested using embryo bioassays with Danio rerio (zebrafish) and Paracentrotus lividus (sea urchin). The No Observed Effect Concentration (NOEC) for triclocarban was 0.256 µg/L for sea urchin and 100 µg/L for zebrafish, whereas NOEC for 4-MBC was 0.32 µg/L for sea urchin and 50 µg/L for zebrafish. Both PCPs impacted embryo development at environmentally relevant concentrations. In comparison with triclocarban and 4-MBC, propylparaben was less toxic for both sea urchin (NOEC = 160 µg/L) and zebrafish (NOEC = 1000 µg/L). Overall, this study further demonstrates the sensitivity of embryo bioassays as a high-throughput approach for testing the toxicity of emerging pollutants. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort

by Martina Landini¹, Ivan Merelli¹, M. Elisabetta Raggi², Nadia Galluccio¹, Francesca Ciceri², Arianna Bonfanti², Serena Camposeo³, Angelo Massagli³, Laura Villa², Erika Salvi⁴, Daniele Cusi^1,5, Massimo Molteni², Luciano Milanesi¹

, Anna Marabotti^2,6

and Alessandra Mezzelani^1,*

¹ Institute of Biomedical Technologies, National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Italy

² Scientific Institute, IRCSS Eugenio Medea, 23842 Bosisio Parini, Italy

³ Scientific Institute, IRCSS Eugenio Medea, 72100 Brindisi, Italy

⁴ Department of Health Sciences, University of Milan, 20142 Milan, Italy

⁵ Sanipedia srl, via Ariosto 21, 20091 Bresso, Italy

⁶ Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy

Int. J. Mol. Sci. 2016, 17(10), 1765; https://doi.org/10.3390/ijms17101765 - 22 Oct 2016

Cited by 18 | Viewed by 5275

Abstract

Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the [...] Read more.

Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype on NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, p-value = 2.58 × 10⁻⁶ for the European controls; odds ratio = 2.42, p-value = 6.33 × 10⁻³ for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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Maternal Chromium Restriction Leads to Glucose Metabolism Imbalance in Mice Offspring through Insulin Signaling and Wnt Signaling Pathways

by Qian Zhang¹, Xiaofang Sun², Xinhua Xiao^1,*, Jia Zheng¹, Ming Li¹, Miao Yu¹, Fan Ping¹, Zhixin Wang¹, Cuijuan Qi¹, Tong Wang¹ and Xiaojing Wang¹

¹ Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China

² Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China

Int. J. Mol. Sci. 2016, 17(10), 1767; https://doi.org/10.3390/ijms17101767 - 22 Oct 2016

Cited by 20 | Viewed by 7919

Abstract

An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a [...] Read more.

An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a chromium-restricted diet (CR) throughout pregnancy and the lactation period. After weaning, some offspring continued the diet diagram (CD-CD or CR-CR), while other offspring were transferred to another diet diagram (CD-CR or CR-CD). At 32 weeks of age, glucose metabolism parameters were measured, and the liver from CR-CD group and CD-CD group was analyzed using a gene array. Quantitative real-time polymerase chain reaction (qPCR) and Western blot were used to verify the result of the gene array. A maternal chromium-restricted diet resulted in obesity, hyperglycemia, hyperinsulinemia, increased area under the curve (AUC) of glucose in oral glucose tolerance testing and homeostasis model assessment of insulin resistance (HOMA-IR). There were 463 genes that differed significantly (>1.5-fold change, p < 0.05) between CR-CD offspring (264 up-regulated genes, 199 down-regulated genes) and control offspring. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis revealed that the insulin signaling pathway and Wnt signaling pathway were in the center of the gene network. Our study provides the first evidence that maternal chromium deficiency influences glucose metabolism in pups through the regulation of insulin signaling and Wnt signaling pathways. Full article

(This article belongs to the Section Biochemistry)

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Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

by Alessandra Ammazzalorso^1,†

, Barbara De Filippis^1,†, Cristina Campestre¹

, Antonio Laghezza²

, Alessandro Marrone¹

, Rosa Amoroso¹

, Paolo Tortorella² and Mariangela Agamennone^1,*

¹ Dipartimento di Farmacia, Università “G. d’Annunzio” Chieti, Via dei Vestini 31, 66100 Chieti, Italy

² Dipartimento di Farmacia-Scienze del Farmaco, Università “A. Moro” Bari, Via Orabona 4, 70125 Bari, Italy

^† These authors contributed equally to the work.

Int. J. Mol. Sci. 2016, 17(10), 1768; https://doi.org/10.3390/ijms17101768 - 22 Oct 2016

Cited by 11 | Viewed by 5253

Abstract

Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of [...] Read more.

Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data. Full article

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

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Open AccessArticle

Trans-Stilbenes in Commercial Grape Juices: Quantification Using HPLC Approaches

by Julia López-Hernández^* and Ana Rodríguez-Bernaldo de Quirós

Faculty of Pharmacy, Department of Analytical Chemistry, Nutrition and Food Science, University of Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, Spain

Int. J. Mol. Sci. 2016, 17(10), 1769; https://doi.org/10.3390/ijms17101769 - 24 Oct 2016

Cited by 15 | Viewed by 4866

Abstract

Trans-stilbenes belong to the group of polyphenolic phytoalexins, and occur in many plant foods. These compounds have received great attention by researchers due to their well-known beneficial health effects. In the present study a chromatographic method that comprises the use of variable [...] Read more.

Trans-stilbenes belong to the group of polyphenolic phytoalexins, and occur in many plant foods. These compounds have received great attention by researchers due to their well-known beneficial health effects. In the present study a chromatographic method that comprises the use of variable wavelength (VWD) and fluorescence (FLD) detectors in series for the analysis of trans-stilbenes is presented. The relation of peak-area obtained with both detectors is proposed as an alternative and complementary approach for the rapid identification of these phenolic compounds. The proposed method was applied to determine trans-stilbenes in commercial fruit juices. Trans-piceid was the most common trans-stilbene found in the samples analyzed. The method was validated in terms of linearity, sensitivity and repeatability. Appropriate sensitivity and good linearity (r² > 0.9991) were achieved. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2016)

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Open AccessArticle

Annexin-1 Mediates Microglial Activation and Migration via the CK2 Pathway during Oxygen–Glucose Deprivation/Reperfusion

by Shuangxi Liu^1,2,3,†, Yan Gao^1,4,†, Xiaoli Yu^1,2, Baoming Zhao^1,2,4, Lu Liu^1,2, Yin Zhao¹, Zhenzhao Luo¹ and Jing Shi^1,2,*

¹ Department of Neurobiology and Key Laboratory of Neurological Diseases of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China

² Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China

³ Medical College, Yichun Uiversity, 576 Xuefu Road, Yichun 336000, China

⁴ Department of Center for Molecular Medicine, Medical College, Hubei University of Arts and Science, Xiangyang 441053, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1770; https://doi.org/10.3390/ijms17101770 - 22 Oct 2016

Cited by 138 | Viewed by 7110

Abstract

Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular [...] Read more.

Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular mechanism. In rat hippocampal slices, OGD/R treatment enhanced the ANXA1 expression in neuron, the formyl peptide receptor (FPRs) expression in microglia, and the microglial activation in the CA1 region (cornu ammonis 1). These effects were reversed by the FPRs antagonist Boc1. The cell membrane currents amplitude of BV-2 microglia (the microglial like cell-line) was increased when treated with Ac2-26, the N-terminal peptide of ANXA1. Ac2-26 treatment enhanced BV-2 microglial migration whereas Boc1 treatment inhibited the migration. In BV-2 microglia, both the expression of the CK2 target phosphorylated α-E-catenin and the binding of casein kinase II (CK2) with α-E-catenin were elevated by Ac2-26, these effects were counteracted by the CK2 inhibitor TBB and small interfering (si) RNA directed against transcripts of CK2 and FPRs. Moreover, both TBB and siRNA-mediated inhibition of CK2 blocked Ac2-26-mediated BV-2 microglia migration. Our findings indicate that ANXA1 promotes microglial activation and migration during OGD/R via FPRs, and CK2 target α-E-catenin phosphorylation is involved in this process. Full article

(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)

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Metabolic Response to XD14 Treatment in Human Breast Cancer Cell Line MCF-7

by Daqiang Pan^1,2, Michel Kather¹, Lucas Willmann^1,3, Manuel Schlimpert^1,4, Christoph Bauer¹, Simon Lagies¹, Karin Schmidtkunz², Steffen U. Eisenhardt⁵, Manfred Jung²

, Stefan Günther² and Bernd Kammerer^1,6,*

¹ Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany

² Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany

³ Institute of Biology II, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany

⁴ Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany

⁵ Department of Plastic and Hand Surgery, University of Freiburg Medical Center, 79106 Freiburg, Germany

⁶ BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany

Int. J. Mol. Sci. 2016, 17(10), 1772; https://doi.org/10.3390/ijms17101772 - 24 Oct 2016

Cited by 9 | Viewed by 6738

Abstract

XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in [...] Read more.

XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in the human breast cancer cell line MCF-7 (Michigan Cancer Foundation-7) treated by XD14. A three-day time series experiment with two concentrations of XD14 was performed. Gas chromatography-mass spectrometry (GC-MS) was applied for untargeted profiling of treated and non-treated MCF-7 cells. The gained data sets were evaluated by several statistical methods: analysis of variance (ANOVA), clustering analysis, principle component analysis (PCA), and partial least squares discriminant analysis (PLS-DA). Cell proliferation was strongly inhibited by treatment with 50 µM XD14. Samples could be discriminated by time and XD14 concentration using PLS-DA. From the 117 identified metabolites, 67 were significantly altered after XD14 treatment. These metabolites include amino acids, fatty acids, Krebs cycle and glycolysis intermediates, as well as compounds of purine and pyrimidine metabolism. This massive intervention in energy metabolism and the lack of available nucleotides could explain the decreased proliferation rate of the cancer cells. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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Translationally Controlled Tumor Protein Stimulates Dopamine Release from PC12 Cells via Ca²⁺-Independent Phospholipase A₂ Pathways

by Jihui Seo, Jeehye Maeng and Hwa-Jung Kim^*

College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea

Int. J. Mol. Sci. 2016, 17(10), 1774; https://doi.org/10.3390/ijms17101774 - 24 Oct 2016

Cited by 7 | Viewed by 5169

Abstract

The translationally controlled tumor protein (TCTP), initially identified as a tumor- and growth-related protein, is also known as a histamine-releasing factor (HRF). TCTP is widely distributed in the neuronal systems, but its function is largely uncharacterized. Here, we report a novel function of [...] Read more.

The translationally controlled tumor protein (TCTP), initially identified as a tumor- and growth-related protein, is also known as a histamine-releasing factor (HRF). TCTP is widely distributed in the neuronal systems, but its function is largely uncharacterized. Here, we report a novel function of TCTP in the neurotransmitter release from a neurosecretory, pheochromocytoma (PC12) cells. Treatment with recombinant TCTP (rTCTP) enhanced both basal and depolarization (50 mM KCl)-evoked [³H]dopamine release in concentration- and time-dependent manners. Interestingly, even though rTCTP induced the increase in intracellular calcium levels ([Ca²⁺]_i), the rTCTP-driven effect on dopamine release was mediated by a Ca²⁺-independent pathway, as evidenced by the fact that Ca²⁺-modulating agents such as Ca²⁺ chelators and a voltage-gated L-type Ca²⁺-channel blocker did not produce any changes in rTCTP-evoked dopamine release. In a study to investigate the involvement of phospholipase A₂ (PLA₂) in rTCTP-induced dopamine release, the inhibitor for Ca²⁺-independent PLA₂ (iPLA₂) produced a significant inhibitory effect on rTCTP-induced dopamine release, whereas this release was not significantly inhibited by Ca²⁺-dependent cytosolic PLA₂ (cPLA₂) and secretory PLA₂ (sPLA₂) inhibitors. We found that rTCTP-induced dopamine release from neuronal PC12 cells was modulated by a Ca²⁺-independent mechanism that involved PLA₂ in the process, suggesting the regulatory role of TCTP in the neuronal functions. Full article

(This article belongs to the Section Biochemistry)

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Progressive Vascular Functional and Structural Damage in a Bronchopulmonary Dysplasia Model in Preterm Rabbits Exposed to Hyperoxia

by Julio Jiménez^1,2, Jute Richter¹, Taro Nagatomo³, Thomas Salaets¹, Rozenn Quarck⁴

, Allard Wagennar⁴, Hongmei Wang⁵, Jeroen Vanoirbeek⁶, Jan Deprest^1,7,* and Jaan Toelen⁸

¹ Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven, 3000 Leuven, Belgium

² Department of Obstetrics and Gynaecology, Clínica Alemana Universidad del Desarrollo, 7650568 Santiago, Chile

³ Department of Pediatrics, Ehime Prefectural Central Hospital, 790-0024 Ehime, Japan

⁴ Respiratory Division, Department of Clinical and Experimental Medicine, University of Leuven, 3000 Leuven, Belgium

⁵ Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, China

⁶ Centre for Environment and Health, Department of Public Health and Primary Care, KU Leuven, 3000 Leuven, Belgium

⁷ Department of Obstetrics and Gynaecology, University College London, WC1E 6HX London, UK

⁸ Division of Woman and Child, University Hospitals Leuven, 3000 Leuven, Belgium

Int. J. Mol. Sci. 2016, 17(10), 1776; https://doi.org/10.3390/ijms17101776 - 24 Oct 2016

Cited by 27 | Viewed by 6398

Abstract

Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and [...] Read more.

Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and can be used as a translational model to test novel treatment options. In preterm rabbits, exposure to hyperoxia leads to parenchymal changes, yet vascular damage has not been studied in this model. In this study we document the early functional and structural changes of the lung vasculature in preterm rabbits that are induced by hyperoxia after birth. Pulmonary artery Doppler measurements, micro-CT barium angiograms and media thickness of peripheral pulmonary arteries were affected after seven days of hyperoxia when compared to controls. The parenchyma was also affected both at the functional and structural level. Lung function testing showed higher tissue resistance and elastance, with a decreased lung compliance and lung capacity. Histologically hyperoxia leads to fewer and larger alveoli with thicker walls, less developed distal airways and more inflammation than normoxia. In conclusion, we show that the rabbit model develops pulmonary hypertension and developmental lung arrest after preterm lung injury, which parallel the early changes in human BPD. Thus it enables the testing of pharmaceutical agents that target the cardiovascular compartment of the lung for further translation towards the clinic. Full article

(This article belongs to the Special Issue Vascular Biology and Therapeutics)

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Review

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Aquaporin-4: A Potential Therapeutic Target for Cerebral Edema

by Guanghui Tang and Guo-Yuan Yang^*

Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China

Int. J. Mol. Sci. 2016, 17(10), 1413; https://doi.org/10.3390/ijms17101413 - 29 Sep 2016

Cited by 58 | Viewed by 8845

Abstract

Aquaporin-4 (AQP4) is a family member of water-channel proteins and is dominantly expressed in the foot process of glial cells surrounding capillaries. The predominant expression at the boundaries between cerebral parenchyma and major fluid compartments suggests the function of aquaporin-4 in water transfer [...] Read more.

Aquaporin-4 (AQP4) is a family member of water-channel proteins and is dominantly expressed in the foot process of glial cells surrounding capillaries. The predominant expression at the boundaries between cerebral parenchyma and major fluid compartments suggests the function of aquaporin-4 in water transfer into and out of the brain parenchyma. Accumulating evidences have suggested that the dysregulation of aquaporin-4 relates to the brain edema resulting from a variety of neuro-disorders, such as ischemic or hemorrhagic stroke, trauma, etc. During edema formation in the brain, aquaporin-4 has been shown to contribute to the astrocytic swelling, while in the resolution phase, it has been seen to facilitate the reabsorption of extracellular fluid. In addition, aquaporin-4-deficient mice are protected from cytotoxic edema produced by water intoxication and brain ischemia. However, aquaporin-4 deletion exacerbates vasogenic edema in the brain of different pathological disorders. Recently, our published data showed that the upregulation of aquaporin-4 in astrocytes probably contributes to the transition from cytotoxic edema to vasogenic edema. In this review, apart from the traditional knowledge, we also introduce our latest findings about the effects of mesenchymal stem cells (MSCs) and microRNA-29b on aquaporin-4, which could provide powerful intervention tools targeting aquaporin-4. Full article

(This article belongs to the Special Issue Aquaporin)

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Histone Posttranslational Modifications of CD4⁺ T Cell in Autoimmune Diseases

by Zijun Wang¹, Heng Yin¹, Chak Sing Lau² and Qianjin Lu^1,*

¹ Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha 410011, China

² Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2016, 17(10), 1547; https://doi.org/10.3390/ijms17101547 - 22 Sep 2016

Cited by 19 | Viewed by 8674

Abstract

The complexity of immune system is tempered by precise regulation to maintain stabilization when exposed to various conditions. A subtle change in gene expression may be magnified when drastic changes are brought about in cellular development and function. Posttranslational modifications (PTMs) timely alter [...] Read more.

The complexity of immune system is tempered by precise regulation to maintain stabilization when exposed to various conditions. A subtle change in gene expression may be magnified when drastic changes are brought about in cellular development and function. Posttranslational modifications (PTMs) timely alter the functional activity of immune system, and work proceeded in these years has begun to throw light upon it. Posttranslational modifications of histone tails have been mentioned in a large scale of biological developments and disease progression, thereby making them a central field to investigate. Conventional assessments of these changes are centered on the transcription factors and cytokines in T cells regulated by variable histone codes to achieve chromatin remodeling, as well as involved in many human diseases, especially autoimmune diseases. We here put forward an essential review of core posttranslational modulations that regulate T cell function and differentiation in the immune system, with a special emphasis on histone modifications in different T helper cell subsets as well as in autoimmune diseases. Full article

(This article belongs to the Section Biochemistry)

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Circulating MicroRNAs as Potential Biomarkers of Exercise Response

by Mája Polakovičová^1,*, Peter Musil², Eugen Laczo³, Dušan Hamar⁴ and Ján Kyselovič²

¹ Hamar Institute for Human Performance, Faculty of Physical Education and Sports, Comenius University Bratislava, Nábr. Arm. Gen. L. Svobodu 9, Bratislava 814 69, Slovakia

² Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, Bratislava 832 32, Slovakia

³ Department of Track & Field, Faculty of Physical Education and Sports, Comenius University Bratislava, Nábr. Arm. Gen. L. Svobodu 9, Bratislava 814 69, Slovakia

⁴ Department of Sport Kinanthropology, Faculty of Physical Education and Sports, Comenius University Bratislava, Nábr. Arm. Gen. L. Svobodu 9, Bratislava 814 69, Slovakia

Int. J. Mol. Sci. 2016, 17(10), 1553; https://doi.org/10.3390/ijms17101553 - 5 Oct 2016

Cited by 85 | Viewed by 9247

Abstract

Systematic physical activity increases physical ﬁtness and exercise capacity that lead to the improvement of health status and athletic performance. Considerable effort is devoted to identifying new biomarkers capable of evaluating exercise performance capacity and progress in training, early detection of overtraining, and [...] Read more.

Systematic physical activity increases physical ﬁtness and exercise capacity that lead to the improvement of health status and athletic performance. Considerable effort is devoted to identifying new biomarkers capable of evaluating exercise performance capacity and progress in training, early detection of overtraining, and monitoring health-related adaptation changes. Recent advances in OMICS technologies have opened new opportunities in the detection of genetic, epigenetic and transcriptomic biomarkers. Very promising are mainly small non-coding microRNAs (miRNAs). miRNAs post-transcriptionally regulate gene expression by binding to mRNA and causing its degradation or inhibiting translation. A growing body of evidence suggests that miRNAs affect many processes and play a crucial role not only in cell differentiation, proliferation and apoptosis, but also affect extracellular matrix composition and maintaining processes of homeostasis. A number of studies have shown changes in distribution proﬁles of circulating miRNAs (c-miRNAs) associated with various diseases and disorders as well as in samples taken under physiological conditions such as pregnancy or physical exercise. This overview aims to summarize the current knowledge related to the response of blood c-miRNAs proﬁles to different modes of exercise and to highlight their potential application as a novel class of biomarkers of physical performance capacity and training adaptation. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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Development of Bt Rice and Bt Maize in China and Their Efficacy in Target Pest Control

by Qingsong Liu¹, Eric Hallerman², Yufa Peng¹ and Yunhe Li^1,*

¹ State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China

² Department of Fish and Wildlife Conservation, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0321, USA

Int. J. Mol. Sci. 2016, 17(10), 1561; https://doi.org/10.3390/ijms17101561 - 18 Oct 2016

Cited by 66 | Viewed by 8475

Abstract

Rice and maize are important cereal crops that serve as staple foods, feed, and industrial material in China. Multiple factors constrain the production of both crops, among which insect pests are an important one. Lepidopteran pests cause enormous yield losses for the crops [...] Read more.

Rice and maize are important cereal crops that serve as staple foods, feed, and industrial material in China. Multiple factors constrain the production of both crops, among which insect pests are an important one. Lepidopteran pests cause enormous yield losses for the crops annually. In order to control these pests, China plays an active role in development and application of genetic engineering (GE) to crops, and dozens of GE rice and GE maize lines expressing insecticidal proteins from the soil bacterium Bacillus thuringiensis (Bt) have been developed. Many lines have entered environmental release, field testing, and preproduction testing, and laboratory and field experiments have shown that most of the Bt rice and Bt maize lines developed in China exhibited effective control of major target lepidopteran pests on rice (Chilo suppressalis, Scirpophaga incertulas, and Cnaphalocrocis medinalis) and maize (Ostrinia furnacalis), demonstrating bright prospects for application. However, none of these Bt lines has yet been commercially planted through this writing in 2016. Challenges and perspectives for development and application of Bt rice and maize in China are discussed. This article provides a general context for colleagues to learn about research and development of Bt crops in China, and may shed light on future work in this field. Full article

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

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Silver Nanoparticle-Mediated Cellular Responses in Various Cell Lines: An in Vitro Model

by Xi-Feng Zhang¹, Wei Shen² and Sangiliyandi Gurunathan^3,*

¹ College of Biological and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China

² Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China

³ Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 143-701, Korea

Int. J. Mol. Sci. 2016, 17(10), 1603; https://doi.org/10.3390/ijms17101603 - 22 Sep 2016

Cited by 221 | Viewed by 12614

Abstract

Silver nanoparticles (AgNPs) have attracted increased interest and are currently used in various industries including medicine, cosmetics, textiles, electronics, and pharmaceuticals, owing to their unique physical and chemical properties, particularly as antimicrobial and anticancer agents. Recently, several studies have reported both beneficial and [...] Read more.

Silver nanoparticles (AgNPs) have attracted increased interest and are currently used in various industries including medicine, cosmetics, textiles, electronics, and pharmaceuticals, owing to their unique physical and chemical properties, particularly as antimicrobial and anticancer agents. Recently, several studies have reported both beneficial and toxic effects of AgNPs on various prokaryotic and eukaryotic systems. To develop nanoparticles for mediated therapy, several laboratories have used a variety of cell lines under in vitro conditions to evaluate the properties, mode of action, differential responses, and mechanisms of action of AgNPs. In vitro models are simple, cost-effective, rapid, and can be used to easily assess efficacy and performance. The cytotoxicity, genotoxicity, and biocompatibility of AgNPs depend on many factors such as size, shape, surface charge, surface coating, solubility, concentration, surface functionalization, distribution of particles, mode of entry, mode of action, growth media, exposure time, and cell type. Cellular responses to AgNPs are different in each cell type and depend on the physical and chemical nature of AgNPs. This review evaluates significant contributions to the literature on biological applications of AgNPs. It begins with an introduction to AgNPs, with particular attention to their overall impact on cellular effects. The main objective of this review is to elucidate the reasons for different cell types exhibiting differential responses to nanoparticles even when they possess similar size, shape, and other parameters. Firstly, we discuss the cellular effects of AgNPs on a variety of cell lines; Secondly, we discuss the mechanisms of action of AgNPs in various cellular systems, and try to elucidate how AgNPs interact with different mammalian cell lines and produce significant effects; Finally, we discuss the cellular activation of various signaling molecules in response to AgNPs, and conclude with future perspectives on research into AgNPs. Full article

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

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Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review

by Takahiro Eitsuka^1,*, Naoto Tatewaki¹, Hiroshi Nishida¹, Kiyotaka Nakagawa² and Teruo Miyazawa^3,4

¹ Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan

² Food & Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan

³ Food and Biotechnology Innovation Project, New Industry Creation Hatchery Center (NICHe), Tohoku University, Sendai, Miyagi 980-8579, Japan

⁴ Food and Health Science Research Unit, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 981-8555, Japan

Int. J. Mol. Sci. 2016, 17(10), 1605; https://doi.org/10.3390/ijms17101605 - 22 Sep 2016

Cited by 33 | Viewed by 8464

Abstract

Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, [...] Read more.

Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-κB suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the α-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of α-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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Extracts of Magnolia Species-Induced Prevention of Diabetic Complications: A Brief Review

by Xuezhong Zhao¹, Fengsheng Li^2,3, Wanqing Sun⁴, Ling Gao⁵, Ki Soo Kim⁶, Kyoung Tae Kim⁶, Lu Cai²

, Zhiguo Zhang^1,2,* and Yang Zheng^1,*

¹ Departments of Cardiology at the First Hospital of Jilin University, Changchun 130021, China

² Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA

³ General Hospital of the PLA Rocket Force, Beijing 100088, China

⁴ National Center for Cardiovascular Diseases China, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China

⁵ Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, China Centers for Disease Control, Beijing 100088, China

⁶ The Bioland Biotec Co., Ltd., Zhangjiang Modern Medical Device Park, Pudong, Shanghai 201203, China

Int. J. Mol. Sci. 2016, 17(10), 1629; https://doi.org/10.3390/ijms17101629 - 24 Sep 2016

Cited by 23 | Viewed by 7597

Abstract

Diabetic complications are the major cause of mortality for the patients with diabetes. Oxidative stress and inflammation have been recognized as important contributors for the development of many diabetic complications, such as diabetic nephropathy, hepatopathy, cardiomyopathy, and other cardiovascular diseases. Several studies have [...] Read more.

Diabetic complications are the major cause of mortality for the patients with diabetes. Oxidative stress and inflammation have been recognized as important contributors for the development of many diabetic complications, such as diabetic nephropathy, hepatopathy, cardiomyopathy, and other cardiovascular diseases. Several studies have established the anti-inflammatory and oxidative roles of bioactive constituents in Magnolia bark, which has been widely used in the traditional herbal medicines in Chinese society. These findings have attracted various scientists to investigate the effect of bioactive constituents in Magnolia bark on diabetic complications. The aim of this review is to present a systematic overview of bioactive constituents in Magnolia bark that induce the prevention of obesity, hyperglycemia, hyperlipidemia, and diabetic complications, including cardiovascular, liver, and kidney. Full article

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

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Interactions between Two Different G Protein-Coupled Receptors in Reproductive Hormone-Producing Cells: The Role of PACAP and Its Receptor PAC1R

by Haruhiko Kanasaki^*, Aki Oride, Tomomi Hara, Tselmeg Mijiddorj, Unurjargal Sukhbaatar and Satoru Kyo

Department of Obstetrics and Gynecology, School of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan

Int. J. Mol. Sci. 2016, 17(10), 1635; https://doi.org/10.3390/ijms17101635 - 26 Sep 2016

Cited by 9 | Viewed by 5729

Abstract

Gonadotropin-releasing hormone (GnRH) and gonadotropins are indispensable hormones for maintaining female reproductive functions. In a similar manner to other endocrine hormones, GnRH and gonadotropins are controlled by their principle regulators. Although it has been previously established that GnRH regulates the synthesis and secretion [...] Read more.

Gonadotropin-releasing hormone (GnRH) and gonadotropins are indispensable hormones for maintaining female reproductive functions. In a similar manner to other endocrine hormones, GnRH and gonadotropins are controlled by their principle regulators. Although it has been previously established that GnRH regulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—both gonadotropins—from pituitary gonadotrophs, it has recently become clear that hypothalamic GnRH is under the control of hypothalamic kisspeptin. Prolactin, which is also known as luteotropic hormone and is released from pituitary lactotrophs, stimulates milk production in mammals. Prolactin is also regulated by hypothalamic factors, and it is thought that prolactin synthesis and release are principally under inhibitory control by dopamine through the dopamine D2 receptor. In addition, although it remains unknown whether it is a physiological regulator, thyrotropin-releasing hormone (TRH) is a strong secretagogue for prolactin. Thus, GnRH, LH and FSH, and prolactin are mainly regulated by hypothalamic kisspeptin, GnRH, and TRH, respectively. However, the synthesis and release of these hormones is also modulated by other neuropeptides in the hypothalamus. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hypothalamic peptide that was first isolated from sheep hypothalamic extracts based on its ability to stimulate cAMP production in anterior pituitary cells. PACAP acts on GnRH neurons and pituitary gonadotrophs and lactotrophs, resulting in the modulation of their hormone producing/secreting functions. Furthermore, the presence of the PACAP type 1 receptor (PAC1R) has been demonstrated in these cells. We have examined how PACAP and PAC1R affect GnRH- and pituitary hormone-secreting cells and interact with their principle regulators. In this review, we describe our understanding of the role of PACAP and PAC1R in the regulation of GnRH neurons, gonadotrophs, and lactotrophs, which are regulated mainly by kisspeptin, GnRH, and TRH, respectively. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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Recent Advances in Understanding Amino Acid Sensing Mechanisms that Regulate mTORC1

by Liufeng Zheng¹, Wei Zhang¹, Yuanfei Zhou^1,2, Fengna Li³, Hongkui Wei^1,2,* and Jian Peng^1,2,*

¹ Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China

² The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China

³ Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China

Int. J. Mol. Sci. 2016, 17(10), 1636; https://doi.org/10.3390/ijms17101636 - 29 Sep 2016

Cited by 79 | Viewed by 11837

Abstract

The mammalian target of rapamycin (mTOR) is the central regulator of mammalian cell growth, and is essential for the formation of two structurally and functionally distinct complexes: mTORC1 and mTORC2. mTORC1 can sense multiple cues such as nutrients, energy status, growth factors and [...] Read more.

The mammalian target of rapamycin (mTOR) is the central regulator of mammalian cell growth, and is essential for the formation of two structurally and functionally distinct complexes: mTORC1 and mTORC2. mTORC1 can sense multiple cues such as nutrients, energy status, growth factors and hormones to control cell growth and proliferation, angiogenesis, autophagy, and metabolism. As one of the key environmental stimuli, amino acids (AAs), especially leucine, glutamine and arginine, play a crucial role in mTORC1 activation, but where and how AAs are sensed and signal to mTORC1 are not fully understood. Classically, AAs activate mTORC1 by Rag GTPases which recruit mTORC1 to lysosomes, where AA signaling initiates. Plasma membrane transceptor L amino acid transporter 1 (LAT1)-4F2hc has dual transporter-receptor function that can sense extracellular AA availability upstream of mTORC1. The lysosomal AA sensors (PAT1 and SLC38A9) and cytoplasmic AA sensors (LRS, Sestrin2 and CASTOR1) also participate in regulating mTORC1 activation. Importantly, AAs can be sensed by plasma membrane receptors, like G protein-coupled receptor (GPCR) T1R1/T1R3, and regulate mTORC1 without being transported into the cells. Furthermore, AA-dependent mTORC1 activation also initiates within Golgi, which is regulated by Golgi-localized AA transporter PAT4. This review provides an overview of the research progress of the AA sensing mechanisms that regulate mTORC1 activity. Full article

(This article belongs to the Special Issue Membrane Protein Based Biosensors 2016)

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Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome

by Yuki Kuwano^*, Kensei Nishida, Yoko Akaike, Ken Kurokawa, Tatsuya Nishikawa, Kiyoshi Masuda and Kazuhito Rokutan

Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan

Int. J. Mol. Sci. 2016, 17(10), 1638; https://doi.org/10.3390/ijms17101638 - 27 Sep 2016

Cited by 23 | Viewed by 7057

Abstract

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase that phosphorylates and activates the apoptotic program through interaction with diverse downstream targets including tumor suppressor p53. HIPK2 is activated by genotoxic stimuli and modulates cell fate following DNA damage. The DNA damage response [...] Read more.

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase that phosphorylates and activates the apoptotic program through interaction with diverse downstream targets including tumor suppressor p53. HIPK2 is activated by genotoxic stimuli and modulates cell fate following DNA damage. The DNA damage response (DDR) is triggered by DNA lesions or chromatin alterations. The DDR regulates DNA repair, cell cycle checkpoint activation, and apoptosis to restore genome integrity and cellular homeostasis. Maintenance of the DDR is essential to prevent development of diseases caused by genomic instability, including cancer, defects of development, and neurodegenerative disorders. Recent studies reveal a novel HIPK2-mediated pathway for DDR through interaction with chromatin remodeling factor homeodomain protein 1γ. In this review, we will highlight the molecular mechanisms of HIPK2 and show its functions as a crucial DDR regulator. Full article

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

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Dissecting Candida albicans Infection from the Perspective of C. albicans Virulence and Omics Approaches on Host–Pathogen Interaction: A Review

by Voon Kin Chin¹, Tze Yan Lee²

, Basir Rusliza³

and Pei Pei Chong^4,*

¹ Department of Medical Microbiology and Parasitology, University Putra Malaysia, Serdang 43400, Selangor, Malaysia

² Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang 43400, Selangor, Malaysia

³ Department of Human Anatomy, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang 43400, Selangor, Malaysia

⁴ Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang 43400, Selangor, Malaysia

Int. J. Mol. Sci. 2016, 17(10), 1643; https://doi.org/10.3390/ijms17101643 - 18 Oct 2016

Cited by 56 | Viewed by 7045

Abstract

Candida bloodstream infections remain the most frequent life-threatening fungal disease, with Candida albicans accounting for 70% to 80% of the Candida isolates recovered from infected patients. In nature, Candida species are part of the normal commensal flora in mammalian hosts. However, they can [...] Read more.

Candida bloodstream infections remain the most frequent life-threatening fungal disease, with Candida albicans accounting for 70% to 80% of the Candida isolates recovered from infected patients. In nature, Candida species are part of the normal commensal flora in mammalian hosts. However, they can transform into pathogens once the host immune system is weakened or breached. More recently, mortality attributed to Candida infections has continued to increase due to both inherent and acquired drug resistance in Candida, the inefficacy of the available antifungal drugs, tedious diagnostic procedures, and a rising number of immunocompromised patients. Adoption of animal models, viz. minihosts, mice, and zebrafish, has brought us closer to unraveling the pathogenesis and complexity of Candida infection in human hosts, leading towards the discovery of biomarkers and identification of potential therapeutic agents. In addition, the advancement of omics technologies offers a holistic view of the Candida-host interaction in a non-targeted and non-biased manner. Hence, in this review, we seek to summarize past and present milestone findings on C. albicans virulence, adoption of animal models in the study of C. albicans infection, and the application of omics technologies in the study of Candida–host interaction. A profound understanding of the interaction between host defense and pathogenesis is imperative for better design of novel immunotherapeutic strategies in future. Full article

(This article belongs to the Special Issue Host-Microbe Interaction)

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Time in Redox Adaptation Processes: From Evolution to Hormesis

by Mireille M. J. P. E. Sthijns^*

, Antje R. Weseler, Aalt Bast and Guido R. M. M. Haenen

Department of Pharmacology and Toxicology, P.O. Box 616, Maastricht University, 6200 MD Maastricht, The Netherlands

Int. J. Mol. Sci. 2016, 17(10), 1649; https://doi.org/10.3390/ijms17101649 - 29 Sep 2016

Cited by 57 | Viewed by 7058

Abstract

Life on Earth has to adapt to the ever changing environment. For example, due to introduction of oxygen in the atmosphere, an antioxidant network evolved to cope with the exposure to oxygen. The adaptive mechanisms of the antioxidant network, specifically the glutathione (GSH) [...] Read more.

Life on Earth has to adapt to the ever changing environment. For example, due to introduction of oxygen in the atmosphere, an antioxidant network evolved to cope with the exposure to oxygen. The adaptive mechanisms of the antioxidant network, specifically the glutathione (GSH) system, are reviewed with a special focus on the time. The quickest adaptive response to oxidative stress is direct enzyme modification, increasing the GSH levels or activating the GSH-dependent protective enzymes. After several hours, a hormetic response is seen at the transcriptional level by up-regulating Nrf2-mediated expression of enzymes involved in GSH synthesis. In the long run, adaptations occur at the epigenetic and genomic level; for example, the ability to synthesize GSH by phototrophic bacteria. Apparently, in an adaptive hormetic response not only the dose or the compound, but also time, should be considered. This is essential for targeted interventions aimed to prevent diseases by successfully coping with changes in the environment e.g., oxidative stress. Full article

(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)

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New Treatment Strategies for Alcohol-Induced Heart Damage

by Joaquim Fernández-Solà^1,* and Ana Planavila Porta²

¹ Alcohol Unit, Department of Internal Medicine, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain

² Departament of Biochemistry and Molecular Biomedicine, Faculty of Biology, Avda Diagonal 643, Universitat de Barcelona, 08028 Barcelona, Spain

Int. J. Mol. Sci. 2016, 17(10), 1651; https://doi.org/10.3390/ijms17101651 - 29 Sep 2016

Cited by 32 | Viewed by 7660

Abstract

High-dose alcohol misuse induces multiple noxious cardiac effects, including myocyte hypertrophy and necrosis, interstitial fibrosis, decreased ventricular contraction and ventricle enlargement. These effects produce diastolic and systolic ventricular dysfunction leading to congestive heart failure, arrhythmias and an increased death rate. There are multiple, [...] Read more.

High-dose alcohol misuse induces multiple noxious cardiac effects, including myocyte hypertrophy and necrosis, interstitial fibrosis, decreased ventricular contraction and ventricle enlargement. These effects produce diastolic and systolic ventricular dysfunction leading to congestive heart failure, arrhythmias and an increased death rate. There are multiple, dose-dependent, synchronic and synergistic mechanisms of alcohol-induced cardiac damage. Ethanol alters membrane permeability and composition, interferes with receptors and intracellular transients, induces oxidative, metabolic and energy damage, decreases protein synthesis, excitation-contraction coupling and increases cell apoptosis. In addition, ethanol decreases myocyte protective and repair mechanisms and their regeneration. Although there are diverse different strategies to directly target alcohol-induced heart damage, they are partially effective, and can only be used as support medication in a multidisciplinary approach. Alcohol abstinence is the preferred goal, but control drinking is useful in alcohol-addicted subjects not able to abstain. Correction of nutrition, ionic and vitamin deficiencies and control of alcohol-related systemic organ damage are compulsory. Recently, several growth factors (myostatin, IGF-1, leptin, ghrelin, miRNA, and ROCK inhibitors) and new cardiomyokines such as FGF21 have been described to regulate cardiac plasticity and decrease cardiac damage, improving cardiac repair mechanisms, and they are promising agents in this field. New potential therapeutic targets aim to control oxidative damage, myocyte hypertrophy, interstitial fibrosis and persistent apoptosis In addition, stem-cell therapy may improve myocyte regeneration. However, these strategies are not yet approved for clinical use. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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Essential Roles of Natural Products and Gaseous Mediators on Neuronal Cell Death or Survival

by Yoshinori Mikami¹

, Sho Kakizawa² and Toshiko Yamazawa^3,*

¹ Department of Physiology, School of Medicine, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan

² Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan

³ Department of Molecular Physiology, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo 105-8461, Japan

Int. J. Mol. Sci. 2016, 17(10), 1652; https://doi.org/10.3390/ijms17101652 - 29 Sep 2016

Cited by 12 | Viewed by 5229

Abstract

Although precise cellular and molecular mechanisms underlying neurodegeneration still remain enigmatic, key factors associated with degenerative disorders, such as glutamate toxicity and oxidative stress, have been recently identified. Accordingly, there has been growing interest in examining the effects of exogenous and endogenous molecules [...] Read more.

Although precise cellular and molecular mechanisms underlying neurodegeneration still remain enigmatic, key factors associated with degenerative disorders, such as glutamate toxicity and oxidative stress, have been recently identified. Accordingly, there has been growing interest in examining the effects of exogenous and endogenous molecules on neuroprotection and neurodegeneration. In this paper, we review recent studies on neuroprotective and/or neurodegenerative effects of natural products, such as caffeic acid and chlorogenic acid, and gaseous mediators, including hydrogen sulfide and nitric oxide. Furthermore, possible molecular mechanisms of these molecules in relation to glutamate signals are discussed. Insight into the pathophysiological role of these molecules will make progress in our understanding of molecular mechanisms underlying neurodegenerative diseases, and is expected to lead to potential therapeutic approaches. Full article

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

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Investigation of Self-Assembly Processes for Chitosan-Based Coagulant-Flocculant Systems: A Mini-Review

by Savi Bhalkaran and Lee D. Wilson^*

Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada

Int. J. Mol. Sci. 2016, 17(10), 1662; https://doi.org/10.3390/ijms17101662 - 30 Sep 2016

Cited by 57 | Viewed by 9223

Abstract

The presence of contaminants in wastewater poses significant challenges to water treatment processes and environmental remediation. The use of coagulation-flocculation represents a facile and efficient way of removing charged particles from water. The formation of stable colloidal flocs is necessary for floc aggregation [...] Read more.

The presence of contaminants in wastewater poses significant challenges to water treatment processes and environmental remediation. The use of coagulation-flocculation represents a facile and efficient way of removing charged particles from water. The formation of stable colloidal flocs is necessary for floc aggregation and, hence, their subsequent removal. Aggregation occurs when these flocs form extended networks through the self-assembly of polyelectrolytes, such as the amine-based polysaccharide (chitosan), which form polymer “bridges” in a floc network. The aim of this overview is to evaluate how the self-assembly process of chitosan and its derivatives is influenced by factors related to the morphology of chitosan (flocculant) and the role of the solution conditions in the flocculation properties of chitosan and its modified forms. Chitosan has been used alone or in conjunction with a salt, such as aluminum sulphate, as an aid for the removal of various waterborne contaminants. Modified chitosan relates to grafted anionic or cationic groups onto the C-6 hydroxyl group or the amine group at C-2 on the glucosamine monomer of chitosan. By varying the parameters, such as molecular weight and the degree of deacetylation of chitosan, pH, reaction and settling time, dosage and temperature, self-assembly can be further investigated. This mini-review places an emphasis on the molecular-level details of the flocculation and the self-assembly processes for the marine-based biopolymer, chitosan. Full article

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

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Implications of Hypoxia in Breast Cancer Metastasis to Bone

by Daniele M. Gilkes^1,2

¹ Department of Oncology, The Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA

² Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA

Int. J. Mol. Sci. 2016, 17(10), 1669; https://doi.org/10.3390/ijms17101669 - 30 Sep 2016

Cited by 49 | Viewed by 8481

Abstract

Most solid tumors contain regions of hypoxia in which increased cell proliferation promotes increased oxygen consumption and the condition is further exacerbated as cancer cells become localized far from a functional blood vessel, further decreasing the oxygen supply. An important mechanism that promotes [...] Read more.

Most solid tumors contain regions of hypoxia in which increased cell proliferation promotes increased oxygen consumption and the condition is further exacerbated as cancer cells become localized far from a functional blood vessel, further decreasing the oxygen supply. An important mechanism that promotes cell adaptation to hypoxic conditions is the expression of hypoxia-inducible factors (HIFs). Hypoxia-inducible factors transcriptionally regulate many genes involved in the invasion and metastasis of breast cancer cells. Patients, whose primary tumor biopsies show high HIF expression levels, have a greater risk of metastasis. The current review will highlight the potential role of hypoxia in breast cancer metastasis to the bone by considering the regulation of many steps in the metastatic process that include invasion, migration, margination and extravasation, as well as homing signals and regulation of the bone microenvironment. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)

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Modulation of Compartmentalised Cyclic Nucleotide Signalling via Local Inhibition of Phosphodiesterase Activity

by Marcella Brescia and Manuela Zaccolo^*

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3TP, UK

Int. J. Mol. Sci. 2016, 17(10), 1672; https://doi.org/10.3390/ijms17101672 - 2 Oct 2016

Cited by 48 | Viewed by 7230

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that degrade the cyclic nucleotides cAMP and cGMP, and play a key role in modulating the amplitude and duration of the signal delivered by these two key intracellular second messengers. Defects in cyclic nucleotide signalling [...] Read more.

Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that degrade the cyclic nucleotides cAMP and cGMP, and play a key role in modulating the amplitude and duration of the signal delivered by these two key intracellular second messengers. Defects in cyclic nucleotide signalling are known to be involved in several pathologies. As a consequence, PDEs have long been recognized as potential drug targets, and they have been the focus of intense research for the development of therapeutic agents. A number of PDE inhibitors are currently available for the treatment of disease, including obstructive pulmonary disease, erectile dysfunction, and heart failure. However, the performance of these drugs is not always satisfactory, due to a lack of PDE-isoform specificity and their consequent adverse side effects. Recent advances in our understanding of compartmentalised cyclic nucleotide signalling and the role of PDEs in local regulation of cAMP and cGMP signals offers the opportunity for the development of novel strategies for therapeutic intervention that may overcome the current limitation of conventional PDE inhibitors. Full article

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

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Plant Resistance Inducers against Pathogens in Solanaceae Species—From Molecular Mechanisms to Field Application

by Erik Alexandersson¹, Tewodros Mulugeta², Åsa Lankinen¹, Erland Liljeroth^1,† and Erik Andreasson^1,*,†

¹ Department of Plant Protection Biology, Swedish University of Agricultural Sciences, P.O. Box 102, 23053 Alnarp, Sweden

² Department of Zoological Science, Addis Ababa University, 1176 Addis Ababa, Ethiopia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1673; https://doi.org/10.3390/ijms17101673 - 2 Oct 2016

Cited by 61 | Viewed by 13534

Abstract

This review provides a current summary of plant resistance inducers (PRIs) that have been successfully used in the Solanaceae plant family to protect against pathogens by activating the plant’s own defence. Solanaceous species include many important crops such as potato and tomato. We [...] Read more.

This review provides a current summary of plant resistance inducers (PRIs) that have been successfully used in the Solanaceae plant family to protect against pathogens by activating the plant’s own defence. Solanaceous species include many important crops such as potato and tomato. We also present findings regarding the molecular processes after application of PRIs, even if the number of such studies still remains limited in this plant family. In general, there is a lack of patterns regarding the efficiency of induced resistance (IR) both between and within solanaceous species. In many cases, a hypersensitivity-like reaction needs to form in order for the PRI to be efficient. “-Omics” studies have already given insight in the complexity of responses, and can explain some of the differences seen in efficacy of PRIs between and within species as well as towards different pathogens. Finally, examples of field applications of PRIs for solanaceous crops are presented and discussed. We predict that PRIs will play a role in future plant protection strategies in Solanaceae crops if they are combined with other means of disease control in different spatial and temporal combinations. Full article

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

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Cancer Cell Colonisation in the Bone Microenvironment

by Casina Kan^1,2, Geoffrey Vargas^1,2, François Le Pape^1,2 and Philippe Clézardin^1,2,*

¹ National Institute of Health and Medical Research (INSERM), UMR 1033, Lyon 69372, France

² Faculty of Medicine RTH Laennec, University of Lyon, Villeurbanne 69372, France

Int. J. Mol. Sci. 2016, 17(10), 1674; https://doi.org/10.3390/ijms17101674 - 4 Oct 2016

Cited by 90 | Viewed by 8025

Abstract

Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow [...] Read more.

Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow epithelial-to-mesenchymal transition, extravasation and migration. Within the bone metastatic niche, disseminated tumour cells may enter a dormancy stage or proliferate to adapt and survive, interacting with bone cells such as hematopoietic stem cells, osteoblasts and osteoclasts. Cross-talk with the bone may alter tumour cell properties and, conversely, tumour cells may also acquire characteristics of the surrounding microenvironment, in a process known as osteomimicry. Alternatively, these cells may also express osteomimetic genes that allow cell survival or favour seeding to the bone marrow. The seeding of tumour cells in the bone disrupts bone-forming and bone-resorbing activities, which can lead to macrometastasis in bone. At present, bone macrometastases are incurable with only palliative treatment available. A better understanding of how these processes influence the early onset of bone metastasis may give insight into potential therapies. This review will focus on the early steps of bone colonisation, once disseminated tumour cells enter the bone marrow. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)

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The Fascinating Effects of Baicalein on Cancer: A Review

by Hui Liu¹, Yonghui Dong¹, Yutong Gao², Zhipeng Du³, Yuting Wang¹, Peng Cheng¹, Anmin Chen¹ and Hui Huang^1,*

¹ Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

² Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

³ Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Int. J. Mol. Sci. 2016, 17(10), 1681; https://doi.org/10.3390/ijms17101681 - 9 Oct 2016

Cited by 185 | Viewed by 12246

Abstract

Cancer is one of the leading causes of death worldwide and a major global health problem. In recent decades, the rates of both mortality and morbidity of cancer have rapidly increased for a variety of reasons. Despite treatment options, there are serious side [...] Read more.

Cancer is one of the leading causes of death worldwide and a major global health problem. In recent decades, the rates of both mortality and morbidity of cancer have rapidly increased for a variety of reasons. Despite treatment options, there are serious side effects associated with chemotherapy drugs and multiple forms of drug resistance that significantly reduce their effects. There is an accumulating amount of evidence on the pharmacological activities of baicalein (e.g., anti-inflammatory, antioxidant, antiviral, and antitumor effects). Furthermore, there has been great progress in elucidating the target mechanisms and signaling pathways of baicalein’s anti-cancer potential. The anti-tumor functions of baicalein are mainly due to its capacities to inhibit complexes of cyclins to regulate the cell cycle, to scavenge oxidative radicals, to attenuate mitogen activated protein kinase (MAPK), protein kinase B (Akt) or mammalian target of rapamycin (mTOR) activities, to induce apoptosis by activating caspase-9/-3 and to inhibit tumorinvasion and metastasis by reducing the expression of matrix metalloproteinase-2/-9 (MMP-2/-9). In this review, we focused on the relevant biological mechanisms of baicalein involved in inhibiting various cancers, such as bladder cancer, breast cancer, and ovarian cancer. Moreover, we also summarized the specific mechanisms by which baicalein inhibited the growth of various tumors in vivo. Taken together, baicalein may be developed as a potential, novel anticancer drug to treat tumors. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Inhalable Antimicrobials for Treatment of Bacterial Biofilm-Associated Sinusitis in Cystic Fibrosis Patients: Challenges and Drug Delivery Approaches

by Sylvia Natalie Kłodzińska, Petra Alexandra Priemel, Thomas Rades

and Hanne Mørck Nielsen^*

Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark

Int. J. Mol. Sci. 2016, 17(10), 1688; https://doi.org/10.3390/ijms17101688 - 9 Oct 2016

Cited by 20 | Viewed by 7529

Abstract

Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa infections in CF patients are [...] Read more.

Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa infections in CF patients are focused mainly on the delivery of antimicrobials to the lower respiratory tract, disregarding the sinuses. However, the sinuses constitute a reservoir for P. aeruginosa growth, leading to re-infection of the lungs, even after clearing an initial lung infection. Eradication of P. aeruginosa from the respiratory tract after a first infection has been shown to delay chronic pulmonary infection with the bacteria for up to two years. The challenges with providing a suitable treatment for bacterial sinusitis include: (i) identifying a suitable antimicrobial compound; (ii) selecting a suitable device to deliver the drug to the sinuses and nasal cavities; and (iii) applying a formulation design, which will mediate delivery of a high dose of the antimicrobial directly to the site of infection. This review highlights currently available inhalable antimicrobial formulations for treatment and management of biofilm infections caused by P. aeruginosa and discusses critical issues related to novel antimicrobial drug formulation design approaches. Full article

(This article belongs to the Special Issue Drug Delivery and Antimicrobial Agents)

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Role of n-3 Polyunsaturated Fatty Acids in Ameliorating the Obesity-Induced Metabolic Syndrome in Animal Models and Humans

by Chao-Wei Huang¹, Yi-Shan Chien¹, Yu-Jen Chen², Kolapo M. Ajuwon³

, Harry M. Mersmann¹ and Shih-Torng Ding^1,2,*

¹ Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan

² Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan

³ Department of Animal Science, Purdue University, West Lafayette, IN 47907-2054, USA

Int. J. Mol. Sci. 2016, 17(10), 1689; https://doi.org/10.3390/ijms17101689 - 9 Oct 2016

Cited by 79 | Viewed by 10799

Abstract

The incidence of obesity and its comorbidities, such as insulin resistance and type II diabetes, are increasing dramatically, perhaps caused by the change in the fatty acid composition of common human diets. Adipose tissue plays a role as the major energy reservoir in [...] Read more.

The incidence of obesity and its comorbidities, such as insulin resistance and type II diabetes, are increasing dramatically, perhaps caused by the change in the fatty acid composition of common human diets. Adipose tissue plays a role as the major energy reservoir in the body. An excess of adipose mass accumulation caused by chronic positive energy balance results in obesity. The n-3 polyunsaturated fatty acids (n-3 PUFA), DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) exert numerous beneficial effects to maintain physiological homeostasis. In the current review, the physiology of n-3 PUFA effects in the body is delineated from studies conducted in both human and animal experiments. Although mechanistic studies in human are limited, numerous studies conducted in animals and models in vitro provide potential molecular mechanisms of the effects of these fatty acids. Three aspects of n-3 PUFA in adipocyte regulation are discussed: (1) lipid metabolism, including adipocyte differentiation, lipolysis and lipogenesis; (2) energy expenditure, such as mitochondrial and peroxisomal fatty acid β-oxidation; and (3) inflammation, including adipokines and specialized pro-resolving lipid mediators. Additionally, the mechanisms by which n-3 PUFA regulate gene expression are highlighted. The beneficial effects of n-3 PUFA may help to reduce the incidence of obesity and its comorbidities. Full article

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

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Do Atypical Antipsychotics Have Antisuicidal Effects? A Hypothesis-Generating Overview

by Maurizio Pompili^1,2,*

, Ross J. Baldessarini^2,3, Alberto Forte^1,2, Denise Erbuto¹, Gianluca Serafini⁴

, Andrea Fiorillo⁵, Mario Amore⁴ and Paolo Girardi¹

¹ Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant’Andrea Hospital, Sapienza University of Rome, Rome 00189, Italy

² International Consortium for Mood and Psychotic Disorders Research, Mailman Research Center, McLean Hospital, Belmont, MA 02468, USA

³ Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA

⁴ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, Genoa 16126, Italy

⁵ Department of Psychiatry, University of Naples SUN, Naples I-80138, Italy

Int. J. Mol. Sci. 2016, 17(10), 1700; https://doi.org/10.3390/ijms17101700 - 11 Oct 2016

Cited by 46 | Viewed by 7236

Abstract

Modern antipsychotic drugs are employed increasingly in the treatment of mood disorders as well as psychoses, stimulating interest in their possible contributions to altering suicidal risk. Clozapine remains the only treatment with an FDA-recognized indication for reducing suicidal risk (in schizophrenia). We carried [...] Read more.

Modern antipsychotic drugs are employed increasingly in the treatment of mood disorders as well as psychoses, stimulating interest in their possible contributions to altering suicidal risk. Clozapine remains the only treatment with an FDA-recognized indication for reducing suicidal risk (in schizophrenia). We carried out a systematic, computerized search for reports of studies involving antipsychotic drug treatment and suicidal behaviors. A total of 19 reports provide data with preliminary support for potential suicide risk-reducing effects of olanzapine, quetiapine, ziprasidone, aripiprazole, and asenapine in addition to clozapine, and provide some support for antipsychotic drug treatment in general. These preliminary findings encourage further testing of antipsychotics for effects on suicidal behavior, making use of explicit, pre-planned assessments of suicidal behavior. Full article

(This article belongs to the Special Issue Antipsychotics)

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New Insights into Various Production Characteristics of Streptococcus thermophilus Strains

by Yanhua Cui^1,*, Tingting Xu¹, Xiaojun Qu², Tong Hu¹, Xu Jiang¹ and Chunyu Zhao¹

¹ Department of Food Science and Engineering, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150090, China

² Institute of Microbiology, Heilongjiang Academy of Sciences, Harbin 150010, China

Int. J. Mol. Sci. 2016, 17(10), 1701; https://doi.org/10.3390/ijms17101701 - 12 Oct 2016

Cited by 74 | Viewed by 9862

Abstract

Streptococcus thermophilus is one of the most valuable homo-fermentative lactic acid bacteria, which, for a long time, has been widely used as a starter for the production of fermented dairy products. The key production characteristics of S. thermophilus, for example the production [...] Read more.

Streptococcus thermophilus is one of the most valuable homo-fermentative lactic acid bacteria, which, for a long time, has been widely used as a starter for the production of fermented dairy products. The key production characteristics of S. thermophilus, for example the production of extracellular polysaccharide, proteolytic enzymes and flavor substances as well as acidifying capacity etc., have an important effect on the quality of dairy products. The acidification capacity of the strains determines the manufacturing time and quality of dairy products. It depends on the sugar utilization ability of strains. The production of extracellular polysaccharide is beneficial for improving the texture of dairy products. Flavor substances increase the acceptability of dairy products. The proteolytic activity of the strain influences not only the absorption of the nitrogen source, but also the formation of flavor substances. Different strains have obvious differences in production characteristics via long-time evolution and adaptation to environment. Gaining new strains with novel and desirable characteristics is an important long-term goal for researchers and the fermenting industry. The understanding of the potential molecular mechanisms behind important characteristics of different strains will promote the screening and breeding of excellent strains. In this paper, key technological and functional properties of different S. thermophilus strains are discussed, including sugar metabolism, proteolytic system and amino acid metabolism, and polysaccharide and flavor substance biosynthesis. At the same time, diversity of genomes and plasmids of S. thermophilus are presented. Advances in research on key production characteristics and molecular levels of S. thermophilus will increase understanding of molecular mechanisms of different strains with different important characteristics, and improve the industrialization control level for fermented foods. Full article

(This article belongs to the Section Biochemistry)

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Modulatory Mechanism of Nociceptive Neuronal Activity by Dietary Constituent Resveratrol

by Mamoru Takeda^1,*, Shiori Takehana¹, Kenta Sekiguchi¹, Yoshiko Kubota² and Yoshihito Shimazu¹

¹ Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan

² FANCL Health Science Research Center, Research Institute, FANCL corporation, 12-13, Kamishinano, Totsuka-ku, Yokohama, Kanagawa 244-0806, Japan

Int. J. Mol. Sci. 2016, 17(10), 1702; https://doi.org/10.3390/ijms17101702 - 11 Oct 2016

Cited by 15 | Viewed by 6704

Abstract

Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. [...] Read more.

Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. Recent reports indicate that resveratrol can modulate neuronal excitability, including nociceptive sensory transmission. As such, it is possible that this dietary constituent could be a complementary alternative medicine (CAM) candidate, specifically a therapeutic agent. The focus of this review is on the mechanisms underlying the modulatory effects of resveratrol on nociceptive neuronal activity associated with pain relief. In addition, we discuss the contribution of resveratrol to the relief of nociceptive and/or pathological pain and its potential role as a functional food and a CAM. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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In Vivo Analysis of Protein–Protein Interactions with Bioluminescence Resonance Energy Transfer (BRET): Progress and Prospects

by Sihuai Sun^†, Xiaobing Yang^†, Yao Wang and Xihui Shen^*

¹ State Key Laboratory of Crop Stress Biology for Arid Areas and College of Life Sciences, Northwest A&F University, Yangling 712100, Shaanxi, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1704; https://doi.org/10.3390/ijms17101704 - 11 Oct 2016

Cited by 34 | Viewed by 10834

Abstract

Proteins are the elementary machinery of life, and their functions are carried out mostly by molecular interactions. Among those interactions, protein–protein interactions (PPIs) are the most important as they participate in or mediate all essential biological processes. However, many common methods for PPI [...] Read more.

Proteins are the elementary machinery of life, and their functions are carried out mostly by molecular interactions. Among those interactions, protein–protein interactions (PPIs) are the most important as they participate in or mediate all essential biological processes. However, many common methods for PPI investigations are slightly unreliable and suffer from various limitations, especially in the studies of dynamic PPIs. To solve this problem, a method called Bioluminescence Resonance Energy Transfer (BRET) was developed about seventeen years ago. Since then, BRET has evolved into a whole class of methods that can be used to survey virtually any kinds of PPIs. Compared to many traditional methods, BRET is highly sensitive, reliable, easy to perform, and relatively inexpensive. However, most importantly, it can be done in vivo and allows the real-time monitoring of dynamic PPIs with the easily detectable light signal, which is extremely valuable for the PPI functional research. This review will take a comprehensive look at this powerful technique, including its principles, comparisons with other methods, experimental approaches, classifications, applications, early developments, recent progress, and prospects. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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T Cell Receptor Excision Circle (TREC) Monitoring after Allogeneic Stem Cell Transplantation; a Predictive Marker for Complications and Clinical Outcome

by Ahmed Gaballa¹, Mikael Sundin^2,3, Arwen Stikvoort¹, Muhamed Abumaree⁴

, Mehmet Uzunel⁵, Darius Sairafi¹ and Michael Uhlin^1,5,*

¹ Department of Oncology and Pathology, Karolinska Institutet, SE-141 86 Stockholm, Sweden

² Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, SE-141 86 Stockholm, Sweden

³ Pediatric Blood Disorders, Immunodeficiency and Stem Cell Transplantation, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, SE-141 86 Stockholm, Sweden

⁴ Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, KSA-11461 Riyadh, Saudi Arabia

⁵ Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, SE-141 86 Stockholm, Sweden

Int. J. Mol. Sci. 2016, 17(10), 1705; https://doi.org/10.3390/ijms17101705 - 11 Oct 2016

Cited by 18 | Viewed by 5583

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of malignant diseases as well as for inborn errors of the metabolism or immune system. Regardless of disease origin, good clinical effects are dependent on proper immune reconstitution. T [...] Read more.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of malignant diseases as well as for inborn errors of the metabolism or immune system. Regardless of disease origin, good clinical effects are dependent on proper immune reconstitution. T cells are responsible for both the beneficial graft-versus-leukemia (GVL) effect against malignant cells and protection against infections. The immune recovery of T cells relies initially on peripheral expansion of mature cells from the graft and later on the differentiation and maturation from donor-derived hematopoietic stem cells. The formation of new T cells occurs in the thymus and as a byproduct, T cell receptor excision circles (TRECs) are released upon rearrangement of the T cell receptor. Detection of TRECs by PCR is a reliable method for estimating the amount of newly formed T cells in the circulation and, indirectly, for estimating thymic function. Here, we discuss the role of TREC analysis in the prediction of clinical outcome after allogeneic HSCT. Due to the pivotal role of T cell reconstitution we propose that TREC analysis should be included as a key indicator in the post-HSCT follow-up. Full article

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

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Drought-Responsive Mechanisms in Plant Leaves Revealed by Proteomics

by Xiaoli Wang, Xiaofeng Cai, Chenxi Xu, Quanhua Wang and Shaojun Dai^*

Development Centre of Plant Germplasm Resources, College of Life and Environmental Sciences, Shanghai Normal University, Shanghai 200234, China

Int. J. Mol. Sci. 2016, 17(10), 1706; https://doi.org/10.3390/ijms17101706 - 18 Oct 2016

Cited by 191 | Viewed by 12491

Abstract

Plant drought tolerance is a complex trait that requires a global view to understand its underlying mechanism. The proteomic aspects of plant drought response have been extensively investigated in model plants, crops and wood plants. In this review, we summarize recent proteomic studies [...] Read more.

Plant drought tolerance is a complex trait that requires a global view to understand its underlying mechanism. The proteomic aspects of plant drought response have been extensively investigated in model plants, crops and wood plants. In this review, we summarize recent proteomic studies on drought response in leaves to reveal the common and specialized drought-responsive mechanisms in different plants. Although drought-responsive proteins exhibit various patterns depending on plant species, genotypes and stress intensity, proteomic analyses show that dominant changes occurred in sensing and signal transduction, reactive oxygen species scavenging, osmotic regulation, gene expression, protein synthesis/turnover, cell structure modulation, as well as carbohydrate and energy metabolism. In combination with physiological and molecular results, proteomic studies in leaves have helped to discover some potential proteins and/or metabolic pathways for drought tolerance. These findings provide new clues for understanding the molecular basis of plant drought tolerance. Full article

(This article belongs to the Special Issue Plant Proteomic Research)

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MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions

by Caterina Catalanotto^*,†, Carlo Cogoni^*,† and Giuseppe Zardo^*,†

¹ Department of Cellular Biotechnologies and Hematology, University of Rome Sapienza, Rome 00179, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1712; https://doi.org/10.3390/ijms17101712 - 13 Oct 2016

Cited by 869 | Viewed by 22873

Abstract

The finding that small non-coding RNAs (ncRNAs) are able to control gene expression in a sequence specific manner has had a massive impact on biology. Recent improvements in high throughput sequencing and computational prediction methods have allowed the discovery and classification of several [...] Read more.

The finding that small non-coding RNAs (ncRNAs) are able to control gene expression in a sequence specific manner has had a massive impact on biology. Recent improvements in high throughput sequencing and computational prediction methods have allowed the discovery and classification of several types of ncRNAs. Based on their precursor structures, biogenesis pathways and modes of action, ncRNAs are classified as small interfering RNAs (siRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), endogenous small interfering RNAs (endo-siRNAs or esiRNAs), promoter associate RNAs (pRNAs), small nucleolar RNAs (snoRNAs) and sno-derived RNAs. Among these, miRNAs appear as important cytoplasmic regulators of gene expression. miRNAs act as post-transcriptional regulators of their messenger RNA (mRNA) targets via mRNA degradation and/or translational repression. However, it is becoming evident that miRNAs also have specific nuclear functions. Among these, the most studied and debated activity is the miRNA-guided transcriptional control of gene expression. Although available data detail quite precisely the effectors of this activity, the mechanisms by which miRNAs identify their gene targets to control transcription are still a matter of debate. Here, we focus on nuclear functions of miRNAs and on alternative mechanisms of target recognition, at the promoter lavel, by miRNAs in carrying out transcriptional gene silencing. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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The Importance of Patient-Specific Factors for Hepatic Drug Response and Toxicity

by Volker M. Lauschke^*

and Magnus Ingelman-Sundberg

Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, SE-17177 Stockholm, Sweden

Int. J. Mol. Sci. 2016, 17(10), 1714; https://doi.org/10.3390/ijms17101714 - 12 Oct 2016

Cited by 76 | Viewed by 9223

Abstract

Responses to drugs and pharmacological treatments differ considerably between individuals. Importantly, only 50%–75% of patients have been shown to react adequately to pharmacological interventions, whereas the others experience either a lack of efficacy or suffer from adverse events. The liver is of central [...] Read more.

Responses to drugs and pharmacological treatments differ considerably between individuals. Importantly, only 50%–75% of patients have been shown to react adequately to pharmacological interventions, whereas the others experience either a lack of efficacy or suffer from adverse events. The liver is of central importance in the metabolism of most drugs. Because of this exposed status, hepatotoxicity is amongst the most common adverse drug reactions and hepatic liabilities are the most prevalent reason for the termination of development programs of novel drug candidates. In recent years, more and more factors were unveiled that shape hepatic drug responses and thus underlie the observed inter-individual variability. In this review, we provide a comprehensive overview of different principle mechanisms of drug hepatotoxicity and illustrate how patient-specific factors, such as genetic, physiological and environmental factors, can shape drug responses. Furthermore, we highlight other parameters, such as concomitantly prescribed medications or liver diseases and how they modulate drug toxicity, pharmacokinetics and dynamics. Finally, we discuss recent progress in the field of in vitro toxicity models and evaluate their utility in reflecting patient-specific factors to study inter-individual differences in drug response and toxicity, as this understanding is necessary to pave the way for a patient-adjusted medicine. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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The Last Ten Years of Advancements in Plant-Derived Recombinant Vaccines against Hepatitis B

by Young Hee Joung¹, Se Hee Park¹, Ki-Beom Moon², Jae-Heung Jeon², Hye-Sun Cho² and Hyun-Soon Kim^2,*

¹ School of Biological Sciences & Technology, Chonnam National University, Gwangju 61186, Korea

² Molecular Biofarming Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Korea

Int. J. Mol. Sci. 2016, 17(10), 1715; https://doi.org/10.3390/ijms17101715 - 13 Oct 2016

Cited by 23 | Viewed by 9791

Abstract

Disease prevention through vaccination is considered to be the greatest contribution to public health over the past century. Every year more than 100 million children are vaccinated with the standard World Health Organization (WHO)-recommended vaccines including hepatitis B (HepB). HepB is the most [...] Read more.

Disease prevention through vaccination is considered to be the greatest contribution to public health over the past century. Every year more than 100 million children are vaccinated with the standard World Health Organization (WHO)-recommended vaccines including hepatitis B (HepB). HepB is the most serious type of liver infection caused by the hepatitis B virus (HBV), however, it can be prevented by currently available recombinant vaccine, which has an excellent record of safety and effectiveness. To date, recombinant vaccines are produced in many systems of bacteria, yeast, insect, and mammalian and plant cells. Among these platforms, the use of plant cells has received considerable attention in terms of intrinsic safety, scalability, and appropriate modification of target proteins. Research groups worldwide have attempted to develop more efficacious plant-derived vaccines for over 30 diseases, most frequently HepB and influenza. More inspiring, approximately 12 plant-made antigens have already been tested in clinical trials, with successful outcomes. In this study, the latest information from the last 10 years on plant-derived antigens, especially hepatitis B surface antigen, approaches are reviewed and breakthroughs regarding the weak points are also discussed. Full article

(This article belongs to the Special Issue Plant-Derived Pharmaceuticals by Molecular Farming 2016)

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The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders

by Susann Pankratz^1,*, Stefan Bittner², Beate E. Kehrel³, Harald F. Langer^4,5, Christoph Kleinschnitz⁶, Sven G. Meuth^1,† and Kerstin Göbel^1,*,†

¹ Department of Neurology, University of Münster, 48149 Münster, Germany

² Department of Neurology, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany

³ Department of Anesthesiology, Intensive Care and Pain Medicine, Experimental and Clinical Hemostasis, University of Münster, 48149 Münster, Germany

⁴ University Clinic for Cardiology and Cardiovascular Medicine, Eberhard Karls-University Tübingen, 72076 Tübingen, Germany

⁵ Section for Cardioimmunology, Eberhard Karls-University Tübingen, 72076 Tübingen, Germany

⁶ Department of Neurology, University Hospital Essen, 45147 Essen, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(10), 1723; https://doi.org/10.3390/ijms17101723 - 14 Oct 2016

Cited by 24 | Viewed by 6152

Abstract

Beyond their indispensable role in hemostasis, platelets have shown to affect the development of inflammatory disorders, as they have been epidemiologically and mechanistically linked to diseases featuring an inflammatory reaction in inflammatory diseases like multiple sclerosis, rheumatoid arthritis and inflammatory bowel disorders. The [...] Read more.

Beyond their indispensable role in hemostasis, platelets have shown to affect the development of inflammatory disorders, as they have been epidemiologically and mechanistically linked to diseases featuring an inflammatory reaction in inflammatory diseases like multiple sclerosis, rheumatoid arthritis and inflammatory bowel disorders. The identification of novel molecular mechanisms linking inflammation and to platelets has highlighted them as new targets for therapeutic interventions. In particular, genetic and pharmacological studies have identified an important role for platelets in neuroinflammation. This review summarizes the main molecular links between platelets and inflammation, focusing on immune regulatory factors, receptors, cellular targets and signaling pathways by which they can amplify inflammatory reactions and that make them potential therapeutic targets. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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UBXD Proteins: A Family of Proteins with Diverse Functions in Cancer

by Khosrow Rezvani

Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD 57069, USA

Int. J. Mol. Sci. 2016, 17(10), 1724; https://doi.org/10.3390/ijms17101724 - 14 Oct 2016

Cited by 19 | Viewed by 8479

Abstract

The UBXD family is a diverse group of UBX (ubiquitin-regulatory X) domain-containing proteins in mammalian cells. Members of this family contain a UBX domain typically located at the carboxyl-terminal of the protein. In contrast to the UBX domain shared by all members of [...] Read more.

The UBXD family is a diverse group of UBX (ubiquitin-regulatory X) domain-containing proteins in mammalian cells. Members of this family contain a UBX domain typically located at the carboxyl-terminal of the protein. In contrast to the UBX domain shared by all members of UBXD family, the amino-terminal domains are diverse and appear to carry out different roles in a subcellular localization-dependent manner. UBXD proteins are principally associated with the endoplasmic reticulum (ER), where they positively or negatively regulate the ER-associated degradation machinery (ERAD). The distinct protein interaction networks of UBXD proteins allow them to have specific functions independent of the ERAD pathway in a cell type- and tissue context-dependent manner. Recent reports have illustrated that a number of mammalian members of the UBXD family play critical roles in several proliferation and apoptosis pathways dysregulated in selected types of cancer. This review covers recent advances that elucidate the therapeutic potential of selected members of the UBXD family that can contribute to tumor growth. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives

by Emanuele D’Amico

, Francesco Patti^*, Aurora Zanghì and Mario Zappia

Multiple Sclerosis Center, Policlinico G. Rodolico, via Santa Sofia, 78 Catania 95123, Italy

Int. J. Mol. Sci. 2016, 17(10), 1725; https://doi.org/10.3390/ijms17101725 - 17 Oct 2016

Cited by 31 | Viewed by 7852

Abstract

Using the term of progressive multiple sclerosis (PMS), we considered a combined population of persons with secondary progressive MS (SPMS) and primary progressive MS (PPMS). These forms of MS cannot be challenged with efficacy by the licensed therapy. In the last years, several [...] Read more.

Using the term of progressive multiple sclerosis (PMS), we considered a combined population of persons with secondary progressive MS (SPMS) and primary progressive MS (PPMS). These forms of MS cannot be challenged with efficacy by the licensed therapy. In the last years, several measures of risk estimation were developed for predicting clinical course in MS, but none is specific for the PMS forms. Personalized medicine is a therapeutic approach, based on identifying what might be the best therapy for an individual patient, taking into account the risk profile. We need to achieve more accurate estimates of useful predictors in PMS, including unconventional and qualitative markers which are not yet currently available or practicable routine diagnostics. The evaluation of an individual patient is based on the profile of disease activity.Within the neurology field, PMS is one of the fastest-moving going into the future. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Regulatory Roles of MicroRNAs in Diabetes

by Juan Feng¹, Wanli Xing^1,2,* and Lan Xie^1,2,*

¹ Medical Systems Biology Research Center, School of Medicine, Tsinghua University, Beijing 100084, China

² National Engineering Research Center for Beijing Biochip Technology, Beijing 102206, China

Int. J. Mol. Sci. 2016, 17(10), 1729; https://doi.org/10.3390/ijms17101729 - 17 Oct 2016

Cited by 119 | Viewed by 8151

Abstract

MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs in eukaryotes, have been recognized as significant regulators of gene expression through post-transcriptional mechanisms. To date, >2000 miRNAs have been identified in the human genome, and they orchestrate a variety of biological and pathological [...] Read more.

MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs in eukaryotes, have been recognized as significant regulators of gene expression through post-transcriptional mechanisms. To date, >2000 miRNAs have been identified in the human genome, and they orchestrate a variety of biological and pathological processes. Disruption of miRNA levels correlates with many diseases, including diabetes mellitus, a complex multifactorial metabolic disorder affecting >400 million people worldwide. miRNAs are involved in the pathogenesis of diabetes mellitus by affecting pancreatic β-cell functions, insulin resistance, or both. In this review, we summarize the investigations of the regulatory roles of important miRNAs in diabetes, as well as the potential of circulating miRNAs as diagnostic markers for diabetes mellitus. Full article

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

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Glycosphingolipid–Protein Interaction in Signal Transduction

by Domenico Russo^1,*, Seetharaman Parashuraman¹ and Giovanni D’Angelo^1,2

¹ Institute of Protein Biochemistry National Research Council, Via P. Castellino 111, Naples 80131, Italy

² Istituto di Ricovero e Cura a Carattere Scientifico SDN, Via Emanuele Gianturco 113, Naples 80143, Italy

Int. J. Mol. Sci. 2016, 17(10), 1732; https://doi.org/10.3390/ijms17101732 - 15 Oct 2016

Cited by 66 | Viewed by 8427

Abstract

Glycosphingolipids (GSLs) are a class of ceramide-based glycolipids essential for embryo development in mammals. The synthesis of specific GSLs depends on the expression of distinctive sets of GSL synthesizing enzymes that is tightly regulated during development. Several reports have described how cell surface [...] Read more.

Glycosphingolipids (GSLs) are a class of ceramide-based glycolipids essential for embryo development in mammals. The synthesis of specific GSLs depends on the expression of distinctive sets of GSL synthesizing enzymes that is tightly regulated during development. Several reports have described how cell surface receptors can be kept in a resting state or activate alternative signalling events as a consequence of their interaction with GSLs. Specific GSLs, indeed, interface with specific protein domains that are found in signalling molecules and which act as GSL sensors to modify signalling responses. The regulation exerted by GSLs on signal transduction is orthogonal to the ligand–receptor axis, as it usually does not directly interfere with the ligand binding to receptors. Due to their properties of adjustable production and orthogonal action on receptors, GSLs add a new dimension to the control of the signalling in development. GSLs can, indeed, dynamically influence progenitor cell response to morphogenetic stimuli, resulting in alternative differentiation fates. Here, we review the available literature on GSL–protein interactions and their effects on cell signalling and development. Full article

(This article belongs to the Special Issue Glycan–Receptor Interaction)

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The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

by Henrieta Škovierová¹, Eva Vidomanová^1,*, Silvia Mahmood¹, Janka Sopková^1,2, Anna Drgová^2,3, Tatiana Červeňová⁴, Erika Halašová^1,5 and Ján Lehotský^2,3

¹ Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia

² Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia

³ Biomedical Center Martin, Department of Neurosciences, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia

⁴ Department of Public Health, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia

⁵ Department of Medical Biology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia

Int. J. Mol. Sci. 2016, 17(10), 1733; https://doi.org/10.3390/ijms17101733 - 20 Oct 2016

Cited by 301 | Viewed by 16152

Abstract

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a [...] Read more.

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a marker or a causative agent of diseases. More and more research data suggest that Hcy is an important indicator for overall health status. This review represents the current understanding of molecular mechanism of Hcy metabolism and its link to hyperhomocysteinemia-related pathologies in humans. The aberrant Hcy metabolism could lead to the redox imbalance and oxidative stress resulting in elevated protein, nucleic acid and carbohydrate oxidation and lipoperoxidation, products known to be involved in cytotoxicity. Additionally, we examine the role of Hcy in thiolation of proteins, which results in their molecular and functional modifications. We also highlight the relationship between the imbalance in Hcy metabolism and pathogenesis of diseases, such as cardiovascular diseases, neurological and psychiatric disorders, chronic kidney disease, bone tissue damages, gastrointestinal disorders, cancer, and congenital defects. Full article

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

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Practical Recommendations for Diagnosis and Management of Respiratory Muscle Weakness in Late-Onset Pompe Disease

by Matthias Boentert^1,*, Hélène Prigent², Katalin Várdi³, Harrison N. Jones⁴, Uwe Mellies⁵, Anita K. Simonds⁶, Stephan Wenninger⁷, Emilia Barrot Cortés⁸ and Marco Confalonieri⁹

¹ Department of Sleep Medicine and Neuromuscular Disorders, Münster University Hospital, Münster 48149, Germany

² Physiology Department and Neuromuscular Home Ventilation Unit, Raymond Poincaré University Hospital, Garches 92380, France

³ Respiratory Rehabilitation and Sleep Center, Törökbálint Chest Hospital, Törökbálint 2045, Hungary

⁴ Department of Surgery, Duke University, Division of Speech Pathology & Audiology, Durham, NC 27710, USA

⁵ Department of Pediatric Pulmonology and Sleep Medicine, University of Duisburg-Essen, Children’s Hospital, Essen 45147, Germany

⁶ Academic and Clinical Department of Sleep and Breathing, Royal Brompton & Harefield NHS Foundation Trust, London SW3 6NP, UK

⁷ Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich 80336, Germany

⁸ Medical-Surgical Unit of Respiratory Diseases, University Hospital Virgen del Rocio, Seville 41013, Spain

⁹ Department of Pulmonology, University Hospital of Cattinara, Trieste 34149, Italy

Int. J. Mol. Sci. 2016, 17(10), 1735; https://doi.org/10.3390/ijms17101735 - 17 Oct 2016

Cited by 42 | Viewed by 7420

Abstract

Pompe disease is an autosomal-recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy (in infants only). In patients with juvenile or adult disease onset, respiratory muscle weakness may decline more rapidly than overall neurological disability. [...] Read more.

Pompe disease is an autosomal-recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy (in infants only). In patients with juvenile or adult disease onset, respiratory muscle weakness may decline more rapidly than overall neurological disability. Sleep-disordered breathing, daytime hypercapnia, and the need for nocturnal ventilation eventually evolve in most patients. Additionally, respiratory muscle weakness leads to decreased cough and impaired airway clearance, increasing the risk of acute respiratory illness. Progressive respiratory muscle weakness is a major cause of morbidity and mortality in late-onset Pompe disease even if enzyme replacement therapy has been established. Practical knowledge of how to detect, monitor and manage respiratory muscle involvement is crucial for optimal patient care. A multidisciplinary approach combining the expertise of neurologists, pulmonologists, and intensive care specialists is needed. Based on the authors’ own experience in over 200 patients, this article conveys expert recommendations for the diagnosis and management of respiratory muscle weakness and its sequelae in late-onset Pompe disease. Full article

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

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Open AccessReview

Viral Metagenomics on Blood-Feeding Arthropods as a Tool for Human Disease Surveillance

by Annika Brinkmann^*, Andreas Nitsche and Claudia Kohl

Robert Koch Institute, Centre for Biological Threats and Special Pathogens, Seestrasse 10, Berlin 13353, Germany

Int. J. Mol. Sci. 2016, 17(10), 1743; https://doi.org/10.3390/ijms17101743 - 19 Oct 2016

Cited by 41 | Viewed by 9021

Abstract

Surveillance and monitoring of viral pathogens circulating in humans and wildlife, together with the identification of emerging infectious diseases (EIDs), are critical for the prediction of future disease outbreaks and epidemics at an early stage. It is advisable to sample a broad range [...] Read more.

Surveillance and monitoring of viral pathogens circulating in humans and wildlife, together with the identification of emerging infectious diseases (EIDs), are critical for the prediction of future disease outbreaks and epidemics at an early stage. It is advisable to sample a broad range of vertebrates and invertebrates at different temporospatial levels on a regular basis to detect possible candidate viruses at their natural source. However, virus surveillance systems can be expensive, costly in terms of finances and resources and inadequate for sampling sufficient numbers of different host species over space and time. Recent publications have presented the concept of a new virus surveillance system, coining the terms “flying biological syringes”, “xenosurveillance” and “vector-enabled metagenomics”. According to these novel and promising surveillance approaches, viral metagenomics on engorged mosquitoes might reflect the viral diversity of numerous mammals, birds and humans, combined in the mosquitoes’ blood meal during feeding on the host. In this review article, we summarize the literature on vector-enabled metagenomics (VEM) techniques and its application in disease surveillance in humans. Furthermore, we highlight the combination of VEM and “invertebrate-derived DNA” (iDNA) analysis to identify the host DNA within the mosquito midgut. Full article

(This article belongs to the Section Biochemistry)

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A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors

by Jerome A. Staal^1,2,*, Yanxin Pei² and Brian R. Rood²

¹ Multiple Sclerosis Department, Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3052, Australia

² Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA

Int. J. Mol. Sci. 2016, 17(10), 1744; https://doi.org/10.3390/ijms17101744 - 19 Oct 2016

Cited by 9 | Viewed by 6228

Abstract

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. [...] Read more.

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits

by Fereidoon Shahidi^1,*

and Adriano Costa De Camargo^1,2

¹ Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X9, Canada

² Department of Agri-Food Industry, Food & Nutrition, “Luiz de Queiroz” College of Agriculture, University of São Paulo, Piracicaba 13418-900, Brazil

Int. J. Mol. Sci. 2016, 17(10), 1745; https://doi.org/10.3390/ijms17101745 - 20 Oct 2016

Cited by 273 | Viewed by 18314

Abstract

Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible [...] Read more.

Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible oils with considerable contents of tocopherols and tocotrienols. Tocopherols are among the most important lipid-soluble antioxidants in food as well as in human and animal tissues. Tocopherols are found in lipid-rich regions of cells (e.g., mitochondrial membranes), fat depots, and lipoproteins such as low-density lipoprotein cholesterol. Their health benefits may also be explained by regulation of gene expression, signal transduction, and modulation of cell functions. Potential health benefits of tocols include prevention of certain types of cancer, heart disease, and other chronic ailments. Although deficiencies of tocopherol are uncommon, a continuous intake from common and novel dietary sources of tocopherols and tocotrienols is advantageous. Thus, this contribution will focus on the relevant literature on common and emerging edible oils as a source of tocols. Potential application and health effects as well as the impact of new cultivars as sources of edible oils and their processing discards are presented. Future trends and drawbacks are also briefly covered. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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Phytocystatins: Defense Proteins against Phytophagous Insects and Acari

by Manuel Martinez¹

, Maria Estrella Santamaria¹

, Mercedes Diaz-Mendoza¹

, Ana Arnaiz¹, Laura Carrillo¹, Felix Ortego² and Isabel Diaz^1,*

¹ Centro de Biotecnologia y Genomica de Plantas, Universidad Politecnica de Madrid (UPM), Instituto Nacional de Investigacion y Tecnología Agraria y Alimentaria (INIA), Campus Montegancedo, Pozuelo de Alarcon, Madrid 28223, Spain

² Departamento de Biologia Medioambiental, Centro de Investigaciones Biologicas, CSIC, Ramiro de Maeztu, 9, Madrid 28040, Spain

Int. J. Mol. Sci. 2016, 17(10), 1747; https://doi.org/10.3390/ijms17101747 - 20 Oct 2016

Cited by 53 | Viewed by 7558

Abstract

This review deals with phytocystatins, focussing on their potential role as defence proteins against phytophagous arthropods. Information about the evolutionary, molecular and biochemical features and inhibitory properties of phytocystatins are presented. Cystatin ability to inhibit heterologous cysteine protease activities is commented on as [...] Read more.

This review deals with phytocystatins, focussing on their potential role as defence proteins against phytophagous arthropods. Information about the evolutionary, molecular and biochemical features and inhibitory properties of phytocystatins are presented. Cystatin ability to inhibit heterologous cysteine protease activities is commented on as well as some approaches of tailoring cystatin specificity to enhance their defence function towards pests. A general landscape on the digestive proteases of phytophagous insects and acari and the remarkable plasticity of their digestive physiology after feeding on cystatins are highlighted. Biotechnological approaches to produce recombinant cystatins to be added to artificial diets or to be sprayed as insecticide–acaricide compounds and the of use cystatins as transgenes are discussed. Multiple examples and applications are included to end with some conclusions and future perspectives. Full article

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

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Critical Analysis of the Melanogenic Pathway in Insects and Higher Animals

by Manickam Sugumaran^* and Hanine Barek

Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA

Int. J. Mol. Sci. 2016, 17(10), 1753; https://doi.org/10.3390/ijms17101753 - 20 Oct 2016

Cited by 146 | Viewed by 15623

Abstract

Animals synthesize melanin pigments for the coloration of their skin and use it for their protection from harmful solar radiation. Insects use melanins even more ingeniously than mammals and employ them for exoskeletal pigmentation, cuticular hardening, wound healing and innate immune responses. In [...] Read more.

Animals synthesize melanin pigments for the coloration of their skin and use it for their protection from harmful solar radiation. Insects use melanins even more ingeniously than mammals and employ them for exoskeletal pigmentation, cuticular hardening, wound healing and innate immune responses. In this review, we discuss the biochemistry of melanogenesis process occurring in higher animals and insects. A special attention is given to number of aspects that are not previously brought to light: (1) the molecular mechanism of dopachrome conversion that leads to the production of two different dihydroxyindoles; (2) the role of catecholamine derivatives other than dopa in melanin production in animals; (3) the critical parts played by various biosynthetic enzymes associated with insect melanogenesis; and (4) the presence of a number of important gaps in both melanogenic and sclerotinogenic pathways. Additionally, importance of the melanogenic process in insect physiology especially in the sclerotization of their exoskeleton, wound healing reactions and innate immune responses is highlighted. The comparative biochemistry of melanization with sclerotization is also discussed. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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Natural Occurring Silks and Their Analogues as Materials for Nerve Conduits

by Christine Radtke

Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

Int. J. Mol. Sci. 2016, 17(10), 1754; https://doi.org/10.3390/ijms17101754 - 20 Oct 2016

Cited by 23 | Viewed by 6205

Abstract

Spider silk and its synthetic derivatives have a light weight in combination with good strength and elasticity. Their high cytocompatibility and low immunogenicity make them well suited for biomaterial products such as nerve conduits. Silk proteins slowly degrade enzymatically in vivo, thus allowing [...] Read more.

Spider silk and its synthetic derivatives have a light weight in combination with good strength and elasticity. Their high cytocompatibility and low immunogenicity make them well suited for biomaterial products such as nerve conduits. Silk proteins slowly degrade enzymatically in vivo, thus allowing for an initial therapeutic effect such as in nerve scaffolding to facilitate endogenous repair processes, and then are removed. Silks are biopolymers naturally produced by many species of arthropods including spiders, caterpillars and mites. The silk fibers are secreted by the labial gland of the larvae of some orders of Holometabola (insects with pupa) or the spinnerets of spiders. The majority of studies using silks for biomedical applications use materials from silkworms or spiders, mostly of the genus Nephila clavipes. Silk is one of the most promising biomaterials with effects not only in nerve regeneration, but in a number of regenerative applications. The development of silks for human biomedical applications is of high scientific and clinical interest. Biomaterials in use for biomedical applications have to meet a number of requirements such as biocompatibility and elicitation of no more than a minor inflammatory response, biodegradability in a reasonable time and specific structural properties. Here we present the current status in the field of silk-based conduit development for nerve repair and discuss current advances with regard to potential clinical transfer of an implantable nerve conduit for enhancement of nerve regeneration. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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Towards Stratified Medicine in Plasma Cell Myeloma

by Philip Egan, Stephen Drain, Caroline Conway, Anthony J. Bjourson and H. Denis Alexander^*

Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, Ulster University, C-TRIC Building, Altnagelvin Area Hospital, Glenshane Road, Derry/Londonderry BT47 6SB, Northern Ireland

Int. J. Mol. Sci. 2016, 17(10), 1760; https://doi.org/10.3390/ijms17101760 - 21 Oct 2016

Cited by 10 | Viewed by 6181

Abstract

Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further [...] Read more.

Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further targeted therapies currently in clinical trials. Whilst treatment decisions are mostly based on a patient’s age, fitness, including the presence of co-morbidities, and tumour burden, significant scope exists for better risk stratification, sub-classification of disease, and predictors of response to specific therapies. Clinical staging, recurring acquired cytogenetic aberrations, and serum biomarkers such as β-2 microglobulin, and free light chains are in widespread use but often fail to predict the disease progression or inform treatment decision making. Recent scientific advances have provided considerable insight into the biology of myeloma. For example, gene expression profiling is already making a contribution to enhanced understanding of the biology of the disease whilst Next Generation Sequencing has revealed great genomic complexity and heterogeneity. Pathways involved in the oncogenesis, proliferation of the tumour and its resistance to apoptosis are being unravelled. Furthermore, knowledge of the tumour cell surface and its interactions with bystander cells and the bone marrow stroma enhance this understanding and provide novel targets for cell and antibody-based therapies. This review will discuss the development in understanding of the biology of the tumour cell and its environment in the bone marrow, the implementation of new therapeutic options contributing to significantly improved outcomes, and the progression towards more personalised medicine in this disorder. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Why Are Omics Technologies Important to Understanding the Role of Nutrition in Inflammatory Bowel Diseases?

by Lynnette R. Ferguson^1,*

and Matthew P. G. Barnett²

¹ Discipline of Nutrition and Dietetics and Auckland Cancer Research Society, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

² Food Nutrition & Health Team, Food & Bio-Based Products Group, AgResearch Limited, Palmerston North 4442, New Zealand

Int. J. Mol. Sci. 2016, 17(10), 1763; https://doi.org/10.3390/ijms17101763 - 21 Oct 2016

Cited by 8 | Viewed by 6427

Abstract

For many years, there has been confusion about the role that nutrition plays in inflammatory bowel diseases (IBD). It is apparent that good dietary advice for one individual may prove inappropriate for another. As with many diseases, genome-wide association studies across large collaborative [...] Read more.

For many years, there has been confusion about the role that nutrition plays in inflammatory bowel diseases (IBD). It is apparent that good dietary advice for one individual may prove inappropriate for another. As with many diseases, genome-wide association studies across large collaborative groups have been important in revealing the role of genetics in IBD, with more than 200 genes associated with susceptibility to the disease. These associations provide clues to explain the differences in nutrient requirements among individuals. In addition to genes directly involved in the control of inflammation, a number of the associated genes play roles in modulating the gut microbiota. Cell line models enable the generation of hypotheses as to how various bioactive dietary components might be especially beneficial for certain genetic groups. Animal models are necessary to mimic aspects of the complex aetiology of IBD, and provide an important link between tissue culture studies and human trials. Once we are sufficiently confident of our hypotheses, we can then take modified diets to an IBD population that is stratified according to genotype. Studies in IBD patients fed a Mediterranean-style diet have been important in validating our hypotheses and as a proof-of-principle for the application of these sensitive omics technologies to aiding in the control of IBD symptoms. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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What Is Breast in the Bone?

by Carrie S. Shemanko^*, Yingying Cong and Amanda Forsyth

Department of Biological Sciences and Arnie Charbonneau Cancer Institute, 2500 University Dr, NW, University of Calgary, Calgary, AB T2N 1N4, Canada

Int. J. Mol. Sci. 2016, 17(10), 1764; https://doi.org/10.3390/ijms17101764 - 22 Oct 2016

Cited by 27 | Viewed by 7970

Abstract

The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is [...] Read more.

The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%–50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural “recycling” of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)

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The Efficacy of Non-Pharmacological Interventions on Brain-Derived Neurotrophic Factor in Schizophrenia: A Systematic Review and Meta-Analysis

by Kenji Sanada^1,2, Iñaki Zorrilla¹, Yusuke Iwata^3,4,5, Cristina Bermúdez-Ampudia¹, Ariel Graff-Guerrero^3,4,6,7, Mónica Martínez-Cengotitabengoa^1,8 and Ana González-Pinto^1,*

¹ CIBERSAM, BioAraba Research Institute, OSI Araba, Department of Psychiatry, Araba University Hospital, University of the Basque Country (EHU/UPV), Olaguibel Street 29, Vitoria 01004, Spain

² Department of Psychiatry, Showa University School of Medicine, 6-11-11 Kitakarasuyama, Setagaya-ku, Tokyo 157-8577, Japan

³ Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada

⁴ Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada

⁵ Department of Neuropsychiatry, School of Medicine, Keio University, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-0016, Japan

⁶ Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada

⁷ Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada

⁸ Universidad Nacional de Educación a Distancia, Centro Asociado de Vitoria, Pedro de Asúa Street 2, Vitoria 01008, Spain

Int. J. Mol. Sci. 2016, 17(10), 1766; https://doi.org/10.3390/ijms17101766 - 24 Oct 2016

Cited by 29 | Viewed by 6707

Abstract

Several studies have investigated the relationship between non-pharmacological interventions (NPIs) and peripheral brain-derived neurotrophic factor (BDNF) in schizophrenia patients. We conducted a systematic review and meta-analysis to review the efficacy of NPIs on peripheral serum and plasma BDNF in subjects with schizophrenia (including [...] Read more.

Several studies have investigated the relationship between non-pharmacological interventions (NPIs) and peripheral brain-derived neurotrophic factor (BDNF) in schizophrenia patients. We conducted a systematic review and meta-analysis to review the efficacy of NPIs on peripheral serum and plasma BDNF in subjects with schizophrenia (including schizoaffective disorder). Meta-analyses were conducted to examine the effects of NPIs on blood BDNF levels by using the standardized mean differences (SMDs) between the intervention groups and controls. In total, six randomized controlled trials with 289 participants were included. Of them, five studies used exercise, physical training or diet products. One study used cognitive training. Overall, the BDNF levels in the NPI group increased significantly compared with the control groups (SMD = 0.95, 95% confidence interval (CI) = 0.07 to 1.83, p = 0.03). Subgroup analyses indicated beneficial effects of a non-exercise intervention on peripheral BDNF levels (SMD = 0.41, 95% CI = 0.08 to 0.74, p = 0.01). Meta-regression analyses showed that the completion rate influenced the variation in SMD (p = 0.01). Despite insufficient evidence to draw a conclusion, our results suggest that use of NPIs as adjunctive treatments, specifically non-exercise interventions, may affect positively serum or plasma BDNF in patients with schizophrenia. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Melatonin as a Potential Agent in the Treatment of Sarcopenia

by Ana Coto-Montes^1,2,*

, Jose A. Boga^2,3, Dun X. Tan² and Russel J. Reiter²

¹ Department of Morphology and Cellular Biology, Medicine Faculty, University of Oviedo, Julian Claveria, s/n, Oviedo 33006, Spain

² Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA

³ Service of Microbiology, Hospital Universitario Central de Asturias, Avenida de Roma, s/n, Oviedo 33011, Spain

Int. J. Mol. Sci. 2016, 17(10), 1771; https://doi.org/10.3390/ijms17101771 - 24 Oct 2016

Cited by 53 | Viewed by 8836

Abstract

Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that [...] Read more.

Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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miR-155: A Novel Target in Allergic Asthma

by Hong Zhou, Junyao Li, Peng Gao, Qi Wang and Jie Zhang^*

Department of Respiratory Medicine, The Second Affiliated Hospital of Jilin University, Changchun 130041, China

Int. J. Mol. Sci. 2016, 17(10), 1773; https://doi.org/10.3390/ijms17101773 - 24 Oct 2016

Cited by 68 | Viewed by 6585

Abstract

MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as [...] Read more.

MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as modulation of immune responses and oncogenesis. Previous studies have identified miR-155 as a crucial positive regulator of Th1 immune response in autoimmune diseases, but as a suppressor of Th2 immunity in allergic disorders. However, recent studies have found new evidence that miR-155 plays an indispensible role in allergic asthma. This review summarizes the recent findings with respect to miR-155 in immune responses and the underlying mechanisms responsible for miR-155-related allergic diseases, as well as the similarities between miR-155 and glucocorticoids in immunity. Full article

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

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Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack

by Michela Bulfoni¹, Matteo Turetta¹

, Fabio Del Ben², Carla Di Loreto^1,3, Antonio Paolo Beltrami¹

and Daniela Cesselli^1,*

¹ Department of Medical and Biological Sciences, University of Udine, Piazzale M. Kolbe 4, 33100 Udine, Italy

² Department of Clinical Pathology, CRO Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy

³ Institute of Pathology, University Hospital of Udine-ASUIUD, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy

Int. J. Mol. Sci. 2016, 17(10), 1775; https://doi.org/10.3390/ijms17101775 - 24 Oct 2016

Cited by 53 | Viewed by 9225

Abstract

Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM⁺/CK⁺) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability [...] Read more.

Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM⁺/CK⁺) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a “surrogate” of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug-resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well. Full article

(This article belongs to the Special Issue Circulating Tumor Cells)

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Development of 12 Microsatellite Markers in Dorcus titanus castanicolor (Motschulsky, 1861) (Lucanidae, Coleoptera) from Korea Using Next-Generation Sequencing

by Tae Hwa Kang¹, Sang Hoon Han^2,* and Sun Jae Park^3,*

¹ Animal Resources Division, National Institute of Biological Resources, 42, Hwangyeong-ro, Seo-gu, Incheon 22689, Korea

² Department of Life Science, College of Natural Science, Kyonggi University, 154-42, Gwanggyosan-ro, Yeongtong-gu, Suwon 16227, Korea

³ Biological Resources Research Department, National Institute of Biological Resources, 42, Hwangyeong-ro, Seo-gu, Incheon 22689, Korea

Int. J. Mol. Sci. 2016, 17(10), 1621; https://doi.org/10.3390/ijms17101621 - 23 Sep 2016

Cited by 5 | Viewed by 5975

Abstract

In the present study, we used next-generation sequencing to develop 12 novel microsatellite markers for genetic structural analysis of Dorcus titanus castanicolor (Lucanidae; Coleoptera), a popular pet insect in China, Korea, and Japan. We identified 52,357 microsatellite loci in 339,287,381 bp of genomic [...] Read more.

In the present study, we used next-generation sequencing to develop 12 novel microsatellite markers for genetic structural analysis of Dorcus titanus castanicolor (Lucanidae; Coleoptera), a popular pet insect in China, Korea, and Japan. We identified 52,357 microsatellite loci in 339,287,381 bp of genomic sequence and selected 19 of the loci based on their PCR amplification efficiency and polymorphism. The 19 selected markers were then tested for the presence of null alleles and linkage disequilibrium. We did not detect any evidence of null alleles; however, four pairs of loci (DT03 and DT11, DT05 and DT26, DT08 and DT26, DT26 and DT35) exhibited linkage disequilibrium. Thus, we assessed the genetic diversity of a D. titanus castanicolor population from the Daejeon region of Korea (n = 22) using 13 markers. Among them, one marker (DT17) deviated from Hardy-Weinberg equilibrium. Therefore, 12 markers may be useful for further analyzing the genetic diversity of D. titanus castanicolor. Full article

(This article belongs to the Section Biochemistry)

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