International Journal of Molecular Sciences

17 pages, 2612 KiB

Open AccessArticle

Sildenafil Attenuates Inflammation and Oxidative Stress in Pelvic Ganglia Neurons after Bilateral Cavernosal Nerve Damage

by Leah A. Garcia¹, Su M. Hlaing¹, Richard A. Gutierrez², Maria D. Sanchez², Istvan Kovanecz^3,4

, Jorge N. Artaza^1,2,5 and Monica G. Ferrini^1,2,5,*

¹ Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA

² Department of Health and Life Science, College of Science and Health, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA

³ Los Angeles Biomedical Research Institute, Harbor-University of California Los Angeles, Torrance, CA 90502, USA

⁴ Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA

⁵ Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA

Int. J. Mol. Sci. 2014, 15(10), 17204-17220; https://doi.org/10.3390/ijms151017204 - 26 Sep 2014

Cited by 35 | Viewed by 8066

Abstract

Erectile dysfunction is a common complication for patients undergoing surgeries for prostate, bladder, and colorectal cancers, due to damage of the nerves associated with the major pelvic ganglia (MPG). Functional re-innervation of target organs depends on the capacity of the neurons to survive [...] Read more.

Erectile dysfunction is a common complication for patients undergoing surgeries for prostate, bladder, and colorectal cancers, due to damage of the nerves associated with the major pelvic ganglia (MPG). Functional re-innervation of target organs depends on the capacity of the neurons to survive and switch towards a regenerative phenotype. PDE5 inhibitors (PDE5i) have been successfully used in promoting the recovery of erectile function after cavernosal nerve damage (BCNR) by up-regulating the expression of neurotrophic factors in MPG. However, little is known about the effects of PDE5i on markers of neuronal damage and oxidative stress after BCNR. This study aimed to investigate the changes in gene and protein expression profiles of inflammatory, anti-inflammatory cytokines and oxidative stress related-pathways in MPG neurons after BCNR and subsequent treatment with sildenafil. Our results showed that BCNR in Fisher-344 rats promoted up-regulation of cytokines (interleukin- 1 (IL-1) β, IL-6, IL-10, transforming growth factor β 1 (TGFβ1), and oxidative stress factors (Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), TNF receptor superfamily member 5 (CD40) that were normalized by sildenafil treatment given in the drinking water. In summary, PDE5i can attenuate the production of damaging factors and can up-regulate the expression of beneficial factors in the MPG that may ameliorate neuropathic pain, promote neuroprotection, and favor nerve regeneration. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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21 pages, 1198 KiB

Open AccessArticle

Reducing Capacity, Chlorogenic Acid Content and Biological Activity in a Collection of Scarlet (Solanum aethiopicum) and Gboma (S. macrocarpon) Eggplants

by Mariola Plazas, Jaime Prohens^*

, Amparo Noelia Cuñat, Santiago Vilanova, Pietro Gramazio, Francisco Javier Herraiz and Isabel Andújar

Instituto de Conservación y Mejora de la Agrodiversidad Valenciana, Universitat Politècnica de València, Camino de Vera 14, 46022 Valencia, Spain

Int. J. Mol. Sci. 2014, 15(10), 17221-17241; https://doi.org/10.3390/ijms151017221 - 26 Sep 2014

Cited by 85 | Viewed by 8839

Abstract

Scarlet (Solanum aethiopicum) and gboma (S. macrocarpon) eggplants are important vegetables in Sub-Saharan Africa. Few studies have been made on these crops regarding the diversity of phenolic content and their biological activity. We have studied the reducing activity, the [...] Read more.

Scarlet (Solanum aethiopicum) and gboma (S. macrocarpon) eggplants are important vegetables in Sub-Saharan Africa. Few studies have been made on these crops regarding the diversity of phenolic content and their biological activity. We have studied the reducing activity, the chlorogenic acid and other phenolic acid contents in a collection of 56 accessions of scarlet eggplant, including the four cultivated groups (Aculeatum, Gilo, Kumba, Shum) and the weedy intermediate S. aethiopicum-S. anguivi types, as well as in eight accessions of gboma eggplant, including the cultivated S. macrocarpon and its wild ancestor, S. dasyphyllum. A sample of the accessions evaluated in this collection has been tested for inhibition of nitric oxide (NO) using macrophage cell cultures. The results show that there is a great diversity in both crops for reducing activity, chlorogenic acid content and chlorogenic acid peak area (% of total phenolic acids). Heritability (H²) for these traits was intermediate to high in both crops. In all samples, chlorogenic acid was the major phenolic acid and accounted for more than 50% of the chromatogram peak area. Considerable differences were found among and within groups for these traits, but the greatest values for total phenolics and chlorogenic acid content were found in S. dasyphyllum. In most groups, reducing activity was positively correlated (with values of up to 0.904 in the Aculeatum group) with chlorogenic acid content. Inhibition of NO was greatest in samples having a high chlorogenic acid content. The results show that both crops are a relevant source of chlorogenic acid and other phenolic acids. The high diversity found also indicates that there are good prospects for breeding new scarlet and gboma eggplant cultivars with improved content in phenolics and bioactive properties. Full article

(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols)

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14 pages, 2667 KiB

Open AccessArticle

Resistin Stimulates Expression of Chemokine Genes in Chondrocytes via Combinatorial Regulation of C/EBPβ and NF-κB

by Ziji Zhang^1,†, Zhiqi Zhang^1,†, Yan Kang¹, Changhe Hou¹, Xin Duan¹, Puyi Sheng¹, Linda J. Sandell^2,* and Weiming Liao^1,*

¹ Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China

² Department of Orthopaedic Surgery, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 17242-17255; https://doi.org/10.3390/ijms151017242 - 26 Sep 2014

Cited by 24 | Viewed by 5288

Abstract

To further investigate the regulation role of two chemokine genes CCL3 and CCL4 in chondrocytes in response to resistin, human primary chondrocytes and T/C-28a2 cells were cultured. The function of resistin on the chemokine genes, and the expression of C/EBPβ, NF-κB [...] Read more.

To further investigate the regulation role of two chemokine genes CCL3 and CCL4 in chondrocytes in response to resistin, human primary chondrocytes and T/C-28a2 cells were cultured. The function of resistin on the chemokine genes, and the expression of C/EBPβ, NF-κB isoforms were tested using qPCR. The methods used to investigate timed co-regulation of C/EBPβ and NF-κB were NF-κB inhibitor (IKK-NBD) and C/EBPβ inhibitor (SB303580) treatments, and subcellular localization, with or without resistin stimulation. Results showed that resistin could increase the up-regulation of chemokine genes independently. Resistin increased the expression of C/EBPβ and NF-κB isoforms. C/EBPβ regulated basal activity and steadily increased over time up to 24h with resistin. NF-κB was up-regulated upon induction with resistin, peaking at 4 h. C/EBPβ and NF-κB co-enhanced the chemokines expression; inhibition of their activity was additive. The timing of activation in chondrocytes was confirmed by subcellular localization of C/EBPβ and c-rel. Chondrocytes react to resistin in a non-restricted cell-specific manner, utilizing C/EBPβ and NF-κB in a combinatorial regulation of chemokine gene expression. The activity of C/EBPβ is augmented by a transient increase in activity of NF-κB, and both transcription factors act independently on the chemokine genes, CCL3 and CCL4. Thus, resistin stimulates CCL3 and CCL4 through combinatorial regulation of C/EBPβ and NF-κB in chondrocytes. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 1801 KiB

Open AccessArticle

Combinatorial Measurement of CDKN1A/p21 and KIF20A Expression for Discrimination of DNA Damage-Induced Clastogenicity

by Rina Sakai^1,2, Yuji Morikawa¹, Chiaki Kondo¹, Hiroyuki Oka¹, Hirofumi Miyajima¹, Kihei Kubo² and Takeki Uehara^1,*

¹ Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan

² Department of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinkuu Ourai Kita, Izumisano, Osaka 598-8531, Japan

Int. J. Mol. Sci. 2014, 15(10), 17256-17269; https://doi.org/10.3390/ijms151017256 - 26 Sep 2014

Cited by 8 | Viewed by 7688

Abstract

In vitro mammalian cytogenetic tests detect chromosomal aberrations and are used for testing the genotoxicity of compounds. This study aimed to identify a supportive genomic biomarker could minimize the risk of misjudgments and aid appropriate decision making in genotoxicity testing. Human lymphoblastoid TK6 [...] Read more.

In vitro mammalian cytogenetic tests detect chromosomal aberrations and are used for testing the genotoxicity of compounds. This study aimed to identify a supportive genomic biomarker could minimize the risk of misjudgments and aid appropriate decision making in genotoxicity testing. Human lymphoblastoid TK6 cells were treated with each of six DNA damage-inducing genotoxins (clastogens) or two genotoxins that do not cause DNA damage. Cells were exposed to each compound for 4 h, and gene expression was comprehensively examined using Affymetrix U133A microarrays. Toxicogenomic analysis revealed characteristic alterations in the expression of genes included in cyclin-dependent kinase inhibitor 1A (CDKN1A/p21)-centered network. The majority of genes included in this network were upregulated on treatment with DNA damage-inducing clastogens. The network, however, also included kinesin family member 20A (KIF20A) downregulated by treatment with all the DNA damage-inducing clastogens. Downregulation of KIF20A expression was successfully confirmed using additional DNA damage-inducing clastogens. Our analysis also demonstrated that nucleic acid constituents falsely downregulated the expression of KIF20A, possibly via p16 activation, independently of the CDKN1A signaling pathway. Our results indicate the potential of KIF20A as a supportive biomarker for clastogenicity judgment and possible mechanisms involved in KIF20A downregulation in DNA damage and non-DNA damage signaling networks. Full article

(This article belongs to the Special Issue Computational Toxicology: Predicting Potential Toxicity of Drugs and Therapeutics)

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14 pages, 2773 KiB

Open AccessArticle

Blocking the Function of Inflammatory Cytokines and Mediators by Using IL-10 and TGF-β: A Potential Biological Immunotherapy for Intervertebral Disc Degeneration in a Beagle Model

by Wei Li¹, Tianyi Liu², Liangliang Wu², Chun Chen¹, Zhiwei Jia¹, Xuedong Bai¹ and Dike Ruan^1,*

¹ Department of Orthopedics, Navy General Hospital, Beijing 100048, China

² Department of Centre Laboratory, General Hospital of People's Liberation Army, Beijing 100853, China

Int. J. Mol. Sci. 2014, 15(10), 17270-17283; https://doi.org/10.3390/ijms151017270 - 26 Sep 2014

Cited by 61 | Viewed by 7820

Abstract

The debilitating effects of lower back pain are a major health issue worldwide. A variety of factors contribute to this, and oftentimes intervertebral disk degeneration (IDD) is an underlying cause of this disorder. Inflammation contributes to IDD, and inflammatory cytokines such as tumor [...] Read more.

The debilitating effects of lower back pain are a major health issue worldwide. A variety of factors contribute to this, and oftentimes intervertebral disk degeneration (IDD) is an underlying cause of this disorder. Inflammation contributes to IDD, and inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, play key roles in the pathology of IDD. Therefore, the development of treatments that inhibit the expression and/or effects of TNF-α and IL-1β in IDD patients should be a promising therapeutic approach to consider. This study characterized the potential to suppress inflammatory cytokine production in degenerative intervertebral disc (NP) cells by treatment with IL-10 and TGF-β in a canine model of IDD. IDD was induced surgically in six male beagles, and degenerative NP cells were isolated and cultured for in vitro studies on cytokine production. Cultured degenerative NP cells were divided into four experimental treatment groups: untreated control, IL-10-treated, TGF-β-treated, and IL-10- plus TGF-β-treated cells. Cultured normal NP cells served as a control group. TNF-α expression was evaluated by fluorescence activated cell sorting (FACS) analysis and enzyme-linked immunosorbent assay (ELISA); moreover, ELISA and real-time PCR were also performed to evaluate the effect of IL-10 and TGF-β on NP cell cytokine expression in vitro. Our results demonstrated that IL-10 and TGF-β treatment suppressed the expression of IL-1β and TNF-α and inhibited the development of inflammatory responses. These data suggest that IL-10 and TGF-β should be evaluated as therapeutic approaches for the treatment of lower back pain mediated by IDD. Full article

(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)

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20 pages, 5373 KiB

Open AccessArticle

Molecular Modeling and MM-PBSA Free Energy Analysis of Endo-1,4-β-Xylanase from Ruminococcus albus 8

by Dongling Zhan^1,2,†, Lei Yu^1,†, Hanyong Jin¹, Shanshan Guan³ and Weiwei Han^1,*

¹ Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130023, China

² College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China

³ State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 17284-17303; https://doi.org/10.3390/ijms151017284 - 26 Sep 2014

Cited by 19 | Viewed by 8165

Abstract

Endo-1,4-β-xylanase (EC 3.2.1.8) is the enzyme from Ruminococcus albus 8 (R. albus 8) (Xyn10A), and catalyzes the degradation of arabinoxylan, which is a major cell wall non-starch polysaccharide of cereals. The crystallographic structure of Xyn10A is still unknown. For this reason, we [...] Read more.

Endo-1,4-β-xylanase (EC 3.2.1.8) is the enzyme from Ruminococcus albus 8 (R. albus 8) (Xyn10A), and catalyzes the degradation of arabinoxylan, which is a major cell wall non-starch polysaccharide of cereals. The crystallographic structure of Xyn10A is still unknown. For this reason, we report a computer-assisted homology study conducted to build its three-dimensional structure based on the known sequence of amino acids of this enzyme. In this study, the best similarity was found with the Clostridium thermocellum (C. thermocellum) N-terminal endo-1,4-β-d-xylanase 10 b. Following the 100 ns molecular dynamics (MD) simulation, a reliable model was obtained for further studies. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methods were used for the substrate xylotetraose having the reactive sugar, which was bound in the −1 subsite of Xyn10A in the ⁴C₁ (chair) and ²S_O (skew boat) ground state conformations. According to the simulations and free energy analysis, Xyn10A binds the substrate with the −1 sugar in the ²S_O conformation 39.27 kcal·mol⁻¹ tighter than the substrate with the sugar in the ⁴C₁ conformation. According to the Xyn10A-²S_O Xylotetraose (X4(sb) interaction energies, the most important subsite for the substrate binding is subsite −1. The results of this study indicate that the substrate is bound in a skew boat conformation with Xyn10A and the −1 sugar subsite proceeds from the ⁴C₁ conformation through ²S_O to the transition state. MM-PBSA free energy analysis indicates that Asn187 and Trp344 in subsite −1 may an important residue for substrate binding. Our findings provide fundamental knowledge that may contribute to further enhancement of enzyme performance through molecular engineering. Full article

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

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14 pages, 6577 KiB

Open AccessArticle

Effect of Melatonin on Human Dental Papilla Cells

by Ryusuke Tachibana, Seiko Tatehara, Shuku Kumasaka, Reiko Tokuyama and Kazuhito Satomura^*

Department of Oral Medicine and Stomatology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan

Int. J. Mol. Sci. 2014, 15(10), 17304-17317; https://doi.org/10.3390/ijms151017304 - 26 Sep 2014

Cited by 18 | Viewed by 6620

Abstract

Melatonin regulates a variety of biological processes, which are the control of circadian rhythms, regulation of seasonal reproductive function and body temperature, free radical scavenging and so on. Our previous studies have shown that various cells exist in human and mouse tooth germs [...] Read more.

Melatonin regulates a variety of biological processes, which are the control of circadian rhythms, regulation of seasonal reproductive function and body temperature, free radical scavenging and so on. Our previous studies have shown that various cells exist in human and mouse tooth germs that express the melatonin 1a receptor (Mel1aR). However, little is known about the effects of melatonin on tooth development and growth. The present study was performed to examine the possibility that melatonin might exert its influence on tooth development. DP-805 cells, a human dental papilla cell line, were shown to express Mel1aR. Expression levels of mRNA for Mel1aR in DP-805 cells increased until 3 days after reaching confluence and decreased thereafter. Real-time reverse transcription-polymerase chain reaction showed that melatonin increased the expression of mRNAs for osteopontin (OPN), osteocalcin (OCN), bone sialoprotein (BSP), dentin matrix protein-1 (DMP-1) and dentin sialophosphoprotin (DSPP). Melatonin also enhanced the mineralized matrix formation in DP-805 cell cultures in a dose-dependent manner. These results strongly suggest that melatonin may play a physiological role in tooth development/growth by regulating the cellular function of odontogenic cells in tooth germs. Full article

(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

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15 pages, 1090 KiB

Open AccessArticle

Isolation and Structure Characterization of an Antioxidative Glycopeptide from Mycelial Culture Broth of a Medicinal Fungus

by Jian-Yong Wu^*

, Xia Chen and Ka-Chai Siu

Department of Applied Biology & Chemical Technology, State Key Laboratory of Chinese Medicine and Molecular Pharmacology in Shenzhen, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong

Int. J. Mol. Sci. 2014, 15(10), 17318-17332; https://doi.org/10.3390/ijms151017318 - 29 Sep 2014

Cited by 13 | Viewed by 6323

Abstract

A novel glycopeptide (Cs-GP1) with an average molecular weight (Mw) of 6.0 kDa was isolated and purified by column chromatography from the lower Mw fraction of exopolysaccharide (EPS) produced by a medicinal fungus Cordyceps sinensis Cs-HK1. Its carbohydrate moiety was [...] Read more.

A novel glycopeptide (Cs-GP1) with an average molecular weight (Mw) of 6.0 kDa was isolated and purified by column chromatography from the lower Mw fraction of exopolysaccharide (EPS) produced by a medicinal fungus Cordyceps sinensis Cs-HK1. Its carbohydrate moiety was mainly composed of glucose and mannose at 3.2:1.0 mole ratio, indicating an O-linked glycopeptide. The peptide chain contained relatively high mole ratios of aspartic acid, glutamic acid and glycine (3.3–3.5 relative to arginine) but relatively low ratios of tyrosine and histidine. The peptide chain sequence analyzed after trypsin digestion by LC-MS was KNGIFQFGEDCAAGSISHELGGFREFREFLKQAGLE. Cs-GP1 exhibited remarkable antioxidant capacity with a Trolox equivalent antioxidant capacity of 1183.8 μmol/g and a ferric reducing ability of 611.1 μmol Fe(II)/g, and significant protective effect against H₂O₂-induced PC12 cell injury at a minimum dose of 10 μg/mL. This is the first report on the structure and bioactivity of an extracellular glycopeptide from the Cordyceps species. Full article

(This article belongs to the Special Issue Bioactive Proteins and Peptides Derived from Food)

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11 pages, 683 KiB

Open AccessArticle

Effect of APE1 T2197G (Asp148Glu) Polymorphism on APE1, XRCC1, PARP1 and OGG1 Expression in Patients with Colorectal Cancer

by Juliana C. Santos^1,2, Alexandre Funck¹, Isabelle J. L. Silva-Fernandes³, Silvia H. B. Rabenhorst³, Carlos A. R. Martinez¹ and Marcelo L. Ribeiro^1,2,*

¹ Laboratory of Microbiology and Molecular Biology, Clinical Pharmacology and Gastroenterology Unit, Sao Francisco University Medical School, Bragança Paulista, SP. 12916-900, Brazil

² Genetics and Molecular Biology, UNICAMP, Universidade Estadual de Campinas, Campinas, SP. 13083-862, Brazil

³ Department of Pathology and Forensic Medicine, Federal University of Ceará, Fortaleza, CE. 60020-181, Brazil

Int. J. Mol. Sci. 2014, 15(10), 17333-17343; https://doi.org/10.3390/ijms151017333 - 29 Sep 2014

Cited by 20 | Viewed by 5506

Abstract

It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients [...] Read more.

It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV) showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1). In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis. Full article

(This article belongs to the Section Biochemistry)

22 pages, 4050 KiB

Open AccessArticle

Gender-Associated Genomic Differences in Colorectal Cancer: Clinical Insight from Feminization of Male Cancer Cells

by Rola H. Ali¹, Makia J. Marafie², Milad S. Bitar³, Fahad Al-Dousari⁴, Samar Ismael⁴, Hussain Bin Haider¹, Waleed Al-Ali¹, Sindhu P. Jacob¹ and Fahd Al-Mulla^1,*

¹ Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait

² Kuwait Medical Genetics Center, Ministry of Health, Safat 13001, Kuwait

³ Department of Pharmacology, Faculty of Medicine, Health Sciences Center, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait

⁴ Department of Forensic Evidence, Ministry of Interior, P.O. Box 12500, Shamiya 71655, Kuwait

Int. J. Mol. Sci. 2014, 15(10), 17344-17365; https://doi.org/10.3390/ijms151017344 - 29 Sep 2014

Cited by 18 | Viewed by 6928

Abstract

Gender-related differences in colorectal cancer (CRC) are not fully understood. Recent studies have shown that CRC arising in females are significantly associated with CpG island methylator phenotype (CIMP-high). Using array comparative genomic hybridization, we analyzed a cohort of 116 CRCs (57 males, 59 [...] Read more.

Gender-related differences in colorectal cancer (CRC) are not fully understood. Recent studies have shown that CRC arising in females are significantly associated with CpG island methylator phenotype (CIMP-high). Using array comparative genomic hybridization, we analyzed a cohort of 116 CRCs (57 males, 59 females) for chromosomal copy number aberrations (CNA) and found that CRC in females had significantly higher numbers of gains involving chromosome arms 1q21.2–q21.3, 4q13.2, 6p21.1 and 16p11.2 and copy number losses of chromosome arm 11q25 compared to males. Interestingly, a subset of male CRCs (46%) exhibited a "feminization" phenomenon in the form of gains of X chromosomes (or an arm of X) and/or losses of the Y chromosome. Feminization of cancer cells was significantly associated with microsatellite-stable CRCs (p-value 0.003) and wild-type BRAF gene status (p-value 0.009). No significant association with other clinicopathological parameters was identified including disease-free survival. In summary, our data show that some CNAs in CRC may be gender specific and that male cancers characterized by feminization may constitute a specific subset of CRCs that warrants further investigation. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 7909 KiB

Open AccessArticle

Intermittently Administered Parathyroid Hormone [1–34] Promotes Tendon-Bone Healing in a Rat Model

by Fanggang Bi, Zhongli Shi, Shuai Jiang, Peng Guo and Shigui Yan^*

Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China

Int. J. Mol. Sci. 2014, 15(10), 17366-17379; https://doi.org/10.3390/ijms151017366 - 29 Sep 2014

Cited by 28 | Viewed by 6163

Abstract

The objective of this study was to investigate whether intermittent administration of parathyroid hormone [1–34] (PTH[1–34]) promotes tendon-bone healing after anterior cruciate ligament (ACL) reconstruction in vivo. A rat model of ACL reconstruction with autograft was established at the left hind leg. [...] Read more.

The objective of this study was to investigate whether intermittent administration of parathyroid hormone [1–34] (PTH[1–34]) promotes tendon-bone healing after anterior cruciate ligament (ACL) reconstruction in vivo. A rat model of ACL reconstruction with autograft was established at the left hind leg. Every day, injections of 60 μg PTH[1–34]/kg subcutaneously were given to the PTH group rats (n = 10) for four weeks, and the controls (n = 10) received saline. The tendon-bone healing process was evaluated by micro-CT, biomechanical test, histological and immunohistochemical analyses. The effects of PTH[1–34] on serum chemistry, bone microarchitecture and expression of the PTH receptor (PTH1R) and osteocalcin were determined. Administration of PTH[1–34] significantly increased serum levels of calcium, alkaline phosphatase (AP), osteocalcin and tartrate-resistant acid phosphatase (TRAP). The expression of PTH1R on both osteocytes and chondrocyte-like cells at the tendon-bone interface was increased in the PTH group. PTH[1–34] also enhanced the thickness and microarchitecture of trabecular bone according to the micro-CT analysis. The results imply that systematically intermittent administration of PTH[1–34] promotes tendon-bone healing at an early stage via up-regulated PTH1R. This method may enable a new strategy for the promotion of tendon-bone healing after ACL reconstruction. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 2567 KiB

Open AccessArticle

Hyperthermia Induces Apoptosis through Endoplasmic Reticulum and Reactive Oxygen Species in Human Osteosarcoma Cells

by Chun-Han Hou¹, Feng-Ling Lin², Sheng-Mon Hou^3,*,† and Ju-Fang Liu^4,*,†

¹ Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei 100, Taiwan

² Department of Dermatology, Sijhih Cathay General Hospital, Taipei 221, Taiwan

³ Department of Orthopedic Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan

⁴ Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 17380-17395; https://doi.org/10.3390/ijms151017380 - 29 Sep 2014

Cited by 84 | Viewed by 8268

Abstract

Osteosarcoma (OS) is a relatively rare form of cancer, but OS is the most commonly diagnosed bone cancer in children and adolescents. Chemotherapy has side effects and induces drug resistance in OS. Since an effective adjuvant therapy was insufficient for treating OS, researching [...] Read more.

Osteosarcoma (OS) is a relatively rare form of cancer, but OS is the most commonly diagnosed bone cancer in children and adolescents. Chemotherapy has side effects and induces drug resistance in OS. Since an effective adjuvant therapy was insufficient for treating OS, researching novel and adequate remedies is critical. Hyperthermia can induce cell death in various cancer cells, and thus, in this study, we investigated the anticancer method of hyperthermia in human OS (U-2 OS) cells. Treatment at 43 °C for 60 min induced apoptosis in human OS cell lines, but not in primary bone cells. Furthermore, hyperthermia was associated with increases of intracellular reactive oxygen species (ROS) and caspase-3 activation in U-2 OS cells. Mitochondrial dysfunction was followed by the release of cytochrome c from the mitochondria, and was accompanied by decreased anti-apoptotic Bcl-2 and Bcl-xL, and increased pro-apoptotic proteins Bak and Bax. Hyperthermia triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels, as well as increased calpain expression and activity. In addition, cells treated with calcium chelator (BAPTA-AM) blocked hyperthermia-induced cell apoptosis in U-2 OS cells. In conclusion, hyperthermia induced cell apoptosis substantially via the ROS, ER stress, mitochondria, and caspase pathways. Thus, hyperthermia may be a novel anticancer method for treating OS. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 1526 KiB

Open AccessArticle

Sequencing and Transcriptional Analysis of the Biosynthesis Gene Cluster of Abscisic Acid-Producing Botrytis cinerea

by Tao Gong^1,2,†, Dan Shu^1,†, Jie Yang¹, Zhong-Tao Ding¹ and Hong Tan^1,*

¹ Key Laboratory of Environmental and Applied Microbiology, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China

² Henan Key Laboratory of Microbial Engineering, Institute of Biology, Henan Academy of Sciences, Zhengzhou 450008, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 17396-17410; https://doi.org/10.3390/ijms151017396 - 29 Sep 2014

Cited by 11 | Viewed by 5760

Abstract

Botrytis cinerea is a model species with great importance as a pathogen of plants and has become used for biotechnological production of ABA. The ABA cluster of B. cinerea is composed of an open reading frame without significant similarities (bcaba3), [...] Read more.

Botrytis cinerea is a model species with great importance as a pathogen of plants and has become used for biotechnological production of ABA. The ABA cluster of B. cinerea is composed of an open reading frame without significant similarities (bcaba3), followed by the genes (bcaba1 and bcaba2) encoding P450 monooxygenases and a gene probably coding for a short-chain dehydrogenase/reductase (bcaba4). In B. cinerea ATCC58025, targeted inactivation of the genes in the cluster suggested at least three genes responsible for the hydroxylation at carbon atom C-1' and C-4' or oxidation at C-4' of ABA. Our group has identified an ABA-overproducing strain, B. cinerea TB-3-H8. To differentiate TB-3-H8 from other B. cinerea strains with the functional ABA cluster, the DNA sequence of the 12.11-kb region containing the cluster of B. cinerea TB-3-H8 was determined. Full-length cDNAs were also isolated for bcaba1, bcaba2, bcaba3 and bcaba4 from B. cinerea TB-3-H8. Sequence comparison of the four genes and their flanking regions respectively derived from B. cinerea TB-3-H8, B05.10 and T4 revealed that major variations were located in intergenic sequences. In B. cinerea TB-3-H8, the expression profiles of the four function genes under ABA high-yield conditions were also analyzed by real-time PCR. Full article

(This article belongs to the Section Biochemistry)

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31 pages, 2146 KiB

Open AccessReview

The Biological Function and Clinical Utilization of CD147 in Human Diseases: A Review of the Current Scientific Literature

by Lijuan Xiong¹, Carl K. Edwards III^2,3 and Lijun Zhou^1,*

¹ Central Laboratory, Navy General Hospital, Beijing 100048, China

² National Key Laboratory of Biotherapy and Cancer Research (NKLB), West China Hospital and Medical School, Sichuan University, Chengdu 610041, China

³ Department of Dermatology, University of Colorado at Denver, Anschutz Medical Center, Aurora, CO 80025, USA

Int. J. Mol. Sci. 2014, 15(10), 17411-17441; https://doi.org/10.3390/ijms151017411 - 29 Sep 2014

Cited by 182 | Viewed by 13582

Abstract

CD147 or EMMPRIN is a member of the immunoglobulin superfamily in humans. It is widely expressed in human tumors and plays a central role in the progression of many cancers by stimulating the secretion of matrix metalloproteinases (MMPs) and cytokines. CD147 regulates cell [...] Read more.

CD147 or EMMPRIN is a member of the immunoglobulin superfamily in humans. It is widely expressed in human tumors and plays a central role in the progression of many cancers by stimulating the secretion of matrix metalloproteinases (MMPs) and cytokines. CD147 regulates cell proliferation, apoptosis, and tumor cell migration, metastasis and differentiation, especially under hypoxic conditions. CD147 is also important to many organ systems. This review will provide a detailed overview of the discovery, characterization, molecular structure, diverse biological functions and regulatory mechanisms of CD147 in human physiological and pathological processes. In particular, recent studies have demonstrated the potential application of CD147 not only as a phenotypic marker of activated regulatory T cells but also as a potential diagnostic marker for early-stage disease. Moreover, CD147 is recognized as an effective therapeutic target for hepatocellular carcinoma (HCC) and other cancers, and exciting clinical progress has been made in HCC treatment using CD147-directed monoclonal antibodies. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 1260 KiB

Open AccessArticle

The Protective Effect of MicroRNA-320 on Left Ventricular Remodeling after Myocardial Ischemia-Reperfusion Injury in the Rat Model

by Chun-Li Song^*, Bin Liu, Hong-Ying Diao, Yong-Feng Shi, Yang-Xue Li, Ji-Chang Zhang, Yang Lu, Guan Wang, Jia Liu, Yun-Peng Yu, Zi-Yuan Guo, Jin-Peng Wang, Zhuo Zhao, Jian-Gen Liu, Yi-Hang Liu, Zhi-Xian Liu, Dan Cai and Qian Li

Department of Cardiology, the Second Hospital of Jilin University, Ziqiang Street No. 218, Nanguan District, Changchun 130000, China

Int. J. Mol. Sci. 2014, 15(10), 17442-17456; https://doi.org/10.3390/ijms151017442 - 29 Sep 2014

Cited by 63 | Viewed by 6738

Abstract

The primary objective of this study investigated the role of microRNA-320 (miR-320) on left ventricular remodeling in the rat model of myocardial ischemia-reperfusion (I/R) injury, and we intended to explore the myocardial mechanism of miR-320-mediated myocardium protection. We collected 120 male Wistar rats [...] Read more.

The primary objective of this study investigated the role of microRNA-320 (miR-320) on left ventricular remodeling in the rat model of myocardial ischemia-reperfusion (I/R) injury, and we intended to explore the myocardial mechanism of miR-320-mediated myocardium protection. We collected 120 male Wistar rats (240–280 g) in this study and then randomly divided them into three groups: (1) sham surgery group (sham group: n = 40); (2) ischemia-reperfusion model group (I/R group: n = 40); and (3) I/R model with antagomir-320 group (I/R + antagomir-320 group: n = 40). Value changes of heart function in transesophageal echocardiography were recorded at various time points (day 1, day 3, day 7, day 15 and day 30) after surgery in each group. Myocardial sections were stained with hematoxylin and eosin (H&E) and examined with optical microscope. The degree of myocardial fibrosis was assessed by Sirius Red staining. Terminal dUTP nick end-labeling (TUNEL) and qRT-PCR methods were used to measure the apoptosis rate and to determine the miR-320 expression levels in myocardial tissues. Transesophageal echocardiography showed that the values of left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP) and ±dp/dt_max in the I/R group were obviously lower than those in the sham group, while the left ventricular end-diastolic pressure (LVEDP) value was higher than that in the sham group. The values of LVEF, LVFS, LVSP and ±dp/dt_max showed a gradual decrease in the I/R group, while the LVEDP value showed an up tendency along with the extension of reperfusion time. The H&E staining revealed that rat myocardial tissue in the I/R group presented extensive myocardial damage; for the I/R + antagomir-320 group, however, the degree of damage in myocardial cells was obviously better than that of the I/R group. The Sirius Red staining results showed that the degree of myocardial fibrosis in the I/R group was more severe along with the extension of the time of reperfusion. For the I/R + antagomir-320 group, the degree of myocardial fibrosis was less severe than that in the I/R group. Tissues samples in both the sham and I/R + antagomir-320 groups showed a lower apoptosis rate compared to I/R group. The qRT-PCR results indicated that miR-320 expression in the I/R group was significantly higher than that in both the sham and I/R + antagomir-320 groups. The expression level of miR-320 is significantly up-regulated in the rat model of myocardial I/R injury, and it may be implicated in the prevention of myocardial I/R injury-triggered left ventricular remodeling. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 311 KiB

Open AccessArticle

A Functional Polymorphism in the 3'-UTR of PXR Interacts with Smoking to Increase Lung Cancer Risk in Southern and Eastern Chinese Smoker

by Lisha Zhang¹, Fuman Qiu¹, Xiaoxiao Lu², Yinyan Li¹, Wenxiang Fang¹, Lan Zhang¹, Yifeng Zhou³, Lei Yang^1,* and Jiachun Lu^1,*

¹ The State Key Lab of Respiratory Disease, the Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China

² School of Arts and Sciences, Colby-Sawyer College, New London, NH 03257, USA

³ Department of Genetics, Collaborative Innovation Center for Environmental Toxicity, Medical College of Soochow University, 199 Renai Road, Suzhou 215123, China

Int. J. Mol. Sci. 2014, 15(10), 17457-17468; https://doi.org/10.3390/ijms151017457 - 29 Sep 2014

Cited by 13 | Viewed by 5026

Abstract

Pregnane X receptor (PXR) is an important member of the nuclear receptor superfamily that copes with various endobiotic and xenobiotic stimuli, such as carcinogens by regulating an array of environmental response genes. Low PXR expression has been shown to promote tumor initiation and [...] Read more.

Pregnane X receptor (PXR) is an important member of the nuclear receptor superfamily that copes with various endobiotic and xenobiotic stimuli, such as carcinogens by regulating an array of environmental response genes. Low PXR expression has been shown to promote tumor initiation and metastasis. The aim of the current study was to investigate whether the single nucleotide polymorphisms (SNPs) of PXR could alter lung cancer susceptibility in Chinese by affecting the function or expression of PXR. We genotyped three putatively functional SNPs of PXR (i.e., rs3814055C>T, rs3732360C>T, and rs3814058C>T) and analyzed their associations with lung cancer risk in a two-stage case-control study with a total of 1559 lung cancer cases and 1679 controls in the southern and eastern Chinese population. We found that in comparison to the rs3814058CC common genotype, the rs3814058T variants (TC/TT) which is located in the 3'-untranslated region (3'-UTR) of PXR conferred a consistently increased risk of lung cancer in both the southern Chinese (odd ratios (OR) = 1.24, 95% confidence interval (CI) = 1.03−1.49) and the eastern Chinese (OR = 1.33, 95% CI = 1.02−1.75). The variants also significantly interacted with smoking on increasing cancer risk (p = 0.023). Moreover, lung cancer tissues with the rs3814058T variants showed significantly lower PXR expression than those with rs3814058CC genotype in the smokers (p = 0.041). These results suggested that the rs3814058C>T polymorphism of PXR interacts with smoking on increasing lung cancer risk in Chinese smokers, which might be a functional genetic biomarker for lung cancer. Full article

(This article belongs to the Section Molecular Toxicology)

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9 pages, 1186 KiB

Open AccessArticle

The Pharmacokinetics and Pharmacodynamics of Lidocaine- Loaded Biodegradable Poly(lactic-co-glycolic acid) Microspheres

by Jianming Liu and Xin Lv^*

Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Yangpu District, Shanghai 200433, China

Int. J. Mol. Sci. 2014, 15(10), 17469-17477; https://doi.org/10.3390/ijms151017469 - 29 Sep 2014

Cited by 18 | Viewed by 7675

Abstract

The purpose of this study was to develop novel lidocaine microspheres. Microspheres were prepared by the oil-in-water (o/w) emulsion technique using poly(d,l-lactide-co-glycolide acid) (PLGA) for the controlled delivery of lidocaine. The average diameter of lidocaine PLGA microspheres was 2.34 ± 0.3 [...] Read more.

The purpose of this study was to develop novel lidocaine microspheres. Microspheres were prepared by the oil-in-water (o/w) emulsion technique using poly(d,l-lactide-co-glycolide acid) (PLGA) for the controlled delivery of lidocaine. The average diameter of lidocaine PLGA microspheres was 2.34 ± 0.3 μm. The poly disperse index was 0.21 ± 0.03, and the zeta potential was +0.34 ± 0.02 mV. The encapsulation efficiency and drug loading of the prepared microspheres were 90.5% ± 4.3% and 11.2% ± 1.4%. In vitro release indicated that the lidocaine microspheres had a well-sustained release efficacy, and in vivo studies showed that the area under the curve of lidocaine in microspheres was 2.02–2.06-fold that of lidocaine injection (p < 0.05). The pharmacodynamics results showed that lidocaine microspheres showed a significant release effect in rats, that the process to achieve efficacy was calm and lasting and that the analgesic effect had a significant dose-dependency. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 862 KiB

Open AccessArticle

Association of CDKN2BAS Polymorphism rs4977574 with Coronary Heart Disease: A Case-Control Study and a Meta-Analysis

by Yi Huang¹

, Huadan Ye², Qingxiao Hong², Xuting Xu², Danjie Jiang², Limin Xu², Dongjun Dai², Jie Sun¹, Xiang Gao^1,* and Shiwei Duan^2,*

¹ Department of Neurosurgery, Ningbo First Hospital, Ningbo 315010, China

² Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo 315211, China

Int. J. Mol. Sci. 2014, 15(10), 17478-17492; https://doi.org/10.3390/ijms151017478 - 29 Sep 2014

Cited by 43 | Viewed by 7081

Abstract

The goal of our study was to explore the significant association between a non-protein coding single nucleotide polymorphism (SNP) rs4977574 of CDKN2BAS gene and coronary heart disease (CHD). A total of 590 CHD cases and 482 non-CHD controls were involved in the present [...] Read more.

The goal of our study was to explore the significant association between a non-protein coding single nucleotide polymorphism (SNP) rs4977574 of CDKN2BAS gene and coronary heart disease (CHD). A total of 590 CHD cases and 482 non-CHD controls were involved in the present association study. A strong association of rs4977574 with CHD was observed in females (genotype: p = 0.002; allele: p = 0.002, odd ratio (OR) = 1.57, 95% confidential interval (CI) = 1.18–2.08). Moreover, rs4977574 was more likely to be a risk variant of CHD under the recessive model in females (χ² = 10.29, p = 0.003, OR = 2.14, 95% CI = 1.31–2.77). A breakdown analysis by age had shown that there was an 87% increased risk of CHD for females younger than 65 years (genotype: χ² = 14.64, degrees of freedom (df) = 2, p = 0.0002; allele: χ² = 11.31, df = 1, p = 0.0008, OR = 1.87, 95% CI = 1.30–2.70). Similar observation was also found in males younger than 65 years (genotype: χ² = 8.63, df = 2, p = 0.04; allele: χ² = 7.55, df = 1, p = 0.006, OR = 1.45, 95% CI = 1.11–1.90). p values were adjusted by age, sex, smoking, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). Meta-analysis of 23 studies among 36,452 cases and 39,781 controls showed a strong association between rs4977574 and the risk of CHD (p < 0.0001, OR = 1.27, 95% CI = 1.22–1.31). Full article

(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)

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25 pages, 1119 KiB

Open AccessReview

DNA and RNA Quadruplex-Binding Proteins

by Václav Brázda^1,*, Lucia Hároníková¹, Jack C. C. Liao^1,2 and Miroslav Fojta^1,3

¹ Institute of Biophysics Academy of Sciences of the Czech Republic, v.v.i., 61265 Brno, Czech Republic

² School of Medicine, University of Queensland, Brisbane 4006, Australia

³ Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic

Int. J. Mol. Sci. 2014, 15(10), 17493-17517; https://doi.org/10.3390/ijms151017493 - 29 Sep 2014

Cited by 208 | Viewed by 17509

Abstract

Four-stranded DNA structures were structurally characterized in vitro by NMR, X-ray and Circular Dichroism spectroscopy in detail. Among the different types of quadruplexes (i-Motifs, minor groove quadruplexes, G-quadruplexes, etc.), the best described are G-quadruplexes which are featured by Hoogsteen base-paring. Sequences with [...] Read more.

Four-stranded DNA structures were structurally characterized in vitro by NMR, X-ray and Circular Dichroism spectroscopy in detail. Among the different types of quadruplexes (i-Motifs, minor groove quadruplexes, G-quadruplexes, etc.), the best described are G-quadruplexes which are featured by Hoogsteen base-paring. Sequences with the potential to form quadruplexes are widely present in genome of all organisms. They are found often in repetitive sequences such as telomeric ones, and also in promoter regions and 5' non-coding sequences. Recently, many proteins with binding affinity to G-quadruplexes have been identified. One of the initially portrayed G-rich regions, the human telomeric sequence (TTAGGG)_n, is recognized by many proteins which can modulate telomerase activity. Sequences with the potential to form G-quadruplexes are often located in promoter regions of various oncogenes. The NHE III₁ region of the c-MYC promoter has been shown to interact with nucleolin protein as well as other G-quadruplex-binding proteins. A number of G-rich sequences are also present in promoter region of estrogen receptor alpha. In addition to DNA quadruplexes, RNA quadruplexes, which are critical in translational regulation, have also been predicted and observed. For example, the RNA quadruplex formation in telomere-repeat-containing RNA is involved in interaction with TRF2 (telomere repeat binding factor 2) and plays key role in telomere regulation. All these fundamental examples suggest the importance of quadruplex structures in cell processes and their understanding may provide better insight into aging and disease development. Full article

(This article belongs to the Special Issue Identification and Roles of the Structure of DNA)

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23 pages, 2133 KiB

Open AccessArticle

A Proteomic Analysis of Human Follicular Fluid: Comparison between Younger and Older Women with Normal FSH Levels

by Mahmoud Hashemitabar¹, Maryam Bahmanzadeh^1,*, Ali Mostafaie², Mahmoud Orazizadeh¹, Marzieh Farimani³ and Roshan Nikbakht⁴

¹ Cellular and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 1579461357, Iran

² Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran

³ Endometr and Endometriosis Research Center, Hamedan University of Medical Sciences, Hamedan 6517789971, Iran

⁴ Fertility and Infertility & Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673166, Iran

Int. J. Mol. Sci. 2014, 15(10), 17518-17540; https://doi.org/10.3390/ijms151017518 - 29 Sep 2014

Cited by 44 | Viewed by 8408

Abstract

The follicular fluid (FF) is produced during folliculogenesis and contains a variety of proteins that play important roles in follicle development and oocyte maturation. Age-related infertility is usually considered as a problem that can be solved by assisted reproduction technology. Therefore, the identiﬁcation [...] Read more.

The follicular fluid (FF) is produced during folliculogenesis and contains a variety of proteins that play important roles in follicle development and oocyte maturation. Age-related infertility is usually considered as a problem that can be solved by assisted reproduction technology. Therefore, the identiﬁcation of novel biomarkers that are linked to reproductive aging is the subject of this study. FF was obtained from healthy younger (20–32 years old) and older (38–42 years old) women undergoing intracytoplasmic sperm injection (ICSI) due to male factor infertility. The FF was analyzed by two-dimensional gel electrophoresis (2-DE). The power of two-dimensional gel electrophoresis and the identiﬁcation of proteins were exploited using matrix-assisted laser desorption-ionization time-of-flight/time-of-flight (MALDI-TOF-TOF) mass spectrometry. Twenty three protein spots showed reproducible and significant changes in the aged compared to the young group. Of these, 19 protein spots could be identified using MALDI-TOF-TOF-MS. As a result of MASCOT search, five unique downregulated proteins were identified in the older group. These were identified as serotransferrin, hemopexin precursor, complement C3, C4 and kininogen. A number of protein markers were found that may help develop diagnostic methods of infertility. Full article

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

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24 pages, 642 KiB

Open AccessArticle

Abscisic Acid (ABA) Regulation of Arabidopsis SR Protein Gene Expression

by Tiago M. D. Cruz, Raquel F. Carvalho, Dale N. Richardson and Paula Duque^*

Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, Oeiras 2780-156, Portugal

Int. J. Mol. Sci. 2014, 15(10), 17541-17564; https://doi.org/10.3390/ijms151017541 - 29 Sep 2014

Cited by 61 | Viewed by 12249

Abstract

Serine/arginine-rich (SR) proteins are major modulators of alternative splicing, a key generator of proteomic diversity and flexible means of regulating gene expression likely to be crucial in plant environmental responses. Indeed, mounting evidence implicates splicing factors in signal transduction of the abscisic acid [...] Read more.

Serine/arginine-rich (SR) proteins are major modulators of alternative splicing, a key generator of proteomic diversity and flexible means of regulating gene expression likely to be crucial in plant environmental responses. Indeed, mounting evidence implicates splicing factors in signal transduction of the abscisic acid (ABA) phytohormone, which plays pivotal roles in the response to various abiotic stresses. Using real-time RT-qPCR, we analyzed total steady-state transcript levels of the 18 SR and two SR-like genes from Arabidopsis thaliana in seedlings treated with ABA and in genetic backgrounds with altered expression of the ABA-biosynthesis ABA2 and the ABA-signaling ABI1 and ABI4 genes. We also searched for ABA-responsive cis elements in the upstream regions of the 20 genes. We found that members of the plant-specific SC35-Like (SCL) Arabidopsis SR protein subfamily are distinctively responsive to exogenous ABA, while the expression of seven SR and SR-related genes is affected by alterations in key components of the ABA pathway. Finally, despite pervasiveness of established ABA-responsive promoter elements in Arabidopsis SR and SR-like genes, their expression is likely governed by additional, yet unidentified cis-acting elements. Overall, this study pinpoints SR34, SR34b, SCL30a, SCL28, SCL33, RS40, SR45 and SR45a as promising candidates for involvement in ABA-mediated stress responses. Full article

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

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12 pages, 3637 KiB

Open AccessArticle

Discovery and in Vivo Evaluation of Novel RGD-Modified Lipid-Polymer Hybrid Nanoparticles for Targeted Drug Delivery

by Yinbo Zhao^1,3,†, Dayong Lin^2,†, Fengbo Wu^1,†, Li Guo³, Gu He^1,*, Liang Ouyang¹

, Xiangrong Song¹, Wei Huang⁴ and Xiang Li^1,*

¹ State Key Laboratory of Biotherapy, Department of Pharmacy and Urology, West China Hospital, Sichuan University, Chengdu 610041, China

² Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial Peopleʼs Hospital, Chengdu 610072, China

³ West China School of Pharmacy, Sichuan University, Chengdu 610041, China

⁴ State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 17565-17576; https://doi.org/10.3390/ijms151017565 - 29 Sep 2014

Cited by 49 | Viewed by 8419

Abstract

In the current study, the lipid-shell and polymer-core hybrid nanoparticles (lpNPs) modified by Arg–Gly–Asp(RGD) peptide, loaded with curcumin (Cur), were developed by emulsification-solvent volatilization method. The RGD-modified hybrid nanoparticles (RGD–lpNPs) could overcome the poor water solubility of Cur to meet the requirement of [...] Read more.

In the current study, the lipid-shell and polymer-core hybrid nanoparticles (lpNPs) modified by Arg–Gly–Asp(RGD) peptide, loaded with curcumin (Cur), were developed by emulsification-solvent volatilization method. The RGD-modified hybrid nanoparticles (RGD–lpNPs) could overcome the poor water solubility of Cur to meet the requirement of intravenous administration and tumor active targeting. The obtained optimal RGD-lpNPs, composed of PLGA (poly(lactic-co-glycolic acid))–mPEG (methoxyl poly(ethylene- glycol)), RGD–polyethylene glycol (PEG)–cholesterol (Chol) copolymers and lipids, had good entrapment efficiency, submicron size and negatively neutral surface charge. The core-shell structure of RGD–lpNPs was verified by TEM. Cytotoxicity analysis demonstrated that the RGD–lpNPs encapsulated Cur retained potent anti-tumor effects. Flow cytometry analysis revealed the cellular uptake of Cur encapsulated in the RGD–lpNPs was increased for human umbilical vein endothelial cells (HUVEC). Furthermore, Cur loaded RGD–lpNPs were more effective in inhibiting tumor growth in a subcutaneous B16 melanoma tumor model. The results of immunofluorescent and immunohistochemical studies by Cur loaded RGD–lpNPs therapies indicated that more apoptotic cells, fewer microvessels, and fewer proliferation-positive cells were observed. In conclusion, RGD–lpNPs encapsulating Cur were developed with enhanced anti-tumor activity in melanoma, and Cur loaded RGD–lpNPs represent an excellent tumor targeted formulation of Cur which might be an attractive candidate for cancer therapy. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles 2014)

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24 pages, 3462 KiB

Open AccessReview

Right or Left: The Role of Nanoparticles in Pulmonary Diseases

by Xuefei Lu^1,2, Tao Zhu², Chunying Chen¹ and Ying Liu^1,*

¹ CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China

² Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China

Int. J. Mol. Sci. 2014, 15(10), 17577-17600; https://doi.org/10.3390/ijms151017577 - 29 Sep 2014

Cited by 85 | Viewed by 12093

Abstract

Due to the rapid development of the nanotechnology industry in the last decade, nanoparticles (NPs) are omnipresent in our everyday life today. Many nanomaterials have been engineered for medical purposes. These purposes include therapy for pulmonary diseases. On other hand, people are endeavoring [...] Read more.

Due to the rapid development of the nanotechnology industry in the last decade, nanoparticles (NPs) are omnipresent in our everyday life today. Many nanomaterials have been engineered for medical purposes. These purposes include therapy for pulmonary diseases. On other hand, people are endeavoring to develop nanomaterials for improvement or replacement of traditional therapies. On the other hand, nanoparticles, as foreign material in human bodies, are reported to have potential adverse effects on the lung, including oxidase stress, inflammation, fibrosis and genotoxicity. Further, these damages could induce pulmonary diseases and even injuries in other tissues. It seems that nanoparticles may exert two-sided effects. Toxic effects of nanomaterials should be considered when their use is developed for therapies. Hence this review will attempt to summarize the two-side roles of nanoparticles in both therapies for pulmonary diseases and initiation of lung diseases and even secondary diseases caused by lung injuries. Determinants of these effects such as physicochemical properties of nanoparticles will also be discussed. Full article

(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)

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21 pages, 2087 KiB

Open AccessArticle

Hope for GWAS: Relevant Risk Genes Uncovered from GWAS Statistical Noise

by Catarina Correia^1,2,3,*, Yoan Diekmann³, Astrid M. Vicente^1,2,3 and José B. Pereira-Leal³

¹ Instituto Nacional de Saúde Doutor Ricardo Jorge, Av. Padre Cruz, Lisboa 1649-016, Portugal

² Centre for Biodiversity, Functional & Integrative Genomics, Faculty of Sciences, University of Lisboa, Lisboa 1749-016, Portugal

³ Instituto Gulbenkian de Ciência, Oeiras 2780-156, Portugal

Int. J. Mol. Sci. 2014, 15(10), 17601-17621; https://doi.org/10.3390/ijms151017601 - 29 Sep 2014

Cited by 2 | Viewed by 6716

Abstract

Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem, [...] Read more.

Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem, aiming to test whether there are indeed risk variants within GWAS statistical noise and to develop a systematic strategy to retrieve these hidden variants. Employing an integrative approach, which combines protein-protein interactions with association data from GWAS for 6 common diseases, we found that associated-genes at less stringent significance levels (p < 0.1) with any of these diseases are functionally connected beyond noise expectation. This functional coherence was used to identify disease-relevant subnetworks, which were shown to be enriched in known genes, outperforming the selection of top GWAS genes. As a proof of principle, we applied this approach to breast cancer, supporting well-known breast cancer genes, while pinpointing novel susceptibility genes for experimental validation. This study reinforces the idea that GWAS are under-analyzed and that missing heritability is rather hidden. It extends the use of protein networks to reveal this missing heritability, thus leveraging the large investment in GWAS that produced so far little tangible gain. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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22 pages, 1740 KiB

Open AccessArticle

Expression of Root-Related Transcription Factors Associated with Flooding Tolerance of Soybean (Glycine max)

by Babu Valliyodan^1,*,†, Tara T. Van Toai^2,†, Jose Donizeti Alves^3,†, Patricia De Fátima P. Goulart⁴, Jeong Dong Lee^5,6, Felix B. Fritschi¹, Mohammed Atiqur Rahman⁷, Rafiq Islam⁷, J. Grover Shannon⁵ and Henry T. Nguyen^1,*

¹ Division of Plant Sciences, University of Missouri, Columbia, MO 65211, USA

² United States Department of Agriculture-Agricultural Research Service, Soil Drainage Research Unit, Columbus, OH 43210, USA

³ Departamento de Biologia, Universidade Federal de Lavras, Lavras, MG 37200-000, Brazil

⁴ Centro Universitário de Lavras—UNILAVRAS, 37200-000, Lavras, MG 37200-000, Brazil

⁵ Division of Plant Sciences, University of Missouri, Delta Center, Portageville, MO 68373, USA

⁶ Division of Plant Biosciences, Kyungpook National University, Daegu 702-701, Korea

⁷ Office of Information Technology, Ohio State University South Centers at Piketon, Columbus, OH 43210, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 17622-17643; https://doi.org/10.3390/ijms151017622 - 29 Sep 2014

Cited by 57 | Viewed by 8539

Abstract

Much research has been conducted on the changes in gene expression of the model plant Arabidopsis to low-oxygen stress. Flooding results in a low oxygen environment in the root zone. However, there is ample evidence that tolerance to soil flooding is more than [...] Read more.

Much research has been conducted on the changes in gene expression of the model plant Arabidopsis to low-oxygen stress. Flooding results in a low oxygen environment in the root zone. However, there is ample evidence that tolerance to soil flooding is more than tolerance to low oxygen alone. In this study, we investigated the physiological response and differential expression of root-related transcription factors (TFs) associated with the tolerance of soybean plants to soil flooding. Differential responses of PI408105A and S99-2281 plants to ten days of soil flooding were evaluated at physiological, morphological and anatomical levels. Gene expression underlying the tolerance response was investigated using qRT-PCR of root-related TFs, known anaerobic genes, and housekeeping genes. Biomass of flood-sensitive S99-2281 roots remained unchanged during the entire 10 days of flooding. Flood-tolerant PI408105A plants exhibited recovery of root growth after 3 days of flooding. Flooding induced the development of aerenchyma and adventitious roots more rapidly in the flood-tolerant than the flood-sensitive genotype. Roots of tolerant plants also contained more ATP than roots of sensitive plants at the 7th and 10th days of flooding. Quantitative transcript analysis identified 132 genes differentially expressed between the two genotypes at one or more time points of flooding. Expression of genes related to the ethylene biosynthesis pathway and formation of adventitious roots was induced earlier and to higher levels in roots of the flood-tolerant genotype. Three potential flood-tolerance TFs which were differentially expressed between the two genotypes during the entire 10-day flooding duration were identified. This study confirmed the expression of anaerobic genes in response to soil flooding. Additionally, the differential expression of TFs associated with soil flooding tolerance was not qualitative but quantitative and temporal. Functional analyses of these genes will be necessary to reveal their potential to enhance flooding tolerance of soybean cultivars. Full article

(This article belongs to the Section Biochemistry)

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23 pages, 707 KiB

Open AccessReview

Circulating RNA Molecules as Biomarkers in Liver Disease

by Liviu S. Enache^1,2,3,*, Elena L. Enache², Christophe Ramière^1,4,5,6,7,8, Olivier Diaz^1,4,5,6,7, Ligia Bancu^2,3, Anca Sin^2,3 and Patrice André^1,4,5,6,7,8

¹ Université de Lyon, Université Lyon 1, Lyon F-69008, France

² University of Medicine and Pharmacy Tirgu Mures, 38 Gh. Marinescu st., Tirgu Mures 540142, Romania

³ Emergency County Clinical Hospital, 50 Gh. Marinescu st., Tirgu Mures 540136, Romania

⁴ Inserm U1111, 21 Avenue Tony Garnier, Lyon F-69007, France

⁵ CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, 21 Avenue Tony Garnier, 69365 Lyon Cedex 07, France

⁶ Ecole Normale Supérieure de Lyon, 15 parvis René Descartes, BP 7000 69342 Lyon Cedex 07, France

⁷ CNRS, UMR5308, 21 avenue Tony Garnier, 69365 Lyon Cedex 07, France

⁸ Hospices Civils de Lyon, Hôpital de la Croix Rousse, Laboratoire de Virologie, Lyon F-69004, France

Int. J. Mol. Sci. 2014, 15(10), 17644-17666; https://doi.org/10.3390/ijms151017644 - 30 Sep 2014

Cited by 47 | Viewed by 7671

Abstract

Liver disease is a major cause of morbidity and mortality worldwide. As in other fields of medicine, there is a stringent need for non-invasive markers to improve patient diagnostics, monitoring and prognostic ability in liver pathology. Cell-free circulating RNA molecules have been recently [...] Read more.

Liver disease is a major cause of morbidity and mortality worldwide. As in other fields of medicine, there is a stringent need for non-invasive markers to improve patient diagnostics, monitoring and prognostic ability in liver pathology. Cell-free circulating RNA molecules have been recently acknowledged as an important source of potential medical biomarkers. However, many aspects related to the biology of these molecules remain to be elucidated. In this review, we summarize current concepts related to the origin, transportation and possible functions of cell-free RNA. We outline current development of extracellular RNA-based biomarkers in the main forms of non-inherited liver disease: chronic viral hepatitis, hepatocellular carcinoma, non-alcoholic fatty liver, hepato-toxicity, and liver transplantation. Despite recent technological advances, the lack of standardization in the assessment of these markers makes their adoption into clinical practice difficult. We thus finally review the main factors influencing quantification of circulating RNA. These factors should be considered in the reporting and interpretation of current findings, as well as in the proper planning of future studies, to improve reliability and reproducibility of results. Full article

(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)

19 pages, 2774 KiB

Open AccessArticle

De Novo Assembly and Characterization of Pericarp Transcriptome and Identification of Candidate Genes Mediating Fruit Cracking in Litchi chinensis Sonn.

by Wei-Cai Li^1,†, Jian-Yang Wu^2,†, Hong-Na Zhang¹, Sheng-You Shi¹, Li-Qin Liu¹, Bo Shu¹, Qing-Zhi Liang¹, Jiang-Hui Xie¹

and Yong-Zan Wei^1,*

¹ Key Laboratory of Tropical Fruit Biology (Ministry of Agriculture), South Subtropical Crops Research Institute, Chinese Academy of Tropical Agricultural Sciences, Zhanjiang 524091, China

² Basic Education College of Zhanjiang Normal University, Zhanjiang 524037, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 17667-17685; https://doi.org/10.3390/ijms151017667 - 30 Sep 2014

Cited by 64 | Viewed by 7641

Abstract

Fruit cracking has long been a topic of great concern for growers and researchers of litchi (Litchi chinensis Sonn.). To understand the molecular mechanisms underlying fruit cracking, high-throughput RNA sequencing (RNA-Seq) was first used for de novo assembly and characterization [...] Read more.

Fruit cracking has long been a topic of great concern for growers and researchers of litchi (Litchi chinensis Sonn.). To understand the molecular mechanisms underlying fruit cracking, high-throughput RNA sequencing (RNA-Seq) was first used for de novo assembly and characterization of the transcriptome of cracking pericarp of litchi. Comparative transcriptomic analyses were performed on non-cracking and cracking fruits. A total of approximately 26 million and 29 million high quality reads were obtained from the two groups of samples, and were assembled into 46,641 unigenes with an average length of 993 bp. These unigenes can be useful resources for future molecular studies of the pericarp in litchi. Furthermore, four genes (LcAQP, 1; LcPIP, 1; LcNIP, 1; LcSIP, 1) involved in water transport, five genes (LcKS, 2; LcGA2ox, 2; LcGID1, 1) involved in GA metabolism, 21 genes (LcCYP707A, 2; LcGT, 9; Lcβ-Glu, 6; LcPP2C, 2; LcABI1, 1; LcABI5, 1) involved in ABA metabolism, 13 genes (LcTPC, 1; Ca²⁺/H⁺ exchanger, 3; Ca²⁺-ATPase, 4; LcCDPK, 2; LcCBL, 3) involved in Ca transport and 24 genes (LcPG, 5; LcEG, 1; LcPE, 3; LcEXP, 5; Lcβ-Gal, 9; LcXET, 1) involved in cell wall metabolism were identified as genes that are differentially expressed in cracked fruits compared to non-cracked fruits. Our results open new doors to further understand the molecular mechanisms behind fruit cracking in litchi and other fruits, especially Sapindaceae plants. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 3500 KiB

Open AccessArticle

EGF Potentiation of VEGF Production Is Cell Density Dependent in H292 EGFR Wild Type NSCLC Cell Line

by Daniel J. Ranayhossaini^1,2, Jin Lu¹, John Mabus³, Alexis Gervais¹, Russell B. Lingham¹ and Natalie Fursov^1,*

¹ Biologics Research, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA

² Department of Pharmacology & Chemical Biology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA

³ Cardiovascular & Metabolic Disease, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA

Int. J. Mol. Sci. 2014, 15(10), 17686-17704; https://doi.org/10.3390/ijms151017686 - 30 Sep 2014

Cited by 10 | Viewed by 7958

Abstract

Non-small cell lung cancer (NSCLC) affects millions of patients each year worldwide. Existing therapies include epidermal growth factor receptor (EGFR) inhibition using small molecules or antibodies with good efficacy. Unfortunately, intrinsic and acquired resistance to EGFR therapy remains a persistent complication for disease [...] Read more.

Non-small cell lung cancer (NSCLC) affects millions of patients each year worldwide. Existing therapies include epidermal growth factor receptor (EGFR) inhibition using small molecules or antibodies with good efficacy. Unfortunately, intrinsic and acquired resistance to EGFR therapy remains a persistent complication for disease treatment. A greater understanding of the role of EGFR in NSCLC etiology is crucial to improving patient outcomes. In this study, the role of EGFR in tumor angiogenesis was examined in H292 NSCLC cells under the pretense that confluent cells would exhibit a more angiogenic and growth-centered phenotype. Indeed, confluent H292 cells potentiated endothelial cell angiogenesis in co-culture models in an EGFR-dependent manner. While confluent H292 cells did not exhibit any change in EGFR protein expression, EGFR localization to the extracellular membrane was increased. EGFR membrane localization coincided with a comparable potentiation of maximal EGFR phosphorylation and was followed by a 3-fold increase in vascular endothelial growth factor A (VEGF-A) production as compared to subconfluent cells. EGFR-mediated VEGF-A production was determined to be dependent on signal transducer and activator of transcription 3 (STAT3) activation and not phosphoinositide 3-kinase (PI3K) signaling. These results identify unique cell density dependent phenotypes within a monoclonal NSCLC cell line and provide a potential mechanism of resistance to anti-EGFR therapy in metastatic NSCLC. Full article

(This article belongs to the Section Biochemistry)

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28 pages, 4397 KiB

Open AccessReview

Local Melatoninergic System as the Protector of Skin Integrity

by Andrzej T. Slominski^1,2,*, Konrad Kleszczyński³, Igor Semak⁴, Zorica Janjetovic¹, Michał A. Żmijewski⁵, Tae-Kang Kim¹, Radomir M. Slominski¹, Russel J. Reiter⁶ and Tobias W. Fischer³

¹ Department of Pathology and Laboratory Medicine, Cancer Research Building, University of Tennessee HSC, 930 Madison Avenue, Memphis, TN 38163, USA

² Department of Medicine, Division of Rheumatology, University of Tennessee HSC, 930 Madison Avenue, Memphis, TN 38163, USA

³ Department of Dermatology, Allergology and Venerology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

⁴ Department of Biochemistry, Belarusian State University, Minsk 220030, Belarus

⁵ Department of Histology, Medical University of Gdańsk, Gdańsk 80-211, Poland

⁶ Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX 78229, USA

Int. J. Mol. Sci. 2014, 15(10), 17705-17732; https://doi.org/10.3390/ijms151017705 - 30 Sep 2014

Cited by 128 | Viewed by 11546

Abstract

The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts [...] Read more.

The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts many effects on cell physiology and tissue homeostasis via membrane bound melatonin receptors, the strong protective effects of melatonin against the UVR-induced skin damage including DNA repair/protection seen at its high (pharmocological) concentrations indicate that these are mainly mediated through receptor-independent mechanisms or perhaps through activation of putative melatonin nuclear receptors. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. In summary, we propose that melatonin can be exploited therapeutically as a protective agent or as a survival factor with anti-genotoxic properties or as a “guardian” of the genome and cellular integrity with clinical applications in UVR-induced pathology that includes carcinogenesis and skin aging. Full article

(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

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18 pages, 2435 KiB

Open AccessArticle

TCDD Induces the Hypoxia-Inducible Factor (HIF)-1α Regulatory Pathway in Human Trophoblastic JAR Cells

by Tien-Ling Liao^1,2,†, Su-Chee Chen^3,†, Chii-Reuy Tzeng^4,5 and Shu-Huei Kao^2,4,*

¹ Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

² School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan

³ Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 110, Taiwan

⁴ Center for Reproductive Medicine & Sciences Taipei Medical University Hospital, Taipei 110, Taiwan

⁵ Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei 110, Taiwan

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2014, 15(10), 17733-17750; https://doi.org/10.3390/ijms151017733 - 30 Sep 2014

Cited by 20 | Viewed by 10594

Abstract

The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the [...] Read more.

The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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14 pages, 2598 KiB

Open AccessArticle

Recombinant Expression of a Novel Fungal Immunomodulatory Protein with Human Tumor Cell Antiproliferative Activity from Nectria haematococca

by Shuying Li¹, Ying Nie¹, Yang Ding¹, Lijun Shi² and Xuanming Tang^1,*

¹ Institute of Agro-products Processing Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Key Laboratory of Agro-products Processing, Ministry of Agriculture, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China

² Institute of Animal Science and Veterinary Medicine, CAAS, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China

Int. J. Mol. Sci. 2014, 15(10), 17751-17764; https://doi.org/10.3390/ijms151017751 - 30 Sep 2014

Cited by 23 | Viewed by 6076

Abstract

To our best knowledge, all of the fungal immunomodulatory proteins (FIPs) have been successfully extracted and identified in Basidomycetes, with only the exception of FIP from ascomycete Nectria haematococca (FIP-nha) discovered through homology alignment most recently. In this work, a gene encoding FIP-nha [...] Read more.

To our best knowledge, all of the fungal immunomodulatory proteins (FIPs) have been successfully extracted and identified in Basidomycetes, with only the exception of FIP from ascomycete Nectria haematococca (FIP-nha) discovered through homology alignment most recently. In this work, a gene encoding FIP-nha was synthesized and recombinantly expressed in an Escherichia coli expression system. SDS-PAGE and MALDI-MS analyses of recombinant FIP-nha (rFIP-nha) indicated that the gene was successfully expressed. The yield of the bioactive FIP-nha protein was 42.7 mg/L. In vitro assays of biological activity indicated that the rFIP-nha caused hemagglutination of human and rabbit red blood cells, signiﬁcantly stimulated mouse spleen lymphocyte proliferation, and enhanced expression of interleukin-2 (IL-2) released from mouse splenocytes, revealing a strong antitumor effect against HL60, HepG2 and MGC823. Through this work, we constructed a rapid and efficient method of FIP production, and suggested that FIP-nha is a valuable candidate for use in future medical care and pharmaceutical products. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 1194 KiB

Open AccessCommunication

Influence of Unmodified and β-Glycerophosphate Cross-Linked Chitosan on Anti-Candida Activity of Clotrimazole in Semi-Solid Delivery Systems

by Emilia Szymańska¹, Katarzyna Winnicka^1,*

, Piotr Wieczorek², Paweł Tomasz Sacha² and Elżbieta Anna Tryniszewska²

¹ Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland

² Department of Microbiological Diagnostics and Infectious Immunology, Faculty of Pharmacy, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland

Int. J. Mol. Sci. 2014, 15(10), 17765-17777; https://doi.org/10.3390/ijms151017765 - 30 Sep 2014

Cited by 20 | Viewed by 7892

Abstract

The combination of an antifungal agent and drug carrier with adjunctive antimicrobial properties represents novel strategy of complex therapy in pharmaceutical technology. The goal of this study was to investigate the unmodified and ion cross-linked chitosan’s influence on anti-Candida activity of clotrimazole [...] Read more.

The combination of an antifungal agent and drug carrier with adjunctive antimicrobial properties represents novel strategy of complex therapy in pharmaceutical technology. The goal of this study was to investigate the unmodified and ion cross-linked chitosan’s influence on anti-Candida activity of clotrimazole used as a model drug in hydrogels. It was particularly crucial to explore whether the chitosans’ structure modification by β-glycerophosphate altered its antifungal properties. Antifungal studies (performed by plate diffusion method according to CLSI reference protocol) revealed that hydrogels obtained with chitosan/β-glycerophosphate displayed lower anti-Candida effect, probably as a result of weakened polycationic properties of chitosan in the presence of ion cross-linker. Designed chitosan hydrogels with clotrimazole were found to be more efficient against tested Candida strains and showed more favorable drug release profile compared to commercially available product. These observations indicate that novel chitosan formulations may be considered as promising semi-solid delivery system of clotrimazole. Full article

(This article belongs to the Special Issue Antimicrobial Polymers)

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12 pages, 634 KiB

Open AccessArticle

The Beneficial Effects of Combined Grape Pomace and Omija Fruit Extracts on Hyperglycemia, Adiposity and Hepatic Steatosis in db/db Mice: A Comparison with Major Index Compounds

by Su-Jung Cho^1,2, Hae-Jin Park^1,2, Un Ju Jung², Hye-Jin Kim³, Byoung Seok Moon³ and Myung-Sook Choi^1,2,*

¹ Department of Food Science and Nutrition, Kyungpook National University, 1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea

² Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea

³ Food Research & Development, CJ Cheiljedang Corporation, Seoul 152-051, Korea

Int. J. Mol. Sci. 2014, 15(10), 17778-17789; https://doi.org/10.3390/ijms151017778 - 30 Sep 2014

Cited by 18 | Viewed by 7051

Abstract

This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is [...] Read more.

This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is a mixture of major components of GO. Mice were fed a normal diet with RS (0.005% resveratrol and 0.02% schizandrin in diet, w/w) or GO (0.3% grape pomace ethanol extract and 0.05% omija fruit ethanol extract in diet, w/w) for seven weeks. RS and GO not only lowered the levels of blood and plasma glucose, HbA_1c, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) with a simultaneous decrease in hepatic gluconeogenic enzymes activities and adiposity, but also improved preservation of the pancreatic β-cells. Plasma leptin and resistin levels were lower while the plasma adiponectin level was higher in the RS and GO groups than in the control group. Especially, GO increased hepatic glucokinase activity and gene expression and improved hepatic steatosis by elevating fatty acid oxidation compared to RS. These findings suggest that GO ameliorates hyperglycemia, adiposity and hepatic steatosis in type 2 diabetic mice. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 377 KiB

Open AccessArticle

Eruca sativa Might Influence the Growth, Survival under Simulated Gastrointestinal Conditions and Some Biological Features of Lactobacillus acidophilus, Lactobacillus plantarum and Lactobacillus rhamnosus Strains

by Florinda Fratianni

, Selenia Pepe, Federica Cardinale, Tiziana Granese, Autilia Cozzolino, Raffaele Coppola and Filomena Nazzaro^*

Institute of Food Science, ISA-CNR, Via Roma, 64, 83100 Avellino, Italy

Int. J. Mol. Sci. 2014, 15(10), 17790-17805; https://doi.org/10.3390/ijms151017790 - 1 Oct 2014

Cited by 9 | Viewed by 5783

Abstract

The growth and viability of three Lactobacillus strains, Lactobacillus acidophilus, Lactobacillus plantarum and Lactobacillus rhamnosus, after their passage through simulated gastric and pancreatic juices were studied as a function of their presence in the growth medium of rocket salad (Eruca [...] Read more.

The growth and viability of three Lactobacillus strains, Lactobacillus acidophilus, Lactobacillus plantarum and Lactobacillus rhamnosus, after their passage through simulated gastric and pancreatic juices were studied as a function of their presence in the growth medium of rocket salad (Eruca sativa). The presence of E. sativa affected some of the biological properties of the strains. For example, L. acidophilus and L. plantarum worked more efficiently in the presence of E. sativa, increasing not only the antioxidant activity of the medium, but also their own antioxidant power and antimicrobial activity; L. rhamnosus was not affected in the same manner. Overall, the presence of vegetables might help to boost, in specific cases, some of the characteristics of lactobacilli, including antioxidant and antimicrobial power. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 1901 KiB

Open AccessArticle

Atrazine Affects Phosphoprotein and Protein Expression in MCF-10A Human Breast Epithelial Cells

by Peixin Huang¹, John Yang^1,* and Qisheng Song^2,*

¹ Department of Agriculture & Environmental Science, Lincoln University of Missouri, Jefferson City, MO 65120, USA

² Division of Plant Sciences, University of Missouri, Columbia, MO 65211, USA

Int. J. Mol. Sci. 2014, 15(10), 17806-17826; https://doi.org/10.3390/ijms151017806 - 1 Oct 2014

Cited by 17 | Viewed by 7473

Abstract

Atrazine, a member of the 2-chloro-s-triazine family of herbicides, is the most widely used pesticide in the world and often detected in agriculture watersheds. Although it was generally considered as an endocrine disruptor, posing a potential threat to human health, the molecular mechanisms [...] Read more.

Atrazine, a member of the 2-chloro-s-triazine family of herbicides, is the most widely used pesticide in the world and often detected in agriculture watersheds. Although it was generally considered as an endocrine disruptor, posing a potential threat to human health, the molecular mechanisms of atrazine effects remain unclear. Using two-dimensional gel electrophoresis, we identified a panel of differentially expressed phosphoproteins and total proteins in human breast epithelial MCF-10A cells after being exposed to environmentally relevant concentrations of atrazine. Atrazine treatments for 6 h resulted in differential expression of 4 phosphoproteins and 8 total-proteins as compared to the control cells (>1.5-fold, p < 0.05). MALDI-TOF MS/MS analysis revealed that the differentially expressed proteins belong to various cellular compartments (nucleus, cytosol, membrane) and varied in function, including those regulating the stress response such as peroxiredoxin I, HSP70 and HSP27; structural proteins such as tropomyosin and profilin 1; and oncogenesis proteins such as ANP32A. Six of the 12 identified proteins were verified by quantitative PCR for their transcript levels. The most up-regulated phosphoprotein by atrazine treatment, ANP32A, was further analyzed for its expression, distribution and cellular localization using Western blot and immunocytochemical approaches. The results revealed that ANP32 expression after atrazine treatment increased dose and time dependently and was primarily located in the nucleus. This study may provide new evidence on the potential toxicity of atrazine in human cells. Full article

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

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11 pages, 388 KiB

Open AccessArticle

Insulin Induces an Increase in Cytosolic Glucose Levels in 3T3-L1 Cells with Inhibited Glycogen Synthase Activation

by Helena H. Chowdhury^1,2, Marko Kreft^1,2,3, Jørgen Jensen⁴ and Robert Zorec^1,2,*

¹ Celica, Biomedical, Tehnološki park 24, 1000 Ljubljana, Slovenia

² Laboratory for Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia

³ Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna pot 111, 1000 Ljubljana, Slovenia

⁴ Department of Physical Performance, Norwegian School of Sports Sciences, P.O. Box N-4014 Ullevål Stadion, 0806 Oslo, Norway

Int. J. Mol. Sci. 2014, 15(10), 17827-17837; https://doi.org/10.3390/ijms151017827 - 2 Oct 2014

Cited by 5 | Viewed by 8227

Abstract

Glucose is an important source of energy for mammalian cells and enters the cytosol via glucose transporters. It has been thought for a long time that glucose entering the cytosol is swiftly phosphorylated in most cell types; hence the levels of free glucose [...] Read more.

Glucose is an important source of energy for mammalian cells and enters the cytosol via glucose transporters. It has been thought for a long time that glucose entering the cytosol is swiftly phosphorylated in most cell types; hence the levels of free glucose are very low, beyond the detection level. However, the introduction of new fluorescence resonance energy transfer-based glucose nanosensors has made it possible to measure intracellular glucose more accurately. Here, we used the fluorescent indicator protein (FLIPglu-600µ) to monitor cytosolic glucose dynamics in mouse 3T3-L1 cells in which glucose utilization for glycogen synthesis was inhibited. The results show that cells exhibit a low resting cytosolic glucose concentration. However, in cells with inhibited glycogen synthase activation, insulin induced a robust increase in cytosolic free glucose. The insulin-induced increase in cytosolic glucose in these cells is due to an imbalance between the glucose transported into the cytosol and the use of glucose in the cytosol. In untreated cells with sensitive glycogen synthase activation, insulin stimulation did not result in a change in the cytosolic glucose level. This is the first report of dynamic measurements of cytosolic glucose levels in cells devoid of the glycogen synthesis pathway. Full article

(This article belongs to the Special Issue Förster Resonance Energy Transfer (FRET) 2015)

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14 pages, 1494 KiB

Open AccessArticle

Electric and Magnetic Field-Assisted Orientational Transitions in the Ensembles of Domains in a Nematic Liquid Crystal on the Polymer Surface

by Alexander M. Parshin^1,2,*, Vladimir A. Gunyakov¹, Victor Y. Zyryanov¹ and Vasily F. Shabanov¹

¹ L. V. Kirensky Institute of Physics, Krasnoyarsk Scientific Centre, Siberian Branch of the Russian Academy of Sciences, Krasnoyarsk 660036, Russia

² Department of Energy, Siberian Federal University, Krasnoyarsk 660041, Russia

Int. J. Mol. Sci. 2014, 15(10), 17838-17851; https://doi.org/10.3390/ijms151017838 - 2 Oct 2014

Cited by 21 | Viewed by 5933

Abstract

Using electro- and magneto-optical techniques, we investigated orientational transitions in the ensembles of domains in a nematic liquid crystal on the polycarbonate film surface under the conditions of competing surface forces that favor radial and uniform planar alignment of nematic molecules. Having analyzed [...] Read more.

Using electro- and magneto-optical techniques, we investigated orientational transitions in the ensembles of domains in a nematic liquid crystal on the polycarbonate film surface under the conditions of competing surface forces that favor radial and uniform planar alignment of nematic molecules. Having analyzed field dependences of the intensity of light passed through a sample, we established the threshold character of the orientational effects, plotted the calculated intensity versus magnetic coherence length, and compared the latter with the equilibrium length that characterizes the balance of forces on the polymer surface. Full article

(This article belongs to the Section Materials Science)

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34 pages, 11229 KiB

Open AccessReview

Intersection of AHR and Wnt Signaling in Development, Health, and Disease

by Andrew J. Schneider, Amanda M. Branam and Richard E. Peterson^*

School of Pharmacy and Molecular and Environmental Toxicology Center University of Wisconsin, Madison, WI 53705, USA

Int. J. Mol. Sci. 2014, 15(10), 17852-17885; https://doi.org/10.3390/ijms151017852 - 3 Oct 2014

Cited by 90 | Viewed by 10949

Abstract

The AHR (aryl hydrocarbon receptor) and Wnt (wingless-related MMTV integration site) signaling pathways have been conserved throughout evolution. Appropriately regulated signaling through each pathway is necessary for normal development and health, while dysregulation can lead to developmental defects and disease. Though both pathways [...] Read more.

The AHR (aryl hydrocarbon receptor) and Wnt (wingless-related MMTV integration site) signaling pathways have been conserved throughout evolution. Appropriately regulated signaling through each pathway is necessary for normal development and health, while dysregulation can lead to developmental defects and disease. Though both pathways have been vigorously studied, there is relatively little research exploring the possibility of crosstalk between these pathways. In this review, we provide a brief background on (1) the roles of both AHR and Wnt signaling in development and disease, and (2) the molecular mechanisms that characterize activation of each pathway. We also discuss the need for careful and complete experimental evaluation of each pathway and describe existing research that explores the intersection of AHR and Wnt signaling. Lastly, to illustrate in detail the intersection of AHR and Wnt signaling, we summarize our recent findings which show that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced disruption of Wnt signaling impairs fetal prostate development. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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15 pages, 1243 KiB

Open AccessArticle

Down-Regulation by Resveratrol of Basic Fibroblast Growth Factor-Stimulated Osteoprotegerin Synthesis through Suppression of Akt in Osteoblasts

by Gen Kuroyanagi^1,2, Takanobu Otsuka¹, Naohiro Yamamoto^1,2, Rie Matsushima-Nishiwaki², Akira Nakakami², Jun Mizutani¹, Osamu Kozawa² and Haruhiko Tokuda^2,3,*

¹ Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan

² Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan

³ Department of Clinical Laboratory, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan

Int. J. Mol. Sci. 2014, 15(10), 17886-17900; https://doi.org/10.3390/ijms151017886 - 6 Oct 2014

Cited by 16 | Viewed by 6518

Abstract

It is firmly established that resveratrol, a natural food compound abundantly found in grape skins and red wine, has beneficial properties for human health. In the present study, we investigated the effect of basic fibroblast growth factor (FGF-2) on osteoprotegerin (OPG) synthesis in [...] Read more.

It is firmly established that resveratrol, a natural food compound abundantly found in grape skins and red wine, has beneficial properties for human health. In the present study, we investigated the effect of basic fibroblast growth factor (FGF-2) on osteoprotegerin (OPG) synthesis in osteoblast-like MC3T3-E1 cells and whether resveratrol affects the OPG synthesis. FGF-2 stimulated both the OPG release and the expression of OPG mRNA. Resveratrol significantly suppressed the FGF-2-stimulated OPG release and the mRNA levels of OPG. SRT1720, an activator of SIRT1, reduced the FGF-2-induced OPG release and the OPG mRNA expression. PD98059, an inhibitor of upstream kinase activating p44/p42 mitogen-activated protein (MAP) kinase, had little effect on the FGF-2-stimulated OPG release. On the other hand, SB203580, an inhibitor of p38 MAP kinase, SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and Akt inhibitor suppressed the OPG release induced by FGF-2. Resveratrol failed to affect the FGF-2-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase or SAPK/JNK. The phosphorylation of Akt induced by FGF-2 was significantly suppressed by resveratrol or SRT1720. These findings strongly suggest that resveratrol down-regulates FGF-2-stimulated OPG synthesis through the suppression of the Akt pathway in osteoblasts and that the inhibitory effect of resveratrol is mediated at least in part by SIRT1 activation. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 3174 KiB

Open AccessReview

Platelets: Still a Therapeutical Target for Haemostatic Disorders

by Reinaldo Barros Geraldo¹, Plínio Cunha Sathler^2,3, André Luiz Lourenço², Max Seidy Saito², Lucio M. Cabral³, Pabulo Henrique Rampelotto^4,*

and Helena Carla Castro^1,2,*

¹ Programa de Pós-graduação em Ciências e Biotecnologia, Instituto de Biologia, Universidade Federal Fluminense (UFF), Niterói CEP 24210-130, RJ, Brazil

² Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24030-215, RJ, Brazil

³ LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-590, RJ, Brazil

⁴ Interdisciplinary Center for Biotechnology Research, Federal University of Pampa, Antônio Trilha Avenue, P.O. Box 1847, São Gabriel/RS 97300-000, Brazil

Int. J. Mol. Sci. 2014, 15(10), 17901-17919; https://doi.org/10.3390/ijms151017901 - 7 Oct 2014

Cited by 11 | Viewed by 10064

Abstract

Platelets are cytoplasmatic fragments from bone marrow megakaryocytes present in blood. In this work, we review the basis of platelet mechanisms, their participation in syndromes and in arterial thrombosis, and their potential as a target for designing new antithrombotic agents. The option of [...] Read more.

Platelets are cytoplasmatic fragments from bone marrow megakaryocytes present in blood. In this work, we review the basis of platelet mechanisms, their participation in syndromes and in arterial thrombosis, and their potential as a target for designing new antithrombotic agents. The option of new biotechnological sources is also explored. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 700 KiB

Open AccessReview

Peripheral and Central Effects of Melatonin on Blood Pressure Regulation

by Olga Pechanova^1,2,*, Ludovit Paulis^1,3 and Fedor Simko^3,4,5

¹ Institute of Normal and Pathological Physiology and Centre of Excellence for Nitric Oxide Research, Slovak Academy of Sciences, Bratislava 81371, Slovak Republic

² Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava 81371, Slovak Republic

³ Department of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava 81371, Slovak Republic

⁴ The Third Clinic of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava 81371, Slovak Republic

⁵ Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava 81371, Slovak Republic

Int. J. Mol. Sci. 2014, 15(10), 17920-17937; https://doi.org/10.3390/ijms151017920 - 8 Oct 2014

Cited by 117 | Viewed by 10861

Abstract

The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. [...] Read more.

The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter-regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology. Full article

(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

25 pages, 3283 KiB

Open AccessReview

Development of 3D in Vitro Technology for Medical Applications

by Keng-Liang Ou^1,2,3,4,5

and Hossein Hosseinkhani^{1,2,3,4,5,6,*}

¹ Nanomedicine Research Center of Taiwan, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan

² Research Center for Biomedical Devices and Prototyping Production, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan

³ Research Center for Biomedical Implants and Microsurgery Devices, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan

⁴ Graduate Institute of Biomedical Materials and Engineering, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan

⁵ Department of Dentistry, Taipei Medical University-Shuang-Ho Hospital, Taipei 110, Taiwan

⁶ Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 10607, Taiwan

Int. J. Mol. Sci. 2014, 15(10), 17938-17962; https://doi.org/10.3390/ijms151017938 - 8 Oct 2014

Cited by 88 | Viewed by 10872

Abstract

In the past few years, biomaterials technologies together with significant efforts on developing biology have revolutionized the process of engineered materials. Three dimensional (3D) in vitro technology aims to develop set of tools that are simple, inexpensive, portable and robust that could be [...] Read more.

In the past few years, biomaterials technologies together with significant efforts on developing biology have revolutionized the process of engineered materials. Three dimensional (3D) in vitro technology aims to develop set of tools that are simple, inexpensive, portable and robust that could be commercialized and used in various fields of biomedical sciences such as drug discovery, diagnostic tools, and therapeutic approaches in regenerative medicine. The proliferation of cells in the 3D scaffold needs an oxygen and nutrition supply. 3D scaffold materials should provide such an environment for cells living in close proximity. 3D scaffolds that are able to regenerate or restore tissue and/or organs have begun to revolutionize medicine and biomedical science. Scaffolds have been used to support and promote the regeneration of tissues. Different processing techniques have been developed to design and fabricate three dimensional scaffolds for tissue engineering implants. Throughout the chapters we discuss in this review, we inform the reader about the potential applications of different 3D in vitro systems that can be applied for fabricating a wider range of novel biomaterials for use in tissue engineering. Full article

(This article belongs to the Special Issue Artificial Organs)

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11 pages, 1453 KiB

Open AccessArticle

FT-IR Microspectrometry Reveals the Variation of Membrane Polarizability due to Epigenomic Effect on Epithelial Ovarian Cancer

by Morris M. H. Hsu¹, Pei-Yu Huang², Yao-Chang Lee²

, Yuang-Chuen Fang¹, Michael W. Y. Chan¹

and Cheng-I Lee^1,*

¹ Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi 62102, Taiwan

² National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan

Int. J. Mol. Sci. 2014, 15(10), 17963-17973; https://doi.org/10.3390/ijms151017963 - 8 Oct 2014

Cited by 12 | Viewed by 6088

Abstract

Ovarian cancer, as well as other cancers, is primarily caused by methylation at cytosines in CpG islands, but the current marker for ovarian cancer is low in sensitivity and failed in early-stage detection. Fourier transform infrared (FT-IR) spectroscopy is powerful in analysis of [...] Read more.

Ovarian cancer, as well as other cancers, is primarily caused by methylation at cytosines in CpG islands, but the current marker for ovarian cancer is low in sensitivity and failed in early-stage detection. Fourier transform infrared (FT-IR) spectroscopy is powerful in analysis of functional groups within molecules, and infrared microscopy illustrates the location of specific groups within single cells. In this study, we applied HPLC and FT-IR microspectrometry to study normal epithelial ovarian cell line immortalized ovarian surface epithelium (IOSE), two epithelial ovarian cell lines (A2780 and CP70) with distinct properties, and the effect of a cancer drug 5-aza-2'-deoxycytidine (5-aza) without labeling. Our results reveal that inhibition of methylation on cytosine with 5-aza initiates the protein expression. Furthermore, paraffin-adsorption kinetic study allows us to distinguish hypermethylated and hypomethyated cells, and this assay can be a potential diagnosis method for cancer screening. Full article

(This article belongs to the Special Issue Bioactive Lipids and Lipidomics)

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26 pages, 2086 KiB

Open AccessArticle

Curcumin-Induced Heme Oxygenase-1 Expression Prevents H₂O₂-Induced Cell Death in Wild Type and Heme Oxygenase-2 Knockout Adipose-Derived Mesenchymal Stem Cells

by Niels A. J. Cremers¹, Ditte M. S. Lundvig¹, Stephanie C. M. Van Dalen², Rik F. Schelbergen², Peter L. E. M. Van Lent², Walter A. Szarek³, Raymond F. Regan⁴, Carine E. Carels¹

and Frank A. D. T. G. Wagener^1,*

¹ Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands

² Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands

³ Department of Chemistry, Queen's University, Kingston, ON K7L 3N6, Canada

⁴ Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA

Int. J. Mol. Sci. 2014, 15(10), 17974-17999; https://doi.org/10.3390/ijms151017974 - 8 Oct 2014

Cited by 42 | Viewed by 9859

Abstract

Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and [...] Read more.

Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H₂O₂. Surprisingly, sensitivity to H₂O₂-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H₂O₂ exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H₂O₂-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H₂O₂-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy. Full article

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

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23 pages, 4705 KiB

Open AccessArticle

FOXO1 Content Is Reduced in Cystic Fibrosis and Increases with IGF-I Treatment

by Arianna Smerieri¹, Luisa Montanini¹, Luigi Maiuri^2,3, Sergio Bernasconi¹ and Maria E. Street^1,*

¹ Department of Pediatrics, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy

² European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy

³ Institute of Pediatrics, University of Foggia, Via Pinto, 71100 Foggia, Italy

Int. J. Mol. Sci. 2014, 15(10), 18000-18022; https://doi.org/10.3390/ijms151018000 - 8 Oct 2014

Cited by 20 | Viewed by 7996

Abstract

Cystic fibrosis-related diabetes is to date the most frequent complication in cystic fibrosis (CF). The mechanisms underlying this condition are not well understood, and a possible role of insulin resistance is debated. We investigated insulin signal transduction in CF. Total insulin receptor, IRS1, [...] Read more.

Cystic fibrosis-related diabetes is to date the most frequent complication in cystic fibrosis (CF). The mechanisms underlying this condition are not well understood, and a possible role of insulin resistance is debated. We investigated insulin signal transduction in CF. Total insulin receptor, IRS1, p85 PI3K, and AKT contents were substantially normal in CF cells (CFBE41o-), whereas winged helix forkhead (FOX)O1 contents were reduced both in baseline conditions and after insulin stimulation. In addition, CF cells showed increased ERK1/2, and reduced β2 arrestin contents. No significant change in SOCS2 was observed. By using a CFTR inhibitor and siRNA, changes in FOXO1 were related to CFTR loss of function. In a CF-affected mouse model, FOXO1 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild-type. Insulin-like growth factor 1 (IGF-I) increased FOXO1 content in vitro and in vivo in muscle and adipose tissue. In conclusion; we present the first description of reduced FOXO1 content in CF, which is compatible with reduced gluconeogenesis and increased adipogenesis, both features of insulin insensitivity. IGF-I treatment was effective in increasing FOXO1, thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis-related diabetes. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)

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17 pages, 573 KiB

Open AccessArticle

Optimization of a DNA Nicking Assay to Evaluate Oenocarpus bataua and Camellia sinensis Antioxidant Capacity

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

Université des Antilles et de la Guyane, UMR QUALITROP, campus universitaire de Troubiran, P.O. Box 792, 97337 Cayenne Cedex, French Guiana, France

Int. J. Mol. Sci. 2014, 15(10), 18023-18039; https://doi.org/10.3390/ijms151018023 - 9 Oct 2014

Cited by 37 | Viewed by 7918

Abstract

This study was aimed at assessing the DNA damage protective activity of different types of extracts (aqueous, methanolic and acetonic) using an in vitro DNA nicking assay. Several parameters were optimized using the pUC18 plasmid, especially FeSO₄, EDTA, solvent concentrations and [...] Read more.

This study was aimed at assessing the DNA damage protective activity of different types of extracts (aqueous, methanolic and acetonic) using an in vitro DNA nicking assay. Several parameters were optimized using the pUC18 plasmid, especially FeSO₄, EDTA, solvent concentrations and incubation time. Special attention has been paid to removing the protective and damaging effect of the solvent and FeSO₄ respectively, as well as to identifying the relevant positive and negative controls. For each solvent, the optimal conditions were determined: (i) for aqueous extracts, 0.33 mM of FeSO₄ and 0.62 mM of EDTA were incubated for 20 min at 37 °C; (ii) for acetone extracts, 1.16% solvent were incubated for 15 min at 37 °C with 1.3 mM of FeSO₄ and 2.5 mM of EDTA and (iii) for methanol extracts, 0.16% solvent, were incubated for 1.5 h at 37 °C with 0.33 mM of FeSO₄ and 0.62 mM of EDTA. Using the optimized conditions, the DNA damage protective activity of aqueous, methanolic and acetonic extracts of an Amazonian palm berry (Oenocarpus bataua) and green tea (Camellia sinensis) was assessed. Aqueous and acetonic Oenocarpus bataua extracts were protective against DNA damage, whereas aqueous, methanolic and acetonic extracts of Camellia sinensis extracts induced DNA damage. Full article

(This article belongs to the Section Biochemistry)

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44 pages, 4607 KiB

Open AccessReview

Novel Formulations for Antimicrobial Peptides

by Ana Maria Carmona-Ribeiro^*

and Letícia Dias De Melo Carrasco

Biocolloids Laboratory, Instituto de Química, Universidade de São Paulo, Av. Lineu Prestes 748, 05508-000 São Paulo, SP, Brazil

Int. J. Mol. Sci. 2014, 15(10), 18040-18083; https://doi.org/10.3390/ijms151018040 - 9 Oct 2014

Cited by 115 | Viewed by 17584

Abstract

Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. [...] Read more.

Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy. Full article

(This article belongs to the Special Issue Antimicrobial Polymers)

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18 pages, 613 KiB

Open AccessReview

The Roles of Monomeric GTP-Binding Proteins in Macroautophagy in Saccharomyces cerevisiae

by Shu Yang and Anne G. Rosenwald^*

Department of Biology, Georgetown University, Washington, DC 20057, USA

Int. J. Mol. Sci. 2014, 15(10), 18084-18101; https://doi.org/10.3390/ijms151018084 - 9 Oct 2014

Cited by 7 | Viewed by 10421

Abstract

Autophagy is a cellular degradation process that sequesters components into a double-membrane structure called the autophagosome, which then fuses with the lysosome or vacuole for hydrolysis and recycling of building blocks. Bulk phase autophagy, also known as macroautophagy, controlled by specific Atg proteins, [...] Read more.

Autophagy is a cellular degradation process that sequesters components into a double-membrane structure called the autophagosome, which then fuses with the lysosome or vacuole for hydrolysis and recycling of building blocks. Bulk phase autophagy, also known as macroautophagy, controlled by specific Atg proteins, can be triggered by a variety of stresses, including starvation. Because autophagy relies extensively on membrane traffic to form the membranous structures, factors that control membrane traffic are essential for autophagy. Among these factors, the monomeric GTP-binding proteins that cycle between active and inactive conformations form an important group. In this review, we summarize the functions of the monomeric GTP-binding proteins in autophagy, especially with reference to experiments in Saccharomyces cerevisiae. Full article

(This article belongs to the Special Issue Regulation of Membrane Trafficking and Its Potential Implications 2014)

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15 pages, 1130 KiB

Open AccessArticle

Orthologs of Human Disease Associated Genes and RNAi Analysis of Silencing Insulin Receptor Gene in Bombyx mori

by Zan Zhang¹, Xiaolu Teng¹, Maohua Chen² and Fei Li^1,*

¹ Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China

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

Int. J. Mol. Sci. 2014, 15(10), 18102-18116; https://doi.org/10.3390/ijms151018102 - 9 Oct 2014

Cited by 15 | Viewed by 6236

Abstract

The silkworm, Bombyx mori L., is an important economic insect that has been domesticated for thousands of years to produce silk. It is our great interest to investigate the possibility of developing the B. mori as human disease model. We searched the orthologs [...] Read more.

The silkworm, Bombyx mori L., is an important economic insect that has been domesticated for thousands of years to produce silk. It is our great interest to investigate the possibility of developing the B. mori as human disease model. We searched the orthologs of human disease associated genes in the B. mori by bi-directional best hits of BLAST and confirmed by searching the OrthoDB. In total, 5006 genes corresponding to 1612 kinds of human diseases had orthologs in the B. mori, among which, there are 25 genes associated with diabetes mellitus. Of these, we selected the insulin receptor gene of the B. mori (Bm-INSR) to study its expression in different tissues and at different developmental stages and tissues. Quantitative PCR showed that Bm-INSR was highly expressed in the Malpighian tubules but expressed at low levels in the testis. It was highly expressed in the 3rd and 4th instar larvae, and adult. We knocked down Bm-INSR expression using RNA interference. The abundance of Bm-INSR transcripts were dramatically reduced to ~4% of the control level at 6 days after dsRNA injection and the RNAi-treated B. mori individuals showed apparent growth inhibition and malformation such as abnormal body color in black, which is the typical symptom of diabetic patients. Our results demonstrate that B. mori has potential use as an animal model for diabetic mellitus research. Full article

(This article belongs to the Section Biochemistry)

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0 pages, 2898 KiB

Open AccessArticle

RETRACTED: Tanshinone IIA Pretreatment Renders Free Flaps against Hypoxic Injury through Activating Wnt Signaling and Upregulating Stem Cell-Related Biomarkers

by Zihan Xu^1,*, Zhenxin Zhang^1,*, Lijun Wu^2,*, Yaowen Sun¹, Yadong Guo¹, Gaoping Qin¹, Shengzhi Mu¹, Ronghui Fan¹, Benfeng Wang¹ and Wenjie Gao¹

¹ Department of Burns and Plastic Surgery, Shaanxi Provincial People's Hospital, Xi'an 710068, China

² Department of Plastic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China

Int. J. Mol. Sci. 2014, 15(10), 18117-18130; https://doi.org/10.3390/ijms151018117 - 9 Oct 2014

Cited by 5 | Viewed by 6176 | Retraction

Abstract

Partial or total flap necrosis after flap transplantation is sometimes clinically encountered in reconstructive surgery, often as a result of a period of hypoxia that exceeds the tolerance of the flap tissue. In this study, we determine whether tanshinone IIA (TSA) pretreatment can [...] Read more.

Partial or total flap necrosis after flap transplantation is sometimes clinically encountered in reconstructive surgery, often as a result of a period of hypoxia that exceeds the tolerance of the flap tissue. In this study, we determine whether tanshinone IIA (TSA) pretreatment can protect flap tissue against hypoxic injury and improve its viability. Primary epithelial cells isolated from the dorsal skin of mice were pretreated with TSA for two weeks. Cell counting kit-8 and Trypan Blue assays were carried out to examine the proliferation of TSA-pretreated cells after exposure to cobalt chloride. Then, Polymerase chain reaction and Western blot analysis were used to determine the expression of β-catenin, GSK-3β, SOX2, and OCT4 in TSA-treated cells. In vivo, after mice were pretreated with TSA for two weeks, a reproducible ischemic flap model was implemented, and the area of surviving tissue in the transplanted flaps was measured. Immunohistochemistry was also conducted to examine the related biomarkers mentioned above. Results show that epidermal cells, pretreated with TSA, showed enhanced resistance to hypoxia. Activation of the Wnt signaling pathway in TSA-pretreated cells was characterized by the upregulation of β-catenin and the downregulation of GSK-3β. The expression of SOX2 and OCT4 controlled by Wnt signaling were also found higher in TSA pretreated epithelial cells. In the reproducible ischaemic flap model, pretreatment with TSA enhanced resistance to hypoxia and increased the area of surviving tissue in transplanted flaps. The expression of Wnt signaling pathway components, stem-cell related biomarkers, and CD34, which are involved in the regeneration of blood vessels, was also upregulated in TSA-pretreated flap tissue. The results show that TSA pretreatment protects free flaps against hypoxic injury and increases the area of surviving tissue by activating Wnt signaling and upregulating stem cell-related biomarkers. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 881 KiB

Open AccessArticle

Thermoase-Derived Flaxseed Protein Hydrolysates and Membrane Ultrafiltration Peptide Fractions Have Systolic Blood Pressure-Lowering Effects in Spontaneously Hypertensive Rats

by Ifeanyi D. Nwachukwu¹, Abraham T. Girgih², Sunday A. Malomo¹, John O. Onuh¹ and Rotimi E. Aluko^1,2,*

¹ Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada

² Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg, MB R3T 2N2, Canada

Int. J. Mol. Sci. 2014, 15(10), 18131-18147; https://doi.org/10.3390/ijms151018131 - 9 Oct 2014

Cited by 44 | Viewed by 6462

Abstract

Thermoase-digested flaxseed protein hydrolysate (FPH) samples and ultrafiltration membrane-separated peptide fractions were initially evaluated for in vitro inhibition of angiotensin I-converting enzyme (ACE) and renin activities. The two most active FPH samples and their corresponding peptide fractions were subsequently tested for in vivo [...] Read more.

Thermoase-digested flaxseed protein hydrolysate (FPH) samples and ultrafiltration membrane-separated peptide fractions were initially evaluated for in vitro inhibition of angiotensin I-converting enzyme (ACE) and renin activities. The two most active FPH samples and their corresponding peptide fractions were subsequently tested for in vivo antihypertensive activity in spontaneously hypertensive rats (SHR). The FPH produced with 3% thermoase digestion showed the highest ACE- and renin-inhibitory activities. Whereas membrane ultrafiltration resulted in significant (p < 0.05) increases in ACE inhibition by the <1 and 1–3 kDa peptides, only a marginal improvement in renin-inhibitory activity was observed for virtually all the samples after membrane ultrafiltration. The FPH samples and membrane fractions were also effective in lowering systolic blood pressure (SBP) in SHR with the largest effect occurring after oral administration (200 mg/kg body weight) of the 1–3 kDa peptide fraction of the 2.5% FPH and the 3–5 kDa fraction of the 3% FPH. Such potent SBP-lowering capacity indicates the potential of flaxseed protein-derived bioactive peptides as ingredients for the formulation of antihypertensive functional foods and nutraceuticals. Full article

(This article belongs to the Special Issue Bioactive Proteins and Peptides Derived from Food)

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14 pages, 2022 KiB

Open AccessArticle

TPX2 Is a Prognostic Marker and Contributes to Growth and Metastasis of Human Hepatocellular Carcinoma

by Yuqi Huang¹, Wenbin Guo² and Heping Kan^1,*

¹ Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

² Department of Urology, the Third Affiliated Hospital, Southern Medical University, Guangzhou 510000, China

Int. J. Mol. Sci. 2014, 15(10), 18148-18161; https://doi.org/10.3390/ijms151018148 - 9 Oct 2014

Cited by 49 | Viewed by 7631

Abstract

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, impacts spindle assembly in human cells. Several studies have demonstrated that TPX2 is overexpressed in different types of human cancers and promotes tumor growth and metastasis. In this study, we found that [...] Read more.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, impacts spindle assembly in human cells. Several studies have demonstrated that TPX2 is overexpressed in different types of human cancers and promotes tumor growth and metastasis. In this study, we found that the expression level of TPX2 was obviously higher in hepatocellular carcinoma (HCC) tissues than in matched nontumor tissues. Elevated expressions of TPX2 mRNA were observed in all HCC cell lines (HepG2, Hep3B, SMMC-7721, Bel-7402 and Huh7) as compared with that in a non-transformed hepatic cell line (LO2). Clinical analysis indicated that the positive expression of TPX2 was significantly correlated with venous infiltration, high Edmondson-Steiner grading and advanced TNM tumor stage in HCC. Furthermore, TPX2 was a novel prognostic marker for predicting 5-year overall survival (OS) and disease-free survival (DFS) of HCC patients. In vitro studies found that TPX2 knockdown significantly inhibited cell proliferation and viability in both Hep3B and HepG2 cells. Moreover, TPX2 knockdown obviously slowed down tumor growth in a nude mouse xenograft model. Otherwise, TPX2 knockdown prominently suppressed HCC cell invasion and migration. In conclusion, these results indicate that TPX2 may serve as a prognostic marker and promotes tumorigenesis and metastasis of HCC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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13 pages, 870 KiB

Open AccessArticle

Towards Global QSAR Model Building for Acute Toxicity: Munro Database Case Study

by Swapnil Chavan^1,*, Ian A. Nicholls^1,2,*

, Björn C. G. Karlsson¹, Annika M. Rosengren¹, Davide Ballabio³, Viviana Consonni³

and Roberto Todeschini³

¹ Bioorganic & Biophysical Chemistry Laboratory, Linnaeus University Centre for Biomaterials Chemistry and Department of Chemistry & Biomedical Sciences, Linnaeus University, Kalmar SE-391 82, Sweden

² Department of Chemistry-BMC, Uppsala University, Box 576, Uppsala SE-751 23, Sweden

³ Milano Chemometrics and QSAR Research Group, Department of Earth and Environmental Sciences, University of Milano-Bicocca, Milano IT-20126, Italy

Int. J. Mol. Sci. 2014, 15(10), 18162-18174; https://doi.org/10.3390/ijms151018162 - 9 Oct 2014

Cited by 38 | Viewed by 8351

Abstract

A series of 436 Munro database chemicals were studied with respect to their corresponding experimental LD₅₀ values to investigate the possibility of establishing a global QSAR model for acute toxicity. Dragon molecular descriptors were used for the QSAR model development and genetic [...] Read more.

A series of 436 Munro database chemicals were studied with respect to their corresponding experimental LD₅₀ values to investigate the possibility of establishing a global QSAR model for acute toxicity. Dragon molecular descriptors were used for the QSAR model development and genetic algorithms were used to select descriptors better correlated with toxicity data. Toxic values were discretized in a qualitative class on the basis of the Globally Harmonized Scheme: the 436 chemicals were divided into 3 classes based on their experimental LD₅₀ values: highly toxic, intermediate toxic and low to non-toxic. The k-nearest neighbor (k-NN) classification method was calibrated on 25 molecular descriptors and gave a non-error rate (NER) equal to 0.66 and 0.57 for internal and external prediction sets, respectively. Even if the classification performances are not optimal, the subsequent analysis of the selected descriptors and their relationship with toxicity levels constitute a step towards the development of a global QSAR model for acute toxicity. Full article

(This article belongs to the Special Issue Computational Toxicology: Predicting Potential Toxicity of Drugs and Therapeutics)

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22 pages, 746 KiB

Open AccessReview

Argon: Systematic Review on Neuro- and Organoprotective Properties of an “Inert” Gas

by Anke Höllig^1,2

, Anita Schug¹, Astrid V. Fahlenkamp², Rolf Rossaint², Mark Coburn^2,* and Argon Organo-Protective Network (AON)^†

¹ Department of Neurosurgery, University RWTH Aachen, 52074 Aachen, Germany

² Department of Anesthesiology, University RWTH Aachen, 52074 Aachen, Germany

^† Members are listed in Appendix.

Int. J. Mol. Sci. 2014, 15(10), 18175-18196; https://doi.org/10.3390/ijms151018175 - 10 Oct 2014

Cited by 52 | Viewed by 10266

Abstract

Argon belongs to the group of noble gases, which are regarded as chemically inert. Astonishingly some of these gases exert biological properties and during the last decades more and more reports demonstrated neuroprotective and organoprotective effects. Recent studies predominately use in vivo or [...] Read more.

Argon belongs to the group of noble gases, which are regarded as chemically inert. Astonishingly some of these gases exert biological properties and during the last decades more and more reports demonstrated neuroprotective and organoprotective effects. Recent studies predominately use in vivo or in vitro models for ischemic pathologies to investigate the effect of argon treatment. Promising data has been published concerning pathologies like cerebral ischemia, traumatic brain injury and hypoxic ischemic encephalopathy. However, models applied and administration of the therapeutic gas vary. Here we provide a systematic review to summarize the available data on argon’s neuro- and organoprotective effects and discuss its possible mechanism of action. We aim to provide a summary to allow further studies with a more homogeneous setting to investigate possible clinical applications of argon. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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9 pages, 1448 KiB

Open AccessArticle

Recombinase Polymerase Amplification (RPA) of CaMV-35S Promoter and nos Terminator for Rapid Detection of Genetically Modified Crops

by Chao Xu^1,†, Liang Li^1,2,†, Wujun Jin^1,2 and Yusong Wan^1,2,*

¹ Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China

² Inspection and Testing Center for Environmental Risk Assessment of Genetic Modified Plant-Related Microorganisms (Beijing), Ministry of Agriculture, Beijing 100081, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18197-18205; https://doi.org/10.3390/ijms151018197 - 10 Oct 2014

Cited by 58 | Viewed by 14460

Abstract

Recombinase polymerase amplification (RPA) is a novel isothermal DNA amplification and detection technology that enables the amplification of DNA within 30 min at a constant temperature of 37–42 °C by simulating in vivo DNA recombination. In this study, based on the regulatory sequence [...] Read more.

Recombinase polymerase amplification (RPA) is a novel isothermal DNA amplification and detection technology that enables the amplification of DNA within 30 min at a constant temperature of 37–42 °C by simulating in vivo DNA recombination. In this study, based on the regulatory sequence of the cauliflower mosaic virus 35S (CaMV-35S) promoter and the Agrobacterium tumefaciens nopaline synthase gene (nos) terminator, which are widely incorporated in genetically modified (GM) crops, we designed two sets of RPA primers and established a real-time RPA detection method for GM crop screening and detection. This method could reliably detect as few as 100 copies of the target molecule in a sample within 15–25 min. Furthermore, the real-time RPA detection method was successfully used to amplify and detect DNA from samples of four major GM crops (maize, rice, cotton, and soybean). With this novel amplification method, the test time was significantly shortened and the reaction process was simplified; thus, this method represents an effective approach to the rapid detection of GM crops. Full article

(This article belongs to the Special Issue Detection and Safety Assessment of Genetically Modified Organisms)

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15 pages, 1869 KiB

Open AccessArticle

Mipu1 Protects H9c2 Myogenic Cells from Hydrogen Peroxide-Induced Apoptosis through Inhibition of the Expression of the Death Receptor Fas

by Guiliang Wang^1,2,†, Lei Jiang^1,*,†, Juan Song¹, Shu-Feng Zhou³, Huali Zhang¹, Kangkai Wang¹ and Xianzhong Xiao^1,*

¹ Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China

² Department of Digestive Internal Medicine, Gannan Medical University Pingxiang Hospital, 128 Guangchang Road, Pingxiang 337055, Jiangxi, China

³ Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18206-18220; https://doi.org/10.3390/ijms151018206 - 10 Oct 2014

Cited by 8 | Viewed by 6050

Abstract

Mipu1 (myocardial ischemic preconditioning upregulated protein 1), a novel rat gene recently identified in our lab, was expressed abundantly and predominantly in the brain and heart and upregulated in myocardium during myocardial ischemia/reperfusion in rats. In our previous study we found that Mipu1 [...] Read more.

Mipu1 (myocardial ischemic preconditioning upregulated protein 1), a novel rat gene recently identified in our lab, was expressed abundantly and predominantly in the brain and heart and upregulated in myocardium during myocardial ischemia/reperfusion in rats. In our previous study we found that Mipu1 was an evolutionarily conserved zinc finger-containing transcription factor. However, whether Mipu1 confers myocardial protection remains unknown. In this study, H9c2 myogenic cells were treated with hydrogen peroxide (H₂O₂) to simulate oxidative stress during myocardial ischemia-reperfusion injury. The expression of Mipu1 at mRNA and protein levels was detected by RT-PCR and Western blotting analysis. To study the effect of Mipu1 on apoptosis and expression of Fas induced by H₂O₂, full-length Mipu1 cDNA and Mipu1-RNAi plasmids were transiently transfected into H9c2 myogenic cells, and flow cytometry was used to quantitate the percentage of apoptotic cells. The expression of Fas was analyzed by Western blotting assay. The DNA binding and transcription activities of Mipu1 to the Fas promoter were detected by chromatin immunoprecipitation and luciferase reporter assays. The results showed that exposure of H9c2 myogenic cells to H₂O₂ resulted in a dose- and time-dependent increase in Mipu1 mRNA and protein levels; Mipu1 over-expression inhibited H₂O₂-induced apoptosis and upregulation of Fas induced by H₂O₂ in H9c2 myogenic cells; and knockdown of Mipu1 by RNAi promoted apoptosis and upregulation of Fas induced by H₂O₂. The chromatin immunoprecipition and reporter assays showed the DNA binding and transcription suppressor activities of Mipu1 to Fas promoter region. These results indicate that Mipu1 protected H9c2 myogenic cells from H₂O₂-induced apoptosis through inhibiting the expression of Fas. Full article

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

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32 pages, 850 KiB

Open AccessReview

Melatonin, Noncoding RNAs, Messenger RNA Stability and Epigenetics—Evidence, Hints, Gaps and Perspectives

by Rüdiger Hardeland

Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, Berliner Str. 28, Göttingen D-37073, Germany

Int. J. Mol. Sci. 2014, 15(10), 18221-18252; https://doi.org/10.3390/ijms151018221 - 10 Oct 2014

Cited by 55 | Viewed by 10172

Abstract

Melatonin is a highly pleiotropic regulator molecule, which influences numerous functions in almost every organ and, thus, up- or down-regulates many genes, frequently in a circadian manner. Our understanding of the mechanisms controlling gene expression is actually now expanding to a previously unforeseen [...] Read more.

Melatonin is a highly pleiotropic regulator molecule, which influences numerous functions in almost every organ and, thus, up- or down-regulates many genes, frequently in a circadian manner. Our understanding of the mechanisms controlling gene expression is actually now expanding to a previously unforeseen extent. In addition to classic actions of transcription factors, gene expression is induced, suppressed or modulated by a number of RNAs and proteins, such as miRNAs, lncRNAs, piRNAs, antisense transcripts, deadenylases, DNA methyltransferases, histone methylation complexes, histone demethylases, histone acetyltransferases and histone deacetylases. Direct or indirect evidence for involvement of melatonin in this network of players has originated in different fields, including studies on central and peripheral circadian oscillators, shift work, cancer, inflammation, oxidative stress, aging, energy expenditure/obesity, diabetes type 2, neuropsychiatric disorders, and neurogenesis. Some of the novel modulators have also been shown to participate in the control of melatonin biosynthesis and melatonin receptor expression. Future work will need to augment the body of evidence on direct epigenetic actions of melatonin and to systematically investigate its role within the network of oscillating epigenetic factors. Moreover, it will be necessary to discriminate between effects observed under conditions of well-operating and deregulated circadian clocks, and to explore the possibilities of correcting epigenetic malprogramming by melatonin. Full article

(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

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14 pages, 2803 KiB

Open AccessReview

Molecular Mechanisms of Host Cytoskeletal Rearrangements by Shigella Invasins

by Jun Hyuck Lee^1,2,*

, HaJeung Park^3,* and Yong Ho Park⁴

¹ Division of Polar Life Sciences, Korea Polar Research Institute, Incheon 406-840, Korea

² Department of Polar Sciences, University of Science and Technology, Incheon 406-840, Korea

³ The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA

⁴ Laboratory of Veterinary Microbiology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea

Int. J. Mol. Sci. 2014, 15(10), 18253-18266; https://doi.org/10.3390/ijms151018253 - 10 Oct 2014

Cited by 17 | Viewed by 12552

Abstract

Pathogen-induced reorganization of the host cell cytoskeleton is a common strategy utilized in host cell invasion by many facultative intracellular bacteria, such as Shigella, Listeria, enteroinvasive E. coli and Salmonella. Shigella is an enteroinvasive intracellular pathogen that preferentially infects human [...] Read more.

Pathogen-induced reorganization of the host cell cytoskeleton is a common strategy utilized in host cell invasion by many facultative intracellular bacteria, such as Shigella, Listeria, enteroinvasive E. coli and Salmonella. Shigella is an enteroinvasive intracellular pathogen that preferentially infects human epithelial cells and causes bacillary dysentery. Invasion of Shigella into intestinal epithelial cells requires extensive remodeling of the actin cytoskeleton with the aid of pathogenic effector proteins injected into the host cell by the activity of the type III secretion system. These so-called Shigella invasins, including IpaA, IpaC, IpgB1, IpgB2 and IpgD, modulate the actin-regulatory system in a concerted manner to guarantee efficient entry of the bacteria into host cells. Full article

(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)

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14 pages, 671 KiB

Open AccessReview

tRNA Modification Enzymes GidA and MnmE: Potential Role in Virulence of Bacterial Pathogens

by Daniel C. Shippy and Amin A. Fadl^*

Department of Animal Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA

Int. J. Mol. Sci. 2014, 15(10), 18267-18280; https://doi.org/10.3390/ijms151018267 - 10 Oct 2014

Cited by 41 | Viewed by 6744

Abstract

Transfer RNA (tRNA) is an RNA molecule that carries amino acids to the ribosomes for protein synthesis. These tRNAs function at the peptidyl (P) and aminoacyl (A) binding sites of the ribosome during translation, with each codon being recognized by a specific tRNA. [...] Read more.

Transfer RNA (tRNA) is an RNA molecule that carries amino acids to the ribosomes for protein synthesis. These tRNAs function at the peptidyl (P) and aminoacyl (A) binding sites of the ribosome during translation, with each codon being recognized by a specific tRNA. Due to this specificity, tRNA modification is essential for translational efficiency. Many enzymes have been implicated in the modification of bacterial tRNAs, and these enzymes may complex with one another or interact individually with the tRNA. Approximately, 100 tRNA modification enzymes have been identified with glucose-inhibited division (GidA) protein and MnmE being two of the enzymes studied. In Escherichia coli and Salmonella, GidA and MnmE bind together to form a functional complex responsible for the proper biosynthesis of 5-methylaminomethyl-2-thiouridine (mnm⁵s²U34) of tRNAs. Studies have implicated this pathway in a major pathogenic regulatory mechanism as deletion of gidA and/or mnmE has attenuated several bacterial pathogens like Salmonella enterica serovar Typhimurium, Pseudomonas syringae, Aeromonas hydrophila, and many others. In this review, we summarize the potential role of the GidA/MnmE tRNA modification pathway in bacterial virulence, interactions with the host, and potential therapeutic strategies resulting from a greater understanding of this regulatory mechanism. Full article

(This article belongs to the Special Issue Functions of Transfer RNAs)

29 pages, 2471 KiB

Open AccessReview

Dielectrophoresis for Bioparticle Manipulation

by Cheng Qian, Haibo Huang^*, Liguo Chen, Xiangpeng Li, Zunbiao Ge, Tao Chen, Zhan Yang

and Lining Sun

Robotics and Microsystems Center, College of Mechanical and Electrical Engineering & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215000, China

Int. J. Mol. Sci. 2014, 15(10), 18281-18309; https://doi.org/10.3390/ijms151018281 - 10 Oct 2014

Cited by 157 | Viewed by 13410

Abstract

As an ideal method to manipulate biological particles, the dielectrophoresis (DEP) technique has been widely used in clinical diagnosis, disease treatment, drug development, immunoassays, cell sorting, etc. This review summarizes the research in the field of bioparticle manipulation based on DEP techniques. Firstly, [...] Read more.

As an ideal method to manipulate biological particles, the dielectrophoresis (DEP) technique has been widely used in clinical diagnosis, disease treatment, drug development, immunoassays, cell sorting, etc. This review summarizes the research in the field of bioparticle manipulation based on DEP techniques. Firstly, the basic principle of DEP and its classical theories are introduced in brief; Secondly, a detailed introduction on the DEP technique used for bioparticle manipulation is presented, in which the applications are classified into five fields: capturing bioparticles to specific regions, focusing bioparticles in the sample, characterizing biomolecular interaction and detecting microorganism, pairing cells for electrofusion and separating different kinds of bioparticles; Thirdly, the effect of DEP on bioparticle viability is analyzed; Finally, the DEP techniques are summarized and future trends in bioparticle manipulation are suggested. Full article

(This article belongs to the Section Biochemistry)

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23 pages, 761 KiB

Open AccessReview

Influence of Sulfur for Oxygen Substitution in the Solvolytic Reactions of Chloroformate Esters and Related Compounds

by Malcolm J. D'Souza^1,*,† and Dennis N. Kevill^2,*,†

¹ Department of Chemistry, Wesley College, 120 N. State Street, Dover, DE 19901-3875, USA

² Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115-2862, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18310-18332; https://doi.org/10.3390/ijms151018310 - 10 Oct 2014

Cited by 7 | Viewed by 9010

Abstract

The replacement of oxygen within a chloroformate ester (ROCOCl) by sulfur can lead to a chlorothioformate (RSCOCl), a chlorothionoformate (ROCSCl), or a chlorodithioformate (RSCSCl). Phenyl chloroformate (PhOCOCl) reacts over the full range of solvents usually included in Grunwald-Winstein equation studies of solvolysis by [...] Read more.

The replacement of oxygen within a chloroformate ester (ROCOCl) by sulfur can lead to a chlorothioformate (RSCOCl), a chlorothionoformate (ROCSCl), or a chlorodithioformate (RSCSCl). Phenyl chloroformate (PhOCOCl) reacts over the full range of solvents usually included in Grunwald-Winstein equation studies of solvolysis by an addition-elimination (A-E) pathway. At the other extreme, phenyl chlorodithioformate (PhSCSCl) reacts across the range by an ionization pathway. The phenyl chlorothioformate (PhSCOCl) and phenyl chlorothionoformate (PhOCSCl) react at remarkably similar rates in a given solvent and there is a dichotomy of behavior with the A-E pathway favored in solvents such as ethanol-water and the ionization mechanism favored in aqueous solvents rich in fluoroalcohol. Alkyl esters behave similarly but with increased tendency to ionization as the alkyl group goes from 1° to 2° to 3°. N,N-Disubstituted carbamoyl halides favor the ionization pathway as do also the considerably faster reacting thiocarbamoyl chlorides. The tendency towards ionization increases as, within the three contributing structures of the resonance hybrid for the formed cation, the atoms carrying positive charge (other than the central carbon) change from oxygen to sulfur to nitrogen, consistent with the relative stabilities of species with positive charge on these atoms. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2015)

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16 pages, 2604 KiB

Open AccessReview

Lactate Transporters in the Context of Prostate Cancer Metabolism: What Do We Know?

by Nelma Pértega-Gomes^1,2 and Fátima Baltazar^1,2,*

¹ Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga 4710-057, Portugal

² ICVS/3B's—PT Government Associate Laboratory, Braga 4710-057, Portugal

Int. J. Mol. Sci. 2014, 15(10), 18333-18348; https://doi.org/10.3390/ijms151018333 - 13 Oct 2014

Cited by 38 | Viewed by 8720

Abstract

Metabolic changes during malignant transformation have been noted for many years in tumours. Otto Warburg first reported that cancer cells preferentially rely on glycolysis for energy production, even in the presence of oxygen, leading to the production of high levels of lactate. The [...] Read more.

Metabolic changes during malignant transformation have been noted for many years in tumours. Otto Warburg first reported that cancer cells preferentially rely on glycolysis for energy production, even in the presence of oxygen, leading to the production of high levels of lactate. The crucial role of lactate efflux and exchange within the tumour microenvironment drew attention to monocarboxylate transporters (MCTs). MCTs have been recognized as promising targets in cancer therapy, and their expression was described in a large variety of tumours; however, studies showing how these isoforms contribute to the acquisition of the malignant phenotype are scarce and still unclear regarding prostate cancer. In this review, we focus on the role for MCTs in cell metabolism, supporting the development and progression of prostate cancer, and discuss the exploitation of the metabolic nature of prostate cancer for therapeutic and diagnostic purposes. Full article

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13 pages, 2351 KiB

Open AccessArticle

Control of Several Emissions during Olive Pomace Thermal Degradation

by Teresa Miranda^1,*

, Sergio Nogales^1,†, Silvia Román^2,†

, Irene Montero^1,†

, José Ignacio Arranz^1,†

and Francisco José Sepúlveda^1,†

¹ Department of Mechanical, Energetic and Materials Engineering, Industrial Engineering School, University of Extremadura, Avda Elvas s/n, 06071 Badajoz, Spain

² Department of Applied Physics, Industrial Engineering School, University of Extremadura, Avda Elvas s/n, 06071 Badajoz, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18349-18361; https://doi.org/10.3390/ijms151018349 - 13 Oct 2014

Cited by 17 | Viewed by 6071

Abstract

Biomass plays an important role as an energy source, being an interesting alternative to fossil fuels due to its environment-friendly and sustainable characteristics. However, due to the exposure of customers to emissions during biomass heating, evolved pollutants should be taken into account and [...] Read more.

Biomass plays an important role as an energy source, being an interesting alternative to fossil fuels due to its environment-friendly and sustainable characteristics. However, due to the exposure of customers to emissions during biomass heating, evolved pollutants should be taken into account and controlled. Changing raw materials or mixing them with another less pollutant biomass could be a suitable step to reduce pollution. This work studied the thermal behaviour of olive pomace, pyrenean oak and their blends under combustion using thermogravimetric analysis. It was possible to monitor the emissions released during the process by coupling mass spectrometry analysis. The experiments were carried out under non-isothermal conditions at the temperature range 25–750 °C and a heating rate of 20 °C·min⁻¹. The following species were analysed: aromatic compounds (benzene and toluene), sulphur emissions (sulphur dioxide), 1,4-dioxin, hydrochloric acid, carbon dioxide and nitrogen oxides. The results indicated that pollutants were mainly evolved in two different stages, which are related to the thermal degradation steps. Thus, depending on the pollutant and raw material composition, different emission profiles were observed. Furthermore, intensity of the emission profiles was related, in some cases, to the composition of the precursor. Full article

(This article belongs to the Special Issue Green Chemistry and the Biorefinery)

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19 pages, 2983 KiB

Open AccessArticle

TRPV1 Activation Exacerbates Hypoxia/Reoxygenation-Induced Apoptosis in H9C2 Cells via Calcium Overload and Mitochondrial Dysfunction

by Zewei Sun^†, Jie Han^†, Wenting Zhao, Yuanyuan Zhang, Shuai Wang, Lifang Ye, Tingting Liu and Liangrong Zheng^*

¹ Department of Cardiology, the First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18362-18380; https://doi.org/10.3390/ijms151018362 - 13 Oct 2014

Cited by 63 | Viewed by 9024

Abstract

Transient potential receptor vanilloid 1 (TRPV1) channels, which are expressed on sensory neurons, elicit cardioprotective effects during ischemia reperfusion injury by stimulating the release of neuropeptides, namely calcitonin gene-related peptide (CGRP) and substance P (SP). Recent studies show that TRPV1 channels are also [...] Read more.

Transient potential receptor vanilloid 1 (TRPV1) channels, which are expressed on sensory neurons, elicit cardioprotective effects during ischemia reperfusion injury by stimulating the release of neuropeptides, namely calcitonin gene-related peptide (CGRP) and substance P (SP). Recent studies show that TRPV1 channels are also expressed on cardiomyocytes and can exacerbate air pollutant-induced apoptosis. However, whether these channels present on cardiomyocytes directly modulate cell death and survival pathways during hypoxia/reoxygenation (H/R) injury remains unclear. In the present study, we investigated the role of TRPV1 in H/R induced apoptosis of H9C2 cardiomyocytes. We demonstrated that TRPV1 was indeed expressed in H9C2 cells, and activated by H/R injury. Although neuropeptide release caused by TRPV1 activation on sensory neurons elicits a cardioprotective effect, we found that capsaicin (CAP; a TRPV1 agonist) treatment of H9C2 cells paradoxically enhanced the level of apoptosis by increasing intracellular calcium and mitochondrial superoxide levels, attenuating mitochondrial membrane potential, and inhibiting mitochondrial biogenesis (measured by the expression of ATP synthase β). In contrast, treatment of cells with capsazepine (CPZ; a TRPV1 antagonist) or TRPV1 siRNA attenuated H/R induced-apoptosis. Furthermore, CAP and CPZ treatment revealed a similar effect on cell viability and mitochondrial superoxide production in primary cardiomyocytes. Finally, using both CGRP_8–37 (a CGRP receptor antagonist) and RP67580 (a SP receptor antagonist) to exclude the confounding effects of neuropeptides, we confirmed aforementioned detrimental effects as TRPV1^−/− mouse hearts exhibited improved cardiac function during ischemia/reperfusion. In summary, direct activation of TRPV1 in myocytes exacerbates H/R-induced apoptosis, likely through calcium overload and associated mitochondrial dysfunction. Our study provides a novel understanding of the role of myocyte TRPV1 channels in ischemia/reperfusion injury that sharply contrasts with its known extracardiac neuronal effects. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2015)

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26 pages, 980 KiB

Open AccessReview

Glycemic Variability and Oxidative Stress: A Link between Diabetes and Cardiovascular Disease?

by Yoshifumi Saisho

Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Int. J. Mol. Sci. 2014, 15(10), 18381-18406; https://doi.org/10.3390/ijms151018381 - 13 Oct 2014

Cited by 152 | Viewed by 12618

Abstract

Diabetes is associated with a two to three-fold increase in risk of cardiovascular disease. However, intensive glucose-lowering therapy aiming at reducing HbA1c to a near-normal level failed to suppress cardiovascular events in recent randomized controlled trials. HbA1c reflects average glucose level rather than [...] Read more.

Diabetes is associated with a two to three-fold increase in risk of cardiovascular disease. However, intensive glucose-lowering therapy aiming at reducing HbA1c to a near-normal level failed to suppress cardiovascular events in recent randomized controlled trials. HbA1c reflects average glucose level rather than glycemic variability. In in vivo and in vitro studies, glycemic variability has been shown to be associated with greater reactive oxygen species production and vascular damage, compared to chronic hyperglycemia. These findings suggest that management of glycemic variability may reduce cardiovascular disease in patients with diabetes; however, clinical studies have shown conflicting results. This review summarizes the current knowledge on glycemic variability and oxidative stress, and discusses the clinical implications. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2015)

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15 pages, 3435 KiB

Open AccessArticle

Improvement of Radiotherapy-Induced Lacrimal Gland Injury by Induced Pluripotent Stem Cell-Derived Conditioned Medium via MDK and Inhibition of the p38/JNK Pathway

by Yanqing Zhang^1,*,†, Chenliang Deng^2,†, Jiang Qian¹, Mingui Zhang¹ and Xiaofeng Li¹

¹ Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai 200031, China

² Department of Plastic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200031, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18407-18421; https://doi.org/10.3390/ijms151018407 - 13 Oct 2014

Cited by 20 | Viewed by 6372

Abstract

Radiation therapy is the most widely used and effective treatment for orbital tumors, but it causes dry eye due to lacrimal gland damage. Induced pluripotent stem cell-derived conditioned medium (iPSC-CM) has been shown to rescue different types of tissue damage. The present study [...] Read more.

Radiation therapy is the most widely used and effective treatment for orbital tumors, but it causes dry eye due to lacrimal gland damage. Induced pluripotent stem cell-derived conditioned medium (iPSC-CM) has been shown to rescue different types of tissue damage. The present study investigated the mechanism of the potential radioprotective effect of IPS cell-derived conditioned medium (iPSC-CM) on gamma-irradiation-induced lacrimal gland injury (RILI) in experimental mice. In this study, we found that iPSC-CM ameliorated RILI. iPSC-CM markedly decreased radiotherapy induced inflammatory processes, predominantly through suppressing p38/JNK signaling. Further signaling pathway analyses indicated that iPSC-CM could suppress Akt (Protein Kinase B, PKB) phosphorylation. High levels of midkine (MDK) were also found in iPSC-CM and could be involved in lacrimal gland regeneration by promoting cell migration and proliferation. Thus, our study indicates that inhibiting the p38/JNK pathway or increasing the MDK level might be a therapeutic target for radiation-induced lacrimal gland injury. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 3756 KiB

Open AccessArticle

Characterization of Paraquat-Induced miRNA Profiling Response in hNPCs Undergoing Proliferation

by Min Huang^1,2,†, Dan Lou^1,3,†, Qian Cai², Xiuli Chang¹, Xinjin Wang¹ and Zhijun Zhou^1,*

¹ School of Public Health/MOE Key Lab of Public Health Safety/WHO Collaborating Center for Occupational Health, Fudan University, Shanghai 200032, China

² Department of Occupational and Environmental Health, School of Public Health, Ningxia Medical University, Yinchuan 750000, China

³ Shanghai Municipal Center for Disease Control & Prevention, Shanghai 200336, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18422-18436; https://doi.org/10.3390/ijms151018422 - 13 Oct 2014

Cited by 18 | Viewed by 6864

Abstract

Aberration during the development of the central nervous system (CNS) due to environmental factors underlies a variety of adverse developmental outcomes. Paraquat (PQ) is a widely studied neurotoxicant that perturbs the normal structure/function of adult CNS. Yet, the impacts of PQ exposure on [...] Read more.

Aberration during the development of the central nervous system (CNS) due to environmental factors underlies a variety of adverse developmental outcomes. Paraquat (PQ) is a widely studied neurotoxicant that perturbs the normal structure/function of adult CNS. Yet, the impacts of PQ exposure on the developing CNS remain unclear. miRNAs represent a class of small non-coding RNA molecules involved in the regulation of neural development. Thus in the present study, we analyzed the impacts of PQ on the miRNome of human neural progenitor cells (hNPCs) during proliferation by using the Exiqon miRCURY™ LNA Array. A total of 66 miRNAs were identified as differentially expressed in proliferating hNPCs upon PQ treatment. miRTarBase prediction identified 1465 mRNAs, including several genes (e.g., nestin, sox1, ngn1) previously proved to be associated with the neural proliferation and differentiation, as target genes of PQ-induced differentially expressed miRNAs. The database for annotation, visualization and integrated discovery (DAVID) bioinformatics analysis showed that target genes were enriched in regulation of cell proliferation and differentiation, cell cycle and apoptosis as well as tumor protein 53 (p53), Wnt, Notch and mitogen-activated protein kinases (MAPK) signaling pathways (p < 0.001). These findings were confirmed by real-time RT-PCR. Based on our results we conclude that PQ-induced impacts on the miRNA profiling of hNPCs undergoing proliferation may underlie the developmental neurotoxicity of PQ. Full article

(This article belongs to the Section Molecular Toxicology)

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16 pages, 4700 KiB

Open AccessArticle

Melatonin Attenuates Intermittent Hypoxia-Induced Lipid Peroxidation and Local Inflammation in Rat Adrenal Medulla

by Yu Liu^1,2, George Lim Tipoe³ and Man Lung Fung^1,*

¹ Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China

² Faculty of Medicine, Shenzhen University, Shenzhen 518060, Guangdong, China

³ Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China

Int. J. Mol. Sci. 2014, 15(10), 18437-18452; https://doi.org/10.3390/ijms151018437 - 13 Oct 2014

Cited by 17 | Viewed by 6778

Abstract

Chronic intermittent hypoxia (CIH) induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested the [...] Read more.

Chronic intermittent hypoxia (CIH) induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested the hypothesis that melatonin ameliorates the CIH-induced lipid peroxidation, local inflammation and cellular injury in rat adrenal medulla. Adult Sprague–Dawley rats were exposed to air (normoxic control) or hypoxia mimicking a severe recurrent sleep apnoeic condition for 14 days. The injection of melatonin (10 mg/kg) or vehicle was given before the daily hypoxic treatment. We found that levels of malondialdehyde and nitrotyrosine were significantly increased in the vehicle-treated hypoxic group, when compared with the normoxic control or hypoxic group treated with melatonin. Also, the protein levels of antioxidant enzymes (superoxide dismutase (SOD)-1 and SOD-2) were significantly lowered in the hypoxic group treated with vehicle but not in the melatonin group. In addition, the level of macrophage infiltration and the expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) and mediators (inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)) were elevated in the vehicle-treated hypoxic group, but were significantly ameliorated by the melatonin treatment. Moreover, the amount of apoptotic cells in the hypoxic groups was significantly less in the melatonin-treated group. In conclusion, CIH-induced lipid peroxidation causes local inflammation and cellular injury in the adrenal medulla. The antioxidant and anti-inflammatory actions of melatonin are indicative of a protective agent against adrenal damage in patients with severe obstructive sleep apnea syndrome. Full article

(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

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13 pages, 5823 KiB

Open AccessArticle

Investigation of the Neuroprotective Impact of Nimodipine on Neuro2a Cells by Means of a Surgery-Like Stress Model

by Eva Herzfeld^1,*, Christian Strauss¹, Sebastian Simmermacher¹, Kaya Bork², Rüdiger Horstkorte², Faramarz Dehghani³ and Christian Scheller¹

¹ Department of Neurosurgery, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany

² Institute for Physiological Chemistry, Martin-Luther University of Halle-Wittenberg, Hollystr. 1, 06114 Halle (Saale), Germany

³ Department of Anatomy and Cell Biology, Martin-Luther University of Halle-Wittenberg, Große Steinstraße 52, 06108 Halle (Saale), Germany

Int. J. Mol. Sci. 2014, 15(10), 18453-18465; https://doi.org/10.3390/ijms151018453 - 14 Oct 2014

Cited by 28 | Viewed by 7068

Abstract

Nimodipine is well characterized for the management of SAH (subarachnoid hemorrhage) and has been shown to promote a better outcome and less DIND (delayed ischemic neurological deficits). In rat experiments, enhanced axonal sprouting and higher survival of motoneurons was demonstrated after cutting or [...] Read more.

Nimodipine is well characterized for the management of SAH (subarachnoid hemorrhage) and has been shown to promote a better outcome and less DIND (delayed ischemic neurological deficits). In rat experiments, enhanced axonal sprouting and higher survival of motoneurons was demonstrated after cutting or crushing the facial nerve by nimodipine. These results were confirmed in clinical trials following vestibular Schwannoma surgery. The mechanism of the protective competence of nimodipine is unknown. Therefore, in this study, we established an in vitro model to examine the survival of Neuro2a cells after different stress stimuli occurring during surgery with or without nimodipine. Nimodipine significantly decreased ethanol-induced cell death of cells up to approximately 9% in all tested concentrations. Heat-induced cell death was diminished by approximately 2.5% by nimodipine. Cell death induced by mechanical treatment was reduced up to 15% by nimodipine. Our findings indicate that nimodipine rescues Neuro2a cells faintly, but significantly, from ethanol-, heat- and mechanically-induced cell death to different extents in a dosage-dependent manner. This model seems suitable for further investigation of the molecular mechanisms involved in the neuroprotective signal pathways influenced by nimodipine. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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18 pages, 4942 KiB

Open AccessArticle

Studies on Properties of Rice Straw/Polymer Nanocomposites Based on Polycaprolactone and Fe₃O₄ Nanoparticles and Evaluation of Antibacterial Activity

by Roshanak Khandanlou^1,*, Mansor B. Ahmad^1,*, Kamyar Shameli¹, Elnaz Saki² and Katayoon Kalantari¹

¹ Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

² Department of Pathology, Faculty of medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

Int. J. Mol. Sci. 2014, 15(10), 18466-18483; https://doi.org/10.3390/ijms151018466 - 14 Oct 2014

Cited by 32 | Viewed by 7433

Abstract

Modified rice straw/Fe₃O₄/polycaprolactone nanocomposites (ORS/Fe₃O₄/ PCL-NCs) have been prepared for the first time using a solution casting method. The RS/Fe₃O₄-NCs were modified with octadecylamine (ODA) as an organic modifier. The prepared [...] Read more.

Modified rice straw/Fe₃O₄/polycaprolactone nanocomposites (ORS/Fe₃O₄/ PCL-NCs) have been prepared for the first time using a solution casting method. The RS/Fe₃O₄-NCs were modified with octadecylamine (ODA) as an organic modifier. The prepared NCs were characterized by using X-ray powder diffraction (XRD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), Thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FT-IR). The XRD results showed that as the intensity of the peaks decreased with the increase of ORS/Fe₃O₄-NCs content in comparison with PCL peaks, the Fe₃O₄-NPs peaks increased from 1.0 to 60.0 wt. %. The TEM and SEM results showed a good dispersion of ORS/Fe₃O₄-NCs in the PCL matrix and the spherical shape of the NPs. The TGA analysis indicated thermal stability of ORS/Fe₃O₄-NCs increased after incorporation with PCL but the thermal stability of ORS/Fe₃O₄/PCL-NCs decreased with the increase of ORS/Fe₃O₄-NCs content. Tensile strength was improved with the addition of 5.0 wt. % of ORS/Fe₃O₄-NCs. The antibacterial activities of the ORS/Fe₃O₄/PCL-NC films were examined against Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus) by diffusion method using nutrient agar. The results indicated that ORS/Fe₃O₄/PCL-NC films possessed a strong antibacterial activity with the increase in the percentage of ORS/Fe₃O₄-NCs in the PCL. Full article

(This article belongs to the Section Materials Science)

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12 pages, 679 KiB

Open AccessReview

Transcriptional Regulation of Programmed Hypertension by Melatonin: An Epigenetic Perspective

by You-Lin Tain^1,2,*

, Li-Tung Huang^1,3

and Julie Y. H. Chan²

¹ Departments of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

² Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

³ Department of Traditional Chinese Medicine, Chang Gung University, Linkow 244, Taiwan

Int. J. Mol. Sci. 2014, 15(10), 18484-18495; https://doi.org/10.3390/ijms151018484 - 14 Oct 2014

Cited by 45 | Viewed by 5968

Abstract

Melatonin is an endogenously produced indoleamine and secreted by the pineal gland. Melatonin has pleiotropic bioactivities and is involved in epigenetic regulation. Suboptimal conditions during maternal and perinatal phases can elicit epigenetic regulation of genes for nephrogenesis and reset physiological responses to develop [...] Read more.

Melatonin is an endogenously produced indoleamine and secreted by the pineal gland. Melatonin has pleiotropic bioactivities and is involved in epigenetic regulation. Suboptimal conditions during maternal and perinatal phases can elicit epigenetic regulation of genes for nephrogenesis and reset physiological responses to develop programmed hypertension. This review discusses the early utility of melatonin to prevent programmed hypertension in later life by epigenetic regulation in the kidney, with an emphasis on: (1) the role of melatonin in epigenetic regulation; (2) the beneficial effects of melatonin on programmed hypertension; (3) epigenetic regulation of maternal melatonin therapy in different developmental windows of offspring kidneys analyzed by whole-genome RNA next-generation sequencing; and (4) current blocks in the application of melatonin in preventing programmed hypertension. Full article

(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

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12 pages, 984 KiB

Open AccessArticle

Preparation and Evaluation of Human-Murine Chimeric Antibody against Protective Antigen of Bacillus anthracis

by Lina Hao¹, Feng Zheng¹, Siping Xiong², Dan Hu¹, Heng Lv¹, Qi Tang², Jin Yang², Zhenqing Feng², Changjun Wang^1,* and Jin Zhu^1,2,*

¹ Huadong Medical Institute of Biotechniques, Nanjing 210002, China

² Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 210029, China

Int. J. Mol. Sci. 2014, 15(10), 18496-18507; https://doi.org/10.3390/ijms151018496 - 14 Oct 2014

Cited by 8 | Viewed by 6127

Abstract

The aim of this research is to develop a human/murine chimeric Fab antibody which neutralizes the anthrax toxin, protective antigen (PA). The chimeric Fab was constructed using variable regions of murine anti-PA monoclonal antibody in combination with constant regions of human IgG. The [...] Read more.

The aim of this research is to develop a human/murine chimeric Fab antibody which neutralizes the anthrax toxin, protective antigen (PA). The chimeric Fab was constructed using variable regions of murine anti-PA monoclonal antibody in combination with constant regions of human IgG. The chimeric PA6-Fab was expressed in E. coli. BL21 and evaluated by ELISA and co-immunoprecipitation- mass spectra. The potency of PA6-Fab to neutralize LeTx was examined in J774A.1 cell viability in vitro and in Fisher 344 rats in vivo. The PA6-Fab did not have domain similarity corresponding to the current anti PA mAbs, but specifically bound to anthrax PA at an affinity of 1.76 nM, and was able to neutralize LeTx in vitro and protected 56.9% cells at 20 μg/mL against anthrax LeTx. One hundred μg PA6-Fab could neutralize 300 μg LeTx in vivo. The PA6-Fab has potential as a therapeutic mAb for treatment of anthrax. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 956 KiB

Open AccessReview

Effects of the Olive-Derived Polyphenol Oleuropein on Human Health

by Barbara Barbaro^1,†, Gabriele Toietta^2,†, Roberta Maggio¹, Mario Arciello^1,3, Mirko Tarocchi⁴, Andrea Galli⁴ and Clara Balsano^5,*

¹ Laboratory of Molecular Virology and Oncology, Francesco Balsano Foundation, Rome 00198, Italy

² Department of Experimental Oncology, Regina Elena National Cancer Institute IRCCS, Rome 00144, Italy

³ Department of Internal Medicine and Medical Specialties, Sapienza University, Rome 00161, Italy

⁴ Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50139, Italy

⁵ Institute of Biology, Molecular Medicine and Nanobiotechnologies (IBMN), National Research Council (CNR), Rome 00185, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18508-18524; https://doi.org/10.3390/ijms151018508 - 14 Oct 2014

Cited by 231 | Viewed by 25382

Abstract

The use of the products derived from the olive tree on human health dates back centuries. In several civilizations, the olive tree had and still has a very strong cultural and religious symbolism. Notably, the official seal and emblem of the World Health [...] Read more.

The use of the products derived from the olive tree on human health dates back centuries. In several civilizations, the olive tree had and still has a very strong cultural and religious symbolism. Notably, the official seal and emblem of the World Health Organization features the rod of Asclepius over a world map surrounded by olive tree branches, chosen as a symbol of peace and health. Recently, accumulating experimental, clinical and epidemiological data have provided support to the traditional beliefs of the beneficial effect provided by olive derivates. In particular, the polyphenols present in olive leaves, olives, virgin (unrefined) olive oil and olive mill waste are potent antioxidant and radical scavengers with anti-tumor and anti-inflammatory properties. Here, we review the positive impact on human health of oleuropein, the most prevalent polyphenol present in olives. In addition, we provide data collected in our laboratory on the role of oleuropein in counteracting lipid accumulation in a mouse model of non-alcoholic fatty liver disease. Full article

(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols)

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15 pages, 1028 KiB

Open AccessArticle

Synthetic Chalcones with Potent Antioxidant Ability on H₂O₂-Induced Apoptosis in PC12 Cells

by Jian-Zhang Wu^1,*,†, Chan-Chan Cheng^1,†, Lai-Lai Shen¹, Zhan-Kun Wang², Shou-Biao Wu¹, Wu-Lan Li³, Su-Hua Chen¹, Rong-Ping Zhou¹ and Pei-Hong Qiu^1,*

¹ Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China

² Institute of Sports Science, Wenzhou Medical University, Wenzhou 325035, China

³ College of Information Science and Computer Engineering, Wenzhou Medical University, Wenzhou 325035, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18525-18539; https://doi.org/10.3390/ijms151018525 - 14 Oct 2014

Cited by 48 | Viewed by 7950

Abstract

Chalcone derivatives (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one and (E)-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one (Compounds 1 and 2) have been demonstrated to be potent anti-inflammatory agents in our previous study. In light of the relationship of intracellular mechanisms between anti-inflammatories and antioxidants, we further designed [...] Read more.

Chalcone derivatives (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one and (E)-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one (Compounds 1 and 2) have been demonstrated to be potent anti-inflammatory agents in our previous study. In light of the relationship of intracellular mechanisms between anti-inflammatories and antioxidants, we further designed and synthesized a series of chalcone derivatives based on 1 and 2, to explore their antioxidant efficacy. The majority of the derivatives exhibited strong protective effects on PC12 (PC12 rat pheochromocytoma) cells exposed to H₂O₂, and all compounds were nontoxic. A preliminary structure-activity relationship was proposed. Compounds 1 and 1d ((E)-2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl) phenyl acrylate) exerted the action in a good dose-dependent manner. Quantitative RT-PCR (qRT-PCR) and western blot analysis showed that 1 and 1d significantly improve the expression of nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-dependent antioxidant genes g-Glutamylcysteine Ligase Catalytic Subunit (GCLC) and heme oxygenase-1 (HO-1) and their corresponding proteins (γ-glutamyl cysteine synthase (γ-GCS) and HO-1) in PC12 cells. Inhibition of GCLC and HO-1 by specific inhibitors, l-buthionine-S-sulfoximine (BSO) and zinc protoporphyrin (ZnPP), respectively, partially reduce the protective effect of 1 and 1d. These data present a series of novel chalcone analogs, especially compounds 1 and 1d, as candidates for treating oxidative stress-related disease by activating the Nrf2-antioxidant responsive element (ARE) pathway. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)

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17 pages, 820 KiB

Open AccessArticle

Nanoparticle Encapsidation of Flock House Virus by Auto Assembly of Tobacco Mosaic Virus Coat Protein

by Payal D. Maharaj¹, Jyothi K. Mallajosyula¹, Gloria Lee¹, Phillip Thi¹, Yiyang Zhou², Christopher M. Kearney² and Alison A. McCormick^1,*

¹ Department of Biological and Pharmaceutical Sciences, Touro University, Vallejo, CA 94594, USA

² Department of Biology, Biomedical Studies Program, Baylor University, Waco, TX 76706, USA

Int. J. Mol. Sci. 2014, 15(10), 18540-18556; https://doi.org/10.3390/ijms151018540 - 14 Oct 2014

Cited by 22 | Viewed by 8384

Abstract

Tobacco Mosaic virus (TMV) coat protein is well known for its ability to self-assemble into supramolecular nanoparticles, either as protein discs or as rods originating from the ~300 bp genomic RNA origin-of-assembly (OA). We have utilized TMV self-assembly characteristics to create a novel [...] Read more.

Tobacco Mosaic virus (TMV) coat protein is well known for its ability to self-assemble into supramolecular nanoparticles, either as protein discs or as rods originating from the ~300 bp genomic RNA origin-of-assembly (OA). We have utilized TMV self-assembly characteristics to create a novel Flock House virus (FHV) RNA nanoparticle. FHV encodes a viral polymerase supporting autonomous replication of the FHV genome, which makes it an attractive candidate for viral transgene expression studies and targeted RNA delivery into host cells. However, FHV viral genome size is strictly limited by native FHV capsid. To determine if this packaging restriction could be eliminated, FHV was adapted to express enhanced green fluorescent protein (GFP), to allow for monitoring of functional FHV RNA activity. Then TMV OA was introduced in six 3' insertion sites, with only site one supporting functional FHV GFP expression. To create nanoparticles, FHV GFP-OA modified genomic RNA was mixed in vitro with TMV coat protein and monitored for encapsidation by agarose electrophoresis and electron microscopy. The production of TMV-like rod shaped nanoparticles indicated that modified FHV RNA can be encapsidated by purified TMV coat protein by self-assembly. This is the first demonstration of replication-independent packaging of the FHV genome by protein self-assembly. Full article

(This article belongs to the Special Issue Supramolecular Polymers and Their Assemblies)

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17 pages, 970 KiB

Open AccessReview

Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System

by Dhifaf Sarhan^*, Padraig D'Arcy and Andreas Lundqvist

Karolinska Institutet, Department of Oncology-Pathology, Stockholm S-17176, Sweden

Int. J. Mol. Sci. 2014, 15(10), 18557-18573; https://doi.org/10.3390/ijms151018557 - 14 Oct 2014

Cited by 22 | Viewed by 9545

Abstract

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of [...] Read more.

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients. Full article

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

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19 pages, 698 KiB

Open AccessReview

Low-Dose Interleukin-2 Therapy: A Driver of an Imbalance between Immune Tolerance and Autoimmunity

by Agata Kosmaczewska

Institute of Immunology and Experimental Therapy, Department of Experimental Therapy, Polish Academy of Sciences, 12 R. Weigla St., 53-114 Wroclaw, Poland

Int. J. Mol. Sci. 2014, 15(10), 18574-18592; https://doi.org/10.3390/ijms151018574 - 15 Oct 2014

Cited by 44 | Viewed by 7293

Abstract

For many years, the role of interleukin-2 (IL-2) in autoimmune responses was established as a cytokine possessing strong pro-inflammatory activity. Studies of the past few years have changed our knowledge on IL-2 in autoimmune chronic inflammation, suggesting its protective role, when administered at [...] Read more.

For many years, the role of interleukin-2 (IL-2) in autoimmune responses was established as a cytokine possessing strong pro-inflammatory activity. Studies of the past few years have changed our knowledge on IL-2 in autoimmune chronic inflammation, suggesting its protective role, when administered at low-doses. The disrupted balance between regulatory and effector T cells (Tregs and Teffs, respectively) is a characteristic of autoimmune diseases, and is dependent on homeostatic cytokines, including IL-2. Actually, inherent defects in the IL-2 signaling pathway and/or levels leading to Treg compromised function and numbers as well as Th17 expansion have been attributed to autoimmune disorders. In this review, we discuss the role of IL-2 in the pathogenesis of autoimmune diseases. In particular, we highlight the impact of the dysregulated IL-2 pathway on disruption of the Treg/Th17 balance, reversal of which appears to be a possible mechanism of the low-dose IL-2 treatment. The negative effects of IL-2 on the differentiation of follicular helper T cells (Tfh) and pathogenic Th17 cells, both of which contribute to autoimmunity, is emphasized in the paper as well. We also compare the current IL-2-based therapies of animal and human subjects with immune-mediated diseases aimed at boosting the Treg population, which is the most IL-2-dependent cell subset desirable for sufficient control of autoimmunity. New perspectives of therapeutic approaches focused on selective delivery of IL-2 to inflamed tissues, thus allowing local activity of IL-2 to be combined with its reduced systemic and pleiotropic toxicity, are also proposed in this paper. Full article

(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)

17 pages, 7820 KiB

Open AccessArticle

Use of Natural Neural Scaffolds Consisting of Engineered Vascular Endothelial Growth Factor Immobilized on Ordered Collagen Fibers Filled in a Collagen Tube for Peripheral Nerve Regeneration in Rats

by Fukai Ma^1,2, Zhifeng Xiao³, Danqing Meng³, Xianglin Hou³, Jianhong Zhu¹, Jianwu Dai^3,* and Ruxiang Xu^2,*

¹ Fudan University Huashan Hospital, Department of Neurosurgery, National Key Laboratory for Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College-Fudan University, 12 Wulumuqi Zhong Rd., Shanghai 200040, China

² The Affiliated Bayi Brain Hospital, the Military General Hospital of Beijing People's Liberation Army, No. 5 Nanmen Cang, Dongcheng District, Beijing 100700, China

³ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing 100190, China

Int. J. Mol. Sci. 2014, 15(10), 18593-18609; https://doi.org/10.3390/ijms151018593 - 15 Oct 2014

Cited by 28 | Viewed by 7588

Abstract

The search for effective strategies for peripheral nerve regeneration has attracted much attention in recent years. In this study, ordered collagen fibers were used as intraluminal fibers after nerve injury in rats. Vascular endothelial growth factor (VEGF) plays an important role in nerve [...] Read more.

The search for effective strategies for peripheral nerve regeneration has attracted much attention in recent years. In this study, ordered collagen fibers were used as intraluminal fibers after nerve injury in rats. Vascular endothelial growth factor (VEGF) plays an important role in nerve regeneration, but its very fast initial burst of activity within a short time has largely limited its clinical use. For the stable binding of VEGF to ordered collagen fibers, we fused a collagen-binding domain (CBD) to VEGF through recombinant DNA technology. Then, we filled the ordered collagen fibers-CBD-VEGF targeting delivery system in a collagen tube to construct natural neural scaffolds, which were then used to bridge transected nerve stumps in a rat sciatic nerve transection model. After transplantation, the natural neural scaffolds showed minimal foreign body reactions and good integration into the host tissue. Oriented collagen fibers in the collagen tube could guide regenerating axons in an oriented manner to the distal, degenerating nerve segment, maximizing the chance of target reinnervation. Functional and histological analyses indicated that the recovery of nerve function in the natural neural scaffolds-treated group was superior to the other grafted groups. The guiding of oriented axonal regeneration and effective delivery systems surmounting the otherwise rapid and short-lived diffusion of growth factors in body fluids are two important strategies in promoting peripheral nerve regeneration. The natural neural scaffolds described take advantage of these two aspects and may produce synergistic effects. These properties qualified the artificial nerve conduits as a putative candidate system for the fabrication of peripheral nerve reconstruction devices. Full article

(This article belongs to the Special Issue Artificial Organs)

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13 pages, 4614 KiB

Open AccessArticle

A Comprehensive Mixture of Tobacco Smoke Components Retards Orthodontic Tooth Movement via the Inhibition of Osteoclastogenesis in a Rat Model

by Maya Nagaie¹, Aki Nishiura^1,*,†,‡, Yoshitomo Honda^2,*,†

, Shin-Ichi Fujiwara³ and Naoyuki Matsumoto¹

¹ Department of Orthodontics, Graduate School of Dentistry, Osaka Dental University, 8-1, Kuzuha Hanazonocho, Hirakata, Osaka 573-1121, Japan

² Institute of Dental Research, Osaka Dental University, 8-1, Kuzuha Hanazonocho, Hirakata, Osaka 573-1121, Japan

³ Department of Chemistry, Osaka Dental University, 8-1, Kuzuha Hanazonocho, Hirakata, Osaka 573-1121, Japan

^† These authors contributed equally to this work.

^‡ Current address: Department of Orthodontics, Graduate School of Dentistry, Osaka Dental University, 1-5-17, Cyu-ouku Otemae, Osaka 540-0008, Japan.

Int. J. Mol. Sci. 2014, 15(10), 18610-18622; https://doi.org/10.3390/ijms151018610 - 15 Oct 2014

Cited by 17 | Viewed by 5785

Abstract

Tobacco smoke is a complex mixture of numerous components. Nevertheless, most experiments have examined the effects of individual chemicals in tobacco smoke. The comprehensive effects of components on tooth movement and bone resorption remain unexplored. Here, we have shown that a comprehensive mixture [...] Read more.

Tobacco smoke is a complex mixture of numerous components. Nevertheless, most experiments have examined the effects of individual chemicals in tobacco smoke. The comprehensive effects of components on tooth movement and bone resorption remain unexplored. Here, we have shown that a comprehensive mixture of tobacco smoke components (TSCs) attenuated bone resorption through osteoclastogenesis inhibition, thereby retarding experimental tooth movement in a rat model. An elastic power chain (PC) inserted between the first and second maxillary molars robustly yielded experimental tooth movement within 10 days. TSC administration effectively retarded tooth movement since day 4. Histological evaluation disclosed that tooth movement induced bone resorption at two sites: in the bone marrow and the peripheral bone near the root. TSC administration significantly reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclastic cells in the bone marrow cavity of the PC-treated dentition. An in vitro study indicated that the inhibitory effects of TSCs on osteoclastogenesis seemed directed more toward preosteoclasts than osteoblasts. These results indicate that the comprehensive mixture of TSCs might be a useful tool for detailed verification of the adverse effects of tobacco smoke, possibly contributing to the development of reliable treatments in various fields associated with bone resorption. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 912 KiB

Open AccessArticle

Concurrent Expression of Oct4 and Nanog Maintains Mesenchymal Stem-Like Property of Human Dental Pulp Cells

by Chuan-En Huang¹, Fang-Wei Hu^1,2, Chuan-Hang Yu^1,2, Lo-Lin Tsai^1,2, Tzu-Hsin Lee^1,2, Ming-Yung Chou^1,2,3 and Cheng-Chia Yu^1,2,3,*

¹ School of Dentistry, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung 40201, Taiwan

² Department of Dentistry, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Rd., Taichung 40201, Taiwan

³ Institute of Oral Sciences, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung 40201, Taiwan

Int. J. Mol. Sci. 2014, 15(10), 18623-18639; https://doi.org/10.3390/ijms151018623 - 15 Oct 2014

Cited by 49 | Viewed by 8423

Abstract

Human dental pulp stem cells (DPSCs), unique mesenchymal stem cells (MSCs) type, exhibit the characteristics of self-renewal and multi-lineage differentiation capacity. Oct4 and Nanog are pluripotent genes. The aim of this study was to determine the physiological functions of Oct4 and Nanog expression [...] Read more.

Human dental pulp stem cells (DPSCs), unique mesenchymal stem cells (MSCs) type, exhibit the characteristics of self-renewal and multi-lineage differentiation capacity. Oct4 and Nanog are pluripotent genes. The aim of this study was to determine the physiological functions of Oct4 and Nanog expression in DPSCs. Herein, we determined the critical role of an Oct4/Nanog axis modulating MSCs properties of DPSCs by lentiviral-mediated co-overexpression or co-knockdown of Oct4/Nanog in DPSCs. MSCs properties including osteogenic/chondrogenic/adipogenic induction differentiation was assayed for expression of osteogenic/chondrogenic/adipogenic markers by quantitative real-time RT-PCR analysis. Initially, we observed that the expression profile of Oct4 and Nanog in dental pulp cells, which exerted properties of MSCs, was significantly up-regulated compared to that of STRO-1⁻CD146⁻ dental pulp cells. Down-regulation of Oct4 and Nanog co-expression significantly reduced the cell proliferation, osteogenic differentiation capability, STRO-1, CD146, and Alkaline phosphatase (ALP) activity of DPSCs. In contrast, co-overexpression of Oct4 and Nanog enhanced the expression level of STRO-1 and CD146, proliferation rate and osteogenic/chondrogenic/adipogenic induction differentiation capability, and expression of osteogenic/chondrogenic/adipogenic induction differentiation markers. Our results suggest that Oct4-Nanog signaling is a regulatory switch to maintain properties in DPSCs. Full article

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19 pages, 1210 KiB

Open AccessArticle

Effect of the Drying Process on the Intensification of Phenolic Compounds Recovery from Grape Pomace Using Accelerated Solvent Extraction

by Hiba N. Rajha^1,2, Walter Ziegler^3,4, Nicolas Louka¹, Zeina Hobaika¹

, Eugene Vorobiev², Herbert G. Boechzelt^3,4 and Richard G. Maroun^1,*

¹ Centre d'Analyses et de Recherche, UR TVA, Faculté des Sciences, Université Saint-Joseph, B.P. 11-514 Riad El Solh, Beirut 1107 2050, Lebanon

² UTC/ESCOM, EA 4297 TIMR, Département de Génie des Procédés Industriels, Laboratoire Transformations Intégrées de la Matière Renouvelable, Université de Technologie de Compiègne, Centre de Recherche de Royallieu, Compiègne Cedex, BP 20529 – 60205, France

³ Institute of Chemistry, Karl-Franzens University of Graz, A-8010 Graz, Austria

⁴ JOANNEUM RESEARCH Forschungsgesellschaft mbH, Institute RESOURCES, A-8010 Graz, Austria

Int. J. Mol. Sci. 2014, 15(10), 18640-18658; https://doi.org/10.3390/ijms151018640 - 15 Oct 2014

Cited by 64 | Viewed by 9727

Abstract

In light of their environmental and economic interests, food byproducts have been increasingly exploited and valorized for their richness in dietary fibers and antioxidants. Phenolic compounds are antioxidant bioactive molecules highly present in grape byproducts. Herein, the accelerated solvent extraction (ASE) of phenolic [...] Read more.

In light of their environmental and economic interests, food byproducts have been increasingly exploited and valorized for their richness in dietary fibers and antioxidants. Phenolic compounds are antioxidant bioactive molecules highly present in grape byproducts. Herein, the accelerated solvent extraction (ASE) of phenolic compounds from wet and dried grape pomace, at 45 °C, was conducted and the highest phenolic compounds yield (PCY) for wet (16.2 g GAE/100 g DM) and dry (7.28 g GAE/100 g DM) grape pomace extracts were obtained with 70% ethanol/water solvent at 140 °C. The PCY obtained from wet pomace was up to two times better compared to the dry byproduct and up to 15 times better compared to the same food matrices treated with conventional methods. With regard to Resveratrol, the corresponding dry pomace extract had a better free radical scavenging activity (49.12%) than the wet extract (39.8%). The drying pretreatment process seems to ameliorate the antiradical activity, especially when the extraction by ASE is performed at temperatures above 100 °C. HPLC-DAD analysis showed that the diversity of the flavonoid and the non-flavonoid compounds found in the extracts was seriously affected by the extraction temperature and the pretreatment of the raw material. This diversity seems to play a key role in the scavenging activity demonstrated by the extracts. Our results emphasize on ASE usage as a promising method for the preparation of highly concentrated and bioactive phenolic extracts that could be used in several industrial applications. Full article

(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols)

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18 pages, 1089 KiB

Open AccessReview

Calcium Signaling and Meiotic Exit at Fertilization in Xenopus Egg

by Alexander A. Tokmakov^1,*, Vasily E. Stefanov², Tetsushi Iwasaki¹, Ken-Ichi Sato³ and Yasuo Fukami¹

¹ Research Center for Environmental Genomics, Kobe University, Kobe 657-8501, Japan

² Department of Biochemistry, St. Petersburg University, St. Petersburg 199034, Russia

³ Department of Molecular Biosciences, Kyoto Sangyo University, Kyoto 603-8555, Japan

Int. J. Mol. Sci. 2014, 15(10), 18659-18676; https://doi.org/10.3390/ijms151018659 - 15 Oct 2014

Cited by 18 | Viewed by 8854

Abstract

Calcium is a universal messenger that mediates egg activation at fertilization in all sexually reproducing species studied. However, signaling pathways leading to calcium generation and the mechanisms of calcium-induced exit from meiotic arrest vary substantially among species. Here, we review the pathways of [...] Read more.

Calcium is a universal messenger that mediates egg activation at fertilization in all sexually reproducing species studied. However, signaling pathways leading to calcium generation and the mechanisms of calcium-induced exit from meiotic arrest vary substantially among species. Here, we review the pathways of calcium signaling and the mechanisms of meiotic exit at fertilization in the eggs of the established developmental model, African clawed frog, Xenopus laevis. We also discuss calcium involvement in the early fertilization-induced events in Xenopus egg, such as membrane depolarization, the increase in intracellular pH, cortical granule exocytosis, cortical contraction, contraction wave, cortical rotation, reformation of the nuclear envelope, sperm chromatin decondensation and sister chromatid segregation. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Sperm-Egg Interaction)

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16 pages, 833 KiB

Open AccessReview

Molecular Mechanisms for the Regulation of Insulin-Stimulated Glucose Uptake by Small Guanosine Triphosphatases in Skeletal Muscle and Adipocytes

by Takaya Satoh

Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan

Int. J. Mol. Sci. 2014, 15(10), 18677-18692; https://doi.org/10.3390/ijms151018677 - 16 Oct 2014

Cited by 93 | Viewed by 11192

Abstract

Insulin is a hormone that regulates the blood glucose level by stimulating various physiological responses in its target tissues. In skeletal muscle and adipose tissue, insulin promotes membrane trafficking of the glucose transporter GLUT4 from GLUT4 storage vesicles to the plasma membrane, thereby [...] Read more.

Insulin is a hormone that regulates the blood glucose level by stimulating various physiological responses in its target tissues. In skeletal muscle and adipose tissue, insulin promotes membrane trafficking of the glucose transporter GLUT4 from GLUT4 storage vesicles to the plasma membrane, thereby facilitating the uptake of glucose from the circulation. Detailed mechanisms underlying insulin-dependent intracellular signal transduction for glucose uptake remain largely unknown. In this article, I give an overview on the recently identified signaling network involving Rab, Ras, and Rho family small guanosine triphosphatases (GTPases) that regulates glucose uptake in insulin-responsive tissues. In particular, the regulatory mechanisms for these small GTPases and the cross-talk between protein kinase and small GTPase cascades are highlighted. Full article

(This article belongs to the Special Issue Regulation of Membrane Trafficking and Its Potential Implications 2014)

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13 pages, 3070 KiB

Open AccessReview

Cardiac Arrhythmias and Sleep-Disordered Breathing in Patients with Heart Failure

by Wolfram Grimm¹ and Ulrich Koehler^2,*

¹ Department of Cardiology, University Hospital of Marburg and Gießen, Philipps-University Marburg, Marburg 35033, Germany

² Sleep Disorder Unit of the Department of Pneumology, University Hospital of Marburg and Gießen, Philipps-University Marburg, Marburg 35033, Germany

Int. J. Mol. Sci. 2014, 15(10), 18693-18705; https://doi.org/10.3390/ijms151018693 - 16 Oct 2014

Cited by 21 | Viewed by 9060

Abstract

The relationship between heart failure (HF), sleep-disordered breathing and cardiac arrhythmias is complex and poorly understood. Whereas the frequency of predominantly obstructive sleep apnea in HF patients is low and similar or moderately higher to that observed in the general population, central sleep [...] Read more.

The relationship between heart failure (HF), sleep-disordered breathing and cardiac arrhythmias is complex and poorly understood. Whereas the frequency of predominantly obstructive sleep apnea in HF patients is low and similar or moderately higher to that observed in the general population, central sleep apnea (CSA) has been observed in approximately 50% of HF patients, depending on the methods used to detect CSA and patient selection. Despite this high prevalence, it is still unclear whether CSA is merely a marker or an independent risk factor for an adverse prognosis in HF patients and whether CSA is associated with an increased risk for supraventricular as well as ventricular arrhythmias in HF patients. The current review focuses on the relationship between CSA and atrial fibrillation as the most common atrial arrhythmia in HF patients, and on the relationship between CSA and ventricular tachycardia and ventricular fibrillation as the most frequent cause of sudden cardiac death in HF patients. Full article

(This article belongs to the Special Issue Pathogenesis of Cardiac Arrhythmias and Heart Failure)

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19 pages, 2351 KiB

Open AccessArticle

Synthesis, X-ray Structure, Spectroscopic Properties and DFT Studies of a Novel Schiff Base

by Kew-Yu Chen^*

and Hsing-Yang Tsai

Department of Chemical Engineering, Feng Chia University, Taichung 40724, Taiwan

Int. J. Mol. Sci. 2014, 15(10), 18706-18724; https://doi.org/10.3390/ijms151018706 - 17 Oct 2014

Cited by 24 | Viewed by 8291

Abstract

A series of Schiff bases, salicylideneaniline derivatives 1–4, was synthesized under mild conditions and characterized by ¹H NMR, HRMS, UV-Vis and fluorescence spectra, and single-crystal X-ray diffraction. In solid and aprotic solvents 1–4 exist mainly as E [...] Read more.

A series of Schiff bases, salicylideneaniline derivatives 1–4, was synthesized under mild conditions and characterized by ¹H NMR, HRMS, UV-Vis and fluorescence spectra, and single-crystal X-ray diffraction. In solid and aprotic solvents 1–4 exist mainly as E conformers that possess an intramolecular six-membered-ring hydrogen bond. A weak intramolecular C–H×××F hydrogen bond is also observed in fluoro-functionalized Schiff base 4, which generates another S(6) ring motif. The C–H×××F hydrogen bond further stabilizes its structure and leads it to form a planar configuration. Compounds 1–3 exhibit solely a long-wavelength proton-transfer tautomer emission, while dipole-functionalized Schiff base 4 shows remarkable dual emission originated from the excited-state intramolecular charge transfer (ESICT) and excited-state intramolecular proton transfer (ESIPT) states. Furthermore, the geometric structures, frontier molecular orbitals (MOs) and the potential energy curves for 1–4 in the ground and the first singlet excited state were fully rationalized by density functional theory (DFT) and time-dependent DFT calculations. Full article

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

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17 pages, 2328 KiB

Open AccessArticle

Caffeic Acid Reduces the Viability and Migration Rate of Oral Carcinoma Cells (SCC-25) Exposed to Low Concentrations of Ethanol

by Arkadiusz Dziedzic^1,*

, Robert Kubina²

, Agata Kabała-Dzik², Robert D. Wojtyczka³

, Tadeusz Morawiec⁴ and Rafał J. Bułdak⁵

¹ Department of Conservative Dentistry with Endodontics, School of Medicine with the Division of Dentistry, Medical University of Silesia in Katowice, Akademicki 17, 41-902 Bytom, Poland

² Department and Institute of Pathology, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Ostrogórska 30, 41-200 Sosnowiec, Poland

³ Department and Institute of Microbiology and Virology, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland

⁴ Department of Oral Surgery, School of Medicine with the Division of Dentistry, Medical University of Silesia in Katowice, Akademicki 17, 41-902 Bytom, Poland

⁵ Department of Physiology, School of Medicine with the Division of Dentistry, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland

Int. J. Mol. Sci. 2014, 15(10), 18725-18741; https://doi.org/10.3390/ijms151018725 - 17 Oct 2014

Cited by 32 | Viewed by 8081

Abstract

Alcohol increases the risk of carcinoma originated from oral epithelium, but the biological effects of ultra-low doses of ethanol on existing carcinoma cells in combination with natural substances are still unclear. A role for ethanol (EtOH), taken in small amounts as an ingredient [...] Read more.

Alcohol increases the risk of carcinoma originated from oral epithelium, but the biological effects of ultra-low doses of ethanol on existing carcinoma cells in combination with natural substances are still unclear. A role for ethanol (EtOH), taken in small amounts as an ingredient of some beverages or mouthwashes to change the growth behavior of established squamous cell carcinoma, has still not been examined sufficiently. We designed an in vitro study to determine the effect of caffeic acid (CFA) on viability and migration ability of malignant oral epithelial keratinocytes, exposed to ultra-low concentrations (maximum 100 mmol/L) EtOH. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-dimethyltetrazolium bromide) and LDH (lactate dehydrogenase) assays were used to assess the cytotoxic effect of EtOH/CFA and the viability of squamous carcinoma SCC-25 cells (ATCC CRL-1628, mobile part of the tongue). Tested EtOH concentrations were: 2.5, 5, 10, 25, 50, and 100 mmol/L, along with an equal CFA concentration of 50 μmol/L. Carcinoma cells’ migration was investigated by monolayer “wound” healing assay. We demonstrated that very low concentrations of EtOH ranging between 2.5 and 10 mmol/L may induce the viability of oral squamous cell carcinoma cells, while the results following addition of CFA reveal an antagonistic effect, attenuating pro-proliferative EtOH activity. The migration rate of oral squamous carcinoma cells can be significantly inhibited by the biological activity of caffeic acid. Full article

(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols)

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5 pages, 621 KiB

Open AccessEditorial

Marketing Netcoatings for Aquaculture

by Robert J. Martin

318 Westover Drive, Asheville, NC 28801, USA

Int. J. Mol. Sci. 2014, 15(10), 18742-18746; https://doi.org/10.3390/ijms151018742 - 17 Oct 2014

Viewed by 4623

Abstract

Unsustainable harvesting of natural fish stocks is driving an ever growing marine aquaculture industry. Part of the aquaculture support industry is net suppliers who provide producers with nets used in confining fish while they are grown to market size. Biofouling must be addressed [...] Read more.

Unsustainable harvesting of natural fish stocks is driving an ever growing marine aquaculture industry. Part of the aquaculture support industry is net suppliers who provide producers with nets used in confining fish while they are grown to market size. Biofouling must be addressed in marine environments to ensure maximum product growth by maintaining water flow and waste removal through the nets. Biofouling is managed with copper and organic biocide based net coatings. The aquaculture industry provides a case study for business issues related to entry of improved fouling management technology into the marketplace. Several major hurdles hinder entry of improved novel technologies into the market. The first hurdle is due to the structure of business relationships. Net suppliers can actually cut their business profits dramatically by introducing improved technologies. A second major hurdle is financial costs of registration and demonstration of efficacy and quality product with a new technology. Costs of registration are prohibitive if only the net coatings market is involved. Demonstration of quality product requires collaboration and a team approach between formulators, net suppliers and farmers. An alternative solution is a vertically integrated business model in which the support business and product production business are part of the same company. Full article

(This article belongs to the Special Issue New Non (Limited)-Toxic Antifouling Solutions)

15 pages, 8803 KiB

Open AccessArticle

Association between the Hypomethylation of Osteopontin and Integrin β3 Promoters and Vascular Smooth Muscle Cell Phenotype Switching in Great Saphenous Varicose Veins

by Han Jiang, Yu Lun, Xiaoyu Wu, Qian Xia, Xiaoyu Zhang, Shijie Xin and Jian Zhang^*

Department of Vascular and Thyroid Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, China

Int. J. Mol. Sci. 2014, 15(10), 18747-18761; https://doi.org/10.3390/ijms151018747 - 17 Oct 2014

Cited by 30 | Viewed by 8237

Abstract

Lower extremity varicose veins are a common condition in vascular surgery and proliferation of vascular smooth muscle cells (VSMCs) in the intima is a significant pathological feature of varicosity. However, the pathogenesis of varicose veins is not fully understood. Osteopontin (OPN) could promote [...] Read more.

Lower extremity varicose veins are a common condition in vascular surgery and proliferation of vascular smooth muscle cells (VSMCs) in the intima is a significant pathological feature of varicosity. However, the pathogenesis of varicose veins is not fully understood. Osteopontin (OPN) could promote the migration and adhesion of VSMCs through the cell surface receptor integrin β3 and the cooperation of OPN and integrin β3 is involved in many vascular diseases. However, the role of OPN and integrin β3 in varicosity remains unclear. In the current study, we found that the methylation levels in the promoter regions of OPN and integrin β3 genes in the VSMCs of varicose veins are reduced and the protein expression of OPN and integrin β3 are increased, compared with normal veins. Furthermore, it was observed that VSMCs in the neointima of varicose veins were transformed into the synthetic phenotype. Collectively, hypomethylation of the promoter regions for OPN and integrin β3 genes may increase the expression of these genes in varicosity, which is closely related to VSMC phenotype switching. Hypomethylation of the promoter regions for OPN and integrin β3 genes may be a key factor in the pathogenesis of varicosity. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 1323 KiB

Open AccessArticle

Squamosamide Derivative FLZ Protects Retinal Pigment Epithelium Cells from Oxidative Stress through Activation of Epidermal Growth Factor Receptor (EGFR)-AKT Signaling

by Li-Bo Cheng^*,†, Chun-Ming Chen^†, Hong Zhong and Li-Juan Zhu^*

¹ Eye Department, Li-yang City Hospital of Traditional Chinese Medicine, Li-Yang City 213300, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18762-18775; https://doi.org/10.3390/ijms151018762 - 17 Oct 2014

Cited by 17 | Viewed by 7652

Abstract

Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the [...] Read more.

Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the pro-survival effect of FLZ in oxidative stressed-RPE cells and studied the underlying signaling mechanisms. Our results showed that FLZ attenuated hydrogen peroxide (H₂O₂)-induced viability decrease and apoptosis in the RPE cell line (ARPE-19 cells) and in primary mouse RPE cells. Western blotting results showed that FLZ activated AKT signaling in RPE cells. The AKT-specific inhibitor, MK-2206, the phosphoinositide 3-kinase (PI3K)/AKT pan inhibitor, wortmannin, and AKT1-shRNA (short hairpin RNA) depletion almost abolished FLZ-mediated pro-survival/anti-apoptosis activity. We discovered that epidermal growth factor receptor (EGFR) trans-activation mediated FLZ-induced AKT activation and the pro-survival effect in RPE cells, and the anti-apoptosis effect of FLZ against H₂O₂ was inhibited by the EGFR inhibitor, PD153035, or by EGFR shRNA-knockdown. In conclusion, FLZ protects RPE cells from oxidative stress through activation of EGFR-AKT signaling, and our results suggest that FLZ might have therapeutic values for AMD. Full article

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

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13 pages, 6239 KiB

Open AccessArticle

Biocompatible PEGylated Fe3O4 Nanoparticles as Photothermal Agents for Near-Infrared Light Modulated Cancer Therapy

by Gang Yuan, Yongjie Yuan, Kan Xu^* and Qi Luo^*

Department of Neurosurgery, the First Hospital of Jilin University, Changchun 130021, China

Int. J. Mol. Sci. 2014, 15(10), 18776-18788; https://doi.org/10.3390/ijms151018776 - 17 Oct 2014

Cited by 50 | Viewed by 9960

Abstract

In accordance with the World Cancer Report, cancer has become the leading cause of mortality worldwide, and various therapeutic strategies have been developed at the same time. In the present study, biocompatible magnetic nanoparticles were designed and synthesized as high-performance photothermal agents for [...] Read more.

In accordance with the World Cancer Report, cancer has become the leading cause of mortality worldwide, and various therapeutic strategies have been developed at the same time. In the present study, biocompatible magnetic nanoparticles were designed and synthesized as high-performance photothermal agents for near-infrared light mediated cancer therapy in vitro. Via a facile one-pot solvothermal method, well-defined PEGylated magnetic nanoparticles (PEG–Fe3O4) were prepared with cheap inhesion as a first step. Due to the successful coating of PEG molecules on the surface of PEG–Fe3O4, these nanoparticles exhibited excellent dispersibility and dissolvability in physiological condition. Cytotoxicity based on MTT assays indicated these nanoparticles revealed high biocompatibility and low toxicity towards both Hela cells and C6 cells. After near-infrared (NIR) laser irradiation, the viabilities of C6 cells were effectively suppressed when incubated with the NIR laser activated PEG–Fe3O4. In addition, detailed photothermal anti-cancer efficacy was evaluated via visual microscope images, demonstrating that our PEG–Fe3O4 were promising for photothermal therapy of cancer cells. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2015)

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15 pages, 924 KiB

Open AccessArticle

Cartilage Turnover Reflected by Metabolic Processing of Type II Collagen: A Novel Marker of Anabolic Function in Chondrocytes

by Natasja Stæhr Gudmann^1,*, Jianxia Wang¹, Sabine Hoielt¹, Pingping Chen¹, Anne Sofie Siebuhr¹, Yi He¹, Thorbjørn G. Christiansen², Morten Asser Karsdal¹ and Anne Christine Bay-Jensen^1,*

¹ Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730 Herlev, Denmark

² Orthopedic Department Z, Gentofte University Hospital, Niels Andersensvej 65, DK-2900 Hellerup, Denmark

Int. J. Mol. Sci. 2014, 15(10), 18789-18803; https://doi.org/10.3390/ijms151018789 - 17 Oct 2014

Cited by 41 | Viewed by 6734

Abstract

The aim of this study was to enable measurement of cartilage formation by a novel biomarker of type II collagen formation. The competitive enzyme-linked immunosorbent assay (ELISA) Pro-C2 was developed and characterized for assessment of the beta splice variant of type II procollagen [...] Read more.

The aim of this study was to enable measurement of cartilage formation by a novel biomarker of type II collagen formation. The competitive enzyme-linked immunosorbent assay (ELISA) Pro-C2 was developed and characterized for assessment of the beta splice variant of type II procollagen (PIIBNP). This is expected to originate primarily from remodeling of hyaline cartilage. A mouse monoclonal antibody (Mab) was raised in mouse, targeting specifically PIIBNP (QDVRQPG) and used in development of the assay. The specificity, sensitivity, 4-parameter fit and stability of the assay were tested. Levels of PIIBNP were quantified in human serum (0.6–2.2 nM), human amniotic fluid (163–188 nM) and sera from different animal species, e.g., fetal bovine serum (851–901 nM) with general good linearity (100% (SD 7.6) recovery) and good intra- and inter-assay variation (CV% < 10). Dose (0.1 to 100 ng/mL) and time (7, 14 and 21 days) dependent release of PIIBNP were evaluated in the conditioned medium from bovine cartilage explants (BEX) and human cartilage explants (HEX) upon stimulation with insulin-like growth factor (IGF-1), transforming growth factor (TGF)-β1 and fibroblastic growth factor-2 (FGF-2). TGF-β1 and IGF-1 in concentrations of 10–100 ng/mL significantly (p < 0.05) induced release of PIIBNP in BEX compared to conditions without treatment (WO). In HEX, IGF-1 100 ng/mL was able to induce a significant increase of PIIBNP after one week compared to WO. FGF-2 did not induce a PIIBNP release in our models. To our knowledge this is the first assay, which is able to specifically evaluate PIIBNP excretion. The Pro-C2 assay seems to provide a promising and novel marker of type II collagen formation. Full article

(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)

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15 pages, 930 KiB

Open AccessArticle

Characterization, Expression Profile, and Promoter Analysis of the Rhodeus uyekii Vitellogenin Ao1 Gene

by Hee Jeong Kong¹, Ju Lan Kim¹, Ji Young Moon¹, Woo-Jin Kim¹, Hyung Soo Kim¹, Jung Youn Park¹, Hyun Kook Cho^2,* and Cheul Min An¹

¹ Biotechnology Research Division, National Fisheries Research and Development Institute, Busan 619-705, Korea

² Department of Molecular Biology, Pusan National University, Busan 609-735, Korea

Int. J. Mol. Sci. 2014, 15(10), 18804-18818; https://doi.org/10.3390/ijms151018804 - 17 Oct 2014

Cited by 12 | Viewed by 6208

Abstract

The fish Vitellogenin (Vg) gene has been applied as a biomarker for exposure to estrogenic compounds in the aquatic environment. In this study, we cloned and characterized Vg cDNA from the Korean rose bitterling Rhodeus uyekii (Ru-Vg). The Ru-Vg cDNA encodes a 1424-amino-acid [...] Read more.

The fish Vitellogenin (Vg) gene has been applied as a biomarker for exposure to estrogenic compounds in the aquatic environment. In this study, we cloned and characterized Vg cDNA from the Korean rose bitterling Rhodeus uyekii (Ru-Vg). The Ru-Vg cDNA encodes a 1424-amino-acid polypeptide that belongs to the VgAo1 family and contains a putative signal peptide, lipovitellin I, phosvitin, and lipovitellin II, but does not contain the vWFD domain or the C-terminal peptide. The deduced Ru-Vg protein has high amino acid identity (73.97%–32.17%) with fish Vg proteins. Pairwise alignment and phylogenetic analysis revealed that Ru-Vg is most closely related to Acheilognathus yamatsutae Vg. Ru-Vg transcripts were detected using quantitative polymerase chain reaction in all tissues tested, with the highest level of expression observed in the ovary. Ru-Vg mRNA was upregulated in R. uyekii hepatopancreas cells in response to treatment with 17β-estradiol (E2) or 17α-ethinylestradiol (EE2). Luciferase reporter expression, driven by the 5'-regulatory region of the Ru-Vg gene spanning from −1020 bp to the start codon was induced by the estrogen receptor and was synergistically activated by treatment with E2 or EE2. These results suggest that R. uyekii and the Ru-Vg gene may be useful as biomarkers for exposure to E2 or EE2. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 833 KiB

Open AccessArticle

Metaphylogenomic and Potential Functionality of the Limpet Patella pellucida’s Gastrointestinal Tract Microbiome

by Magda Dudek, Jessica Adams, Martin Swain, Matthew Hegarty, Sharon Huws and Joe Gallagher^*

Institute of Biological, Environmental & Rural Sciences (IBERS), Aberystwyth University, Gogerddan, Aberystwyth, Ceredigion, Wales SY23 3EE, UK

Int. J. Mol. Sci. 2014, 15(10), 18819-18839; https://doi.org/10.3390/ijms151018819 - 20 Oct 2014

Cited by 14 | Viewed by 8919

Abstract

This study investigated the microbial diversity associated with the digestive tract of the seaweed grazing marine limpet Patella pellucida. Using a modified indirect DNA extraction protocol and performing metagenomic profiling based on specific prokaryotic marker genes, the abundance of bacterial groups was [...] Read more.

This study investigated the microbial diversity associated with the digestive tract of the seaweed grazing marine limpet Patella pellucida. Using a modified indirect DNA extraction protocol and performing metagenomic profiling based on specific prokaryotic marker genes, the abundance of bacterial groups was identified from the analyzed metagenome. The members of three significantly abundant phyla of Proteobacteria, Firmicutes and Bacteroidetes were characterized through the literature and their predicted functions towards the host, as well as potential applications in the industrial environment assessed. Full article

(This article belongs to the Special Issue Metagenomics: a Powerful Lens Viewing the Microbial World)

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16 pages, 3543 KiB

Open AccessArticle

Fucoidan, a Sulfated Polysaccharide, Inhibits Osteoclast Differentiation and Function by Modulating RANKL Signaling

by Young Woo Kim¹, Seung-Hoon Baek¹, Sang-Han Lee^2,3

, Tae-Ho Kim^4,5,* and Shin-Yoon Kim^1,4,*

¹ Department of Orthopedic Surgery, Kyungpook National University School of Medicine, Daegu 700-422, Korea

² Department of Food Science & Biotechnology, Kyungpook National University, Daegu 702-701, Korea

³ Food & Bio-Industry Research Institute, Kyungpook National University, Daegu 702-701, Korea

⁴ Skeletal Diseases Genome Research Center, Kyungpook National University, Daegu 700-721, Korea

⁵ Biomedical Research Institute, Kyungpook National University Hospital, Daegu 700-721, Korea

Int. J. Mol. Sci. 2014, 15(10), 18840-18855; https://doi.org/10.3390/ijms151018840 - 20 Oct 2014

Cited by 32 | Viewed by 9376

Abstract

Multinucleated osteoclasts differentiate from hematopoietic progenitors of the monocyte/macrophage lineage. Because of its pivotal role in bone resorption, regulation of osteoclast differentiation is a potential therapeutic approach to the treatment of erosive bone disease. In this study, we have found that fucoidan, a [...] Read more.

Multinucleated osteoclasts differentiate from hematopoietic progenitors of the monocyte/macrophage lineage. Because of its pivotal role in bone resorption, regulation of osteoclast differentiation is a potential therapeutic approach to the treatment of erosive bone disease. In this study, we have found that fucoidan, a sulfated polysaccharide extracted from brown seaweed, inhibited osteoclast differentiation. In particular, addition of fucoidan into the early stage osteoclast cultures significantly inhibited receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced osteoclast formation, thus suggesting that fucoidan affects osteoclast progenitors. Furthermore, fucoidan significantly inhibited the activation of RANKL-dependent mitogen-activated protein kinases (MAPKs) such as JNK, ERK, and p38, and also c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. In addition, the activation of NF-κB, which is an upstream transcription factor modulating NFATc1 expression, was alleviated in the fucoidan-treated cells. These results collectively suggest that fucoidan inhibits osteoclastogenesis from bone marrow macrophages by inhibiting RANKL-induced p38, JNK, ERK and NF-κB activation, and by downregulating the expression of genes that partake in both osteoclast differentiation and resorption. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)

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36 pages, 2195 KiB

Open AccessReview

Computer-Aided Targeting of the PI3K/Akt/mTOR Pathway: Toxicity Reduction and Therapeutic Opportunities

by Tan Li and Guanyu Wang^*

Department of Biology, South University of Science and Technology of China, 1088 Xueyuan Rd., Shenzhen 518055, China

Int. J. Mol. Sci. 2014, 15(10), 18856-18891; https://doi.org/10.3390/ijms151018856 - 20 Oct 2014

Cited by 73 | Viewed by 9931

Abstract

The PI3K/Akt/mTOR pathway plays an essential role in a wide range of biological functions, including metabolism, macromolecular synthesis, cell growth, proliferation and survival. Its versatility, however, makes it a conspicuous target of many pathogens; and the consequential deregulations of this pathway often lead [...] Read more.

The PI3K/Akt/mTOR pathway plays an essential role in a wide range of biological functions, including metabolism, macromolecular synthesis, cell growth, proliferation and survival. Its versatility, however, makes it a conspicuous target of many pathogens; and the consequential deregulations of this pathway often lead to complications, such as tumorigenesis, type 2 diabetes and cardiovascular diseases. Molecular targeted therapy, aimed at modulating the deregulated pathway, holds great promise for controlling these diseases, though side effects may be inevitable, given the ubiquity of the pathway in cell functions. Here, we review a variety of factors found to modulate the PI3K/Akt/mTOR pathway, including gene mutations, certain metabolites, inflammatory factors, chemical toxicants, drugs found to rectify the pathway, as well as viruses that hijack the pathway for their own synthetic purposes. Furthermore, this evidence of PI3K/Akt/mTOR pathway alteration and related pathogenesis has inspired the exploration of computer-aided targeting of this pathway to optimize therapeutic strategies. Herein, we discuss several possible options, using computer-aided targeting, to reduce the toxicity of molecularly-targeted therapy, including mathematical modeling, to reveal system-level control mechanisms and to confer a low-dosage combination therapy, the potential of PP2A as a therapeutic target, the formulation of parameters to identify patients who would most benefit from specific targeted therapies and molecular dynamics simulations and docking studies to discover drugs that are isoform specific or mutation selective so as to avoid undesired broad inhibitions. We hope this review will stimulate novel ideas for pharmaceutical discovery and deepen our understanding of curability and toxicity by targeting the PI3K/Akt/mTOR pathway. Full article

(This article belongs to the Special Issue Computational Toxicology: Predicting Potential Toxicity of Drugs and Therapeutics)

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27 pages, 5856 KiB

Open AccessArticle

Protein Profiles Reveal Diverse Responsive Signaling Pathways in Kernels of Two Maize Inbred Lines with Contrasting Drought Sensitivity

by Liming Yang^1,2,3,†, Tingbo Jiang^4,†, Jake C. Fountain², Brian T. Scully¹, Robert D. Lee⁵, Robert C. Kemerait², Sixue Chen⁶ and Baozhu Guo^1,*

¹ USDA-ARS, Crop Protection and Management Research Unit, Tifton, GA 31793, USA

² Department of Plant Pathology, University of Georgia, Tifton, GA 31793, USA

³ School of Life Sciences, Huaiyin Normal University, Huaian 223300, China

⁴ State Key Laboratory of Tree Genetics and Breeding, Northeast Forestry University, Harbin 150040, China

⁵ Department of Crop and Soil Sciences, University of Georgia, Tifton, GA 31793, USA

⁶ Department of Biology, Genetics Institute, and Plant Molecular & Cellular Biology Program, University of Florida, Gainesville, FL 32611, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18892-18918; https://doi.org/10.3390/ijms151018892 - 20 Oct 2014

Cited by 35 | Viewed by 8095

Abstract

Drought stress is a major factor that contributes to disease susceptibility and yield loss in agricultural crops. To identify drought responsive proteins and explore metabolic pathways involved in maize tolerance to drought stress, two maize lines (B73 and Lo964) with contrasting drought sensitivity [...] Read more.

Drought stress is a major factor that contributes to disease susceptibility and yield loss in agricultural crops. To identify drought responsive proteins and explore metabolic pathways involved in maize tolerance to drought stress, two maize lines (B73 and Lo964) with contrasting drought sensitivity were examined. The treatments of drought and well water were applied at 14 days after pollination (DAP), and protein profiles were investigated in developing kernels (35 DAP) using iTRAQ (isobaric tags for relative and absolute quantitation). Proteomic analysis showed that 70 and 36 proteins were significantly altered in their expression under drought treatments in B73 and Lo964, respectively. The numbers and levels of differentially expressed proteins were generally higher in the sensitive genotype, B73, implying an increased sensitivity to drought given the function of the observed differentially expressed proteins, such as redox homeostasis, cell rescue/defense, hormone regulation and protein biosynthesis and degradation. Lo964 possessed a more stable status with fewer differentially expressed proteins. However, B73 seems to rapidly initiate signaling pathways in response to drought through adjusting diverse defense pathways. These changes in protein expression allow for the production of a drought stress-responsive network in maize kernels. Full article

(This article belongs to the Section Biochemistry)

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22 pages, 3377 KiB

Open AccessArticle

Protective Effects of a New Phloretin Derivative against UVB-Induced Damage in Skin Cell Model and Human Volunteers

by Seoungwoo Shin

, Hyunwoo Kum, Dehun Ryu, Minkyung Kim, Eunsun Jung^* and Deokhoon Park^*

Biospectrum Life Science Institute, Seoungnam City, Gyunggi Do 462-807, Korea

Int. J. Mol. Sci. 2014, 15(10), 18919-18940; https://doi.org/10.3390/ijms151018919 - 20 Oct 2014

Cited by 40 | Viewed by 9487

Abstract

The phenolic compound phloretin is a prominent member of the chemical class of dihydrochalcones. Phloretin is specifically found in apple and apple juice and known for its biological properties. We were particularly interested in its potential dermo-cosmetic applications. However, practical limitations of phloretin [...] Read more.

The phenolic compound phloretin is a prominent member of the chemical class of dihydrochalcones. Phloretin is specifically found in apple and apple juice and known for its biological properties. We were particularly interested in its potential dermo-cosmetic applications. However, practical limitations of phloretin do exist due to its poor water-solubility. Phloretin was sulfonated with sulfuric acid (98%, wt) and mixed with saturated salt water to produce phloretin 3',3-disulfonate in order to increase its water-solubility. Here we reported the photoprotective effect of phloretin 3',3-disulfonate (PS), a new semi-synthetic derivative of phloretin. Results showed that PS attenuated cyclobutane pyrimidine dimer (CPDs) formation, glutathione (GSH) depletion and apoptosis induced by ultraviolet B (UVB). The photoprotective effect of PS is tightly correlated to the enhancement of nucleotide excision repair (NER) gene expression. Furthemore, PS had inhibitory effects on UVB-induced release of the inflammatory mediators, such as IL-6 and prostaglandin-E₂. We also confirmed the safety and clinical efficacy of PS on human skin. Overall, the results demonstrated significant benefits of PS on the protection of keratinocytes against UVB-induced injuries and suggested its potential use in skin photoprotection. Full article

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

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26 pages, 2426 KiB

Open AccessReview

Metabolomics of Genetically Modified Crops

by Carolina Simó, Clara Ibáez, Alberto Valdés

, Alejandro Cifuentes

and Virginia García-Cañas^*

Laboratory of Foodomics, Institute of Food Science Research (CIAL), Spanish National Research Council (CSIC), Nicolas Cabrera 9, Cantoblanco Campus, Madrid 28049, Spain

Int. J. Mol. Sci. 2014, 15(10), 18941-18966; https://doi.org/10.3390/ijms151018941 - 20 Oct 2014

Cited by 79 | Viewed by 12566

Abstract

Metabolomic-based approaches are increasingly applied to analyse genetically modified organisms (GMOs) making it possible to obtain broader and deeper information on the composition of GMOs compared to that obtained from traditional analytical approaches. The combination in metabolomics of advanced analytical methods and bioinformatics [...] Read more.

Metabolomic-based approaches are increasingly applied to analyse genetically modified organisms (GMOs) making it possible to obtain broader and deeper information on the composition of GMOs compared to that obtained from traditional analytical approaches. The combination in metabolomics of advanced analytical methods and bioinformatics tools provides wide chemical compositional data that contributes to corroborate (or not) the substantial equivalence and occurrence of unintended changes resulting from genetic transformation. This review provides insight into recent progress in metabolomics studies on transgenic crops focusing mainly in papers published in the last decade. Full article

(This article belongs to the Special Issue Detection and Safety Assessment of Genetically Modified Organisms)

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18 pages, 687 KiB

Open AccessReview

Extrusion Pretreatment of Lignocellulosic Biomass: A Review

by Jun Zheng and Lars Rehmann^*

Department of Chemical and Biochemical Engineering, University of Western Ontario, 1151 Richmond Street, London, ON N6A 3K7, Canada

Int. J. Mol. Sci. 2014, 15(10), 18967-18984; https://doi.org/10.3390/ijms151018967 - 20 Oct 2014

Cited by 166 | Viewed by 11520

Abstract

Bioconversion of lignocellulosic biomass to bioethanol has shown environmental, economic and energetic advantages in comparison to bioethanol produced from sugar or starch. However, the pretreatment process for increasing the enzymatic accessibility and improving the digestibility of cellulose is hindered by many physical-chemical, structural [...] Read more.

Bioconversion of lignocellulosic biomass to bioethanol has shown environmental, economic and energetic advantages in comparison to bioethanol produced from sugar or starch. However, the pretreatment process for increasing the enzymatic accessibility and improving the digestibility of cellulose is hindered by many physical-chemical, structural and compositional factors, which make these materials difficult to be used as feedstocks for ethanol production. A wide range of pretreatment methods has been developed to alter or remove structural and compositional impediments to (enzymatic) hydrolysis over the last few decades; however, only a few of them can be used at commercial scale due to economic feasibility. This paper will give an overview of extrusion pretreatment for bioethanol production with a special focus on twin-screw extruders. An economic assessment of this pretreatment is also discussed to determine its feasibility for future industrial cellulosic ethanol plant designs. Full article

(This article belongs to the Special Issue Green Chemistry and the Biorefinery)

15 pages, 1018 KiB

Open AccessReview

Large Intervening Non-Coding RNA HOTAIR Is an Indicator of Poor Prognosis and a Therapeutic Target in Human Cancers

by Yanlan Yao¹, Jinming Li^2,*,† and Lunan Wang^2,*,†

¹ National Center for Clinical Laboratories, Graduate School of Peking Union Medical College, Beijing Hospital of the Ministry of Health, No. 1 Dahua Road, Beijing 100083, China

² National Center for Clinical Laboratories, Beijing Hospital of the Ministry of Health, No. 1 Dahua Road, Beijing 100083, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 18985-18999; https://doi.org/10.3390/ijms151018985 - 20 Oct 2014

Cited by 74 | Viewed by 9351

Abstract

In the human genome, the fraction of protein-coding genes that are stably transcribed is only up to 2%, with the remaining numerous RNAs having no protein-coding function. These non-coding RNAs (ncRNAs) have received considerable attention in cancer research in recent years. Breakthroughs have [...] Read more.

In the human genome, the fraction of protein-coding genes that are stably transcribed is only up to 2%, with the remaining numerous RNAs having no protein-coding function. These non-coding RNAs (ncRNAs) have received considerable attention in cancer research in recent years. Breakthroughs have been made in understanding microRNAs and small interfering RNAs, but larger RNAs such as long ncRNAs (lncRNAs) remain an enigma. One lncRNA, HOX antisense intergenic RNA (HOTAIR), has been shown to be dysregulated in many types of cancer, including breast cancer, colorectal cancer, and hepatoma. HOTAIR functions as a regulatory molecule in a wide variety of biological processes. However, its mechanism of action has not been clearly elucidated. It is widely believed that HOTAIR mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Further study of HOTAIR-related pathways and the role of HOTAIR in tumorigenesis and tumor progression may identify new treatment targets. In this review, we will focus on the characteristics of HOTAIR, as well as data pertaining to its mechanism and its association with cancers. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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18 pages, 4493 KiB

Open AccessArticle

CYP24A1 Expression Inversely Correlates with Melanoma Progression: Clinic-Pathological Studies

by Anna A. Brożyna^1,2,*, Cezary Jochymski², Zorica Janjetovic³, Wojciech Jóźwicki^1,2, Robert C. Tuckey⁴ and Andrzej T. Slominski^3,5,*

¹ Department of Tumor Pathology and Pathomorphology, the Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-796 Bygoszcz, Poland

² Department of Tumor Pathology and Pathomorphology, Oncology Centre-Prof. Franciszek Łukaszczyk Memorial Hospital, 85-796 Bygoszcz, Poland

³ Departments of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA

⁴ School of Chemistry and Biochemistry, the University of Western Australia, Crawley, WA 6009, Australia

⁵ Division of Rheumatology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA

Int. J. Mol. Sci. 2014, 15(10), 19000-19017; https://doi.org/10.3390/ijms151019000 - 20 Oct 2014

Cited by 42 | Viewed by 7721

Abstract

The major role of 24-hydroxylase (CYP24A1) is to maintain 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3) homeostasis. Recently, it has been discovered that CYP24A1 also catalyses the hydroxylation of 20(OH)D3, producing dihydroxy-derivatives that show very effective antitumorigenic activities. Previously we showed a negative correlation of [...] Read more.

The major role of 24-hydroxylase (CYP24A1) is to maintain 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3) homeostasis. Recently, it has been discovered that CYP24A1 also catalyses the hydroxylation of 20(OH)D3, producing dihydroxy-derivatives that show very effective antitumorigenic activities. Previously we showed a negative correlation of vitamin D receptor (VDR) and CYP27B1 expression with progression, aggressiveness and overall or disease-free survivals of skin melanomas. Therefore, we analyzed CYP24A1 expression in relation to clinicopathomorphological features of nevi, skin melanomas and metastases. In melanocytic tumors, the level of CYP24A1 was higher than in the normal epidermis. The statistically highest mean CYP24A1 level was found in nevi and early stage melanomas. With melanoma progression, CYP24A1 levels decreased and in advanced stages were comparable to the normal epidermis and metastases. Furthermore, the CYP24A1 expression positively correlated with VDR and CYP27B1, and negatively correlated with mitotic activity. Lower CYP24A1 levels correlated with the presence of ulceration, necrosis, nodular type and amelanotic phenotypes. Moreover, a lack of detectable CYP24A1 expression was related to shorter overall and disease-free survival. In conclusion, the local vitamin D endocrine system affects melanoma behavior and an elevated level of CYP24A1 appears to have an important impact on the formation of melanocytic nevi and melanomagenesis, or progression, at early stages of tumor development. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 6717 KiB

Open AccessArticle

Exercise Preconditioning Protects against Spinal Cord Injury in Rats by Upregulating Neuronal and Astroglial Heat Shock Protein 72

by Cheng-Kuei Chang^1,2,†, Willy Chou^3,4,†

, Hung-Jung Lin^5,6, Yi-Ching Huang⁷, Ling-Yu Tang⁵, Mao-Tsun Lin^8,* and Ching-Ping Chang^5,*

¹ Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei 110, Taiwan

² Neurosurgical Department, Taipei Medical University Shuang-Ho Hospital, Taipei 235, Taiwan

³ Physical Medicine and Rehabilitation Department, Chi Mei Medical Center, Tainan 710, Taiwan

⁴ Department of Leisure Management, Cha Nan University of Pharmacy and Science, Tainan 717, Taiwan

⁵ Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan

⁶ Department of Emergency Medicine, Chi Mei Medical Center, Tainan 710, Taiwan

⁷ Department of Radiology, Chi Mei Medical Center, Liouying, Tainan 736, Taiwan

⁸ Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 19018-19036; https://doi.org/10.3390/ijms151019018 - 20 Oct 2014

Cited by 21 | Viewed by 6892

Abstract

The heat shock protein 72 (HSP 72) is a universal marker of stress protein whose expression can be induced by physical exercise. Here we report that, in a localized model of spinal cord injury (SCI), exercised rats (given pre-SCI exercise) had significantly higher [...] Read more.

The heat shock protein 72 (HSP 72) is a universal marker of stress protein whose expression can be induced by physical exercise. Here we report that, in a localized model of spinal cord injury (SCI), exercised rats (given pre-SCI exercise) had significantly higher levels of neuronal and astroglial HSP 72, a lower functional deficit, fewer spinal cord contusions, and fewer apoptotic cells than did non-exercised rats. pSUPER plasmid expressing HSP 72 small interfering RNA (SiRNA-HSP 72) was injected into the injured spinal cords. In addition to reducing neuronal and astroglial HSP 72, the (SiRNA-HSP 72) significantly attenuated the beneficial effects of exercise preconditioning in reducing functional deficits as well as spinal cord contusion and apoptosis. Because exercise preconditioning induces increased neuronal and astroglial levels of HSP 72 in the gray matter of normal spinal cord tissue, exercise preconditioning promoted functional recovery in rats after SCI by upregulating neuronal and astroglial HSP 72 in the gray matter of the injured spinal cord. We reveal an important function of neuronal and astroglial HSP 72 in protecting neuronal and astroglial apoptosis in the injured spinal cord. We conclude that HSP 72-mediated exercise preconditioning is a promising strategy for facilitating functional recovery from SCI. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 814 KiB

Open AccessArticle

ToxDBScan: Large-Scale Similarity Screening of Toxicological Databases for Drug Candidates

by Michael Römer^*, Linus Backert, Johannes Eichner and Andreas Zell

Center of Bioinformatics Tuebingen (ZBIT), University of Tuebingen, Tübingen 72074, Germany

Int. J. Mol. Sci. 2014, 15(10), 19037-19055; https://doi.org/10.3390/ijms151019037 - 21 Oct 2014

Cited by 7 | Viewed by 6853

Abstract

We present a new tool for hepatocarcinogenicity evaluation of drug candidates in rodents. ToxDBScan is a web tool offering quick and easy similarity screening of new drug candidates against two large-scale public databases, which contain expression profiles for substances with known carcinogenic profiles: [...] Read more.

We present a new tool for hepatocarcinogenicity evaluation of drug candidates in rodents. ToxDBScan is a web tool offering quick and easy similarity screening of new drug candidates against two large-scale public databases, which contain expression profiles for substances with known carcinogenic profiles: TG-GATEs and DrugMatrix. ToxDBScan uses a set similarity score that computes the putative similarity based on similar expression of genes to identify chemicals with similar genotoxic and hepatocarcinogenic potential. We propose using a discretized representation of expression profiles, which use only information on up- or down-regulation of genes as relevant features. Therefore, only the deregulated genes are required as input. ToxDBScan provides an extensive report on similar compounds, which includes additional information on compounds, differential genes and pathway enrichments. We evaluated ToxDBScan with expression data from 15 chemicals with known hepatocarcinogenic potential and observed a sensitivity of 88 Based on the identified chemicals, we achieved perfect classification of the independent test set. ToxDBScan is publicly available from the ZBIT Bioinformatics Toolbox. Full article

(This article belongs to the Special Issue Computational Toxicology: Predicting Potential Toxicity of Drugs and Therapeutics)

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18 pages, 8072 KiB

Open AccessArticle

Neuroprotective Role of Liver Growth Factor “LGF” in an Experimental Model of Cerebellar Ataxia

by Lucía Calatrava-Ferreras^1,†, Rafael Gonzalo-Gobernado^1,†

, Diana Reimers¹, Antonio S. Herranz¹, Adriano Jiménez-Escrig², Juan José Díaz-Gil³, María José Casarejos¹, María Teresa Montero-Vega⁴ and Eulalia Bazán^1,*

¹ Service of Neurobiology, Ramón y Cajal Institute for Health Research (IRYCIS), Madrid 28034, Spain

² Service of Neurology, Ramón y Cajal Hospital, Madrid 28034, Spain

³ Service of Experimental Biochemistry, Puerta de Hierro-Majadahonda Hospital, Madrid 28222, Spain

⁴ Service of Biochemistry, Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid 28034, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 19056-19073; https://doi.org/10.3390/ijms151019056 - 21 Oct 2014

Cited by 6 | Viewed by 7045

Abstract

Cerebellar ataxias (CA) comprise a heterogeneous group of neurodegenerative diseases characterized by a lack of motor coordination. They are caused by disturbances in the cerebellum and its associated circuitries, so the major therapeutic goal is to correct cerebellar dysfunction. Neurotrophic factors enhance the [...] Read more.

Cerebellar ataxias (CA) comprise a heterogeneous group of neurodegenerative diseases characterized by a lack of motor coordination. They are caused by disturbances in the cerebellum and its associated circuitries, so the major therapeutic goal is to correct cerebellar dysfunction. Neurotrophic factors enhance the survival and differentiation of selected types of neurons. Liver growth factor (LGF) is a hepatic mitogen that shows biological activity in neuroregenerative therapies. We investigate the potential therapeutic activity of LGF in the 3-acetylpiridine (3-AP) rat model of CA. This model of CA consists in the lesion of the inferior olive-induced by 3-AP (40 mg/kg). Ataxic rats were treated with 5 µg/rat LGF or vehicle during 3 weeks, analyzing: (a) motor coordination by using the rota-rod test; and (b) the immunohistochemical and biochemical evolution of several parameters related with the olivo-cerebellar function. Motor coordination improved in 3-AP-lesioned rats that received LGF treatment. LGF up-regulated NeuN and Bcl-2 protein levels in the brainstem, and increased calbindin expression and the number of neurons receiving calbindin-positive projections in the cerebellum. LGF also reduced extracellular glutamate and GABA concentrations and microglia activation in the cerebellum. In view of these results, we propose LGF as a potential therapeutic agent in cerebellar ataxias. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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18 pages, 885 KiB

Open AccessArticle

Active Transport Can Greatly Enhance Cdc20:Mad2 Formation

by Bashar Ibrahim^1,2,3,*,†

and Richard Henze^3,†

¹ Al-Qunfudah University College, Umm Al-Qura University, 1109 Makkah Al-Mukarramah, Saudi Arabia

² Al-Qunfudah Center for Scientific Research (QCSR), 21912 Al-Qunfudah, Saudi Arabia

³ Bio Systems Analysis Group, Institute of Computer Science, Jena Center for Bioinformatics and Friedrich Schiller University, 07743 Jena, Germany

Int. J. Mol. Sci. 2014, 15(10), 19074-19091; https://doi.org/10.3390/ijms151019074 - 21 Oct 2014

Cited by 12 | Viewed by 7311

Abstract

To guarantee genomic integrity and viability, the cell must ensure proper distribution of the replicated chromosomes among the two daughter cells in mitosis. The mitotic spindle assembly checkpoint (SAC) is a central regulatory mechanism to achieve this goal. A dysfunction of this checkpoint [...] Read more.

To guarantee genomic integrity and viability, the cell must ensure proper distribution of the replicated chromosomes among the two daughter cells in mitosis. The mitotic spindle assembly checkpoint (SAC) is a central regulatory mechanism to achieve this goal. A dysfunction of this checkpoint may lead to aneuploidy and likely contributes to the development of cancer. Kinetochores of unattached or misaligned chromosomes are thought to generate a diffusible “wait-anaphase” signal, which is the basis for downstream events to inhibit the anaphase promoting complex/cyclosome (APC/C). The rate of Cdc20:C-Mad2 complex formation at the kinetochore is a key regulatory factor in the context of APC/C inhibition. Computer simulations of a quantitative SAC model show that the formation of Cdc20:C-Mad2 is too slow for checkpoint maintenance when cytosolic O-Mad2 has to encounter kinetochores by diffusion alone. Here, we show that an active transport of O-Mad2 towards the spindle mid-zone increases the efficiency of Mad2-activation. Our in-silico data indicate that this mechanism can greatly enhance the formation of Cdc20:Mad2 and furthermore gives an explanation on how the “wait-anaphase” signal can dissolve abruptly within a short time. Our results help to understand parts of the SAC mechanism that remain unclear. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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14 pages, 5426 KiB

Open AccessArticle

Enhanced Production of Bioactive Isoprenoid Compounds from Cell Suspension Cultures of Artemisia annua L. Using β-Cyclodextrins

by Francesca Rizzello, Angelo De Paolis, Miriana Durante

, Federica Blando

, Giovanni Mita

and Sofia Caretto^*

Istituto di Scienze delle Produzioni Alimentari—CNR, Via Prov.le Monteroni, 73100 Lecce, Italy

Int. J. Mol. Sci. 2014, 15(10), 19092-19105; https://doi.org/10.3390/ijms151019092 - 21 Oct 2014

Cited by 23 | Viewed by 7360

Abstract

Plant cell cultures as valuable tools for the production of specific metabolites can be greatly improved by the application of elicitors including cyclodextrins (CDs) for enhancing the yields of the desired plant compounds. Here the effects of 2,6-dimethyl-β-cyclodextrins (DIMEB) on the production of [...] Read more.

Plant cell cultures as valuable tools for the production of specific metabolites can be greatly improved by the application of elicitors including cyclodextrins (CDs) for enhancing the yields of the desired plant compounds. Here the effects of 2,6-dimethyl-β-cyclodextrins (DIMEB) on the production of carotenoids and quinones from Artemisia annua L. cell suspension cultures were investigated. The addition of 50 mM DIMEB induced an early increase of intracellular carotenoid and quinone contents, which could be observed to a higher extent for lutein (10-fold), Q9 (3-fold) and Q10 (2.5-fold). Real Time PCR analysis revealed that the expression of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) gene in DIMEB treated cell cultures after three days was 2.5-fold higher than in untreated samples, thus suggesting that the DIMEB induced increase of carotenoids and quinones could be due to the induction of the plastidial isoprenoid biosynthetic route. In addition, the DIMEB treatment induced an enhanced release of carotenoids and quinones into the culture medium of A. annua cell suspension cultures possibly due to the ability of CDs to form inclusion complexes with hydrophobic molecules. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 3044 KiB

Open AccessArticle

Protein/Arabinoxylans Gels: Effect of Mass Ratio on the Rheological, Microstructural and Diffusional Characteristics

by Claudia M. Berlanga-Reyes¹, Elizabeth Carvajal-Millan^1,*

, Kevin B. Hicks², Madhav P. Yadav², Agustín Rascón-Chu¹, Jaime Lizardi-Mendoza¹

, Alma R. Toledo-Guillén¹ and Alma R. Islas-Rubio¹

¹ Research Center for Food and Development, CIAD, Hermosillo, Sonora 83000, Mexico

² Eastern Regional Research Center, Agricultural Research Service, US Department of Agriculture, 600 East Mermaid Lane, Wyndmoor, PA 19038, USA

Int. J. Mol. Sci. 2014, 15(10), 19106-19118; https://doi.org/10.3390/ijms151019106 - 21 Oct 2014

Cited by 22 | Viewed by 6027

Abstract

Wheat bran arabinoxylan (WBAX) gels entrapping standard model proteins at different mass ratios were formed. The entrapment of protein affected the gel elasticity and viscosity values, which decreased from 177 to 138 Pa. The presence of protein did not modify the covalent cross-links [...] Read more.

Wheat bran arabinoxylan (WBAX) gels entrapping standard model proteins at different mass ratios were formed. The entrapment of protein affected the gel elasticity and viscosity values, which decreased from 177 to 138 Pa. The presence of protein did not modify the covalent cross-links content of the gel. The distribution of protein through the network was investigated by confocal laser scanning microscopy. In mixed gels, protein aggregates forming clusters were detected at protein/polysaccharide ratios higher than 0.25. These clusters were not homogeneously distributed, suggesting that WBAX and protein are located in two different phases. The apparent diffusion coefficient (Dm) of proteins during release from mixed gels was investigated for mass ratios of 0.06 and 0.12. For insulin, Dm increased significantly from 2.64 × 10⁻⁷ to 3.20 × 10⁻⁷ cm²/s as the mass ratio augmented from 0.06 to 0.12. No significant difference was found for Dm values of ovalbumin and bovine serum albumin released from the mixed gels. The results indicate that homogeneous protein/WBAX gels can be formed at low mass ratios, allowing the estimation of Dm by using an analytical solution of the second Fick’s law. Full article

(This article belongs to the Special Issue Supramolecular Polymers and Their Assemblies)

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15 pages, 2083 KiB

Open AccessArticle

Bistable Switch in let-7 miRNA Biogenesis Pathway Involving Lin28

by Fei Shi¹, Wenbao Yu^2,* and Xia Wang^3,*

¹ College of Veterinary Medicine, Sichuan Agricultural University, Ya'an 625014, Sichuan, China

² Department of Statistics, Seoul National University, Seoul 151-742, Korea

³ School of Medical Engineering, Hefei University of Technology, Hefei 230009, Anhui, China

Int. J. Mol. Sci. 2014, 15(10), 19119-19133; https://doi.org/10.3390/ijms151019119 - 21 Oct 2014

Cited by 5 | Viewed by 6323

Abstract

miRNAs are small noncoding RNAs capable of regulating gene expression at the post-transcriptional level. A growing body of evidence demonstrated that let-7 family of miRNAs, as one of the highly conserved miRNAs, plays an important role in cell differentiation and development, as well [...] Read more.

miRNAs are small noncoding RNAs capable of regulating gene expression at the post-transcriptional level. A growing body of evidence demonstrated that let-7 family of miRNAs, as one of the highly conserved miRNAs, plays an important role in cell differentiation and development, as well as tumor suppressor function depending on their levels of expression. To explore the physiological significance of let-7 in regulating cell fate decisions, we present a coarse grained model of let-7 biogenesis network, in which let-7 and its regulator Lin28 inhibit mutually. The dynamics of this minimal network architecture indicates that, as the concentration of Lin28 increases, the system undergoes a transition from monostability to a bistability and then to a one-way switch with increasing strength of positive feedback of let-7, while in the absence of Lin28 inhibition, the system loses bistability. Moreover, the ratio of degradation rates of let-7 and Lin28 is critical for the switching sensitivity and resistance to stimulus fluctuations. These findings may highlight why let-7 is required for normal gene expression in the context of embryonic development and oncogenesis, which will facilitate the development of approaches to exploit this regulatory pathway by manipulating Lin28/let-7 axis for novel treatments of human diseases. Full article

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

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13 pages, 3269 KiB

Open AccessArticle

Genetic Analysis of 430 Chinese Cynodon dactylon Accessions Using Sequence-Related Amplified Polymorphism Markers

by Chunqiong Huang^*, Guodao Liu^*, Changjun Bai and Wenqiang Wang

Tropical Crops Genetic Resources Institute, Chinese Academy of Tropical Agricultural Sciences, Key Laboratory of Crop Gene Resources and Germplasm Enhancement in Southern China, Ministry of Agriculture, Danzhou 571737, China

Int. J. Mol. Sci. 2014, 15(10), 19134-19146; https://doi.org/10.3390/ijms151019134 - 21 Oct 2014

Cited by 14 | Viewed by 5772

Abstract

Although Cynodon dactylon (C. dactylon) is widely distributed in China, information on its genetic diversity within the germplasm pool is limited. The objective of this study was to reveal the genetic variation and relationships of 430 C. dactylon accessions collected from [...] Read more.

Although Cynodon dactylon (C. dactylon) is widely distributed in China, information on its genetic diversity within the germplasm pool is limited. The objective of this study was to reveal the genetic variation and relationships of 430 C. dactylon accessions collected from 22 Chinese provinces using sequence-related amplified polymorphism (SRAP) markers. Fifteen primer pairs were used to amplify specific C. dactylon genomic sequences. A total of 481 SRAP fragments were generated, with fragment sizes ranging from 260–1800 base pairs (bp). Genetic similarity coefficients (GSC) among the 430 accessions averaged 0.72 and ranged from 0.53–0.96. Cluster analysis conducted by two methods, namely the unweighted pair-group method with arithmetic averages (UPGMA) and principle coordinate analysis (PCoA), separated the accessions into eight distinct groups. Our findings verify that Chinese C. dactylon germplasms have rich genetic diversity, which is an excellent basis for C. dactylon breeding for new cultivars. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 3053 KiB

Open AccessArticle

Identification and Molecular Characterization of a Chitin-Binding Protein from the Beet Webworm, Loxostege sticticalis L.

by Jiao Yin¹, Shuang Yang¹, Kebin Li¹, Wei Guo^2,* and Yazhong Cao^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 Plant Science and Technology College, Beijing University of Agriculture, Beijing 102206, China

Int. J. Mol. Sci. 2014, 15(10), 19147-19161; https://doi.org/10.3390/ijms151019147 - 22 Oct 2014

Cited by 10 | Viewed by 6238

Abstract

As the first crucial barrier in the midgut of insects, the peritrophic membrane (PM) plays an important role in preventing external invasion. PM proteins, as the major components of the PM, determine the structure and function of this membrane. A new PM protein, [...] Read more.

As the first crucial barrier in the midgut of insects, the peritrophic membrane (PM) plays an important role in preventing external invasion. PM proteins, as the major components of the PM, determine the structure and function of this membrane. A new PM protein, named LstiCBP, from the PM of Loxostege sticticalis larvae was identified using cDNA library screening. The full cDNA of LstiCBP is 2606 bp in length and contains a 2403 bp ORF that encodes an 808-amino acid preprotein with a 15-amino acid as signal peptide. The deduced protein sequence of the cDNA contains 8 cysteine-rich chitin-binding domains (CBDs). Recombinant LstiCBP was successfully expressed in BL21 cells using recombinant plasmid DNA and showed high chitin-binding activity. LstiCBP expression was detected in the midgut at both the transcriptional and translational levels; however, the biochemical and physiological functions of LstiCBP in L. sticticalis require further investigation. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 12187 KiB

Open AccessArticle

Molecular Characteristics and Biochemical Functions of VpPR10s from Vitis pseudoreticulata Associated with Biotic and Abiotic Stresses

by Lan Wang^1,2,3,†, Jinyu Wei^1,2,3,†, Ying Zou^1,2,3, Keyao Xu^1,2,3, Yuejin Wang^1,2,3, Lu Cui^4,* and Yan Xu^1,2,3,*

¹ State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling 712100, Shaanxi, China

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

³ Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Yangling 712100, Shaanxi, China

⁴ College of Food Science Engineering, Northwest A&F University, Yangling 712100, Shaanxi, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(10), 19162-19182; https://doi.org/10.3390/ijms151019162 - 22 Oct 2014

Cited by 19 | Viewed by 6461

Abstract

Grapes are one of the world’s oldest and most important fruit crops. They are of high economic value in many countries, but the susceptibility of the dominant winegrape species Vitis vinifera to fungal disease is a significant problem. The Chinese wild grape species [...] Read more.

Grapes are one of the world’s oldest and most important fruit crops. They are of high economic value in many countries, but the susceptibility of the dominant winegrape species Vitis vinifera to fungal disease is a significant problem. The Chinese wild grape species are a rich source of disease-resistance genes and these can be used to discover how disease resistance in V. vinifera grapevines might be enhanced. Pathogenesis-related (PR) 10 proteins are involved in the disease-response. Here, we use the genomic DNA of the Chinese wild species Vitis pseudoreticulata accession “Baihe-35-1” as the template to design specific primers based on VvPR10s sequences. We used overlap extension PCR to obtain the sequences: VpPR10.4, VpPR10.6, VpPR10.7 and VpPR10.9. The coding sequences of the VpPR10s were then cloned into the pGEX-4T-1 vector. The purified proteins VpPR10.4, VpPR10.6, VpPR10.7 and VpPR10.9 were used to analyse nuclease activity. Meanwhile, functional analysis of VpPR10s under different biotic and abiotic stresses was carried out to further clarify the disease-resistance mechanisms of the Chinese wild grapevine VpPR10 genes. The analysis of protein structure indicates that VpPR10.4 and VpPR10.7 had the P-loop domain and the Bet v 1 motif, which are a consistent feature of plant PR10. However, there was no P-loop domain or Bet v 1 motif in VpPR10.9 and we could not find the Bet v 1 motif in VpPR10.6. The results of the nuclease activity assay and of the functional analyses of VpPR10s under different biotic and abiotic stresses also confirm that VpPR10.4 and VpPR10.7 proteins have marked RNase, DNase, anti-fungal activities and respond to abiotic stresses. The VpPR10.6 and VpPR10.9 proteins do not have these activities and functions. Full article

(This article belongs to the Section Biochemistry)

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20 pages, 708 KiB

Open AccessReview

Culinary Herbs and Spices: Their Bioactive Properties, the Contribution of Polyphenols and the Challenges in Deducing Their True Health Benefits

by Elizabeth I. Opara^1,*

and Magali Chohan²

¹ School of Life Sciences, Kingston University, Penrhyn Road, Kingston upon Thames KT1 2EE, UK

² School of Sport, Health and Applied Science, St. Mary's University, Waldegrave Road, Strawberry Hill, Twickenham TW1 4SX, UK

Int. J. Mol. Sci. 2014, 15(10), 19183-19202; https://doi.org/10.3390/ijms151019183 - 22 Oct 2014

Cited by 165 | Viewed by 26878

Abstract

Herbs and spices have been used for both culinary and medicinal purposes for centuries. Over the last decade, research into their role as contributors of dietary polyphenols, known to possess a number of properties associated with reducing the risk of developing chronic non-communicable [...] Read more.

Herbs and spices have been used for both culinary and medicinal purposes for centuries. Over the last decade, research into their role as contributors of dietary polyphenols, known to possess a number of properties associated with reducing the risk of developing chronic non-communicable diseases, has increased. However, bearing in mind how these foods are consumed, normally in small quantities and in combination with other foods, it is unclear what their true benefit is from a health perspective. The aim of this review is to use the literature to discuss how preparative and digestive processes, bioavailability and interactions between foods may influence the bioactive properties of these foods, and whether or not polyphenols are responsible for these properties. Furthermore, this review aims to highlight the challenges that need to be addressed so as to determine the true benefits of these foods and the mechanisms of action that underpin their purported efficacy. Full article

(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols)

23 pages, 2308 KiB

Open AccessReview

Glutathionylation of the L-type Ca²⁺ Channel in Oxidative Stress-Induced Pathology of the Heart

by Victoria P. A. Johnstone¹

and Livia C. Hool^1,2,*

¹ School of Anatomy, Physiology and Human Biology, the University of Western Australia, Crawley 6009, WA, Australia

² Victor Chang Cardiac Research Institute, Darlinghurst 2010, NSW, Australia

Int. J. Mol. Sci. 2014, 15(10), 19203-19225; https://doi.org/10.3390/ijms151019203 - 22 Oct 2014

Cited by 18 | Viewed by 6568

Abstract

There is mounting evidence to suggest that protein glutathionylation is a key process contributing to the development of pathology. Glutathionylation occurs as a result of posttranslational modification of a protein and involves the addition of a glutathione moiety at cysteine residues. Such modification [...] Read more.

There is mounting evidence to suggest that protein glutathionylation is a key process contributing to the development of pathology. Glutathionylation occurs as a result of posttranslational modification of a protein and involves the addition of a glutathione moiety at cysteine residues. Such modification can occur on a number of proteins, and exerts a variety of functional consequences. The L-type Ca²⁺ channel has been identified as a glutathionylation target that participates in the development of cardiac pathology. Ca²⁺ influx via the L-type Ca²⁺ channel increases production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes during periods of oxidative stress. This induces a persistent increase in channel open probability, and the resulting constitutive increase in Ca²⁺ influx amplifies the cross-talk between the mitochondria and the channel. Novel strategies utilising targeted peptide delivery to uncouple mitochondrial ROS and Ca²⁺ flux via the L-type Ca²⁺ channel following ischemia-reperfusion have delivered promising results, and have proven capable of restoring appropriate mitochondrial function in myocytes and in vivo. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2015)

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13 pages, 1231 KiB

Open AccessReview

Stem Cell Treatment for Alzheimer’s Disease

by Ming Li¹, Kequan Guo² and Susumu Ikehara^1,*

¹ Department of Stem Cell Disorders, Kansai Medical University, 2-5-1 Shinmachi, Hirakata City, Osaka 573-1010, Japan

² Department of Cardiac Surgery, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, China

Int. J. Mol. Sci. 2014, 15(10), 19226-19238; https://doi.org/10.3390/ijms151019226 - 23 Oct 2014

Cited by 48 | Viewed by 15930

Abstract

Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder that induces dementia in older people. It was first reported in 1907 by Alois Alzheimer, who characterized the disease as causing memory loss and cognitive impairment. Pathologic characteristics of AD are β-amyloid plaques, neurofibrillary [...] Read more.

Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder that induces dementia in older people. It was first reported in 1907 by Alois Alzheimer, who characterized the disease as causing memory loss and cognitive impairment. Pathologic characteristics of AD are β-amyloid plaques, neurofibrillary tangles and neurodegeneration. Current therapies only target the relief of symptoms using various drugs, and do not cure the disease. Recently, stem cell therapy has been shown to be a potential approach to various diseases, including neurodegenerative disorders, and in this review, we focus on stem cell therapies for AD. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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14 pages, 1706 KiB

Open AccessArticle

Heparin Assisted Photochemical Synthesis of Gold Nanoparticles and Their Performance as SERS Substrates

by Maria Del Pilar Rodríguez-Torres¹, Luis Armando Díaz-Torres^1,* and Sergio Romero-Servin²

¹ Grupo de Espectroscopia de Materiales Avanzados y Nanoestructurados (GEMANA), Centro de Investigaciones en Óptica, A.C. Loma del Bosque 115, León, Guanajuato, C.P. 37150, Mexico

² Centro de Investigaciones en Óptica, A.C., Loma del Bosque 115, León, Guanajuato, C.P. 37150, Mexico

Int. J. Mol. Sci. 2014, 15(10), 19239-19252; https://doi.org/10.3390/ijms151019239 - 23 Oct 2014

Cited by 41 | Viewed by 9894

Abstract

Reactive and pharmaceutical-grade heparins were used as biologically compatible reducing and stabilizing agents to photochemically synthesize colloidal gold nanoparticles. Aggregates and anisotropic shapes were obtained photochemically under UV black-light lamp irradiation (λ = 366 nm). Heparin-functionalized gold nanoparticles were characterized by Scanning Electron [...] Read more.

Reactive and pharmaceutical-grade heparins were used as biologically compatible reducing and stabilizing agents to photochemically synthesize colloidal gold nanoparticles. Aggregates and anisotropic shapes were obtained photochemically under UV black-light lamp irradiation (λ = 366 nm). Heparin-functionalized gold nanoparticles were characterized by Scanning Electron Microscopy and UV-Vis spectroscopy. The negatively charged colloids were used for the Surface Enhanced Raman Spectroscopy (SERS) analysis of differently charged analytes (dyes). Measurements of pH were taken to inspect how the acidity of the medium affects the colloid-analyte interaction. SERS spectra were taken by mixing the dyes and the colloidal solutions without further functionalization or addition of any aggregating agent. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles 2014)

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12 pages, 4204 KiB

Open AccessArticle

DRAM1 Protects Neuroblastoma Cells from Oxygen-Glucose Deprivation/Reperfusion-Induced Injury via Autophagy

by Mengqiang Yu, Yugang Jiang^*, Qingliang Feng, Yi'an Ouyang and Jie Gan

Department of Neurosurgery, Second Xiangya Hospital of Central South University, Changsha 410011, China

Int. J. Mol. Sci. 2014, 15(10), 19253-19264; https://doi.org/10.3390/ijms151019253 - 23 Oct 2014

Cited by 26 | Viewed by 7847

Abstract

DNA damage-regulated autophagy modulator protein 1 (DRAM1), a multi-pass membrane lysosomal protein, is reportedly a tumor protein p53 (TP53) target gene involved in autophagy. During cerebral ischemia/reperfusion (I/R) injury, DRAM1 protein expression is increased, and autophagy is activated. However, the functional [...] Read more.

DNA damage-regulated autophagy modulator protein 1 (DRAM1), a multi-pass membrane lysosomal protein, is reportedly a tumor protein p53 (TP53) target gene involved in autophagy. During cerebral ischemia/reperfusion (I/R) injury, DRAM1 protein expression is increased, and autophagy is activated. However, the functional significance of DRAM1 and the relationship between DRAM1 and autophagy in brain I/R remains uncertain. The aim of this study is to investigate whether DRAM1 mediates autophagy activation in cerebral I/R injury and to explore its possible effects and mechanisms. We adopt the oxygen-glucose deprivation and reperfusion (OGD/R) Neuro-2a cell model to mimic cerebral I/R conditions in vitro, and RNA interference is used to knock down DRAM1 expression in this model. Cell viability assay is performed using the LIVE/DEAD viability/cytotoxicity kit. Cell phenotypic changes are analyzed through Western blot assays. Autophagy flux is monitored through the tandem red fluorescent protein–Green fluorescent protein–microtubule associated protein 1 light chain 3 (RFP–GFP–LC3) construct. The expression levels of DRAM1 and microtubule associated protein 1 light chain 3II/I (LC3II/I) are strongly up-regulated in Neuro-2a cells after OGD/R treatment and peaked at the 12 h reperfusion time point. The autophagy-specific inhibitor 3-Methyladenine (3-MA) inhibits the expression of DRAM1 and LC3II/I and exacerbates OGD/R-induced cell injury. Furthermore, DRAM1 knockdown aggravates OGD/R-induced cell injury and significantly blocks autophagy through decreasing autophagosome-lysosome fusion. In conclusion, our data demonstrate that DRAM1 knockdown in Neuro-2a cells inhibits autophagy by blocking autophagosome-lysosome fusion and exacerbated OGD/R-induced cell injury. Thus, DRAM1 might constitute a new therapeutic target for I/R diseases. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 1264 KiB

Open AccessArticle

Effects of SC-560 in Combination with Cisplatin or Taxol on Angiogenesis in Human Ovarian Cancer Xenografts

by Wei Li^*, Liang Wan, Ling-Yun Zhai and Jane Wang

Department of Gynecology, Nanjing Medical University of Hangzhou Hospital, 261 Huansha Road, Hangzhou 310006, China

Int. J. Mol. Sci. 2014, 15(10), 19265-19280; https://doi.org/10.3390/ijms151019265 - 23 Oct 2014

Cited by 11 | Viewed by 6311

Abstract

This study was designed to evaluate the effect of cyclooxygenase-1 (COX-1) inhibitor, SC-560, combined with cisplatin or taxol, on angiogenesis in human ovarian cancer xenografts. Mice were treated with intraperitoneal (i.p.) injections of SC-560 6 mg/kg/day, i.p. injections of cisplatin 3 mg/kg every [...] Read more.

This study was designed to evaluate the effect of cyclooxygenase-1 (COX-1) inhibitor, SC-560, combined with cisplatin or taxol, on angiogenesis in human ovarian cancer xenografts. Mice were treated with intraperitoneal (i.p.) injections of SC-560 6 mg/kg/day, i.p. injections of cisplatin 3 mg/kg every other day and i.p. injections of taxol 20 mg/kg once a week for 21 days. Vascular endothelial growth factor (VEGF) mRNA levels were detected by reverse transcription-polymerase chain reaction (RT-PCR); microvessel density (MVD) was determined by immunohistochemistry; and prostaglandin E₂ (PGE₂) levels were determined using ELISA. Expression levels of VEGF mRNA and MVD in treatment groups were inhibited significantly when compared with the control group (p < 0.05 for all), and SC-560 combined with cisplatin displayed a greater reduction in the expression of VEGF and MVD than SC-560 or cisplatin alone (p < 0.05). SC-560 combined with taxol showed a greater inhibition on VEGF mRNA expression than SC-560 or taxol alone (p < 0.05). The level of PGE₂ in treatment groups was significantly reduced when compared with the control group (p < 0.01 for all). These findings may indicate that cisplatin or taxol supplemented by SC-560 in human ovarian cancer xenografts enhances the inhibition effect of cisplatin or taxol alone on angiogenesis. Full article

(This article belongs to the Section Biochemistry)

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26 pages, 5024 KiB

Open AccessArticle

Interferon Regulatory Factor-1 (IRF-1) Is Involved in the Induction of Phosphatidylserine Receptor (PSR) in Response to dsRNA Virus Infection and Contributes to Apoptotic Cell Clearance in CHSE-214 Cell

by Hsin-Chia Kung¹, Øystein Evensen², Jiann-Ruey Hong³, Chia-Yu Kuo⁴, Chun-Hsi Tso⁴, Fang-Huar Ngou⁴, Ming-Wei Lu^4,5,* and Jen-Leih Wu^1,*

¹ Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11574, Taiwan

² Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo 0454, Norway

³ Institute of Biotechnology, National Cheng-Kung University, Tainan 70101, Taiwan

⁴ Department of Aquaculture, National Taiwan Ocean University, Keelung 20224, Taiwan

⁵ Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 20224, Taiwan

Int. J. Mol. Sci. 2014, 15(10), 19281-19306; https://doi.org/10.3390/ijms151019281 - 23 Oct 2014

Cited by 15 | Viewed by 9898

Abstract

The phosphatidylserine receptor (PSR) recognizes a surface marker on apoptotic cells and initiates engulfment. This receptor is important for effective apoptotic cell clearance and maintains normal tissue homeostasis and regulation of the immune response. However, the regulation of PSR expression remains poorly understood. [...] Read more.

The phosphatidylserine receptor (PSR) recognizes a surface marker on apoptotic cells and initiates engulfment. This receptor is important for effective apoptotic cell clearance and maintains normal tissue homeostasis and regulation of the immune response. However, the regulation of PSR expression remains poorly understood. In this study, we determined that interferon regulatory factor-1 (IRF-1) was dramatically upregulated upon viral infection in the fish cell. We observed apoptosis in virus-infected cells and found that both PSR and IRF-1 increased simultaneously. Based on a bioinformatics promoter assay, IRF-1 binding sites were identified in the PSR promoter. Compared to normal viral infection, we found that PSR expression was delayed, viral replication was increased and virus-induced apoptosis was inhibited following IRF-1 suppression with morpholino oligonucleotides. A luciferase assay to analyze promoter activity revealed a decreasing trend after the deletion of the IRF-1 binding site on PSR promoter. The results of this study indicated that infectious pancreatic necrosis virus (IPNV) infection induced both the apoptotic and interferon (IFN) pathways, and IRF-1 was involved in regulating PSR expression to induce anti-viral effects. Therefore, this work suggests that PSR expression in salmonid cells during IPNV infection is activated when IRF-1 binds the PSR promoter. This is the first report to show the potential role of IRF-1 in triggering the induction of apoptotic cell clearance-related genes during viral infection and demonstrates the extensive crosstalk between the apoptotic and innate immune response pathways. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 714 KiB

Open AccessArticle

Antioxidant and Immunoregulatory Activity of Polysaccharides from Quinoa (Chenopodium quinoa Willd.)

by Yang Yao, Zhenxing Shi and Guixing Ren^*

Institute of Crop Science, Chinese Academy of Agricultural Sciences, Beijing 100081, China

Int. J. Mol. Sci. 2014, 15(10), 19307-19318; https://doi.org/10.3390/ijms151019307 - 23 Oct 2014

Cited by 66 | Viewed by 10191

Abstract

The water-extractable (QWP) and the alkali-extractable (QAP) polysaccharides from quinoa (named QWP and QAP, respectively) and their four polysaccharide sub-fractions (QWP-1, QWP-2, QAP-1 and QAP-2), were isolated and purified by anion-exchange and gel filtration chromatography. QWP-1 and QWP-2 were composed of Rha, Ara, [...] Read more.

The water-extractable (QWP) and the alkali-extractable (QAP) polysaccharides from quinoa (named QWP and QAP, respectively) and their four polysaccharide sub-fractions (QWP-1, QWP-2, QAP-1 and QAP-2), were isolated and purified by anion-exchange and gel filtration chromatography. QWP-1 and QWP-2 were composed of Rha, Ara, Gal and GalA. QAP-1 and QAP-2 were composed of Rha, Ara, Man, Gal and GalA. Antioxidant and immunoregulatory activities of the polysaccharides were evaluated. The results showed that QWP-1, QWP-2, QAP-1 and QAP-2 had significant antioxidant and immunoregulatory activities. The results suggest that QWP-1, QWP-2, QAP-1 and QAP-2 could be used as potential antioxidants and immunomodulators. Full article

(This article belongs to the Special Issue Bioactive Carbohydrates and Peptides)

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Int. J. Mol. Sci., Volume 15, Issue 10 (October 2014) – 120 articles , Pages 17204-19329

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