International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Acknowledgement to Reviewers of International Journal of Molecular Sciences 2013

by IJMS Editorial Office

Int. J. Mol. Sci. 2014, 15(3), 3444-3480; https://doi.org/10.3390/ijms15033444 - 25 Feb 2014

Viewed by 10213

Abstract

The editors of International Journal of Molecular Sciences would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2013. [...] Full article

Research

Jump to: Editorial, Review, Other

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Open AccessArticle

Galectin-9 Induced Myeloid Suppressor Cells Expand Regulatory T Cells in an IL-10-Dependent Manner in CVB3-Induced Acute Myocarditis

by Yingying Zhang, Li Jiang, Mengying Zhang and Kun Lv

Int. J. Mol. Sci. 2014, 15(3), 3356-3372; https://doi.org/10.3390/ijms15033356 - 25 Feb 2014

Cited by 12 | Viewed by 5883

Abstract

The objective of the study was to explore the effects of galectin-9 on myeloid suppressor cells in Coxsackievirus B3 (CVB3)-induced myocarditis and the possible mechanisms involved. For this purpose, BALB/c male mice were infected with CVB3 on day 0 and then received intraperitoneal [...] Read more.

The objective of the study was to explore the effects of galectin-9 on myeloid suppressor cells in Coxsackievirus B3 (CVB3)-induced myocarditis and the possible mechanisms involved. For this purpose, BALB/c male mice were infected with CVB3 on day 0 and then received intraperitoneal (IP) administration of recombinant galectin-9 or phosphate-buffered saline (PBS) daily from day 3 to day 7. The phenotypes and functions of myeloid suppressor cells were evaluated. The role and mechanism of myeloid suppressor cells and subsets in CVB3-induced myocarditis in vitro were explored. We found that galectin-9 remarkably increased the frequencies of CD11b⁺Gr-1⁺ cells in the cardiac tissue and spleen with myocarditis. Ly-6G⁺ cells were decreased and Ly-6C⁺ cells were increased in galectin-9-treated mice. In addition, CD11b⁺Gr-1⁺ cells were highly effective in suppressing CD4⁺ T cells. Moreover, our data demonstrate that CD11b⁺Gr-1⁺ cells are capable of expanding regulatory T cells (Tregs) from a preexisting population of natural Tregs, which depends on IL-10 but not TGF-β. Our results indicate that galectin-9 therapy may represent a useful approach to ameliorate CVB3-induced myocarditis. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Development of Lipid-Shell and Polymer Core Nanoparticles with Water-Soluble Salidroside for Anti-Cancer Therapy

by Dai-Long Fang, Yan Chen, Bei Xu, Ke Ren, Zhi-Yao He, Li-Li He, Yi Lei, Chun-Mei Fan and Xiang-Rong Song

Int. J. Mol. Sci. 2014, 15(3), 3373-3388; https://doi.org/10.3390/ijms15033373 - 25 Feb 2014

Cited by 71 | Viewed by 10363

Abstract

Salidroside (Sal) is a potent antitumor drug with high water-solubility. The clinic application of Sal in cancer therapy has been significantly restricted by poor oral absorption and low tumor cell uptake. To solve this problem, lipid-shell and polymer-core nanoparticles (Sal-LPNPs) loaded with Sal [...] Read more.

Salidroside (Sal) is a potent antitumor drug with high water-solubility. The clinic application of Sal in cancer therapy has been significantly restricted by poor oral absorption and low tumor cell uptake. To solve this problem, lipid-shell and polymer-core nanoparticles (Sal-LPNPs) loaded with Sal were developed by a double emulsification method. The processing parameters including the polymer types, organic phase, PVA types and amount were systemically investigated. The obtained optimal Sal-LPNPs, composed of PLGA-PEG-PLGA triblock copolymers and lipids, had high entrapment efficiency (65%), submicron size (150 nm) and negatively charged surface (−23 mV). DSC analysis demonstrated the successful encapsulation of Sal into LPNPs. The core-shell structure of Sal-LPNPs was verified by TEM. Sal released slowly from the LPNPs without apparent burst release. MTT assay revealed that 4T1 and PANC-1 cancer cell lines were sensitive to Sal treatment. Sal-LPNPs had significantly higher antitumor activities than free Sal in 4T1 and PANC-1 cells. The data indicate that LPNPs are a promising Sal vehicle for anti-cancer therapy and worthy of further investigation. Full article

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

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Open AccessArticle

Improved Establishment of Embryonic Stem (ES) Cell Lines from the Chinese Kunming Mice by Hybridization with 129 Mice

by Shumin Yu, Xingrong Yan, Huanhuan Liu, Xin Cai, Suizhong Cao, Liuhong Shen, Zhicai Zuo, Junliang Deng, Xiaoping Ma, Ya Wang and Zhihua Ren

Int. J. Mol. Sci. 2014, 15(3), 3389-3402; https://doi.org/10.3390/ijms15033389 - 25 Feb 2014

Cited by 9 | Viewed by 6014

Abstract

Chinese Kunming mice (Mus musculus Km), widely used as laboratory animals throughout China, remain very refractory for embryonic stem (ES) cell isolation. The present study was aimed to evaluate the effects of hybridization with 129/Sv mice, and culture media containing fetal bovine [...] Read more.

Chinese Kunming mice (Mus musculus Km), widely used as laboratory animals throughout China, remain very refractory for embryonic stem (ES) cell isolation. The present study was aimed to evaluate the effects of hybridization with 129/Sv mice, and culture media containing fetal bovine serum (FBS) or Knockout serum replacement (KSR) on ES cell isolation from Kunming mice. The results demonstrated that ES cells had been effectively isolated from the hybrid embryos of Kunming and 129/Sv mice using all three media containing 15% FBS, 15% KSR and their mixture of 14% KSR and 1% FBS, individually. These isolated ES cells had maintained in vitro undifferentiated for a long time, exhibiting all features specific for mouse ES cells. In addition, the rates of ES cell isolation in the medium containing 14% KSR and 1% FBS, was 46.67% and significantly higher than those in another two media containing only FBS or KSR (p < 0.05). Contrarily, no ES cell line had been established from Kunming mouse inbred embryos using the same protocols. These results suggested that ES cells with long-term self-renewal ability could be efficiently generated from hybrid embryos of Kunming and 129/Sv mice, and a small volume of FBS was necessary to isolate ES cells in the KSR medium when embryos and early ES cells cultured. Full article

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Open AccessArticle

Genistein-Inhibited Cancer Stem Cell-Like Properties and Reduced Chemoresistance of Gastric Cancer

by Weifeng Huang, Chunpeng Wan, Qicong Luo, Zhengjie Huang and Qi Luo

Int. J. Mol. Sci. 2014, 15(3), 3432-3443; https://doi.org/10.3390/ijms15033432 - 25 Feb 2014

Cited by 86 | Viewed by 8814

Abstract

Genistein, the predominant isoflavone found in soy products, has exerted its anticarcinogenic effect in many different tumor types in vitro and in vivo. Accumulating evidence in recent years has strongly indicated the existence of cancer stem cells in gastric cancer. Here, we [...] Read more.

Genistein, the predominant isoflavone found in soy products, has exerted its anticarcinogenic effect in many different tumor types in vitro and in vivo. Accumulating evidence in recent years has strongly indicated the existence of cancer stem cells in gastric cancer. Here, we showed that low doses of genistein (15 µM), extracted from Millettia nitida Benth var hirsutissima Z Wei, inhibit tumor cell self-renewal in two types of gastric cancer cells by colony formation assay and tumor sphere formation assay. Treatment of gastric cancer cells with genistein reduced its chemoresistance to 5-Fu (fluorouracil) and ciplatin. Further results indicated that the reduced chemoresistance may be associated with the inhibition of ABCG2 expression and ERK 1/2 activity. Furthermore, genistein reduced tumor mass in the xenograft model. Together, genistein inhibited gastric cancer stem cell-like properties and reduced its chemoresistance. Our results provide a further rationale and experimental basis for using the genistein to improve treatment of patients with gastric cancer. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Purification and Characterization of Aporphine Alkaloids from Leaves of Nelumbo nucifera Gaertn and Their Effects on Glucose Consumption in 3T3-L1 Adipocytes

by Chengjun Ma, Jinjun Wang, Hongmei Chu, Xiaoxiao Zhang, Zhenhua Wang, Honglun Wang and Gang Li

Int. J. Mol. Sci. 2014, 15(3), 3481-3494; https://doi.org/10.3390/ijms15033481 - 26 Feb 2014

Cited by 58 | Viewed by 8969

Abstract

Aporphine alkaloids from the leaves of Nelumbo nucifera Gaertn are substances of great interest because of their important pharmacological activities, particularly anti-diabetic, anti-obesity, anti-hyperlipidemic, anti-oxidant, and anti-HIV’s activities. In order to produce large amounts of pure alkaloid for research purposes, a novel method [...] Read more.

Aporphine alkaloids from the leaves of Nelumbo nucifera Gaertn are substances of great interest because of their important pharmacological activities, particularly anti-diabetic, anti-obesity, anti-hyperlipidemic, anti-oxidant, and anti-HIV’s activities. In order to produce large amounts of pure alkaloid for research purposes, a novel method using high-speed counter-current chromatography (HSCCC) was developed. Without any initial cleanup steps, four main aporphine alkaloids, including 2-hydroxy-1-methoxyaporphine, pronuciferine, nuciferine and roemerine were successfully purified from the crude extract by HSCCC in one step. The separation was performed with a simple two-phase solvent system composed of n-hexane-ethyl acetate-methanol-acetonitrile-water (5:3:3:2.5:5, v/v/v/v/v). In each operation, 100 mg crude extracts was separated and yielded 6.3 mg of 2-hydroxy-1-methoxyaporphine (95.1% purity), 1.1 mg of pronuciferine (96.8% purity), 8.5 mg of nuciferine (98.9% purity), and 2.7 mg of roemerine (97.4%) respectively. The chemical structure of four aporphine alkaloids are identified by means of electrospray ionization MS (ESI-MS) and nuclear magnetic resonance (NMR) analysis. Moreover, the effects of four separated aporphine alkaloids on insulin-stimulated glucose consumption were examined in 3T3-L1 adipocytes. The results showed that 2-hydroxy-1-methoxyaporphine and pronuciferine increased the glucose consumption significantly as rosiglitazone did. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

HBx Protein Promotes Oval Cell Proliferation by Up-Regulation of Cyclin D1 via Activation of the MEK/ERK and PI3K/Akt Pathways

by Heng-Yi Wang, Sheng-Li Yang, Hui-Fang Liang and Chang-Hai Li

Int. J. Mol. Sci. 2014, 15(3), 3507-3518; https://doi.org/10.3390/ijms15033507 - 26 Feb 2014

Cited by 47 | Viewed by 6436

Abstract

Growing evidence has shown that hepatic oval cells, also named liver progenitor cells, play an important role in the process of liver regeneration in various liver diseases. Oval cell proliferation has been reported in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and chronic [...] Read more.

Growing evidence has shown that hepatic oval cells, also named liver progenitor cells, play an important role in the process of liver regeneration in various liver diseases. Oval cell proliferation has been reported in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and chronic liver disease. Studies have found expression of HBV surface and core antigens in oval cells in the livers of patients with HCC, suggesting that HBV infection of oval cells could be a mechanism of human hepatocarcinogenesis. In addition, there is evidence of multiplication of HBV in oval cell culture. However, little research has been performed to explore the role of HBV-encoded proteins in the proliferation of hepatic oval cells. Previously, we successfully transfected the HBV x (HBx) gene, one of the four genes in the HBV genome, into a rat LE/6 oval cell line. In this study, we tested whether or not the transfected HBx gene could affect oval cell proliferation in vitro. Our results show that overexpression of HBx promotes the proliferation of oval cells and increases cyclin D1 expression, assessed at both the mRNA and protein levels. We also found that HBx activated the PI-3K/Akt and MEK/ERK1/2 pathways in HBx-transfected oval cells. Furthermore, the HBx-induced increases in cyclin D1 expression and oval cell proliferation were completely abolished by treatment with either MEK inhibitor PD184352 or PI-3K inhibitor LY294002. These results demonstrated that HBx has the ability to promote oval cell proliferation in vitro, and its stimulatory effects on cell proliferation and expression of cyclin D1 depend on the activation of the MEK/ERK and PI3K/Akt signaling pathways in cultured oval cells. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Docetaxel-Loaded Chitosan Microspheres as a Lung Targeted Drug Delivery System: In Vitro and in Vivo Evaluation

by Hao Wang, Yongdong Xu and Xiao Zhou

Int. J. Mol. Sci. 2014, 15(3), 3519-3532; https://doi.org/10.3390/ijms15033519 - 26 Feb 2014

Cited by 58 | Viewed by 7265

Abstract

The aim of this study was to prepare docetaxel-loaded chitosan microspheres and to evaluate their in vitro and in vivo characteristics. Glutaraldehyde crosslinked microspheres were prepared using a water-in-oil emulsification method, and characterized in terms of the morphological examination, particle size distribution, encapsulation [...] Read more.

The aim of this study was to prepare docetaxel-loaded chitosan microspheres and to evaluate their in vitro and in vivo characteristics. Glutaraldehyde crosslinked microspheres were prepared using a water-in-oil emulsification method, and characterized in terms of the morphological examination, particle size distribution, encapsulation ratio, drug-loading coefficient and in vitro release. Pharmacokinetics and biodistribution studies were used to evaluate that microspheres have more advantage than the conventional formulations. The emulsion crosslinking method was simple to prepare microspheres and easy to scale up. The formed microspheres were spherical in shape, with a smooth surface and the size was uniform (9.6 ± 0.8 µm); the encapsulation efficiency and drug loading of prepared microspheres were 88.1% ± 3.5% and 18.7% ± 1.2%, respectively. In vitro release indicated that the DTX microspheres had a well-sustained release efficacy and in vivo studies showed that the microspheres were found to release the drug to a maximum extent in the target tissue (lung). The prepared microspheres were found to possess suitable physico-chemical properties and the particle size range. The sustained release of DTX from microspheres revealed its applicability as drug delivery system to minimize the exposure of healthy tissues while increasing the accumulation of therapeutic drug in target sites. Full article

(This article belongs to the Section Materials Science)

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Open AccessArticle

Association between Single Nucleotide Polymorphism rs1044925 and the Risk of Coronary Artery Disease and Ischemic Stroke

by Dong-Feng Wu, Rui-Xing Yin, Xiao-Li Cao and Wu-Xian Chen

Int. J. Mol. Sci. 2014, 15(3), 3546-3559; https://doi.org/10.3390/ijms15033546 - 26 Feb 2014

Cited by 17 | Viewed by 5741

Abstract

The present study was performed to clarify the association between the acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) single nucleotide polymorphism (SNP) rs1044925 and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Guangxi Han population. Polymerase chain reaction and restriction [...] Read more.

The present study was performed to clarify the association between the acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) single nucleotide polymorphism (SNP) rs1044925 and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Guangxi Han population. Polymerase chain reaction and restriction fragment length polymorphism was performed to determine the genotypes of the ACAT-1 SNP rs1044925 in 1730 unrelated subjects (CAD, 587; IS, 555; and healthy controls; 588). The genotypic and allelic frequencies of rs1044925 were significantly different between the CAD patients and controls (p = 0.015) and borderline different between the IS patients and controls (p = 0.05). The AC/CC genotypes and C allele were associated with a decreased risk of CAD and IS (CAD: p = 0.014 for AC/CC vs. AA, p = 0.022 for C vs. A; IS: p = 0.014 for AC/CC vs. AA; p = 0.017 for C vs. A). The AC/CC genotypes in the healthy controls, but not in CAD or IS patients, were associated with an increased serum high-density lipoprotein cholesterol (HDL-C) concentration. The present study shows that the C allele carriers of ACAT-1 rs1044925 were associated with an increased serum HDL-C level in the healthy controls and decreased risk in CAD and IS patients. Full article

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

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Open AccessArticle

Activation of VCAM-1 and Its Associated Molecule CD44 Leads to Increased Malignant Potential of Breast Cancer Cells

by Pei-Chen Wang, Ching-Chieh Weng, You-Syuan Hou, Shu-Fang Jian, Kuan-Te Fang, Ming-Feng Hou and Kuang-Hung Cheng

Int. J. Mol. Sci. 2014, 15(3), 3560-3579; https://doi.org/10.3390/ijms15033560 - 27 Feb 2014

Cited by 43 | Viewed by 8929

Abstract

VCAM-1 (CD106), a transmembrane glycoprotein, was first reported to play an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (α4β1). In the present study, we observed that VCAM-1 expression can be induced in many breast [...] Read more.

VCAM-1 (CD106), a transmembrane glycoprotein, was first reported to play an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (α4β1). In the present study, we observed that VCAM-1 expression can be induced in many breast cancer epithelial cells by cytokine stimulation in vitro and its up-regulation directly correlated with advanced clinical breast cancer stage. We found that VCAM-1 over-expression in the NMuMG breast epithelial cells controls the epithelial and mesenchymal transition (EMT) program to increase cell motility rates and promote chemoresistance to doxorubicin and cisplatin in vitro. Conversely, in the established MDAMB231 metastatic breast cancer cell line, we confirmed that knockdown of endogenous VCAM-1 expression reduced cell proliferation and inhibited TGFβ1 or IL-6 mediated cell migration, and increased chemosensitivity. Furthermore, we demonstrated that knockdown of endogenous VCAM-1 expression in MDAMB231 cells reduced tumor formation in a SCID xenograft mouse model. Signaling studies showed that VCAM-1 physically associates with CD44 and enhances CD44 and ABCG2 expression. Our findings uncover the possible mechanism of VCAM-1 activation facilitating breast cancer progression, and suggest that targeting VCAM-1 is an attractive strategy for therapeutic intervention. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Non-Specific Inhibition of Ischemia- and Acidosis-Induced Intracellular Calcium Elevations and Membrane Currents by α-Phenyl-N-tert-butylnitrone, Butylated Hydroxytoluene and Trolox

by Christopher Katnik and Javier Cuevas

Int. J. Mol. Sci. 2014, 15(3), 3596-3611; https://doi.org/10.3390/ijms15033596 - 27 Feb 2014

Cited by 4 | Viewed by 5386

Abstract

Ischemia, and subsequent acidosis, induces neuronal death following brain injury. Oxidative stress is believed to be a key component of this neuronal degeneration. Acute chemical ischemia (azide in the absence of external glucose) and acidosis (external media buffered to pH 6.0) produce increases [...] Read more.

Ischemia, and subsequent acidosis, induces neuronal death following brain injury. Oxidative stress is believed to be a key component of this neuronal degeneration. Acute chemical ischemia (azide in the absence of external glucose) and acidosis (external media buffered to pH 6.0) produce increases in intracellular calcium concentration ([Ca²⁺]_i) and inward membrane currents in cultured rat cortical neurons. Two α-tocopherol analogues, trolox and butylated hydroxytoluene (BHT), and the spin trapping molecule α-Phenyl-N-tert-butylnitrone (PBN) were used to determine the role of free radicals in these responses. PBN and BHT inhibited the initial transient increases in [Ca²⁺]_i, produced by ischemia, acidosis and acidic ischemia and increased steady state levels in response to acidosis and the acidic ischemia. BHT and PBN also potentiated the rate at which [Ca²⁺]_i increased after the initial transients during acidic ischemia. Trolox inhibited peak and sustained increases in [Ca²⁺]_i during ischemia. BHT inhibited ischemia induced initial inward currents and trolox inhibited initial inward currents activated by acidosis and acidic ischemia. Given the inconsistent results obtained using these antioxidants, it is unlikely their effects were due to elimination of free radicals. Instead, it appears these compounds have non-specific effects on the ion channels and exchangers responsible for these responses. Full article

(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)

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Open AccessArticle

Transport of Glial Cell Line-Derived Neurotrophic Factor into Liposomes across the Blood-Brain Barrier: In Vitro and in Vivo Studies

by Shaoling Wu, Guoqi Li, Xiao Li, Caina Lin, Ding Yu, Shuo Luan and Chao Ma

Int. J. Mol. Sci. 2014, 15(3), 3612-3623; https://doi.org/10.3390/ijms15033612 - 27 Feb 2014

Cited by 16 | Viewed by 5567

Abstract

Glial cell line-derived neurotrophic factor (GDNF) was encapsulated into liposomes in order to protect it from enzyme degradation in vivo and promote its permeability across the blood-brain barrier (BBB). In this study, GDNF conventional liposomes (GDNF-L) and GDNF target sterically stabilized liposomes (GDNF-SSL-T) [...] Read more.

Glial cell line-derived neurotrophic factor (GDNF) was encapsulated into liposomes in order to protect it from enzyme degradation in vivo and promote its permeability across the blood-brain barrier (BBB). In this study, GDNF conventional liposomes (GDNF-L) and GDNF target sterically stabilized liposomes (GDNF-SSL-T) were prepared. The average size of liposomes was below 90 nm. A primary model of BBB was established and evaluated by transendothelial electrical resistance (TEER) and permeability. This BBB model was employed to study the permeability of GDNF liposomes in vitro. The results indicated that the liposomes could enhance transport of GDNF across the BBB and GDNF-SSL-T had achieved the best transport efficacy. The distribution of GDNF liposomes was studied in vivo. Free GDNF and GDNF-L were eliminated rapidly in the circulation. GDNF-SSL-T has a prolonged circulation time in the blood and favorable brain delivery. The values of the area under the curve (AUC_{(0–1 h)}) in the brain of GDNF-SSL-T was 8.1 times and 6.8 times more than that of free GDNF and GDNF-L, respectively. These results showed that GDNF-SSL-T realized the aim of targeted delivery of therapeutic proteins to central nervous system. Full article

(This article belongs to the Section Materials Science)

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Open AccessArticle

Anthelmintic Activities of Aporphine from Nelumbo nucifera Gaertn. cv. Rosa-plena against Hymenolepis nana

by Rong-Jyh Lin, Mei-Hsuan Wu, Yi-Hsuan Ma, Li-Yu Chung, Chung-Yi Chen and Chuan-Min Yen

Int. J. Mol. Sci. 2014, 15(3), 3624-3639; https://doi.org/10.3390/ijms15033624 - 27 Feb 2014

Cited by 38 | Viewed by 8753

Abstract

Nelumbo nucifera Gaertn. cv. Rosa-plena (Nelumbonaceae), commonly known as lotus, is a perennial aquatic plant grown and consumed throughout Asia. All parts of N. nucifera have been used for various medicinal purposes in oriental medicine. From the leaves of Nelumbo nucifera [...] Read more.

Nelumbo nucifera Gaertn. cv. Rosa-plena (Nelumbonaceae), commonly known as lotus, is a perennial aquatic plant grown and consumed throughout Asia. All parts of N. nucifera have been used for various medicinal purposes in oriental medicine. From the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena (an aquatic plant), liriodenine (1), lysicamine (2), (-)-anonaine (3), (-)-asimilobine (4), (-)-caaverine (5), (-)-N-methylasimilobine (6), (-)-nuciferine (7), (-)-nornuciferine (8), (-)-roemerine (9), 7-hydroxydehydronuciferine (10) and cepharadione B (11) were isolated and identification and anthelmintic activities of aporphine was evaluated against Anisakis simplex and Hymenolepis nana. This study found that the above constituents killed H. nana or reduced their spontaneous movements (oscillation/peristalsis). However, the above constituents at various concentrations demonstrated no larvicidal effect or ability to halt spontaneous parasite movement for 72 h against A. simplex, respectively. In addition, according to an assay of cestocidal activity against H. nana and nematocidal activity against A. simplex, we found that the above compounds showed greater lethal efficacy on H. nana than against A. simplex. Further investigation showed that these above constituents have effects against peroxyl radicals under cestocidal effect. Together, these findings suggest that these constituents of Nelumbo nucifera Gaertn. cv. Rosa-plena might be used as anthelmintic agents against H. nana. Full article

(This article belongs to the Section Biochemistry)

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Open AccessCommunication

A Proteomic Approach of Bradyrhizobium/Aeschynomene Root and Stem Symbioses Reveals the Importance of the fixA Locus for Symbiosis

by Nathanael Delmotte, Samuel Mondy, Benoit Alunni, Joel Fardoux, Clémence Chaintreuil, Julia A. Vorholt, Eric Giraud and Benjamin Gourion

Int. J. Mol. Sci. 2014, 15(3), 3660-3670; https://doi.org/10.3390/ijms15033660 - 28 Feb 2014

Cited by 13 | Viewed by 8118

Abstract

Rhizobia are soil bacteria that are able to form symbiosis with plant hosts of the legume family. These associations result in the formation of organs, called nodules in which bacteria fix atmospheric nitrogen to the benefit of the plant. Most of our knowledge [...] Read more.

Rhizobia are soil bacteria that are able to form symbiosis with plant hosts of the legume family. These associations result in the formation of organs, called nodules in which bacteria fix atmospheric nitrogen to the benefit of the plant. Most of our knowledge on the metabolism and the physiology of the bacteria during symbiosis derives from studying roots nodules of terrestrial plants. Here we used a proteomics approach to investigate the bacterial physiology of photosynthetic Bradyrhizobium sp. ORS278 during the symbiotic process with the semi aquatical plant Aeschynomene indica that forms root and stem nodules. We analyzed the proteomes of bacteria extracted from each type of nodule. First, we analyzed the bacteroid proteome at two different time points and found only minor variation between the bacterial proteomes of 2-week- and 3-week-old nodules. High conservation of the bacteroid proteome was also found when comparing stem nodules and root nodules. Among the stem nodule specific proteins were those related to the phototrophic ability of Bradyrhizobium sp. ORS278. Furthermore, we compared our data with those obtained during an extensive genetic screen previously published. The symbiotic role of four candidate genes which corresponding proteins were found massively produced in the nodules but not identified during this screening was examined. Mutant analysis suggested that in addition to the EtfAB system, the fixA locus is required for symbiotic efficiency. Full article

(This article belongs to the Special Issue Symbiotic Nitrogen Fixation in Legume Nodules: Metabolism and Regulatory Mechanisms)

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Open AccessArticle

Multilineage Potential Research of Bovine Amniotic Fluid Mesenchymal Stem Cells

by Yuhua Gao, Zhiqiang Zhu, Yuhua Zhao, Jinlian Hua, Yuehui Ma and Weijun Guan

Int. J. Mol. Sci. 2014, 15(3), 3698-3710; https://doi.org/10.3390/ijms15033698 - 28 Feb 2014

Cited by 37 | Viewed by 7744

Abstract

The use of amnion and amniotic fluid (AF) are abundant sources of mesenchymal stem cells (MSCs) that can be harvested at low cost and do not pose ethical conflicts. In human and veterinary research, stem cells derived from these tissues are promising candidates [...] Read more.

The use of amnion and amniotic fluid (AF) are abundant sources of mesenchymal stem cells (MSCs) that can be harvested at low cost and do not pose ethical conflicts. In human and veterinary research, stem cells derived from these tissues are promising candidates for disease treatment, specifically for their plasticity, their reduced immunogenicity, and high anti-inflammatory potential. This work aimed to obtain and characterize bovine amniotic fluid mesenchymal stem cells (AFMSC). The bovine AF from the amniotic cavity of pregnant gilts in the early stages of gestation (3- and 4-m-old bovine embryos) was collected. AFMSCs exhibit a fibroblastic-like morphology only starting from the fourth passage, being heterogeneous during the primary culture. Immunofluorescence results showed that AFMSCs were positive for β-integrin, CD44, CD73 and CD166, but negative for CD34, CD45. Meanwhile, AFMSCs expressed ES cell markers, such as Oct4, and when appropriately induced, are capable of differentiating into ectodermal and mesodermal lineages. This study reinforces the emerging importance of these cells as ideal tools in veterinary medicine; future studies aimed at a deeper evaluation of their immunological properties will allow a better understanding of their role in cellular therapy. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Exposure to Diflubenzuron Results in an Up-Regulation of a Chitin Synthase 1 Gene in Citrus Red Mite, Panonychus citri (Acari: Tetranychidae)

by Wen-Kai Xia, Tian-Bo Ding, Jin-Zhi Niu, Chong-Yu Liao, Rui Zhong, Wen-Jia Yang, Bin Liu, Wei Dou and Jin-Jun Wang

Int. J. Mol. Sci. 2014, 15(3), 3711-3728; https://doi.org/10.3390/ijms15033711 - 28 Feb 2014

Cited by 24 | Viewed by 7514

Abstract

Chitin synthase synthesizes chitin, which is critical for the arthropod exoskeleton. In this study, we cloned the cDNA sequences of a chitin synthase 1 gene, PcCHS1, in the citrus red mite, Panonychus citri (McGregor), which is one of the most economically important [...] Read more.

Chitin synthase synthesizes chitin, which is critical for the arthropod exoskeleton. In this study, we cloned the cDNA sequences of a chitin synthase 1 gene, PcCHS1, in the citrus red mite, Panonychus citri (McGregor), which is one of the most economically important pests of citrus worldwide. The full-length cDNA of PcCHS1 contains an open reading frame of 4605 bp of nucleotides, which encodes a protein of 1535 amino acid residues with a predicted molecular mass of 175.0 kDa. A phylogenetic analysis showed that PcCHS1 was most closely related to CHS1 from Tetranychus urticae. During P. citri development, PcCHS1 was constantly expressed in all stages but highly expressed in the egg stage (114.8-fold higher than in the adult). When larvae were exposed to diflubenzuron (DFB) for 6 h, the mite had a significantly high mortality rate, and the mRNA expression levels of PcCHS1 were significantly enhanced. These results indicate a promising use of DFB to control P. citri, by possibly acting as an inhibitor in chitin synthesis as indicated by the up-regulation of PcCHS1 after exposure to DFB. Full article

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Open AccessArticle

Effect of NK4 Transduction in Bone Marrow-Derived Mesenchymal Stem Cells on Biological Characteristics of Pancreatic Cancer Cells

by Yun-Peng Sun, Ben-Long Zhang, Jian-Wen Duan, Huan-Huan Wu, Ben-Quan Wang, Zheng-Ping Yu, Wen-Jun Yang, Yun-Feng Shan, Meng-Tao Zhou and Qi-Yu Zhang

Int. J. Mol. Sci. 2014, 15(3), 3729-3745; https://doi.org/10.3390/ijms15033729 - 3 Mar 2014

Cited by 17 | Viewed by 6504

Abstract

Pancreatic cancer usually has a poor prognosis, and no gene therapy has yet been developed that is effective to treat it. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine [...] Read more.

Pancreatic cancer usually has a poor prognosis, and no gene therapy has yet been developed that is effective to treat it. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting pancreatic cancer. First, we successfully extracted MSCs from SD rats. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF) which comprising the N-terminal and the subsequent four kringle domains of HGF, by an adenoviral vector. Then, we confirmed that rat MSCs preferentially migrate to pancreatic cancer cells. Last, MSCs expressing NK4 (NK4-MSCs) strongly inhibited proliferation and migration of the pancreatic cancer cell line SW1990 after co-culture. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting pancreatic cancer. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

by Ivo Bendix, Meray Serdar, Josephine Herz, Clarissa Von Haefen, Fatme Nasser, Benjamin Rohrer, Stefanie Endesfelder, Ursula Felderhoff-Mueser, Claudia D. Spies and Marco Sifringer

Int. J. Mol. Sci. 2014, 15(3), 3784-3798; https://doi.org/10.3390/ijms15033784 - 3 Mar 2014

Cited by 5 | Viewed by 7496

Abstract

Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect [...] Read more.

Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix. Full article

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

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Open AccessArticle

Comparative Transcriptional Profiling of Three Super-Hybrid Rice Combinations

by Yonggang Peng, Gang Wei, Lei Zhang, Guozhen Liu, Xiaoli Wei and Zhen Zhu

Int. J. Mol. Sci. 2014, 15(3), 3799-3815; https://doi.org/10.3390/ijms15033799 - 3 Mar 2014

Cited by 7 | Viewed by 6880

Abstract

Utilization of heterosis has significantly increased rice yields. However, its mechanism remains unclear. In this study, comparative transcriptional profiles of three super-hybrid rice combinations, LY2163, LY2186 and LYP9, at the flowering and filling stages, were created using rice whole-genome oligonucleotide microarray. [...] Read more.

Utilization of heterosis has significantly increased rice yields. However, its mechanism remains unclear. In this study, comparative transcriptional profiles of three super-hybrid rice combinations, LY2163, LY2186 and LYP9, at the flowering and filling stages, were created using rice whole-genome oligonucleotide microarray. The LY2163, LY2186 and LYP9 hybrids yielded 1193, 1630 and 1046 differentially expressed genes (DGs), accounting for 3.2%, 4.4% and 2.8% of the total number of genes (36,926), respectively, after using the z-test (p < 0.01). Functional category analysis showed that the DGs in each hybrid combination were mainly classified into the carbohydrate metabolism and energy metabolism categories. Further analysis of the metabolic pathways showed that DGs were significantly enriched in the carbon fixation pathway (p < 0.01) for all three combinations. Over 80% of the DGs were located in rice quantitative trait loci (QTLs) of the Gramene database, of which more than 90% were located in the yield related QTLs in all three combinations, which suggested that there was a correlation between DGs and rice heterosis. Pathway Studio analysis showed the presence of DGs in the circadian regulatory network of all three hybrid combinations, which suggested that the circadian clock had a role in rice heterosis. Our results provide information that can help to elucidate the molecular mechanism underlying rice heterosis. Full article

(This article belongs to the Section Biochemistry)

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Graphical abstract

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Open AccessArticle

Role of A20 in cIAP-2 Protection against Tumor Necrosis Factor α (TNF-α)-Mediated Apoptosis in Endothelial Cells

by Shuzhen Guo, Angela F. Messmer-Blust, Jiaping Wu, Xiaoxiao Song, Melissa J. Philbrick, Jue-Lon Shie, Jamal S. Rana and Jian Li

Int. J. Mol. Sci. 2014, 15(3), 3816-3833; https://doi.org/10.3390/ijms15033816 - 3 Mar 2014

Cited by 22 | Viewed by 8989

Abstract

Tumor necrosis factor α (TNF-α) influences endothelial cell viability by altering the regulatory molecules involved in induction or suppression of apoptosis. However, the underlying mechanisms are still not completely understood. In this study, we demonstrated that A20 (also known as TNFAIP3, tumor necrosis [...] Read more.

Tumor necrosis factor α (TNF-α) influences endothelial cell viability by altering the regulatory molecules involved in induction or suppression of apoptosis. However, the underlying mechanisms are still not completely understood. In this study, we demonstrated that A20 (also known as TNFAIP3, tumor necrosis factor α-induced protein 3, and an anti-apoptotic protein) regulates the inhibitor of apoptosis protein-2 (cIAP-2) expression upon TNF-α induction in endothelial cells. Inhibition of A20 expression by its siRNA resulted in attenuating expression of TNF-α-induced cIAP-2, yet not cIAP-1 or XIAP. A20-induced cIAP-2 expression can be blocked by the inhibition of phosphatidyl inositol-3 kinase (PI3-K), but not nuclear factor (NF)-κB, while concomitantly increasing the number of endothelial apoptotic cells and caspase 3 activation. Moreover, TNF-α-mediated induction of apoptosis was enhanced by A20 inhibition, which could be rescued by cIAP-2. Taken together, these results identify A20 as a cytoprotective factor involved in cIAP-2 inhibitory pathway of TNF-α-induced apoptosis. This is consistent with the idea that endothelial cell viability is dependent on interactions between inducers and suppressors of apoptosis, susceptible to modulation by TNF-α. Full article

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

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Open AccessCommunication

Novel Missense Mutation in the NOD2 Gene in a Patient with Early Onset Ulcerative Colitis: Causal or Chance Association?

by Martina Girardelli, Josef Vuch, Alberto Tommasini, Sergio Crovella and Anna Monica Bianco

Int. J. Mol. Sci. 2014, 15(3), 3834-3841; https://doi.org/10.3390/ijms15033834 - 3 Mar 2014

Cited by 8 | Viewed by 5959

Abstract

Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain [...] Read more.

Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn’s disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G p.K953E) and two already described missense variants in the IL10RA gene (S159G and G351R). The new NOD2 missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. Although cumulative effect of these variations in the early onset of the disease can be only hypothesized, we demonstrated that family information and in silico studies can be used to predict association with the disease. Full article

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

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Open AccessArticle

Inhibition of Aflatoxin Synthesis in Aspergillus flavus by Three Structurally Modified Lentinans

by Jinyou Ma, Haizhen Mo, Ying Chen, Ding Ding and Liangbin Hu

Int. J. Mol. Sci. 2014, 15(3), 3860-3870; https://doi.org/10.3390/ijms15033860 - 4 Mar 2014

Cited by 14 | Viewed by 6013

Abstract

The chemical properties of β-glucans leading to their inhibition on aflatoxin (AF) production by Aspergillus flavus remain unclear. In this study, structurally modified lentinan derivatives were prepared by carboxymethylation, sulfation, and phosphorylation to explore their inhibition activity to AF synthesis. The results demonstrated [...] Read more.

The chemical properties of β-glucans leading to their inhibition on aflatoxin (AF) production by Aspergillus flavus remain unclear. In this study, structurally modified lentinan derivatives were prepared by carboxymethylation, sulfation, and phosphorylation to explore their inhibition activity to AF synthesis. The results demonstrated that inhibitory activity of lentinan decreased at higher or lower concentrations than 200 μg/mL. Compared with lentinan, the sulphated derivatives only performed a reduced optimal inhibition rate at a higher concentration. The phosphorylated derivatives achieved complete inhibition of AF production at 50 μg/mL, but the inhibitory activity was attenuated with an increase of concentration. The minimum concentration of carboxymethylated derivatives to completely inhibit AF synthesis was the same as that of the original lentinan, whereas their inhibition activity was not reduced at the increasing concentration. RT-PCR analyses were conducted to understand the effects of lentinan and its carboxymethylated derivatives on the transcription of certain genes associated with AF biosynthesis. The results showed that lentinan delayed the transcription of aflQ, whereas its carboxymethylated derivatives promoted the transcriptions of all the tested genes. Our results revealed that some chemical group features apart from the β-bond could play the vital role in the prevention of AF formation by polysaccharide, and highlighted the structural modifications which could promote its practicability in the control of aflatoxin contamination. Full article

(This article belongs to the Special Issue Nutritional Control of Metabolism)

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Isolation and Characterization of the Brassinosteroid Receptor Gene (GmBRI1) from Glycine max

by Miao Wang, Shi Sun, Cunxiang Wu, Tianfu Han and Qingyu Wang

Int. J. Mol. Sci. 2014, 15(3), 3871-3888; https://doi.org/10.3390/ijms15033871 - 4 Mar 2014

Cited by 23 | Viewed by 7677

Abstract

Brassinosteroids (BRs) constitute a group of steroidal phytohormones that contribute to a wide range of plant growth and development functions. The genetic modulation of BR receptor genes, which play major roles in the BR signaling pathway, can create semi-dwarf plants that have great [...] Read more.

Brassinosteroids (BRs) constitute a group of steroidal phytohormones that contribute to a wide range of plant growth and development functions. The genetic modulation of BR receptor genes, which play major roles in the BR signaling pathway, can create semi-dwarf plants that have great advantages in crop production. In this study, a brassinosteroid insensitive gene homologous with AtBRI1 and other BRIs was isolated from Glycine max and designated as GmBRI1. A bioinformatic analysis revealed that GmBRI1 shares a conserved kinase domain and 25 tandem leucine-rich repeats (LRRs) that are characteristic of a BR receptor for BR reception and reaction and bear a striking similarity in protein tertiary structure to AtBRI1. GmBRI1 transcripts were more abundant in soybean hypocotyls and could be upregulated in response to exogenous BR treatment. The transformation of GmBRI1 into the Arabidopsis dwarf mutant bri1-5 restored the phenotype, especially regarding pod size and plant height. Additionally, this complementation is a consequence of a restored BR signaling pathway demonstrated in the light/dark analysis, root inhibition assay and BR-response gene expression. Therefore, GmBRI1 functions as a BR receptor to alter BR-mediated signaling and is valuable for improving plant architecture and enhancing the yield of soybean. Full article

(This article belongs to the Special Issue Plant Cell Compartmentation and Volume Control)

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Osthole Suppresses the Migratory Ability of Human Glioblastoma Multiforme Cells via Inhibition of Focal Adhesion Kinase-Mediated Matrix Metalloproteinase-13 Expression

by Cheng-Fang Tsai, Wei-Lan Yeh, Jia-Hong Chen, Chingju Lin, Shiang-Suo Huang and Dah-Yuu Lu

Int. J. Mol. Sci. 2014, 15(3), 3889-3903; https://doi.org/10.3390/ijms15033889 - 4 Mar 2014

Cited by 23 | Viewed by 6366

Abstract

Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the [...] Read more.

Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK) is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP)-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Synthesis of Analogues of Gingerol and Shogaol, the Active Pungent Principles from the Rhizomes of Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation Effects

by Hung-Cheng Shih, Ching-Yuh Chern, Ping-Chung Kuo, You-Cheng Wu, Yu-Yi Chan, Yu-Ren Liao, Che-Ming Teng and Tian-Shung Wu

Int. J. Mol. Sci. 2014, 15(3), 3926-3951; https://doi.org/10.3390/ijms15033926 - 4 Mar 2014

Cited by 40 | Viewed by 10191

Abstract

The present study was aimed at discovering novel biologically active compounds based on the skeletons of gingerol and shogaol, the pungent principles from the rhizomes of Zingiber officinale. Therefore, eight groups of analogues were synthesized and examined for their inhibitory activities of [...] Read more.

The present study was aimed at discovering novel biologically active compounds based on the skeletons of gingerol and shogaol, the pungent principles from the rhizomes of Zingiber officinale. Therefore, eight groups of analogues were synthesized and examined for their inhibitory activities of platelet aggregation induced by arachidonic acid, collagen, platelet activating factor, and thrombin. Among the tested compounds, [6]-paradol (5b) exhibited the most significant anti-platelet aggregation activity. It was the most potent candidate, which could be used in further investigation to explore new drug leads. Full article

(This article belongs to the Section Biochemistry)

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Antioxidant Properties and PC12 Cell Protective Effects of a Novel Curcumin Analogue (2E,6E)-2,6-Bis(3,5- dimethoxybenzylidene)cyclohexanone (MCH)

by Gui-Zhen Ao, Xiao-Jing Chu, Yuan-Yuan Ji and Jian-Wen Wang

Int. J. Mol. Sci. 2014, 15(3), 3970-3988; https://doi.org/10.3390/ijms15033970 - 5 Mar 2014

Cited by 16 | Viewed by 7108

Abstract

The antioxidative properties of a novel curcumin analogue (2E,6E)-2,6-bis(3,5-dimethoxybenzylidene)cyclohexanone (MCH) were assessed by several in vitro models, including superoxide anion, hydroxyl radical and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and PC12 cell protection from H₂O₂ damage. MCH displayed [...] Read more.

The antioxidative properties of a novel curcumin analogue (2E,6E)-2,6-bis(3,5-dimethoxybenzylidene)cyclohexanone (MCH) were assessed by several in vitro models, including superoxide anion, hydroxyl radical and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and PC12 cell protection from H₂O₂ damage. MCH displayed superior O₂^•− quenching abilities compared to curcumin and vitamin C. In vitro stability of MCH was also improved compared with curcumin. Exposure of PC12 cells to 150 µM H₂O₂ caused a decrease of antioxidant enzyme activities, glutathione (GSH) loss, an increase in malondialdehyde (MDA) level, and leakage of lactate dehydrogenase (LDH), cell apoptosis and reduction in cell viability. Pretreatment of the cells with MCH at 0.63–5.00 µM before H₂O₂ exposure significantly attenuated those changes in a dose-dependent manner. MCH enhanced cellular expression of transcription factor NF-E2-related factor 2 (Nrf2) at the transcriptional level. Moreover, MCH could mitigate intracellular accumulation of reactive oxygen species (ROS), the loss of mitochondrial membrane potential (MMP), and the increase of cleaved caspase-3 activity induced by H₂O₂. These results show that MCH protects PC12 cells from H₂O₂ injury by modulating endogenous antioxidant enzymes, scavenging ROS, activating the Nrf2 cytoprotective pathway and prevention of apoptosis. Full article

(This article belongs to the Section Biochemistry)

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miR-21 Promotes Human Nucleus Pulposus Cell Proliferation through PTEN/AKT Signaling

by Hongzhe Liu, Xiangwang Huang, Xiangyang Liu, Sheng Xiao, Yi Zhang, Tiecheng Xiang, Xiongjie Shen, Guoping Wang and Bin Sheng

Int. J. Mol. Sci. 2014, 15(3), 4007-4018; https://doi.org/10.3390/ijms15034007 - 5 Mar 2014

Cited by 86 | Viewed by 6878

Abstract

The precise role of nucleus pulposus cell proliferation in the pathogenesis of intervertebral disc degeneration remains to be elucidated. Recent findings have revealed that microRNAs, a class of small noncoding RNAs, may regulate cell proliferation in many pathological conditions. Here, we showed that [...] Read more.

The precise role of nucleus pulposus cell proliferation in the pathogenesis of intervertebral disc degeneration remains to be elucidated. Recent findings have revealed that microRNAs, a class of small noncoding RNAs, may regulate cell proliferation in many pathological conditions. Here, we showed that miR-21 was significantly upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues that were isolated from patients with idiopathic scoliosis and that miR-10b levels were associated with disc degeneration grade. Moreover, bioinformatics target prediction identified PTEN as a putative target of miR-21. miR-21 inhibited PTEN expression by directly targeting the 3'UTR, and this inhibition was abolished through miR-21 binding site mutations. miR-21 overexpression stimulated cell proliferation and AKT signaling pathway activation, which led to cyclin D1 translation. Additionally, the increase in proliferation and cyclin D1 expression induced by miR-21 overexpression was almost completely blocked by Ly294002, an AKT inhibitor. Taken together, aberrant miR-21 upregulation in intervertebral disc degeneration could target PTEN, which would contribute to abnormal nucleus pulposus cell proliferation through derepressing the Akt pathway. Our study also underscores the potential of miR-21 and the PTEN/Akt pathway as novel therapeutic targets in intervertebral disc degeneration. Full article

(This article belongs to the Section Biochemistry)

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The Effect and Mechanism of Tamoxifen-Induced Hepatocyte Steatosis in Vitro

by Fei Zhao, Ping Xie, Jiali Jiang, Lingqiang Zhang, Wei An and Yutao Zhan

Int. J. Mol. Sci. 2014, 15(3), 4019-4030; https://doi.org/10.3390/ijms15034019 - 5 Mar 2014

Cited by 56 | Viewed by 9120

Abstract

The aim of this study was to determine the effect and mechanism of tamoxifen (TAM)-induced steatosis in vitro. HepG 2 (Human hepatocellular liver carcinoma cell line) cells were treated with different concentrations of TAM for 72 h. Steatosis of hepatocytes was determined [...] Read more.

The aim of this study was to determine the effect and mechanism of tamoxifen (TAM)-induced steatosis in vitro. HepG 2 (Human hepatocellular liver carcinoma cell line) cells were treated with different concentrations of TAM for 72 h. Steatosis of hepatocytes was determined after Oil Red O staining and measurement of triglyceride (TG) concentration. The expressions of genes in the TG homeostasis pathway, including sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase (SCD), carnitine palmitoyltransferase 1 (CPT1) and microsomal triglyceride transfer protein (MTP), were examined using quantitative real-time PCR and Western blot analysis. Cell proliferation was examined using the cell counting kit-8 (CCK-8) assay. We found that hepatocytes treated with TAM had: (1) induced hepatocyte steatosis and increased hepatocyte TG; (2) upregulation of SREBP-1c, FAS, ACC, SCD and MTP mRNA expressions (300%, 600%, 70%, 130% and 160%, respectively); (3) corresponding upregulation of protein expression; and (4) no difference in HepG 2 cell proliferation. Our results suggest that TAM can induce hepatocyte steatosis in vitro and that the enhancement of fatty acid synthesis through the upregulations of SREBP-1c and its downstream target genes (FAS, ACC and SCD) may be the key mechanism of TAM-induced hepatocyte steatosis. Full article

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

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Open AccessArticle

Role of miR-191/425 Cluster in Tumorigenesis and Diagnosis of Gastric Cancer

by Wei-Zhao Peng, Ren Ma, Fang Wang, Jia Yu and Zhi-Bin Liu

Int. J. Mol. Sci. 2014, 15(3), 4031-4048; https://doi.org/10.3390/ijms15034031 - 5 Mar 2014

Cited by 59 | Viewed by 7685

Abstract

Gastric cancer (GC) is among the most frequent types of cancer worldwide. Therefore, understanding the biology of GC tumorigenesis is important for appropriate diagnosis and patient surveillance. The miR-191/425 cluster has been reported to be overexpressed in various human cancers, but the tumorigenic [...] Read more.

Gastric cancer (GC) is among the most frequent types of cancer worldwide. Therefore, understanding the biology of GC tumorigenesis is important for appropriate diagnosis and patient surveillance. The miR-191/425 cluster has been reported to be overexpressed in various human cancers, but the tumorigenic role and clinical significance of miR-191/425 overexpression in gastric carcinogenesis is currently undefined. In this study, the expression of miR-191 and miR-425 in GC tissue and serum was assessed, and the relationship between miRNA expression and clinicopathological data was analyzed. We found that miR-191 and miR-425 were both significantly increased in human GC tissues relative to adjacent normal controls. In addition, miR-191 levels correlated with GC tumor stage and metastatic state. Furthermore, the level of serum miR-191 was significantly higher in the GC group than in the control group when using serum miR-16 as an endogenous control. Finally, inhibition of miR-191 or miR-425 in the GC cell lines HGC-27 not only reduced cell proliferation and cell cycle progression but also impaired cell migration and invasion. Taken together, our results revealed the oncogenic roles of miR-191 and miR-425 in gastric carcinogenesis, and indicated the potential use of serum miR-191 as a novel and stable biomarker for GC diagnosis. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer and Its Role in Tailored Cancer Therapy)

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Perineural Dexmedetomidine Attenuates Inflammation in Rat Sciatic Nerve via the NF-κB Pathway

by Yan Huang, Yi Lu, Lei Zhang, Jia Yan, Jue Jiang and Hong Jiang

Int. J. Mol. Sci. 2014, 15(3), 4049-4059; https://doi.org/10.3390/ijms15034049 - 6 Mar 2014

Cited by 58 | Viewed by 8039

Abstract

Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-κB enters the nucleus and promotes the transcription of its target genes, including those encoding the [...] Read more.

Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-κB enters the nucleus and promotes the transcription of its target genes, including those encoding the pro-inflammatory cytokines IL-6 and TNF-α. In this study, we established a rat model that simulates a clinical surgical procedure to investigate the anti-inflammatory effect of perineural administration of dexmedetomidine and the underlying mechanism. Dexmedetomidine reduced the sciatic nerve levels of IL-6 and TNF-α at both the mRNA and protein level. Dexmedetomidine also inhibited the translocation of activated NF-κB to the nucleus and the binding activity of NF-κB. The anti-inflammatory effect is confirmed to be dose-dependent. Finally, pyrrolidine dithiocarbamate also reduced the levels of IL-6 and TNF-α and the activation of NF-κB. In conclusion, dexmedetomidine inhibited the nuclear translocation and binding activity of activated NF-κB, thus reducing inflammatory cytokines. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessArticle

Long Non-Coding RNA HOTAIR Promotes Cell Migration and Invasion via Down-Regulation of RNA Binding Motif Protein 38 in Hepatocellular Carcinoma Cells

by Chaofeng Ding, Shaobing Cheng, Zhe Yang, Zhen Lv, Heng Xiao, Chengli Du, Chuanhui Peng, Haiyang Xie, Lin Zhou, Jian Wu and Shusen Zheng

Int. J. Mol. Sci. 2014, 15(3), 4060-4076; https://doi.org/10.3390/ijms15034060 - 6 Mar 2014

Cited by 145 | Viewed by 11245

Abstract

Long non-coding RNA HOTAIR exerts regulatory functions in various biological processes in cancer cells, such as proliferation, apoptosis, mobility, and invasion. We previously found that HOX transcript antisense RNA (HOTAIR) is a negative prognostic factor and exhibits oncogenic activity in hepatocellular carcinoma (HCC). [...] Read more.

Long non-coding RNA HOTAIR exerts regulatory functions in various biological processes in cancer cells, such as proliferation, apoptosis, mobility, and invasion. We previously found that HOX transcript antisense RNA (HOTAIR) is a negative prognostic factor and exhibits oncogenic activity in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the role and molecular mechanism of HOTAIR in promoting HCC cell migration and invasion. Firstly, we profiled its gene expression pattern by microarray analysis of HOTAIR loss in Bel-7402 HCC cell line. The results showed that 129 genes were significantly down-regulated, while 167 genes were significantly up-regulated (fold change >2, p < 0.05). Bioinformatics analysis indicated that RNA binding proteins were involved in this biological process. HOTAIR suppression using RNAi strategy with HepG2 and Bel-7402 cells increased the mRNA and protein expression levels of RNA binding motif protein 38 (RBM38). Moreover, the expression levels of RBM38 in HCC specimens were significantly lower than paired adjacent noncancerous tissues. In addition, knockdown of HOTAIR resulted in a decrease of cell migration and invasion, which could be specifically rescued by down-regulation of RBM38. Taken together, HOTAIR could promote migration and invasion of HCC cells by inhibiting RBM38, which indicated critical roles of HOTAIR and RBM38 in HCC progression. Full article

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

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Influence of Diet, Menstruation and Genetic Factors on Iron Status: A Cross-Sectional Study in Spanish Women of Childbearing Age

by Ruth Blanco-Rojo, Laura Toxqui, Ana M. López-Parra, Carlos Baeza-Richer, Ana M. Pérez-Granados, Eduardo Arroyo-Pardo and M. Pilar Vaquero

Int. J. Mol. Sci. 2014, 15(3), 4077-4087; https://doi.org/10.3390/ijms15034077 - 6 Mar 2014

Cited by 36 | Viewed by 9243

Abstract

The aim of this study was to investigate the combined influence of diet, menstruation and genetic factors on iron status in Spanish menstruating women (n = 142). Dietary intake was assessed by a 72-h detailed dietary report and menstrual blood loss by [...] Read more.

The aim of this study was to investigate the combined influence of diet, menstruation and genetic factors on iron status in Spanish menstruating women (n = 142). Dietary intake was assessed by a 72-h detailed dietary report and menstrual blood loss by a questionnaire, to determine a Menstrual Blood Loss Coefficient (MBLC). Five selected SNPs were genotyped: rs3811647, rs1799852 (Tf gene); rs1375515 (CACNA2D3 gene); and rs1800562 and rs1799945 (HFE gene, mutations C282Y and H63D, respectively). Iron biomarkers were determined and cluster analysis was performed. Differences among clusters in dietary intake, menstrual blood loss parameters and genotype frequencies distribution were studied. A categorical regression was performed to identify factors associated with cluster belonging. Three clusters were identified: women with poor iron status close to developing iron deficiency anemia (Cluster 1, n = 26); women with mild iron deficiency (Cluster 2, n = 59) and women with normal iron status (Cluster 3, n = 57). Three independent factors, red meat consumption, MBLC and mutation C282Y, were included in the model that better explained cluster belonging (R² = 0.142, p < 0.001). In conclusion, the combination of high red meat consumption, low menstrual blood loss and the HFE C282Y mutation may protect from iron deficiency in women of childbearing age. These findings could be useful to implement adequate strategies to prevent iron deficiency anemia. Full article

(This article belongs to the Special Issue Nutritional Control of Metabolism)

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Endogenous Nitric-Oxide Synthase Inhibitor ADMA after Acute Brain Injury

by Carla S. Jung, Christian Wispel, Klaus Zweckberger, Christopher Beynon, Daniel Hertle, Oliver W. Sakowitz and Andreas W. Unterberg

Int. J. Mol. Sci. 2014, 15(3), 4088-4103; https://doi.org/10.3390/ijms15034088 - 6 Mar 2014

Cited by 12 | Viewed by 7101

Abstract

Previous results on nitric oxide (NO) metabolism after traumatic brain injury (TBI) show variations in NO availability and controversial effects of exogenous nitric oxide synthase (NOS)-inhibitors. Furthermore, elevated levels of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) were reported in cerebro-spinal fluid (CSF) [...] Read more.

Previous results on nitric oxide (NO) metabolism after traumatic brain injury (TBI) show variations in NO availability and controversial effects of exogenous nitric oxide synthase (NOS)-inhibitors. Furthermore, elevated levels of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) were reported in cerebro-spinal fluid (CSF) after traumatic subarachnoid hemorrhage (SAH). Therefore, we examined whether ADMA and the enzymes involved in NO- and ADMA-metabolism are expressed in brain tissue after TBI and if time-dependent changes occur. TBI was induced by controlled cortical impact injury (CCII) and neurological performance was monitored. Expression of NOS, ADMA, dimethylarginine dimethylaminohydrolases (DDAH) and protein-arginine methyltransferase 1 (PRMT1) was determined by immunostaining in different brain regions and at various time-points after CCII. ADMA and PRMT1 expression decreased in all animals after TBI compared to the control group, while DDAH1 and DDAH2 expression increased in comparison to controls. Furthermore, perilesionally ADMA is positively correlated with neuroscore performance, while DDAH1 and DDAH2 are negatively correlated. ADMA and its metabolizing enzymes show significant temporal changes after TBI and may be new targets in TBI treatment. Full article

(This article belongs to the Special Issue ADMA and Nitrergic System)

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Influence of Interferon-Alpha Combined with Chemo (Radio) Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

by Svetlana Karakhanova, Beate Mosl, Sabine Harig, Katharina Von Ahn, Jasmin Fritz, Jan Schmidt, Dirk Jäger, Jens Werner and Alexandr V. Bazhin

Int. J. Mol. Sci. 2014, 15(3), 4104-4125; https://doi.org/10.3390/ijms15034104 - 7 Mar 2014

Cited by 15 | Viewed by 7816

Abstract

Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer [...] Read more.

Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy. Full article

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

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Alcohol Induced Hepatic Degeneration in a Hepatitis C Virus Core Protein Transgenic Mouse Model

by Dong-Hyung Noh, Eun-Joo Lee, Ah-Young Kim, Eun-Mi Lee, Chang-Woo Min, Kyung-Ku Kang, Myeong-Mi Lee, Sang-Hyeob Kim, Soo-Eun Sung, Meeyul Hwang, Dae-Yeul Yu and Kyu-Shik Jeong

Int. J. Mol. Sci. 2014, 15(3), 4126-4141; https://doi.org/10.3390/ijms15034126 - 7 Mar 2014

Cited by 2 | Viewed by 7249

Abstract

Hepatitis C virus (HCV) has become a major public health issue. It is prevalent in most countries. HCV infection frequently begins without clinical symptoms, before progressing to persistent viremia, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) in the majority of patients (70% to [...] Read more.

Hepatitis C virus (HCV) has become a major public health issue. It is prevalent in most countries. HCV infection frequently begins without clinical symptoms, before progressing to persistent viremia, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) in the majority of patients (70% to 80%). Alcohol is an independent cofactor that accelerates the development of HCC in chronic hepatitis C patients. The purpose of the current study was to evaluate ethanol-induced hepatic changes in HCV core-Tg mice and mutant core Tg mice. Wild type (NTG), core wild-Tg mice (TG-K), mutant core 116-Tg mice (TG-116) and mutant core 99-Tg mice (TG-99) were used in this investigation. All groups were given drinking water with 10% ethanol and 5% sucrose for 13 weeks. To observe liver morphological changes, we performed histopathological and immunohistochemical examinations. Histopathologically, NTG, TG-K and TG-116 mice showed moderate centrilobular necrosis, while severe centrilobular necrosis and hepatocyte dissociation were observed in TG-99 mice with increasing lymphocyte infiltration and piecemeal necrosis. In all groups, a small amount of collagen fiber was found, principally in portal areas. None of the mice were found to have myofibroblasts based on immunohistochemical staining specific for α-SMA. CYP2E1-positive cells were clearly detected in the centrilobular area in all groups. In the TG-99 mice, we also observed cells positive for CK8/18, TGF-β1 and phosphorylated (p)-Smad2/3 and p21 around the necrotic hepatocytes in the centrilobular area (p < 0.01). Based on our data, alcohol intake induced piecemeal necrosis and hepatocyte dissociation in the TG-99 mice. These phenomena involved activation of the TGF-β1/p-Smad2/3/p21 signaling pathway in hepatocytes. Data from this study will be useful for elucidating the association between alcohol intake and HCV infection. Full article

(This article belongs to the Section Biochemistry)

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Construction and Analysis of Siberian Tiger Bacterial Artificial Chromosome Library with Approximately 6.5-Fold Genome Equivalent Coverage

by Changqing Liu, Chunyu Bai, Yu Guo, Dan Liu, Taofeng Lu, Xiangchen Li, Jianzhang Ma, Yuehui Ma and Weijun Guan

Int. J. Mol. Sci. 2014, 15(3), 4189-4200; https://doi.org/10.3390/ijms15034189 - 7 Mar 2014

Viewed by 6359

Abstract

Bacterial artificial chromosome (BAC) libraries are extremely valuable for the genome-wide genetic dissection of complex organisms. The Siberian tiger, one of the most well-known wild primitive carnivores in China, is an endangered animal. In order to promote research on its genome, a high-redundancy [...] Read more.

Bacterial artificial chromosome (BAC) libraries are extremely valuable for the genome-wide genetic dissection of complex organisms. The Siberian tiger, one of the most well-known wild primitive carnivores in China, is an endangered animal. In order to promote research on its genome, a high-redundancy BAC library of the Siberian tiger was constructed and characterized. The library is divided into two sub-libraries prepared from blood cells and two sub-libraries prepared from fibroblasts. This BAC library contains 153,600 individually archived clones; for PCR-based screening of the library, BACs were placed into 40 superpools of 10 × 384-deep well microplates. The average insert size of BAC clones was estimated to be 116.5 kb, representing approximately 6.46 genome equivalents of the haploid genome and affording a 98.86% statistical probability of obtaining at least one clone containing a unique DNA sequence. Screening the library with 19 microsatellite markers and a SRY sequence revealed that each of these markers were present in the library; the average number of positive clones per marker was 6.74 (range 2 to 12), consistent with 6.46 coverage of the tiger genome. Additionally, we identified 72 microsatellite markers that could potentially be used as genetic markers. This BAC library will serve as a valuable resource for physical mapping, comparative genomic study and large-scale genome sequencing in the tiger. Full article

(This article belongs to the Section Biochemistry)

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Synergistic Enhancement of Cancer Therapy Using a Combination of Ceramide and Docetaxel

by Li-Xia Feng, Min Li, Yong-Jun Liu, Shao-Mei Yang and Na Zhang

Int. J. Mol. Sci. 2014, 15(3), 4201-4220; https://doi.org/10.3390/ijms15034201 - 10 Mar 2014

Cited by 35 | Viewed by 7126

Abstract

Ceramide (CE)-based combination therapy (CE combination) as a novel therapeutic strategy has attracted great attention in the field of anti-cancer therapy. The principal purposes of this study were to investigate the synergistic effect of CE in combination with docetaxel (DTX) (CE + DTX) [...] Read more.

Ceramide (CE)-based combination therapy (CE combination) as a novel therapeutic strategy has attracted great attention in the field of anti-cancer therapy. The principal purposes of this study were to investigate the synergistic effect of CE in combination with docetaxel (DTX) (CE + DTX) and to explore the synergy mechanisms of CE + DTX. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and combination index (CI) assay showed that simultaneous administration of CE and DTX with a molar ratio of 0.5:1 could generate the optimal synergistic effect on murine malignant melanoma cell (B16, CI = 0.31) and human breast carcinoma cell (MCF-7, CI = 0.48). The apoptosis, cell cycle, and cytoskeleton destruction study demonstrated that CE could target and destruct the microfilament actin, subsequently activate Caspase-3 and induce apoptosis. Meanwhile, DTX could target and disrupt the microtubules cytoskeleton, leading to a high proportion of cancer cells in G2/M-phase arrest. Moreover, CE plus DTX could cause a synergistic destruction of cytoskeleton, which resulted in a significantly higher apoptosis and a significantly higher arrest in G2/M arrest comparing with either agent alone (p < 0.01). The in vivo antitumor study evaluated in B16 tumor-bearing mice also validated the synergistic effects. All these results suggested that CE could enhance the antitumor activity of DTX in a synergistic manner, which suggest promising application prospects of CE + DTX combination treatment. Full article

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

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Structure of N-Terminal Sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser of Aβ-Peptide with Phospholipase A₂ from Venom of Andaman Cobra Sub-Species Naja naja sagittifera at 2.0 Å Resolution

by Zeenat Mirza, Vikram Gopalakrishna Pillai and Wei-Zhu Zhong

Int. J. Mol. Sci. 2014, 15(3), 4221-4236; https://doi.org/10.3390/ijms15034221 - 10 Mar 2014

Cited by 3 | Viewed by 7780

Abstract

Alzheimer’s disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD’s neuropathology. Studies have implicated the varied role of phospholipase A₂ [...] Read more.

Alzheimer’s disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD’s neuropathology. Studies have implicated the varied role of phospholipase A₂ (PLA₂) in brain where it contributes to neuronal growth and inflammatory response. Overall contour and chemical nature of the substrate-binding channel in the low molecular weight PLA₂s are similar. This study involves the reductionist fragment-based approach to understand the structure adopted by N-terminal fragment of Alzheimer’s Aβ peptide in its complex with PLA₂. In the current communication, we report the structure determined by X-ray crystallography of N-terminal sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser (DAEFRHDS) of Aβ-peptide with a Group I PLA₂ purified from venom of Andaman Cobra sub-species Naja naja sagittifera at 2.0 Å resolution (Protein Data Bank (PDB) Code: 3JQ5). This is probably the first attempt to structurally establish interaction between amyloid-β peptide fragment and hydrophobic substrate binding site of PLA₂ involving H bond and van der Waals interactions. We speculate that higher affinity between Aβ and PLA₂ has the therapeutic potential of decreasing the Aβ–Aβ interaction, thereby reducing the amyloid aggregation and plaque formation in AD. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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The First Insight into the Metabolite Profiling of Grapes from Three Vitis vinifera L. Cultivars of Two Controlled Appellation (DOC) Regions

by António Teixeira, Viviana Martins, Henrique Noronha, José Eiras-Dias and Hernâni Gerós

Int. J. Mol. Sci. 2014, 15(3), 4237-4254; https://doi.org/10.3390/ijms15034237 - 10 Mar 2014

Cited by 20 | Viewed by 9261

Abstract

The characterization of the metabolites accumulated in the grapes of specific cultivars grown in different climates is of particular importance for viticulturists and enologists. In the present study, the metabolite profiling of grapes from the cultivars, Alvarinho, Arinto and Padeiro de Basto, of [...] Read more.

The characterization of the metabolites accumulated in the grapes of specific cultivars grown in different climates is of particular importance for viticulturists and enologists. In the present study, the metabolite profiling of grapes from the cultivars, Alvarinho, Arinto and Padeiro de Basto, of two Portuguese Controlled Denomination of Origin (DOC) regions (Vinho Verde and Lisboa) was investigated by gas chromatography-coupled time-of-flight mass spectrometry (GC-TOF-MS) and an amino acid analyzer. Primary metabolites, including sugars, organic acids and amino acids, and some secondary metabolites were identified. Tartaric and malic acids and free amino acids accumulated more in grapes from vines of the DOC region of Vinho Verde than DOC Lisboa, but a principal component analysis (PCA) plot showed that besides the DOC region, the grape cultivar also accounted for the variance in the relative abundance of metabolites. Grapes from the cultivar, Alvarinho, were particularly rich in malic acid and tartaric acids in both DOC regions, but sucrose accumulated more in the DOC region of Vinho Verde. Full article

(This article belongs to the Section Biochemistry)

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Synthesis, Antifungal Activities and Qualitative Structure Activity Relationship of Carabrone Hydrazone Derivatives as Potential Antifungal Agents

by Hao Wang, Shuang-Xi Ren, Ze-Yu He, De-Long Wang, Xiao-Nan Yan, Jun-Tao Feng and Xing Zhang

Int. J. Mol. Sci. 2014, 15(3), 4257-4272; https://doi.org/10.3390/ijms15034257 - 11 Mar 2014

Cited by 29 | Viewed by 6778

Abstract

Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium [...] Read more.

Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents. Full article

(This article belongs to the Section Biochemistry)

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Polymorphisms in DNA Repair Genes (APEX1, XPD, XRCC1 and XRCC3) and Risk of Preeclampsia in a Mexican Mestizo Population

by Ada Sandoval-Carrillo, Edna M. Méndez-Hernández, Fernando Vazquez-Alaniz, Marisela Aguilar-Durán, Alfredo Téllez-Valencia, Marcelo Barraza-Salas, Francisco X. Castellanos-Juárez, Osmel La Llave-León and José M. Salas-Pacheco

Int. J. Mol. Sci. 2014, 15(3), 4273-4283; https://doi.org/10.3390/ijms15034273 - 11 Mar 2014

Cited by 11 | Viewed by 6472

Abstract

Variations in genes involved in DNA repair systems have been proposed as risk factors for the development of preeclampsia (PE). We conducted a case-control study to investigate the association of Human apurinic/apyrimidinic (AP) endonuclease (APEX1) Asp148Glu (rs1130409), Xeroderma Pigmentosum group D [...] Read more.

Variations in genes involved in DNA repair systems have been proposed as risk factors for the development of preeclampsia (PE). We conducted a case-control study to investigate the association of Human apurinic/apyrimidinic (AP) endonuclease (APEX1) Asp148Glu (rs1130409), Xeroderma Pigmentosum group D (XPD) Lys751Gln (rs13181), X-ray repair cross-complementing group 1 (XRCC) Arg399Gln (rs25487) and X-ray repair cross-complementing group 3 (XRCC3) Thr241Met (rs861539) polymorphisms with PE in a Mexican population. Samples of 202 cases and 350 controls were genotyped using RTPCR. Association analyses based on a χ² test and binary logistic regression were performed to determine the odds ratio (OR) and a 95% confidence interval (95% CI) for each polymorphism. The allelic frequencies of APEX1 Asp148Glu polymorphism showed statistical significant differences between preeclamptic and normal women (p = 0.036). Although neither of the polymorphisms proved to be a risk factor for the disease, the APEX1 Asp148Glu polymorphism showed a tendency of association (OR: 1.74, 95% CI = 0.96–3.14) and a significant trend (p for trend = 0.048). A subgroup analyses revealed differences in the allelic frequencies of APEX1 Asp148Glu polymorphism between women with mild preeclampsia and severe preeclampsia (p = 0.035). In conclusion, our results reveal no association between XPD Lys751Gln, XRCC Arg399Gln and XRCC3 Thr241Met polymorphisms and the risk of PE in a Mexican mestizo population; however, the results in the APEX1 Asp148Glu polymorphism suggest the need for future studies using a larger sample size. Full article

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

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Detection of Borreliae in Archived Sera from Patients with Clinically Suspect Lyme Disease

by Sin Hang Lee, Jessica S. Vigliotti, Veronica S. Vigliotti, William Jones and David M. Shearer

Int. J. Mol. Sci. 2014, 15(3), 4284-4298; https://doi.org/10.3390/ijms15034284 - 11 Mar 2014

Cited by 28 | Viewed by 12284

Abstract

The diagnoses of Lyme disease based on clinical manifestations, serological findings and detection of infectious agents often contradict each other. We tested 52 blind-coded serum samples, including 20 pre-treatment and 12 post-treatment sera from clinically suspect Lyme disease patients, for the presence of [...] Read more.

The diagnoses of Lyme disease based on clinical manifestations, serological findings and detection of infectious agents often contradict each other. We tested 52 blind-coded serum samples, including 20 pre-treatment and 12 post-treatment sera from clinically suspect Lyme disease patients, for the presence of residual Lyme disease infectious agents, using nested PCR amplification of a signature segment of the borrelial 16S ribosomal RNA gene for detection and direct DNA sequencing of the PCR amplicon for molecular validation. These archived sera were split from the samples drawn for the 2-tier serology tests performed by a CDC-approved laboratory, and are used as reference materials for evaluating new diagnostic reagents. Of the 12 post-treatment serum samples, we found DNA evidence of a novel borrelia of uncertain significance in one, which was also positive for the 2-tier serology test. The rest of the post-treatment sera and all 20 control sera were PCR-negative. Of the 20 pre-treatment sera from clinically suspect early Lyme disease patients, we found Borrelia miyamotoi in one which was 2-tier serology-negative, and a Borrelia burgdorferi in two—one negative and one positive for 2-tier serology. We conclude that a sensitive and reliable DNA-based test is needed to support the diagnosis of Lyme disease and Lyme disease-like borreliosis. Full article

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

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The Effect of Physical and Chemical Cues on Hepatocellular Function and Morphology

by Shimaa A. Abdellatef, Akihiko Ohi, Toshihide Nabatame and Akiyoshi Taniguchi

Int. J. Mol. Sci. 2014, 15(3), 4299-4317; https://doi.org/10.3390/ijms15034299 - 11 Mar 2014

Cited by 7 | Viewed by 7873

Abstract

Physical topographical features and/or chemical stimuli to the extracellular matrix (ECM) provide essential cues that manipulate cell functions. From the physical point of view, contoured nanostructures are very important for cell behavior in general, and for cellular functions. From the chemical point of [...] Read more.

Physical topographical features and/or chemical stimuli to the extracellular matrix (ECM) provide essential cues that manipulate cell functions. From the physical point of view, contoured nanostructures are very important for cell behavior in general, and for cellular functions. From the chemical point of view, ECM proteins containing an RGD sequence are known to alter cell functions. In this study, the influence of integrated physical and chemical cues on a liver cell line (HepG2) was investigated. To mimic the physical cues provided by the ECM, amorphous TiO₂ nanogratings with specific dimensional and geometrical characteristics (nanogratings 90 nm wide and 150 nm apart) were fabricated. To mimic the chemical cues provided by the ECM, the TiO₂ inorganic film was modified by immobilization of the RGD motif. The hepatic cell line morphological and functional changes induced by simultaneously combining these diversified cues were investigated, including cellular alignment and the expression of different functional proteins. The combination of nanopatterns and surface modification with RGD induced cellular alignment and expression of functional proteins, indicating that physical and chemical cues are important factors for optimizing hepatocyte function. Full article

(This article belongs to the Special Issue Interaction between Nano-Structure Materials and Cells)

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The Pro-Apoptotic Role of the Regulatory Feedback Loop between miR-124 and PKM1/HNF4α in Colorectal Cancer Cells

by Yan Sun, Xiaoping Zhao, Man Luo, Yuhong Zhou, Weiying Ren, Kefen Wu, Xi Li, Jiping Shen and Yu Hu

Int. J. Mol. Sci. 2014, 15(3), 4318-4332; https://doi.org/10.3390/ijms15034318 - 11 Mar 2014

Cited by 26 | Viewed by 7461

Abstract

Accumulating evidence indicates that miRNA regulatory circuits play important roles in tumorigenesis. We previously reported that miR-124 is correlated with prognosis of colorectal cancer due to PKM-dependent regulation of glycolysis. However, the mechanism by which miR-124 regulates apoptosis in colorectal cancer remains largely [...] Read more.

Accumulating evidence indicates that miRNA regulatory circuits play important roles in tumorigenesis. We previously reported that miR-124 is correlated with prognosis of colorectal cancer due to PKM-dependent regulation of glycolysis. However, the mechanism by which miR-124 regulates apoptosis in colorectal cancer remains largely elusive. Here, we show that miR-124 induced significant apoptosis in a panel of colorectal cancer cell lines. The mitochondrial apoptosis pathway was activated by miR-124. Furthermore, the pro-apoptotic role of miR-124 was dependent on the status of PKM1/2 level. PKM1 was required for miR-124-induced apoptosis. Via direct protein-protein interaction, PKM1 promoted HNF4α binding to the promoter region of miR-124 and transcribing miR-124. Moreover, HNF4α or PKM1 had a more dramatic effect on colorectal cancer cell apoptosis in the presence of miR-124. However, inhibition of miR-124 blocked cell apoptosis induced by HNF4α or PKM1. These data indicate that miR-124 not only alters the expression of genes involved in glucose metabolism but also stimulates cancer cell apoptosis. In addition, the positive feedback loop between miR-124 and PKM1/HNF4α plays an important role in colorectal cancer cell apoptosis; it suggests that disrupting this regulatory circuit might be a potential therapeutic tool for colorectal cancer treatment. Full article

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

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Comparative Proteomic Analysis of Differential Responses of Pinus massoniana and Taxus wallichiana var. mairei to Simulated Acid Rain

by Wen-Jun Hu, Juan Chen, Ting-Wu Liu, Martin Simon, Wen-Hua Wang, Juan Chen, Fei-Hua Wu, Xiang Liu, Zhi-Jun Shen and Hai-Lei Zheng

Int. J. Mol. Sci. 2014, 15(3), 4333-4355; https://doi.org/10.3390/ijms15034333 - 12 Mar 2014

Cited by 20 | Viewed by 6477

Abstract

Acid rain (AR), a serious environmental issue, severely affects plant growth and development. As the gymnosperms of conifer woody plants, Pinus massoniana (AR-sensitive) and Taxus wallichiana var. mairei (AR-resistant) are widely distributed in southern China. Under AR stress, significant necrosis and collapsed [...] Read more.

Acid rain (AR), a serious environmental issue, severely affects plant growth and development. As the gymnosperms of conifer woody plants, Pinus massoniana (AR-sensitive) and Taxus wallichiana var. mairei (AR-resistant) are widely distributed in southern China. Under AR stress, significant necrosis and collapsed lesions were found in P. massoniana needles with remarkable yellowing and wilting tips, whereas T. wallichiana var. mairei did not exhibit chlorosis and visible damage. Due to the activation of a large number of stress-related genes and the synthesis of various functional proteins to counteract AR stress, it is important to study the differences in AR-tolerance mechanisms by comparative proteomic analysis of tolerant and sensitive species. This study revealed a total of 65 and 26 differentially expressed proteins that were identified in P. massoniana and T. wallichiana var. mairei, respectively. Among them, proteins involved in metabolism, photosynthesis, signal transduction and transcription were drastically down-regulated in P. massoniana, whereas most of the proteins participating in metabolism, cell structure, photosynthesis and transcription were increased in T. wallichiana var. mairei. These results suggest the distinct patterns of protein expression in the two woody species in response to AR, allowing a deeper understanding of diversity on AR tolerance in forest tree species. Full article

(This article belongs to the Section Biochemistry)

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Intratumoral Decorin Gene Delivery by AAV Vector Inhibits Brain Glioblastomas and Prolongs Survival of Animals by Inducing Cell Differentiation

by Hsin-I Ma, Dueng-Yuan Hueng, Hao-Ai Shui, Jun-Ming Han, Chi-Hsien Wang, Ying-Hsiu Lai, Shi-Yuan Cheng, Xiao Xiao, Ming-Teh Chen and Yi-Ping Yang

Int. J. Mol. Sci. 2014, 15(3), 4393-4414; https://doi.org/10.3390/ijms15034393 - 12 Mar 2014

Cited by 31 | Viewed by 7474

Abstract

Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of [...] Read more.

Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of nude mice through an adeno-associated viral (AAV2) gene delivery system. Decorin expression from the AAV vector in vitro inhibited cultured U87MG cell growth by induction of cell differentiation. Intracranial injection of AAV-decorin vector to the glioma-bearing nude mice in vivo significantly suppressed brain tumor growth and prolonged survival when compared to control non-treated mice bearing the same U87MG tumors. Proteomics analysis on protein expression profiles in the U87MG glioma cells after AAV-mediated decorin gene transfer revealed up- and down-regulation of important proteins. Differentially expressed proteins between control and AAV-decorin-transduced cells were identified through MALDI-TOF MS and database mining. We found that a number of important proteins that are involved in apoptosis, transcription, chemotherapy resistance, mitosis, and fatty acid metabolism have been altered as a result of decorin overexpression. These findings offer valuable insight into the mechanisms of the anti-glioblastoma effects of decorin. In addition, AAV-mediated decorin gene delivery warrants further investigation as a potential therapeutic approach for brain tumors. Full article

(This article belongs to the Section Biochemistry)

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Carvacrol and trans-Cinnamaldehyde Reduce Clostridium difficile Toxin Production and Cytotoxicity in Vitro

by Shankumar Mooyottu, Anup Kollanoor-Johny, Genevieve Flock, Laurent Bouillaut, Abhinav Upadhyay, Abraham L. Sonenshein and Kumar Venkitanarayanan

Int. J. Mol. Sci. 2014, 15(3), 4415-4430; https://doi.org/10.3390/ijms15034415 - 12 Mar 2014

Cited by 55 | Viewed by 8626

Abstract

Clostridium difficile is a nosocomial pathogen that causes a serious toxin-mediated enteric disease in humans. Reducing C. difficile toxin production could significantly minimize its pathogenicity and improve disease outcomes in humans. This study investigated the efficacy of two, food-grade, plant-derived compounds, namely trans [...] Read more.

Clostridium difficile is a nosocomial pathogen that causes a serious toxin-mediated enteric disease in humans. Reducing C. difficile toxin production could significantly minimize its pathogenicity and improve disease outcomes in humans. This study investigated the efficacy of two, food-grade, plant-derived compounds, namely trans-cinnamaldehyde (TC) and carvacrol (CR) in reducing C. difficile toxin production and cytotoxicity in vitro. Three hypervirulent C. difficile isolates were grown with or without the sub-inhibitory concentrations of TC or CR, and the culture supernatant and the bacterial pellet were collected for total toxin quantitation, Vero cell cytotoxicity assay and RT-qPCR analysis of toxin-encoding genes. The effect of CR and TC on a codY mutant and wild type C. difficile was also investigated. Carvacrol and TC substantially reduced C. difficile toxin production and cytotoxicity on Vero cells. The plant compounds also significantly down-regulated toxin production genes. Carvacrol and TC did not inhibit toxin production in the codY mutant of C. difficile, suggesting a potential codY-mediated anti-toxigenic mechanism of the plant compounds. The antitoxigenic concentrations of CR and TC did not inhibit the growth of beneficial gut bacteria. Our results suggest that CR and TC could potentially be used to control C. difficile, and warrant future studies in vivo. Full article

(This article belongs to the Section Biochemistry)

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Transplanted Neural Stem Cells Modulate Regulatory T, γδ T Cells and Corresponding Cytokines after Intracerebral Hemorrhage in Rats

by Lu Gao, Qin Lu, Li-Jie Huang, Lin-Hui Ruan, Jian-Jing Yang, Wei-Long Huang, Wei-Shan ZhuGe, Yong-Liang Zhang, Biao Fu, Kun-Lin Jin and Qi-Chuan ZhuGe

Int. J. Mol. Sci. 2014, 15(3), 4431-4441; https://doi.org/10.3390/ijms15034431 - 13 Mar 2014

Cited by 43 | Viewed by 7409

Abstract

The immune system, particularly T lymphocytes and cytokines, has been implicated in the progression of brain injury after intracerebral hemorrhage (ICH). Although studies have shown that transplanted neural stem cells (NSCs) protect the central nervous system (CNS) from inflammatory damage, their effects on [...] Read more.

The immune system, particularly T lymphocytes and cytokines, has been implicated in the progression of brain injury after intracerebral hemorrhage (ICH). Although studies have shown that transplanted neural stem cells (NSCs) protect the central nervous system (CNS) from inflammatory damage, their effects on subpopulations of T lymphocytes and their corresponding cytokines are largely unexplored. Here, rats were subjected to ICH and NSCs were intracerebrally injected at 3 h after ICH. The profiles of subpopulations of T cells in the brain and peripheral blood were analyzed by flow cytometry. We found that regulatory T (Treg) cells in the brain and peripheral blood were increased, but γδT cells (gamma delta T cells) were decreased, along with increased anti-inflammatory cytokines (IL-4, IL-10 and TGF-β) and decreased pro-inflammatory cytokines (IL-6, and IFN-γ), compared to the vehicle-treated control. Our data suggest that transplanted NSCs protect brain injury after ICH via modulation of Treg and γδT cell infiltration and anti- and pro-inflammatory cytokine release. Full article

(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)

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Comparison of the Osteogenic Potential of Titanium- and Modified Zirconia-Based Bioceramics

by Young-Dan Cho, Ji-Cheol Shin, Hye-Lee Kim, Myagmar Gerelmaa, Hyung-In Yoon, Hyun-Mo Ryoo, Dae-Joon Kim and Jung-Suk Han

Int. J. Mol. Sci. 2014, 15(3), 4442-4452; https://doi.org/10.3390/ijms15034442 - 13 Mar 2014

Cited by 16 | Viewed by 7451

Abstract

Zirconia is now favored over titanium for use in dental implant materials because of its superior aesthetic qualities. However, zirconia is susceptible to degradation at lower temperatures. In order to address this issue, we have developed modified zirconia implants that contain tantalum oxide [...] Read more.

Zirconia is now favored over titanium for use in dental implant materials because of its superior aesthetic qualities. However, zirconia is susceptible to degradation at lower temperatures. In order to address this issue, we have developed modified zirconia implants that contain tantalum oxide or niobium oxide. Cells attached as efficiently to the zirconia implants as to titanium-based materials, irrespective of surface roughness. Cell proliferation on the polished surface was higher than that on the rough surfaces, but the converse was true for the osteogenic response. Cells on yttrium (Y)/tantalum (Ta)- and yttrium (Y)/niobium (Nb)-stabilized tetragonal zirconia polycrystals (TZP) discs ((Y, Ta)-TZP and (Y, Nb)-TZP, respectively) had a similar proliferative potential as those grown on anodized titanium. The osteogenic potential of MC3T3-E1 pre-osteoblast cells on (Y, Ta)-TZP and (Y, Nb)-TZP was similar to that of cells grown on rough-surface titanium. These data demonstrate that improved zirconia implants, which are resistant to temperature-induced degradation, retain the desirable clinical properties of structural stability and support of an osteogenic response. Full article

(This article belongs to the Special Issue Interaction between Nano-Structure Materials and Cells)

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Exercise Pretreatment Promotes Mitochondrial Dynamic Protein OPA1 Expression after Cerebral Ischemia in Rats

by Li Zhang, Zhijie He, Qi Zhang, Yi Wu, Xiaojiao Yang, Wenxiu Niu, Yongshan Hu and Jie Jia

Int. J. Mol. Sci. 2014, 15(3), 4453-4463; https://doi.org/10.3390/ijms15034453 - 13 Mar 2014

Cited by 41 | Viewed by 6905

Abstract

Exercise training is a neuroprotective strategy in cerebral ischemic injury, but the underlying mechanisms are not yet clear. In the present study, we investigated the effects of treadmill exercise pretreatment on the expression of mitochondrial dynamic proteins. We examined the expression of OPA1 [...] Read more.

Exercise training is a neuroprotective strategy in cerebral ischemic injury, but the underlying mechanisms are not yet clear. In the present study, we investigated the effects of treadmill exercise pretreatment on the expression of mitochondrial dynamic proteins. We examined the expression of OPA1/DLP1/MFF/Mfn1/Mfn2, which regulatesmitochondrial fusion and fission, and cytochrome C oxidase subunits (COX subunits), which regulatemitochondrial functions, after middle cerebral artery occlusion (MCAO) in rats. T2-weighted magnetic resonance imaging (MRI) was evaluated as indices of brain edema after ischemia as well. Treadmill training pretreatment increased the expression levels of OPA1 and COXII/III/IV and alleviated brain edema, indicating that exercise pretreatment provided neuroprotection in cerebral ischemic injury via the regulation of mitochondrial dynamics and functions. Full article

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Effect of Nitrate on Nodule and Root Growth of Soybean (Glycine max (L.) Merr.)

by Akinori Saito, Sayuri Tanabata, Takanari Tanabata, Seiya Tajima, Manabu Ueno, Shinji Ishikawa, Norikuni Ohtake, Kuni Sueyoshi and Takuji Ohyama

Int. J. Mol. Sci. 2014, 15(3), 4464-4480; https://doi.org/10.3390/ijms15034464 - 13 Mar 2014

Cited by 84 | Viewed by 9446

Abstract

The application of combined nitrogen, especially nitrate, to soybean plants is known to strongly inhibit nodule formation, growth and nitrogen fixation. In the present study, we measured the effects of supplying 5 mM nitrate on the growth of nodules, primary root, and lateral [...] Read more.

The application of combined nitrogen, especially nitrate, to soybean plants is known to strongly inhibit nodule formation, growth and nitrogen fixation. In the present study, we measured the effects of supplying 5 mM nitrate on the growth of nodules, primary root, and lateral roots under light at 28 °C or dark at 18 °C conditions. Photographs of the nodulated roots were periodically taken by a digital camera at 1-h intervals, and the size of the nodules was measured with newly developed computer software. Nodule growth was depressed approximately 7 h after the addition of nitrate under light conditions. The nodule growth rate under dark conditions was almost half that under light conditions, and nodule growth was further suppressed by the addition of 5 mM nitrate. Similar results were observed for the extending growth rate of the primary root as those for nodule growth supplied with 5 mM nitrate under light/dark conditions. In contrast, the growth of lateral roots was promoted by the addition of 5 mM nitrate. The 2D-PAGE profiles of nodule protein showed similar patterns between the 0 and 5 mM nitrate treatments, which suggested that metabolic integrity may be maintained with the 5 mM nitrate treatment. Further studies are required to confirm whether light or temperature condition may give the primary effect on the growth of nodules and roots. Full article

(This article belongs to the Special Issue Symbiotic Nitrogen Fixation in Legume Nodules: Metabolism and Regulatory Mechanisms)

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Proteomic Analysis of the Follicular Fluid of Tianzhu White Yak during Diestrus

by Jinzhong Tao, Guoshun Zhao, Xingxu Zhao, Fadi Li, Xiaohu Wu, Junjie Hu and Yong Zhang

Int. J. Mol. Sci. 2014, 15(3), 4481-4491; https://doi.org/10.3390/ijms15034481 - 13 Mar 2014

Cited by 4 | Viewed by 5804

Abstract

The aim of this study was to identify differentially expressed proteins in the follicular fluid of Tianzhu white yak during diestrus. Follicles obtained from female yak were divided into four groups according to their diameter: 0–2, 2–4, 4–6 mm, and greater than 6 [...] Read more.

The aim of this study was to identify differentially expressed proteins in the follicular fluid of Tianzhu white yak during diestrus. Follicles obtained from female yak were divided into four groups according to their diameter: 0–2, 2–4, 4–6 mm, and greater than 6 mm. The follicular fluid was directly aspirated from the follicles and mixed according to follicular size, and two-dimensional gel electrophoresis was carried out on the crude follicular fluid samples. Thirty-four differentially expressed spots were generated from these four sizes of follicles. Fourteen of these spots were analyzed by MALDI-TOF/TOF-MS and identified as: AS3MT, VDP, ANKRD6, C10orf107 protein, MRP4, MAPKAP1, AGO3, profilin-β-actin, SPT2 homolog, AGP, AR, RNF20, obscurin-like-1, and one unnamed protein. These proteins were first reported in follicular fluid, in addition to VDP and AGP. Based on existing knowledge of their function and patterns of expression, we hypothesize that most of these differentially expressed proteins play a role in ovarian follicular growth and development, dominant follicle selection, or follicular atresia and development of oocytes; however, the function of the other differentially expressed proteins in reproduction remains ambiguous. Full article

(This article belongs to the Section Biochemistry)

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Towards Controlling the Glycoform: A Model Framework Linking Extracellular Metabolites to Antibody Glycosylation

by Philip M. Jedrzejewski, Ioscani Jimenez Del Val, Antony Constantinou, Anne Dell, Stuart M. Haslam, Karen M. Polizzi and Cleo Kontoravdi

Int. J. Mol. Sci. 2014, 15(3), 4492-4522; https://doi.org/10.3390/ijms15034492 - 14 Mar 2014

Cited by 70 | Viewed by 11490

Abstract

Glycoproteins represent the largest group of the growing number of biologically-derived medicines. The associated glycan structures and their distribution are known to have a large impact on pharmacokinetics. A modelling framework was developed to provide a link from the extracellular environment and its [...] Read more.

Glycoproteins represent the largest group of the growing number of biologically-derived medicines. The associated glycan structures and their distribution are known to have a large impact on pharmacokinetics. A modelling framework was developed to provide a link from the extracellular environment and its effect on intracellular metabolites to the distribution of glycans on the constant region of an antibody product. The main focus of this work is the mechanistic in silico reconstruction of the nucleotide sugar donor (NSD) metabolic network by means of 34 species mass balances and the saturation kinetics rates of the 60 metabolic reactions involved. NSDs are the co-substrates of the glycosylation process in the Golgi apparatus and their simulated dynamic intracellular concentration profiles were linked to an existing model describing the distribution of N-linked glycan structures of the antibody constant region. The modelling framework also describes the growth dynamics of the cell population by means of modified Monod kinetics. Simulation results match well to experimental data from a murine hybridoma cell line. The result is a modelling platform which is able to describe the product glycoform based on extracellular conditions. It represents a first step towards the in silico prediction of the glycoform of a biotherapeutic and provides a platform for the optimisation of bioprocess conditions with respect to product quality. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins)

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A Preliminary X-ray Study of Murine Tnfaip8/Oxi-α

by Daeun Lee, Mi-Sun Kim, Jimin Park, Gil-Ja Jhon, Jin H. Son and Dong Hae Shin

Int. J. Mol. Sci. 2014, 15(3), 4523-4530; https://doi.org/10.3390/ijms15034523 - 14 Mar 2014

Cited by 4 | Viewed by 6674

Abstract

Tnfaip8/oxidative stress regulated gene-α (Oxi-α) is a novel protein expressed specifically in brain dopaminergic neurons and its over-expression has been reported to protect dopaminergic cells against OS-induced cell death. In this study, murine C165S mutant Tnfaip8/Oxi-α has been crystallized and X-ray data have [...] Read more.

Tnfaip8/oxidative stress regulated gene-α (Oxi-α) is a novel protein expressed specifically in brain dopaminergic neurons and its over-expression has been reported to protect dopaminergic cells against OS-induced cell death. In this study, murine C165S mutant Tnfaip8/Oxi-α has been crystallized and X-ray data have been collected to 1.8 Å using synchrotron radiation. The crystal belonged to the primitive orthorhombic space group P2₁2₁2, with unit-cell parameters a = 66.9, b = 72.3, c = 93.5 Å. A full structural determination is under way in order to provide insights into the structure-function relationships of this protein. Full article

(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)

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New Unsymmetrically Benzene-Fused Bis (Tetrathiafulvalene): Synthesis, Characterization, Electrochemical Properties and Electrical Conductivity of Their Materials

by Tahar Abbaz, Amel Bendjeddou, Abdelkrim Gouasmia, Didier Villemin and Takashi Shirahata

Int. J. Mol. Sci. 2014, 15(3), 4550-4564; https://doi.org/10.3390/ijms15034550 - 17 Mar 2014

Cited by 6 | Viewed by 5458

Abstract

The synthesis of new unsymmetrically benzene-fused bis (tetrathiafulvalene) has been carried out by a cross-coupling reaction of the respective 4,5-dialkyl-1,3-dithiole-2-selenone 6–9 with 2-(4-(p-nitrophenyl)-1,3-dithiole-2-ylidene)-1,3,5,7-tetrathia-s-indacene-6-one 5 prepared by olefination of 4-(p-nitrophenyl)-1,3-dithiole-2-selenone 3 and 1,3,5,7-tetrathia-s-indacene-2,6-dione 4. The conversion of [...] Read more.

The synthesis of new unsymmetrically benzene-fused bis (tetrathiafulvalene) has been carried out by a cross-coupling reaction of the respective 4,5-dialkyl-1,3-dithiole-2-selenone 6–9 with 2-(4-(p-nitrophenyl)-1,3-dithiole-2-ylidene)-1,3,5,7-tetrathia-s-indacene-6-one 5 prepared by olefination of 4-(p-nitrophenyl)-1,3-dithiole-2-selenone 3 and 1,3,5,7-tetrathia-s-indacene-2,6-dione 4. The conversion of the nitro moiety 10a–d to amino 11a–d then dibenzylamine 12a–d groups respectively used reduction and alkylation methods. The electron donor ability of these new compounds has been measured by cyclic voltammetry (CV) technique. Charge transfer complexes with tetracyanoquino-dimethane (TCNQ) were prepared by chemical redox reactions. The complexes have been proven to give conducting materials. Full article

(This article belongs to the Section Materials Science)

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Open AccessArticle

New Insights on Plant Cell Elongation: A Role for Acetylcholine

by Gian-Pietro Di Sansebastiano, Silvia Fornaciari, Fabrizio Barozzi, Gabriella Piro and Laura Arru

Int. J. Mol. Sci. 2014, 15(3), 4565-4582; https://doi.org/10.3390/ijms15034565 - 17 Mar 2014

Cited by 33 | Viewed by 7845

Abstract

We investigated the effect of auxin and acetylcholine on the expression of the tomato expansin gene LeEXPA2, a specific expansin gene expressed in elongating tomato hypocotyl segments. Since auxin interferes with clathrin-mediated endocytosis, in order to regulate cellular and developmental responses we [...] Read more.

We investigated the effect of auxin and acetylcholine on the expression of the tomato expansin gene LeEXPA2, a specific expansin gene expressed in elongating tomato hypocotyl segments. Since auxin interferes with clathrin-mediated endocytosis, in order to regulate cellular and developmental responses we produced protoplasts from tomato elongating hypocotyls and followed the endocytotic marker, FM4-64, internalization in response to treatments. Tomato protoplasts were observed during auxin and acetylcholine treatments after transient expression of chimerical markers of volume-control related compartments such as vacuoles. Here we describe the contribution of auxin and acetylcholine to LeEXPA2 expression regulation and we support the hypothesis that a possible subcellular target of acetylcholine signal is the vesicular transport, shedding some light on the characterization of this small molecule as local mediator in the plant physiological response. Full article

(This article belongs to the Special Issue Plant Cell Compartmentation and Volume Control)

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Open AccessArticle

Transcriptome Expression Profiling in Response to Drought Stress in Paulownia australis

by Yanpeng Dong, Guoqiang Fan, Zhenli Zhao and Minjie Deng

Int. J. Mol. Sci. 2014, 15(3), 4583-4607; https://doi.org/10.3390/ijms15034583 - 17 Mar 2014

Cited by 21 | Viewed by 6550

Abstract

The response and adaptation to drought remains poorly understood for Paulownia australis. To investigate this issue, transcriptome profiling of four P. australis accessions (two diploid and the other two autotetraploid) under water stress condition were studied using Illumina Genome Analyzer IIx [...] Read more.

The response and adaptation to drought remains poorly understood for Paulownia australis. To investigate this issue, transcriptome profiling of four P. australis accessions (two diploid and the other two autotetraploid) under water stress condition were studied using Illumina Genome Analyzer IIx analysis. The current study aimed to identify genes of P. australis metabolism pathways that might be involved in this plant’s response to water deficit. Potted seedlings were subjected to well-watered conditions and drought stress, respectively. More than 290 million raw transcript reads were assembled into 111,660 unigenes, with a mean length of 1013 bp. Clusters of orthologous groups, gene ontology and the Kyoto Encyclopedia of Genes and Genomes annotations analyses were performed on the unigenes. Many differentially expressed genes and several metabolic pathways were identified. Quantitative real-time polymerase chain reaction was used to verify the expression patterns of 14 genes. Our study identified altered gene expression in P. australis induced by drought stress and provided a comprehensive map of drought-responsive genes and pathways in this species. To our knowledge, this is the first publicly available global transcriptome study of P. australis. This study provides a valuable genetic resource for this species. Full article

(This article belongs to the Section Biochemistry)

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8-Alkylcoumarins from the Fruits of Cnidium monnieri Protect against Hydrogen Peroxide Induced Oxidative Stress Damage

by Chi-I Chang, Wan-Chiao Hu, Che-Piao Shen, Ban-Dar Hsu, Wei-Yong Lin, Ping-Jyun Sung, Wei-Hsien Wang, Jin-Bin Wu and Yueh-Hsiung Kuo

Int. J. Mol. Sci. 2014, 15(3), 4608-4618; https://doi.org/10.3390/ijms15034608 - 17 Mar 2014

Cited by 13 | Viewed by 5797

Abstract

Three new 8-alkylcoumarins, 7-O-methylphellodenol-B (1), 7-methoxy-8-(3-methyl- 2,3-epoxy-1-oxobutyl)chromen-2-one (2), and 3'-O-methylvaginol (3), together with seven known compounds (4–10) were isolated from the fruits of Cnidium monnieri. Their structures [...] Read more.

Three new 8-alkylcoumarins, 7-O-methylphellodenol-B (1), 7-methoxy-8-(3-methyl- 2,3-epoxy-1-oxobutyl)chromen-2-one (2), and 3'-O-methylvaginol (3), together with seven known compounds (4–10) were isolated from the fruits of Cnidium monnieri. Their structures were determined by detailed analysis of spectroscopic data and comparison with the data of known analogues. All the isolates were evaluated the cytoprotective activity by MTS cell proliferation assay and the results showed that all the three new 8-alkylcoumarins exhibited cytoprotective effect on Neuro-2a neuroblastoma cells injured by hydrogen peroxide. Full article

(This article belongs to the Section Biochemistry)

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Testosterone Reduces Knee Passive Range of Motion and Expression of Relaxin Receptor Isoforms via 5α-Dihydrotestosterone and Androgen Receptor Binding

by Firouzeh Dehghan, Sekaran Muniandy, Ashril Yusof and Naguib Salleh

Int. J. Mol. Sci. 2014, 15(3), 4619-4634; https://doi.org/10.3390/ijms15034619 - 17 Mar 2014

Cited by 19 | Viewed by 7008

Abstract

Ovarian steroids such as estrogen and progesterone have been reported to influence knee laxity. The effect of testosterone, however, remains unknown. This study investigated the effect of testosterone on the knee range of motion (ROM) and the molecular mechanisms that might involve changes [...] Read more.

Ovarian steroids such as estrogen and progesterone have been reported to influence knee laxity. The effect of testosterone, however, remains unknown. This study investigated the effect of testosterone on the knee range of motion (ROM) and the molecular mechanisms that might involve changes in the expression of relaxin receptor isoforms, Rxfp1 and Rxfp2 in the patella tendon and lateral collateral ligament of the female rat knee. Ovariectomized adult female Wistar rats received three days treatment with peanut oil (control), testosterone (125 and 250 μg/kg) and testosterone (125 and 250 μg/kg) plus flutamide, an androgen receptor blocker or finasteride, a 5α-reductase inhibitor. Duplicate groups received similar treatment however in the presence of relaxin (25 ng/kg). A day after the last drug injection, knee passive ROM was measured by using a digital miniature goniometer. Both tendon and ligament were harvested and then analysed for protein and mRNA expression for Rxfp1 and Rxfp2 respectively. Knee passive ROM, Rxfp1 and Rxfp2 expression were significantly reduced following treatment with testosterone. Flutamide or finasteride administration antagonized the testosterone effect. Concomitant administration of testosterone and relaxin did not result in a significant change in knee ROM as compared to testosterone only treatment; however this was significantly increased following flutamide or finasteride addition. Testosterone effect on knee passive ROM is likely mediated via dihydro-testosterone (DHT), and involves downregulation of Rxfp1 and Rxfp2 expression, which may provide the mechanism underlying testosterone-induced decrease in female knee laxity. Full article

(This article belongs to the Section Biochemistry)

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Genome-Wide Analysis of the RNA Helicase Gene Family in Gossypium raimondii

by Jie Chen, Yujuan Zhang, Jubo Liu, Minxuan Xia, Wei Wang and Fafu Shen

Int. J. Mol. Sci. 2014, 15(3), 4635-4656; https://doi.org/10.3390/ijms15034635 - 17 Mar 2014

Cited by 23 | Viewed by 8365

Abstract

The RNA helicases, which help to unwind stable RNA duplexes, and have important roles in RNA metabolism, belong to a class of motor proteins that play important roles in plant development and responses to stress. Although this family of genes has been the [...] Read more.

The RNA helicases, which help to unwind stable RNA duplexes, and have important roles in RNA metabolism, belong to a class of motor proteins that play important roles in plant development and responses to stress. Although this family of genes has been the subject of systematic investigation in Arabidopsis, rice, and tomato, it has not yet been characterized in cotton. In this study, we identified 161 putative RNA helicase genes in the genome of the diploid cotton species Gossypium raimondii. We classified these genes into three subfamilies, based on the presence of either a DEAD-box (51 genes), DEAH-box (52 genes), or DExD/H-box (58 genes) in their coding regions. Chromosome location analysis showed that the genes that encode RNA helicases are distributed across all 13 chromosomes of G. raimondii. Syntenic analysis revealed that 62 of the 161 G. raimondii helicase genes (38.5%) are within the identified syntenic blocks. Sixty-six (40.99%) helicase genes from G. raimondii have one or several putative orthologs in tomato. Additionally, GrDEADs have more conserved gene structures and more simple domains than GrDEAHs and GrDExD/Hs. Transcriptome sequencing data demonstrated that many of these helicases, especially GrDEADs, are highly expressed at the fiber initiation stage and in mature leaves. To our knowledge, this is the first report of a genome-wide analysis of the RNA helicase gene family in cotton. Full article

(This article belongs to the Section Biochemistry)

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Influence of Green, Red and Blue Light Emitting Diodes on Multiprotein Complex Proteins and Photosynthetic Activity under Different Light Intensities in Lettuce Leaves (Lactuca sativa L.)

by Sowbiya Muneer, Eun Jeong Kim, Jeong Suk Park and Jeong Hyun Lee

Int. J. Mol. Sci. 2014, 15(3), 4657-4670; https://doi.org/10.3390/ijms15034657 - 17 Mar 2014

Cited by 245 | Viewed by 33666

Abstract

The objective of this study was to investigate the response of light emitting diodes (LEDs) at different light intensities (70 and 80 for green LEDs, 88 and 238 for red LEDs and 80 and 238 μmol m⁻² s⁻¹ for blue LEDs) [...] Read more.

The objective of this study was to investigate the response of light emitting diodes (LEDs) at different light intensities (70 and 80 for green LEDs, 88 and 238 for red LEDs and 80 and 238 μmol m⁻² s⁻¹ for blue LEDs) at three wavelengths in lettuce leaves. Lettuce leaves were exposed to (522 nm), red (639 nm) and blue (470 nm) LEDs of different light intensities. Thylakoid multiprotein complex proteins and photosynthetic metabolism were then investigated. Biomass and photosynthetic parameters increased with an increasing light intensity under blue LED illumination and decreased when illuminated with red and green LEDs with decreased light intensity. The expression of multiprotein complex proteins including PSII-core dimer and PSII-core monomer using blue LEDs illumination was higher at higher light intensity (238 μmol m⁻² s⁻¹) and was lowered with decreased light intensity (70–80 μmol m⁻² s⁻¹). The responses of chloroplast sub-compartment proteins, including those active in stomatal opening and closing, and leaf physiological responses at different light intensities, indicated induced growth enhancement upon illumination with blue LEDs. High intensity blue LEDs promote plant growth by controlling the integrity of chloroplast proteins that optimize photosynthetic performance in the natural environment. Full article

(This article belongs to the Section Biochemistry)

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Nitric Oxide Functions as a Signal in Ultraviolet-B-Induced Baicalin Accumulation in Scutellaria baicalensis Suspension Cultures

by Jin-Jie Zhang, Xue-Qin Li, Jun-Wei Sun and Song-Heng Jin

Int. J. Mol. Sci. 2014, 15(3), 4733-4746; https://doi.org/10.3390/ijms15034733 - 18 Mar 2014

Cited by 16 | Viewed by 7133

Abstract

Stress induced by ultraviolet-B (UV-B) irradiation stimulates the accumulation of various secondary metabolites in plants. Nitric oxide (NO) serves as an important secondary messenger in UV-B stress-induced signal transduction pathways. NO can be synthesized in plants by either enzymatic catalysis or an inorganic [...] Read more.

Stress induced by ultraviolet-B (UV-B) irradiation stimulates the accumulation of various secondary metabolites in plants. Nitric oxide (NO) serves as an important secondary messenger in UV-B stress-induced signal transduction pathways. NO can be synthesized in plants by either enzymatic catalysis or an inorganic nitrogen pathway. The effects of UV-B irradiation on the production of baicalin and the associated molecular pathways in plant cells are poorly understood. In this study, nitric oxide synthase (NOS) activity, NO release and the generation of baicalin were investigated in cell suspension cultures of Scutellaria baicalensis exposed to UV-B irradiation. UV-B irradiation significantly increased NOS activity, NO release and baicalin biosynthesis in S. baicalensis cells. Additionally, exogenous NO supplied by the NO donor, sodium nitroprusside (SNP), led to a similar increase in the baicalin content as the UV-B treatment. The NOS inhibitor, N^ω-nitro-l-arginine (LNNA), and NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) partially inhibited UV-B-induced NO release and baicalin accumulation. These results suggest that NO is generated by NOS or NOS-like enzymes and plays an important role in baicalin biosynthesis as part of the defense response of S. baicalensis cells to UV-B irradiation. Full article

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

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Over-Expression of Platelet-Derived Growth Factor-D Promotes Tumor Growth and Invasion in Endometrial Cancer

by Yuan Wang, Haifeng Qiu, Weixu Hu, Shaoru Li and Jinjin Yu

Int. J. Mol. Sci. 2014, 15(3), 4780-4794; https://doi.org/10.3390/ijms15034780 - 18 Mar 2014

Cited by 28 | Viewed by 6730

Abstract

The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human [...] Read more.

The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001), and high level of PDGF-D was correlated with late stage (p = 0.003), deep myometrium invasion (p < 0.001) and lympha vascular space invasion (p = 0.006). In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we propose targeting PDGF-D to be a potent strategy for endometrial cancer treatment. Full article

(This article belongs to the Section Biochemistry)

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Identification of the Novel Interacting Partners of the Mammalian Target of Rapamycin Complex 1 in Human CCRF-CEM and HEK293 Cells

by Hazir Rahman, Muhammad Qasim, Michael Oellerich and Abdul R. Asif

Int. J. Mol. Sci. 2014, 15(3), 4823-4836; https://doi.org/10.3390/ijms15034823 - 18 Mar 2014

Cited by 8 | Viewed by 8352

Abstract

The present study was undertaken to identify proteins that interact with the mammalian target of rapamycin complex 1 (mTORC1) to enable it to carry out its crucial cell signaling functions. Endogenous and myc-tag mTORC1 was purified, in-gel tryptic digested and then identified by [...] Read more.

The present study was undertaken to identify proteins that interact with the mammalian target of rapamycin complex 1 (mTORC1) to enable it to carry out its crucial cell signaling functions. Endogenous and myc-tag mTORC1 was purified, in-gel tryptic digested and then identified by nano-LC ESI Q-TOF MS/MS analysis. A total of nine novel interacting proteins were identified in both endogenous and myc-tag mTORC1 purifications. These new mTORC1 interacting partners include heterogeneous nuclear ribonucleoproteins A2/B1, enhancer of mRNA decapping protein 4, 60S acidic ribosomal protein, P0, nucleolin, dynamin 2, glyceraldehyde 3 phosphate dehydrogenase, 2-oxoglutarate dehydrogenase, glycosyl transferase 25 family member 1 and prohibitin 2. Furthermore hnRNP A2/B1 and dynamin 2 interaction with mTORC1 was confirmed on immunoblotting. The present study has for the first time identified novel interacting partners of mTORC1 in human T lymphoblasts (CCRF-CEM) and human embryonic kidney (HEK293) cells. These new interacting proteins may offer new targets for therapeutic interventions in human diseases caused by perturbed mTORC1 signaling. Full article

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

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Dimers of G-Protein Coupled Receptors as Versatile Storage and Response Units

by Michael S. Parker, Renu Sah, Ambikaipakan Balasubramaniam, Edwards A. Park, Floyd R. Sallee and Steven L. Parker

Int. J. Mol. Sci. 2014, 15(3), 4856-4877; https://doi.org/10.3390/ijms15034856 - 19 Mar 2014

Cited by 2 | Viewed by 6514

Abstract

The status and use of transmembrane, extracellular and intracellular domains in oligomerization of heptahelical G-protein coupled receptors (GPCRs) are reviewed and for transmembrane assemblies also supplemented by new experimental evidence. The transmembrane-linked GPCR oligomers typically have as the minimal unit an asymmetric ~180 [...] Read more.

The status and use of transmembrane, extracellular and intracellular domains in oligomerization of heptahelical G-protein coupled receptors (GPCRs) are reviewed and for transmembrane assemblies also supplemented by new experimental evidence. The transmembrane-linked GPCR oligomers typically have as the minimal unit an asymmetric ~180 kDa pentamer consisting of receptor homodimer or heterodimer and a G-protein αβγ subunit heterotrimer. With neuropeptide Y (NPY) receptors, this assembly is converted to ~90 kDa receptor monomer-Gα complex by receptor and Gα agonists, and dimers/heteropentamers are depleted by neutralization of Gαi subunits by pertussis toxin. Employing gradient centrifugation, quantification and other characterization of GPCR dimers at the level of physically isolated and identified heteropentamers is feasible with labeled agonists that do not dissociate upon solubilization. This is demonstrated with three neuropeptide Y (NPY) receptors and could apply to many receptors that use large peptidic agonists. Full article

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

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Comparative Molecular Dynamics Simulations of Mitogen-Activated Protein Kinase-Activated Protein Kinase 5

by Inger Lindin, Yimingjiang Wuxiuer, Aina Westrheim Ravna, Ugo Moens and Ingebrigt Sylte

Int. J. Mol. Sci. 2014, 15(3), 4878-4902; https://doi.org/10.3390/ijms15034878 - 19 Mar 2014

Cited by 7 | Viewed by 11409

Abstract

The mitogen-activated protein kinase-activated protein kinase MK5 is a substrate of the mitogen-activated protein kinases p38, ERK3 and ERK4. Cell culture and animal studies have demonstrated that MK5 is involved in tumour suppression and promotion, embryogenesis, anxiety, cell motility and cell cycle regulation [...] Read more.

The mitogen-activated protein kinase-activated protein kinase MK5 is a substrate of the mitogen-activated protein kinases p38, ERK3 and ERK4. Cell culture and animal studies have demonstrated that MK5 is involved in tumour suppression and promotion, embryogenesis, anxiety, cell motility and cell cycle regulation. In the present study, homology models of MK5 were used for molecular dynamics (MD) simulations of: (1) MK5 alone; (2) MK5 in complex with an inhibitor; and (3) MK5 in complex with the interaction partner p38α. The calculations showed that the inhibitor occupied the active site and disrupted the intramolecular network of amino acids. However, intramolecular interactions consistent with an inactive protein kinase fold were not formed. MD with p38α showed that not only the p38 docking region, but also amino acids in the activation segment, αH helix, P-loop, regulatory phosphorylation region and the C-terminal of MK5 may be involved in forming a very stable MK5-p38α complex, and that p38α binding decreases the residual fluctuation of the MK5 model. Electrostatic Potential Surface (EPS) calculations of MK5 and p38α showed that electrostatic interactions are important for recognition and binding. Full article

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

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Phosphosite Mapping of HIP-55 Protein in Mammalian Cells

by Ning Liu, Ningning Sun, Xiang Gao and Zijian Li

Int. J. Mol. Sci. 2014, 15(3), 4903-4914; https://doi.org/10.3390/ijms15034903 - 19 Mar 2014

Cited by 5 | Viewed by 6455

Abstract

In the present study, hematopoietic progenitor kinase 1 (HPK1)-interacting protein of 55 kDa (HIP-55) protein was over-expressed in HEK293 cells, which was genetically attached with 6x His tag. The protein was purified by nickel-charged resin and was then subjected to [...] Read more.

In the present study, hematopoietic progenitor kinase 1 (HPK1)-interacting protein of 55 kDa (HIP-55) protein was over-expressed in HEK293 cells, which was genetically attached with 6x His tag. The protein was purified by nickel-charged resin and was then subjected to tryptic digestion. The phosphorylated peptides within the HIP-55 protein were enriched by TiO₂ affinity chromatography, followed by mass spectrometry analysis. Fourteen phosphorylation sites along the primary structure of HIP-55 protein were identified, most of which had not been previously reported. Our results indicate that bio-mass spectrometry coupled with manual interpretation can be used to successfully identify the phosphorylation modification in HIP-55 protein in HEK293 cells. Full article

(This article belongs to the Special Issue Mass Spectrometry Application in Biology)

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iNR-Drug: Predicting the Interaction of Drugs with Nuclear Receptors in Cellular Networking

by Yue-Nong Fan, Xuan Xiao, Jian-Liang Min and Kuo-Chen Chou

Int. J. Mol. Sci. 2014, 15(3), 4915-4937; https://doi.org/10.3390/ijms15034915 - 19 Mar 2014

Cited by 84 | Viewed by 9372

Abstract

Nuclear receptors (NRs) are closely associated with various major diseases such as cancer, diabetes, inflammatory disease, and osteoporosis. Therefore, NRs have become a frequent target for drug development. During the process of developing drugs against these diseases by targeting NRs, we are often [...] Read more.

Nuclear receptors (NRs) are closely associated with various major diseases such as cancer, diabetes, inflammatory disease, and osteoporosis. Therefore, NRs have become a frequent target for drug development. During the process of developing drugs against these diseases by targeting NRs, we are often facing a problem: Given a NR and chemical compound, can we identify whether they are really in interaction with each other in a cell? To address this problem, a predictor called “iNR-Drug” was developed. In the predictor, the drug compound concerned was formulated by a 256-D (dimensional) vector derived from its molecular fingerprint, and the NR by a 500-D vector formed by incorporating its sequential evolution information and physicochemical features into the general form of pseudo amino acid composition, and the prediction engine was operated by the SVM (support vector machine) algorithm. Compared with the existing prediction methods in this area, iNR-Drug not only can yield a higher success rate, but is also featured by a user-friendly web-server established at http://www.jci-bioinfo.cn/iNR-Drug/, which is particularly useful for most experimental scientists to obtain their desired data in a timely manner. It is anticipated that the iNR-Drug server may become a useful high throughput tool for both basic research and drug development, and that the current approach may be easily extended to study the interactions of drug with other targets as well. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Exogenous Asymmetric Dimethylarginine (ADMA) in Pathogenesis of Ischemia-Reperfusion-Induced Gastric Lesions: Interaction with Protective Nitric Oxide (NO) and Calcitonin Gene-Related Peptide (CGRP)

by Marcin Magierowski, Katarzyna Jasnos, Zbigniew Sliwowski, Marcin Surmiak, Gracjana Krzysiek-Maczka, Agata Ptak-Belowska, Slawomir Kwiecien and Tomasz Brzozowski

Int. J. Mol. Sci. 2014, 15(3), 4946-4964; https://doi.org/10.3390/ijms15034946 - 20 Mar 2014

Cited by 23 | Viewed by 6794

Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthesis inhibitor and pro-inflammatory factor. We investigated the role of ADMA in rat gastric mucosa compromised through 30 min of gastric ischemia (I) and 3 h of reperfusion (R). These I/R animals were pretreated [...] Read more.

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthesis inhibitor and pro-inflammatory factor. We investigated the role of ADMA in rat gastric mucosa compromised through 30 min of gastric ischemia (I) and 3 h of reperfusion (R). These I/R animals were pretreated with ADMA with or without the combination of l-arginine, calcitonin gene-related peptide (CGRP) or a small dose of capsaicin, all of which are known to afford protection against gastric lesions, or with a farnesoid X receptor (FXR) agonist, GW 4064, to increase the metabolism of ADMA. In the second series, ADMA was administered to capsaicin-denervated rats. The area of gastric damage was measured with planimetry, gastric blood flow (GBF) was determined by H₂-gas clearance, and plasma ADMA and CGRP levels were determined using ELISA and RIA. ADMA significantly increased I/R-induced gastric injury while significantly decreasing GBF, the luminal NO content, and the plasma level of CGRP. This effect of ADMA was significantly attenuated by pretreatment with CGRP, l-arginine, capsaicin, or a PGE₂ analogue. In GW4064 pretreated animals, the I/R injury was significantly reduced and this effect was abolished by co-treatment with ADMA. I/R damage potentiated by ADMA was exacerbated in capsaicin-denervated animals with a further reduction of CGRP. Plasma levels of IL-10 were significantly decreased while malonylodialdehyde (MDA) and plasma TNF-α contents were significantly increased by ADMA. In conclusion, ADMA aggravates I/R-induced gastric lesions due to a decrease of GBF, which is mediated by a fall in NO and CGRP release, and the enhancement of lipid peroxidation and its pro-inflammatory properties. Full article

(This article belongs to the Special Issue ADMA and Nitrergic System)

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Investigation into Variation of Endogenous Metabolites in Bone Marrow Cells and Plasma in C3H/He Mice Exposed to Benzene

by Rongli Sun, Juan Zhang, Lihong Yin and Yuepu Pu

Int. J. Mol. Sci. 2014, 15(3), 4994-5010; https://doi.org/10.3390/ijms15034994 - 20 Mar 2014

Cited by 28 | Viewed by 6688

Abstract

Benzene is identified as a carcinogen. Continued exposure of benzene may eventually lead to damage to the bone marrow, accompanied by pancytopenia, aplastic anemia or leukemia. This paper explores the variations of endogenous metabolites to provide possible clues for the molecular mechanism of [...] Read more.

Benzene is identified as a carcinogen. Continued exposure of benzene may eventually lead to damage to the bone marrow, accompanied by pancytopenia, aplastic anemia or leukemia. This paper explores the variations of endogenous metabolites to provide possible clues for the molecular mechanism of benzene-induced hematotoxicity. Liquid chromatography coupled with time of flight-mass spectrometry (LC-TOF-MS) and principal component analysis (PCA) was applied to investigate the variation of endogenous metabolites in bone marrow cells and plasma of male C3H/He mice. The mice were injected subcutaneously with benzene (0, 300, 600 mg/day) once daily for seven days. The body weights, relative organ weights, blood parameters and bone marrow smears were also analyzed. The results indicated that benzene caused disturbances in the metabolism of oxidation of fatty acids and essential amino acids (lysine, phenylalanine and tyrosine) in bone marrow cells. Moreover, fatty acid oxidation was also disturbed in plasma and thus might be a common disturbed metabolic pathway induced by benzene in multiple organs. This study aims to investigate the underlying molecular mechanisms involved in benzene hematotoxicity, especially in bone marrow cells. Full article

(This article belongs to the Special Issue Mass Spectrometry Application in Biology)

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Bovine Induced Pluripotent Stem Cells Are More Resistant to Apoptosis than Testicular Cells in Response to Mono-(2-ethylhexyl) Phthalate

by Ying-Chu Lin, Kung-Kai Kuo, Kenly Wuputra, Shih-Han Lin, Chia-Chen Ku, Ya-Han Yang, Shin-Wei Wang, Sheng-Wen Wang, Deng-Chyang Wu, Chun-Chien Wu, Chee-Yin Chai, Cheng-Lung Lin, Chang-Shen Lin, Masayuki Kajitani, Hiroyuki Miyoshi, Yukio Nakamura, Shinichi Hashimoto, Kouji Matsushima, Chunyuan Jin, Shau-Ku Huang, Shigeo Saito and Kazunari K. Yokoyama Show full author list Hide full author list

Int. J. Mol. Sci. 2014, 15(3), 5011-5031; https://doi.org/10.3390/ijms15035011 - 20 Mar 2014

Cited by 21 | Viewed by 8148

Abstract

Although the androgen receptor (AR) has been implicated in the promotion of apoptosis in testicular cells (TSCs), the molecular pathway underlying AR-mediated apoptosis and its sensitivity to environmental hormones in TSCs and induced pluripotent stem cells (iPSCs) remain unclear. We generated the iPSCs [...] Read more.

Although the androgen receptor (AR) has been implicated in the promotion of apoptosis in testicular cells (TSCs), the molecular pathway underlying AR-mediated apoptosis and its sensitivity to environmental hormones in TSCs and induced pluripotent stem cells (iPSCs) remain unclear. We generated the iPSCs from bovine TSCs via the electroporation of OCT4. The established iPSCs were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4 to maintain and stabilize the expression of stemness genes and their pluripotency. Apoptosis signaling was assessed after exposure to mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate. Here, we report that iPSCs were more resistant to MEHP-induced apoptosis than were original TSCs. MEHP also repressed the expression of AR and inactivated WNT signaling, and then led to the commitment of cells to apoptosis via the cyclin dependent kinase inhibitor p21^CIP1. The loss of the frizzed receptor 7 and the gain of p21^CIP were responsible for the stimulatory effect of MEHP on AR-mediated apoptosis. Our results suggest that testicular iPSCs can be used to study the signaling pathways involved in the response to environmental disruptors, and to assess the toxicity of environmental endocrine disruptors in terms of the maintenance of stemness and pluripotency. Full article

(This article belongs to the Section Biochemistry)

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Atmospheric Oxidation Mechanism and Kinetic Studies for OH and NO₃ Radical-Initiated Reaction of Methyl Methacrylate

by Rui Gao, Ledong Zhu, Qingzhu Zhang and Wenxing Wang

Int. J. Mol. Sci. 2014, 15(3), 5032-5044; https://doi.org/10.3390/ijms15035032 - 20 Mar 2014

Cited by 14 | Viewed by 8088

Abstract

The mechanism for OH and NO₃ radical-initiated oxidation reactions of methyl methacrylate (MMA) was investigated by using density functional theory (DFT) molecular orbital theory. Geometrical parameters of the reactants, intermediates, transition states, and products were fully optimized at the B3LYP/6-31G(d,p) level. Detailed [...] Read more.

The mechanism for OH and NO₃ radical-initiated oxidation reactions of methyl methacrylate (MMA) was investigated by using density functional theory (DFT) molecular orbital theory. Geometrical parameters of the reactants, intermediates, transition states, and products were fully optimized at the B3LYP/6-31G(d,p) level. Detailed oxidation pathways were presented and discussed. The rate constants were deduced by the canonical variational transition-state (CVT) theory with the small-curvature tunneling (SCT) correction and the multichannel Rice-Ramspergere-Kassele-Marcus (RRKM) theory, based on the potential energy surface profiles over the general atmospheric temperature range of 180–370 K. The calculated results were in reasonable agreement with experimental measurement. Full article

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

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A Caspase-Dependent Pathway Is Involved in Wnt/β-Catenin Signaling Promoted Apoptosis in Bacillus Calmette-Guerin Infected RAW264.7 Macrophages

by Xiaoling Wu, Guangcun Deng, Xiujing Hao, Yong Li, Jin Zeng, Chunyan Ma, Yulong He, Xiaoming Liu and Yujiong Wang

Int. J. Mol. Sci. 2014, 15(3), 5045-5062; https://doi.org/10.3390/ijms15035045 - 21 Mar 2014

Cited by 62 | Viewed by 9552

Abstract

Apoptosis of alveolar macrophages following Mycobacterium tuberculosis infection have been demonstrated to play a central role in the pathogenesis of tuberculosis. In the present study, we found that Wnt/β-catenin signaling possesses the potential to promote macrophage apoptosis in response to mycobacterial infection. In [...] Read more.

Apoptosis of alveolar macrophages following Mycobacterium tuberculosis infection have been demonstrated to play a central role in the pathogenesis of tuberculosis. In the present study, we found that Wnt/β-catenin signaling possesses the potential to promote macrophage apoptosis in response to mycobacterial infection. In agreement with other findings, an activation Wnt/β-catenin signaling was observed in murine macrophage RAW264.7 cells upon Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection at a multiple-of-infection of 10, which was accompanied with up-regulation of pro-inflammatory cytokines TNF-α and IL-6 production. However, the BCG-induced TNF-α and IL-6 secretion could be significantly reduced when the cells were exposed to a canonical Wnt signaling ligand, Wnt3a. Importantly, the activation of Wnt/β-catenin signaling was able to further promote apoptosis in BCG-infected RAW264.7 cells in part by a mitochondria-dependent apoptosis pathway. Immunoblotting analysis further demonstrated that Wnt/β-catenin signaling-induced cell apoptosis partly through a caspase-dependent apoptosis mechanism by down-regulation of anti-apoptotic protein Mcl-1, and up-regulation of pro-apoptotic proteins Bax and cleaved-caspase-3, as well as enhancement of caspase-3 activity in BCG-infected RAW264.7 cells. These data may imply an underlying mechanism of alveolar macrophages in response to mycobacterial infection, by which the pathogen induces Wnt/β-catenin signaling activation, which in turn represses mycobacterium-trigged inflammatory responses and promotes mycobacteria-infected cell apoptosis. Full article

(This article belongs to the Section Biochemistry)

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A Chrysanthemum Heat Shock Protein Confers Tolerance to Abiotic Stress

by Aiping Song, Xirong Zhu, Fadi Chen, Haishun Gao, Jiafu Jiang and Sumei Chen

Int. J. Mol. Sci. 2014, 15(3), 5063-5078; https://doi.org/10.3390/ijms15035063 - 21 Mar 2014

Cited by 86 | Viewed by 8853

Abstract

Heat shock proteins are associated with protection against various abiotic stresses. Here, the isolation of a chrysanthemum cDNA belonging to the HSP70 family is reported. The cDNA, designated CgHSP70, encodes a 647-residue polypeptide, of estimated molecular mass 70.90 kDa and pI 5.12. [...] Read more.

Heat shock proteins are associated with protection against various abiotic stresses. Here, the isolation of a chrysanthemum cDNA belonging to the HSP70 family is reported. The cDNA, designated CgHSP70, encodes a 647-residue polypeptide, of estimated molecular mass 70.90 kDa and pI 5.12. A sub-cellular localization assay indicated that the cDNA product is deposited in the cytoplasm and nucleus. The performance of Arabidopsis thaliana plants constitutively expressing CgHSP70 demonstrated that the gene enhances tolerance to heat, drought and salinity. When CgHSP70 was stably over-expressed in chrysanthemum, the plants showed an increased peroxidase (POD) activity, higher proline content and inhibited malondialdehyde (MDA) content. After heat stress, drought or salinity the transgenic plants were better able to recover, demonstrating CgHSP70 positive effect. Full article

(This article belongs to the Special Issue Plant Cell Compartmentation and Volume Control)

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Differential Transcriptome Analysis between Paulownia fortunei and Its Synthesized Autopolyploid

by Xiaoshen Zhang, Minjie Deng and Guoqiang Fan

Int. J. Mol. Sci. 2014, 15(3), 5079-5093; https://doi.org/10.3390/ijms15035079 - 21 Mar 2014

Cited by 32 | Viewed by 7406

Abstract

Paulownia fortunei is an ecologically and economically important tree species that is widely used as timber and chemical pulp. Its autotetraploid, which carries a number of valuable traits, was successfully induced with colchicine. To identify differences in gene expression between P. fortunei and [...] Read more.

Paulownia fortunei is an ecologically and economically important tree species that is widely used as timber and chemical pulp. Its autotetraploid, which carries a number of valuable traits, was successfully induced with colchicine. To identify differences in gene expression between P. fortunei and its synthesized autotetraploid, we performed transcriptome sequencing using an Illumina Genome Analyzer IIx (GAIIx). About 94.8 million reads were generated and assembled into 383,056 transcripts, including 18,984 transcripts with a complete open reading frame. A conducted Basic Local Alignment Search Tool (BLAST) search indicated that 16,004 complete transcripts had significant hits in the National Center for Biotechnology Information (NCBI) non-redundant database. The complete transcripts were given functional assignments using three public protein databases. One thousand one hundred fifty eight differentially expressed complete transcripts were screened through a digital abundance analysis, including transcripts involved in energy metabolism and epigenetic regulation. Finally, the expression levels of several transcripts were confirmed by quantitative real-time PCR. Our results suggested that polyploidization caused epigenetic-related changes, which subsequently resulted in gene expression variation between diploid and autotetraploid P. fortunei. This might be the main mechanism affected by the polyploidization. Our results represent an extensive survey of the P. fortunei transcriptome and will facilitate subsequent functional genomics research in P. fortunei. Moreover, the gene expression profiles of P. fortunei and its autopolyploid will provide a valuable resource for the study of polyploidization. Full article

(This article belongs to the Section Biochemistry)

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Synthesis and Biological Evaluation of 2-Aminobenzamide Derivatives as Antimicrobial Agents: Opening/Closing Pharmacophore Site

by Yahia N. Mabkhot, Abdullah M. Al-Majid, Assem Barakat, Salim S. Al-Showiman, Munirah S. Al-Har, Smaail Radi, Muhammad Moazzam Naseer and Taibi B. Hadda

Int. J. Mol. Sci. 2014, 15(3), 5115-5127; https://doi.org/10.3390/ijms15035115 - 21 Mar 2014

Cited by 31 | Viewed by 7521

Abstract

A series of new 2-aminobenzamide derivatives (1–10) has been synthesized in good to excellent yields by adopting both conventional and/or a time-efficient microwave assisted methodologies starting from isatoic anhydride (ISA) and characterized on the basis of their physical, spectral [...] Read more.

A series of new 2-aminobenzamide derivatives (1–10) has been synthesized in good to excellent yields by adopting both conventional and/or a time-efficient microwave assisted methodologies starting from isatoic anhydride (ISA) and characterized on the basis of their physical, spectral and microanalytical data. Selected compounds of this series were then tested against various bacterial (Bacillus subtilis (RCMB 000107) and Staphylococcus aureus (RCMB 000106). Pseudomonas aeruginosa (RCMB 000102) and Escherichia coli (RCMB 000103) and fungal strains (Saccharomyces cerevisiae (RCMB 006002), Aspergillus fumigatus (RCMB 002003) and Candida albicans (RCMB 005002) to explore their potential as antimicrobial agents. Compound 5 was found to be the most active compound among those tested, which showed excellent antifungal activity against Aspergillus fumigatus (RCMB 002003) more potent than standard Clotrimazole, and moderate to good antibacterial and antifungal activity against most of the other strains of bacteria and fungi. Furthermore, potential pharmacophore sites were identified and their activity was related with the structures in the solution. Full article

(This article belongs to the Section Biochemistry)

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Application of Computational Methods for the Design of BACE-1 Inhibitors: Validation of in Silico Modelling

by Marek Bajda, Jakub Jończyk, Barbara Malawska and Sławomir Filipek

Int. J. Mol. Sci. 2014, 15(3), 5128-5139; https://doi.org/10.3390/ijms15035128 - 24 Mar 2014

Cited by 18 | Viewed by 7738

Abstract

β-Secretase (BACE-1) constitutes an important target for search of anti-Alzheimer’s drugs. The first inhibitors of this enzyme were peptidic compounds with high molecular weight and low bioavailability. Therefore, the search for new efficient non-peptidic inhibitors has been undertaken by many scientific groups. We [...] Read more.

β-Secretase (BACE-1) constitutes an important target for search of anti-Alzheimer’s drugs. The first inhibitors of this enzyme were peptidic compounds with high molecular weight and low bioavailability. Therefore, the search for new efficient non-peptidic inhibitors has been undertaken by many scientific groups. We started our work from the development of in silico methodology for the design of novel BACE-1 ligands. It was validated on the basis of crystal structures of complexes with inhibitors, redocking, cross-docking and training/test sets of reference ligands. The presented procedure of assessment of the novel compounds as β-secretase inhibitors could be widely used in the design process. Full article

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

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Structure and Antitumor and Immunomodulatory Activities of a Water-Soluble Polysaccharide from Dimocarpus longan Pulp

by Fa-Yan Meng, Yuan-Ling Ning, Jia Qi, Zhou He, Jiang Jie, Juan-Juan Lin, Yan-Jun Huang, Fu-Sen Li and Xue-Hua Li

Int. J. Mol. Sci. 2014, 15(3), 5140-5162; https://doi.org/10.3390/ijms15035140 - 24 Mar 2014

Cited by 51 | Viewed by 8566

Abstract

A new water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR), gas chromatography (GC) and nuclear magnetic resonance (NMR) [...] Read more.

A new water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR), gas chromatography (GC) and nuclear magnetic resonance (NMR) analysis. The results indicated that the molecular weight of the sample was 1.1 × 10⁵ Da. Monosaccharide composition analysis revealed that LP1 was composed of Glc, GalA, Ara and Gal in a molar ratio of 5.39:1.04:0.74:0.21. Structural analysis indicated that LP1 consisted of a backbone of →4)-α-d-Glcp-(1→4)-α-d-GalpA-(1→4)-α-d-Glcp-(1→4)-β-d-Glcp-(1→ units with poly saccharide side chains composed of →2)-β-d-Fruf-(1→2)-l-sorbose-(1→ attached to the O-6 position of the α-d-Glcp residues. In vitro experiments indicated that LP1 had significantly high antitumor activity against SKOV3 and HO8910 tumor cells, with inhibition percentages of 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon-γ (IFN-γ), increased the activity of murine macrophages and enhanced B- and T-lymphocyte proliferation. The results of this study demonstrate that LP1 has potential applications as a natural antitumor agent with immunomodulatory activity. Full article

(This article belongs to the Section Materials Science)

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Albumin Suppresses Human Hepatocellular Carcinoma Proliferation and the Cell Cycle

by Shunsuke Nojiri and Takashi Joh

Int. J. Mol. Sci. 2014, 15(3), 5163-5174; https://doi.org/10.3390/ijms15035163 - 24 Mar 2014

Cited by 78 | Viewed by 8713

Abstract

Many investigations have revealed that a low recurrence rate of hepatocellular carcinoma (HCC) is associated with high serum albumin levels in patients; therefore, high levels of serum albumin are a major indicator of a favorable prognosis. However, the mechanism inhibiting the proliferation of [...] Read more.

Many investigations have revealed that a low recurrence rate of hepatocellular carcinoma (HCC) is associated with high serum albumin levels in patients; therefore, high levels of serum albumin are a major indicator of a favorable prognosis. However, the mechanism inhibiting the proliferation of HCC has not yet been elucidated, so we investigated the effect of serum albumin on HCC cell proliferation. Hep3B was cultured in MEM with no serum or containing 5 g/dL human albumin. As control samples, Prionex was added to generate the same osmotic pressure as albumin. After 24-h incubation, the expressions of α-fetoprotein (AFP), p53, p21, and p57 were evaluated with real-time PCR using total RNA extracted from the liver. Protein expressions and the phosphorylation of Rb (retinoblastoma) were determined by Western blot analysis using total protein extracted from the liver. For flow cytometric analysis of the cell cycle, FACS analysis was performed. The percentages of cell cycle distribution were evaluated by PI staining, and all samples were analyzed employing FACScalibur (BD) with appropriate software (ModFit LT; BD). The cell proliferation assay was performed by counting cells with using a Scepter handy automated cell counter (Millipore). The mRNA levels of AFP relative to Alb(−): Alb(−), Alb(+), and Prionex, were 1, 0.7 ± 0.2 (p < 0.001 for Alb(−)), and 1 ± 0.3, respectively. The mRNA levels of p21 were 1, 1.58 ± 0.4 (p = 0.007 for Alb(−) and p = 0.004 for Prionex), and 0.8 ± 0.2, respectively. The mRNA levels of p57 were 1, 4.4 ± 1.4 (p = 0.002 for Alb(−) and Prionex), and 1.0 ± 0.1, respectively. The protein expression levels of Rb were similar in all culture media. The phosphorylation of P807/811 and P780 of Rb protein was reduced in Alb(+). More cells in the G0/G1 phase and fewer cells in S and G2/M phases were obtained in Alb(+) than in Alb(−) (G0/G1: 60.9%, 67.7%, 61.5%; G2/M: 16.5%, 13.1%, 15.6%; S: 22.6%, 19.2%, 23.0%, Alb(−), Alb(+), Prionex, respectively). The same results were obtained in HepG2. Cell proliferation was inhibited in 5 g/dL albumin medium in both HepG2 cells and Hep3B cells in 24 h culture by counting cell numbers. The presence of albumin in serum reduces the phosphorylation of Rb proteins and enhances the expression of p21 and p57, following an increase in the G0/G1 cell population, and suppresses cell proliferation. These results suggest that albumin itself suppresses the proliferation of hepatocellular carcinoma. Full article

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

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Identification of Proteins of Altered Abundance in Oil Palm Infected with Ganoderma boninense

by Jameel R. Al-Obaidi, Yusmin Mohd-Yusuf, Nurhanani Razali, Jaime Jacqueline Jayapalan, Chin-Chong Tey, Normahnani Md-Noh, Sarni Mat Junit, Rofina Yasmin Othman and Onn Haji Hashim

Int. J. Mol. Sci. 2014, 15(3), 5175-5192; https://doi.org/10.3390/ijms15035175 - 24 Mar 2014

Cited by 28 | Viewed by 9018

Abstract

Basal stem rot is a common disease that affects oil palm, causing loss of yield and finally killing the trees. The disease, caused by fungus Ganoderma boninense, devastates thousands of hectares of oil palm plantings in Southeast Asia every year. In the [...] Read more.

Basal stem rot is a common disease that affects oil palm, causing loss of yield and finally killing the trees. The disease, caused by fungus Ganoderma boninense, devastates thousands of hectares of oil palm plantings in Southeast Asia every year. In the present study, root proteins of healthy oil palm seedlings, and those infected with G. boninense, were analyzed by 2-dimensional gel electrophoresis (2-DE). When the 2-DE profiles were analyzed for proteins, which exhibit consistent significant change of abundance upon infection with G. boninense, 21 passed our screening criteria. Subsequent analyses by mass spectrometry and database search identified caffeoyl-CoA O-methyltransferase, caffeic acid O-methyltransferase, enolase, fructokinase, cysteine synthase, malate dehydrogenase, and ATP synthase as among proteins of which abundances were markedly altered. Full article

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

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Genotoxic Anti-Cancer Agents and Their Relationship to DNA Damage, Mitosis, and Checkpoint Adaptation in Proliferating Cancer Cells

by Lucy H. Swift and Roy M. Golsteyn

Int. J. Mol. Sci. 2014, 15(3), 3403-3431; https://doi.org/10.3390/ijms15033403 - 25 Feb 2014

Cited by 151 | Viewed by 14271

Abstract

When a human cell detects damaged DNA, it initiates the DNA damage response (DDR) that permits it to repair the damage and avoid transmitting it to daughter cells. Despite this response, changes to the genome occur and some cells, such as proliferating cancer [...] Read more.

When a human cell detects damaged DNA, it initiates the DNA damage response (DDR) that permits it to repair the damage and avoid transmitting it to daughter cells. Despite this response, changes to the genome occur and some cells, such as proliferating cancer cells, are prone to genome instability. The cellular processes that lead to genomic changes after a genotoxic event are not well understood. Our research focuses on the relationship between genotoxic cancer drugs and checkpoint adaptation, which is the process of mitosis with damaged DNA. We examine the types of DNA damage induced by widely used cancer drugs and describe their effects upon proliferating cancer cells. There is evidence that cell death caused by genotoxic cancer drugs in some cases includes exiting a DNA damage cell cycle arrest and entry into mitosis. Furthermore, some cells are able to survive this process at a time when the genome is most susceptible to change or rearrangement. Checkpoint adaptation is poorly characterised in human cells; we predict that increasing our understanding of this pathway may help to understand genomic instability in cancer cells and provide insight into methods to improve the efficacy of current cancer therapies. Full article

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

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Notes on the Epidemiology of Multiple Sclerosis, with Special Reference to Dietary Habits

by Klaus Lauer

Int. J. Mol. Sci. 2014, 15(3), 3533-3545; https://doi.org/10.3390/ijms15033533 - 26 Feb 2014

Cited by 20 | Viewed by 8576

Abstract

A hypothesis, based primarily on the occurrence of multiple sclerosis (MS) in the Faroe Islands and supported by numerous analytical epidemiological studies, is described. It proposes that MS is caused by the interaction of a virus disease with intestinal pathology, e.g., infectious mononucleosis, [...] Read more.

A hypothesis, based primarily on the occurrence of multiple sclerosis (MS) in the Faroe Islands and supported by numerous analytical epidemiological studies, is described. It proposes that MS is caused by the interaction of a virus disease with intestinal pathology, e.g., infectious mononucleosis, and application of smoked and nitrate/nitrite-cured meat products in the diet during circumscribed time intervals. The biological mechanisms might involve a break of tolerance by an alteration of self within the central nervous system, by nitrophenylated compounds conjugated to animal tissue, in particular to proteins occurring in the central nervous system. Further research is needed. Full article

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

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Interactive Association of Drugs Binding to Human Serum Albumin

by Feng Yang, Yao Zhang and Hong Liang

Int. J. Mol. Sci. 2014, 15(3), 3580-3595; https://doi.org/10.3390/ijms15033580 - 27 Feb 2014

Cited by 295 | Viewed by 19221

Abstract

Human serum albumin (HSA) is an abundant plasma protein, which attracts great interest in the pharmaceutical industry since it can bind a remarkable variety of drugs impacting their delivery and efficacy and ultimately altering the drug’s pharmacokinetic and pharmacodynamic properties. Additionally, HSA is [...] Read more.

Human serum albumin (HSA) is an abundant plasma protein, which attracts great interest in the pharmaceutical industry since it can bind a remarkable variety of drugs impacting their delivery and efficacy and ultimately altering the drug’s pharmacokinetic and pharmacodynamic properties. Additionally, HSA is widely used in clinical settings as a drug delivery system due to its potential for improving targeting while decreasing the side effects of drugs. It is thus of great importance from the viewpoint of pharmaceutical sciences to clarify the structure, function, and properties of HSA–drug complexes. This review will succinctly outline the properties of binding site of drugs in IIA subdomain within the structure of HSA. We will also give an overview on the binding characterization of interactive association of drugs to human serum albumin that may potentially lead to significant clinical applications. Full article

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

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An Overview of Poly(lactic-co-glycolic) Acid (PLGA)-Based Biomaterials for Bone Tissue Engineering

by Piergiorgio Gentile, Valeria Chiono, Irene Carmagnola and Paul V. Hatton

Int. J. Mol. Sci. 2014, 15(3), 3640-3659; https://doi.org/10.3390/ijms15033640 - 28 Feb 2014

Cited by 1233 | Viewed by 43116

Abstract

Poly(lactic-co-glycolic) acid (PLGA) has attracted considerable interest as a base material for biomedical applications due to its: (i) biocompatibility; (ii) tailored biodegradation rate (depending on the molecular weight and copolymer ratio); (iii) approval for clinical use in humans by the U.S. [...] Read more.

Poly(lactic-co-glycolic) acid (PLGA) has attracted considerable interest as a base material for biomedical applications due to its: (i) biocompatibility; (ii) tailored biodegradation rate (depending on the molecular weight and copolymer ratio); (iii) approval for clinical use in humans by the U.S. Food and Drug Administration (FDA); (iv) potential to modify surface properties to provide better interaction with biological materials; and (v) suitability for export to countries and cultures where implantation of animal-derived products is unpopular. This paper critically reviews the scientific challenge of manufacturing PLGA-based materials with suitable properties and shapes for specific biomedical applications, with special emphasis on bone tissue engineering. The analysis of the state of the art in the field reveals the presence of current innovative techniques for scaffolds and material manufacturing that are currently opening the way to prepare biomimetic PLGA substrates able to modulate cell interaction for improved substitution, restoration, or enhancement of bone tissue function. Full article

(This article belongs to the Special Issue Biomimetic and Functional Materials)

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Nanotoxicity Overview: Nano-Threat to Susceptible Populations

by Yang Li, Yi Zhang and Bing Yan

Int. J. Mol. Sci. 2014, 15(3), 3671-3697; https://doi.org/10.3390/ijms15033671 - 28 Feb 2014

Cited by 89 | Viewed by 11575

Abstract

Due to the increasing applications of nanomaterials and nanotechnology, potential danger of nanoparticle exposure has become a critical issue. However, recent nanotoxicity studies have mainly focused on the health risks to healthy adult population. The nanotoxicity effects on susceptible populations (such as pregnant, [...] Read more.

Due to the increasing applications of nanomaterials and nanotechnology, potential danger of nanoparticle exposure has become a critical issue. However, recent nanotoxicity studies have mainly focused on the health risks to healthy adult population. The nanotoxicity effects on susceptible populations (such as pregnant, neonate, diseased, and aged populations) have been overlooked. Due to the alterations in physiological structures and functions in susceptible populations, they often suffer more damage from the same exposure. Thus, it is urgent to understand the effects of nanoparticle exposure on these populations. In order to fill this gap, the potential effects of nanoparticles to pregnant females, neonate, diseased, and aged population, as well as the possible underlying mechanisms are reviewed in this article. Investigations show that responses from susceptible population to nanoparticle exposure are often more severe. Reduced protection mechanism, compromised immunity, and impaired self-repair ability in these susceptible populations may contribute to the aggravated toxicity effects. This review will help minimize adverse effects of nanoparticles to susceptible population in future nanotechnology applications. Full article

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

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Killing Me Softly—Future Challenges in Apoptosis Research

by Mike-Andrew Westhoff, Oliver Brühl, Lisa Nonnenmacher, Georg Karpel-Massler and Klaus-Michael Debatin

Int. J. Mol. Sci. 2014, 15(3), 3746-3767; https://doi.org/10.3390/ijms15033746 - 3 Mar 2014

Cited by 26 | Viewed by 10115

Abstract

The induction of apoptosis, a highly regulated and clearly defined mode of cell dying, is a vital tenet of modern cancer therapy. In this review we focus on three aspects of apoptosis research which we believe are the most crucial and most exciting [...] Read more.

The induction of apoptosis, a highly regulated and clearly defined mode of cell dying, is a vital tenet of modern cancer therapy. In this review we focus on three aspects of apoptosis research which we believe are the most crucial and most exciting areas currently investigated and that will need to be better understood in order to enhance the efficacy of therapeutic measures. First, we discuss which target to select for cancer therapy and argue that not the cancer cell as such, but its interaction with the microenvironment is a more promising and genetically stable site of attack. Second, the complexity of combination therapy is elucidated using the PI3-K-mediated signaling network as a specific example. Here we show that the current clinical approach to sensitize malignancies to apoptosis by maximal, prolonged inhibition of so-called survival pathways can actually be counter productive. Third, we propose that under certain conditions which will need to be clearly defined in future, chronification of a tumor might be preferable to the attempt at a cure. Finally, we discuss further problems with utilizing apoptosis induction in cancer therapy and propose a novel potential therapeutic approach that combines the previously discussed features. Full article

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

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Three-Dimensional Structural Aspects of Protein–Polysaccharide Interactions

by Masamichi Nagae and Yoshiki Yamaguchi

Int. J. Mol. Sci. 2014, 15(3), 3768-3783; https://doi.org/10.3390/ijms15033768 - 3 Mar 2014

Cited by 35 | Viewed by 10068

Abstract

Linear polysaccharides are typically composed of repeating mono- or disaccharide units and are ubiquitous among living organisms. Polysaccharide diversity arises from chain-length variation, branching, and additional modifications. Structural diversity is associated with various physiological functions, which are often regulated by cognate polysaccharide-binding proteins. [...] Read more.

Linear polysaccharides are typically composed of repeating mono- or disaccharide units and are ubiquitous among living organisms. Polysaccharide diversity arises from chain-length variation, branching, and additional modifications. Structural diversity is associated with various physiological functions, which are often regulated by cognate polysaccharide-binding proteins. Proteins that interact with linear polysaccharides have been identified or developed, such as galectins and polysaccharide-specific antibodies, respectively. Currently, data is accumulating on the three-dimensional structure of polysaccharide-binding proteins. These proteins are classified into two types: exo-type and endo-type. The former group specifically interacts with the terminal units of polysaccharides, whereas the latter with internal units. In this review, we describe the structural aspects of exo-type and endo-type protein-polysaccharide interactions. Further, we discuss the structural basis for affinity and specificity enhancement in the face of inherently weak binding interactions. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins)

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Calcium Imaging Perspectives in Plants

by Chidananda Nagamangala Kanchiswamy, Mickael Malnoy, Andrea Occhipinti and Massimo E. Maffei

Int. J. Mol. Sci. 2014, 15(3), 3842-3859; https://doi.org/10.3390/ijms15033842 - 4 Mar 2014

Cited by 43 | Viewed by 12816

Abstract

The calcium ion (Ca²⁺) is a versatile intracellular messenger. It provides dynamic regulation of a vast array of gene transcriptions, protein kinases, transcription factors and other complex downstream signaling cascades. For the past six decades, intracellular Ca²⁺ concentration has been [...] Read more.

The calcium ion (Ca²⁺) is a versatile intracellular messenger. It provides dynamic regulation of a vast array of gene transcriptions, protein kinases, transcription factors and other complex downstream signaling cascades. For the past six decades, intracellular Ca²⁺ concentration has been significantly studied and still many studies are under way. Our understanding of Ca²⁺ signaling and the corresponding physiological phenomenon is growing exponentially. Here we focus on the improvements made in the development of probes used for Ca²⁺ imaging and expanding the application of Ca²⁺ imaging in plant science research. Full article

(This article belongs to the Special Issue Plant Cell Compartmentation and Volume Control)

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Nanomedicine-Based Neuroprotective Strategies in Patient Specific-iPSC and Personalized Medicine

by Shih-Fan Jang, Wei-Hsiu Liu, Wen-Shin Song, Kuan-Lin Chiang, Hsin-I Ma, Chung-Lan Kao and Ming-Teh Chen

Int. J. Mol. Sci. 2014, 15(3), 3904-3925; https://doi.org/10.3390/ijms15033904 - 4 Mar 2014

Cited by 12 | Viewed by 8914

Abstract

In recent decades, nanotechnology has attracted major interests in view of drug delivery systems and therapies against diseases, such as cancer, neurodegenerative diseases, and many others. Nanotechnology provides the opportunity for nanoscale particles or molecules (so called “Nanomedicine”) to be delivered to the [...] Read more.

In recent decades, nanotechnology has attracted major interests in view of drug delivery systems and therapies against diseases, such as cancer, neurodegenerative diseases, and many others. Nanotechnology provides the opportunity for nanoscale particles or molecules (so called “Nanomedicine”) to be delivered to the targeted sites, thereby, reducing toxicity (or side effects) and improving drug bioavailability. Nowadays, a great deal of nano-structured particles/vehicles has been discovered, including polymeric nanoparticles, lipid-based nanoparticles, and mesoporous silica nanoparticles. Nanomedical utilizations have already been well developed in many different aspects, including disease treatment, diagnostic, medical devices designing, and visualization (i.e., cell trafficking). However, while quite a few successful progressions on chemotherapy using nanotechnology have been developed, the implementations of nanoparticles on stem cell research are still sparsely populated. Stem cell applications and therapies are being considered to offer an outstanding potential in the treatment for numbers of maladies. Human induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state. Although the exact mechanisms underlying are still unclear, iPSCs are already being considered as useful tools for drug development/screening and modeling of diseases. Recently, personalized medicines have drawn great attentions in biological and pharmaceutical studies. Generally speaking, personalized medicine is a therapeutic model that offers a customized healthcare/cure being tailored to a specific patient based on his own genetic information. Consequently, the combination of nanomedicine and iPSCs could actually be the potent arms for remedies in transplantation medicine and personalized medicine. This review will focus on current use of nanoparticles on therapeutical applications, nanomedicine-based neuroprotective manipulations in patient specific-iPSCs and personalized medicine. Full article

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

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Mitochondria in the Center of Human Eosinophil Apoptosis and Survival

by Pinja Ilmarinen, Eeva Moilanen and Hannu Kankaanranta

Int. J. Mol. Sci. 2014, 15(3), 3952-3969; https://doi.org/10.3390/ijms15033952 - 5 Mar 2014

Cited by 30 | Viewed by 9125

Abstract

Eosinophils are abundantly present in most phenotypes of asthma and they contribute to the maintenance and exacerbations of the disease. Regulators of eosinophil longevity play critical roles in determining whether eosinophils accumulate into the airways of asthmatics. Several cytokines enhance eosinophil survival promoting [...] Read more.

Eosinophils are abundantly present in most phenotypes of asthma and they contribute to the maintenance and exacerbations of the disease. Regulators of eosinophil longevity play critical roles in determining whether eosinophils accumulate into the airways of asthmatics. Several cytokines enhance eosinophil survival promoting eosinophilic airway inflammation while for example glucocorticoids, the most important anti-inflammatory drugs used to treat asthma, promote the intrinsic pathway of eosinophil apoptosis and by this mechanism contribute to the resolution of eosinophilic airway inflammation. Mitochondria seem to play central roles in both intrinsic mitochondrion-centered and extrinsic receptor-mediated pathways of apoptosis in eosinophils. Mitochondria may also be important for survival signalling. In addition to glucocorticoids, another important agent that regulates human eosinophil longevity via mitochondrial route is nitric oxide, which is present in increased amounts in the airways of asthmatics. Nitric oxide seems to be able to trigger both survival and apoptosis in eosinophils. This review discusses the current evidence of the mechanisms of induced eosinophil apoptosis and survival focusing on the role of mitochondria and clinically relevant stimulants, such as glucocorticoids and nitric oxide. Full article

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

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Increased Circulatory Asymmetric Dimethylarginine and Multiple Organ Failure: Bile Duct Ligation in Rat as a Model

by Jiunn-Ming Sheen, Yu-Chieh Chen, You-Lin Tain and Li-Tung Huang

Int. J. Mol. Sci. 2014, 15(3), 3989-4006; https://doi.org/10.3390/ijms15033989 - 5 Mar 2014

Cited by 21 | Viewed by 9411

Abstract

Bile duct ligation (BDL)-treated rats exhibit cholestasis, increased systemic oxidative stress, and liver fibrosis, which ultimately lead to liver cirrhosis. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase that can decrease the synthesis of nitric oxide. BDL rats have higher [...] Read more.

Bile duct ligation (BDL)-treated rats exhibit cholestasis, increased systemic oxidative stress, and liver fibrosis, which ultimately lead to liver cirrhosis. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase that can decrease the synthesis of nitric oxide. BDL rats have higher plasma and hepatic ADMA levels, which may be due to increased hepatic protein arginine methyltransferase-1 and decreased dimethylarginine dimethylaminohydrolase expression. BDL rats also exhibit renal and brain damage characterized by increased tissue ADMA concentrations. The increased plasma ADMA levels and multiple organ damages seen here are also observed following multiple organ failures associated with critical illness. This review discusses the dysregulation of ADMA in major organs in BDL rats and the role of increased ADMA in multiple organ damages. Full article

(This article belongs to the Special Issue ADMA and Nitrergic System)

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Exosomes Derived from Mesenchymal Stem Cells

by Bo Yu, Xiaomin Zhang and Xiaorong Li

Int. J. Mol. Sci. 2014, 15(3), 4142-4157; https://doi.org/10.3390/ijms15034142 - 7 Mar 2014

Cited by 614 | Viewed by 31681

Abstract

The functional mechanisms of mesenchymal stem cells (MSCs) have become a research focus in recent years. Accumulating evidence supports the notion that MSCs act in a paracrine manner. Therefore, the biological factors in conditioned medium, including exosomes and soluble factors, derived from MSC [...] Read more.

The functional mechanisms of mesenchymal stem cells (MSCs) have become a research focus in recent years. Accumulating evidence supports the notion that MSCs act in a paracrine manner. Therefore, the biological factors in conditioned medium, including exosomes and soluble factors, derived from MSC cultures are being explored extensively. The results from most investigations show that MSC-conditioned medium or its components mediate some biological functions of MSCs. Several studies have reported that MSC-derived exosomes have functions similar to those of MSCs, such as repairing tissue damage, suppressing inflammatory responses, and modulating the immune system. However, the mechanisms are still not fully understood and the results remain controversial. Compared with cells, exosomes are more stable and reservable, have no risk of aneuploidy, a lower possibility of immune rejection following in vivo allogeneic administration, and may provide an alternative therapy for various diseases. In this review, we summarize the properties and biological functions of MSC-derived exosomes and discuss the related mechanisms. Full article

(This article belongs to the Section Biochemistry)

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Modulation of Gut Microbiota in the Management of Metabolic Disorders: The Prospects and Challenges

by Omotayo O. Erejuwa, Siti A. Sulaiman and Mohd S. Ab Wahab

Int. J. Mol. Sci. 2014, 15(3), 4158-4188; https://doi.org/10.3390/ijms15034158 - 7 Mar 2014

Cited by 102 | Viewed by 12827

Abstract

The gut microbiota plays a number of important roles including digestion, metabolism, extraction of nutrients, synthesis of vitamins, prevention against pathogen colonization, and modulation of the immune system. Alterations or changes in composition and biodiversity of the gut microbiota have been associated with [...] Read more.

The gut microbiota plays a number of important roles including digestion, metabolism, extraction of nutrients, synthesis of vitamins, prevention against pathogen colonization, and modulation of the immune system. Alterations or changes in composition and biodiversity of the gut microbiota have been associated with many gastrointestinal tract (GIT) disorders such as inflammatory bowel disease and colon cancer. Recent evidence suggests that altered composition and diversity of gut microbiota may play a role in the increased prevalence of metabolic diseases. This review article has two main objectives. First, it underscores approaches (such as probiotics, prebiotics, antimicrobial agents, bariatric surgery, and weight loss strategies) and their prospects in modulating the gut microbiota in the management of metabolic diseases. Second, it highlights some of the current challenges and discusses areas of future research as it relates to the gut microbiota and metabolic diseases. The prospect of modulating the gut microbiota seems promising. However, considering that research investigating the role of gut microbiota in metabolic diseases is still in its infancy, more rigorous and well-designed in vitro, animal and clinical studies are needed. Full article

(This article belongs to the Section Biochemistry)

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Sphingolipids: Key Regulators of Apoptosis and Pivotal Players in Cancer Drug Resistance

by Paola Giussani, Cristina Tringali, Laura Riboni, Paola Viani and Bruno Venerando

Int. J. Mol. Sci. 2014, 15(3), 4356-4392; https://doi.org/10.3390/ijms15034356 - 12 Mar 2014

Cited by 95 | Viewed by 15082

Abstract

Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used [...] Read more.

Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used by cancer cells to evade apoptosis could be translated in an improvement of therapies. Among many tools acquired by cancer cells to this end, the de-regulated synthesis and metabolism of sphingolipids have been well documented. Sphingolipids are known to play many structural and signalling roles in cells, as they are involved in the control of growth, survival, adhesion, and motility. In particular, in order to increase survival, cancer cells: (a) counteract the accumulation of ceramide that is endowed with pro-apoptotic potential and is induced by many drugs; (b) increase the synthesis of sphingosine-1-phosphate and glucosylceramide that are pro-survivals signals; (c) modify the synthesis and the metabolism of complex glycosphingolipids, particularly increasing the levels of modified species of gangliosides such as 9-O acetylated GD3 (αNeu5Ac(2-8)αNeu5Ac(2-3)βGal(1-4)βGlc(1-1)Cer) or N-glycolyl GM3 (αNeu5Ac (2-3)βGal(1-4)βGlc(1-1)Cer) and de-N-acetyl GM3 (NeuNH(2)βGal(1-4)βGlc(1-1)Cer) endowed with anti-apoptotic roles and of globoside Gb3 related to a higher expression of the multidrug resistance gene MDR1. In light of this evidence, the employment of chemical or genetic approaches specifically targeting sphingolipid dysregulations appears a promising tool for the improvement of current chemotherapy efficacy. Full article

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

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Structural and Molecular Modeling Features of P2X Receptors

by Luiz Anastacio Alves, João Herminio Martins Da Silva, Dinarte Neto Moreira Ferreira, Antonio Augusto Fidalgo-Neto, Pedro Celso Nogueira Teixeira, Cristina Alves Magalhães De Souza, Ernesto Raúl Caffarena and Mônica Santos De Freitas

Int. J. Mol. Sci. 2014, 15(3), 4531-4549; https://doi.org/10.3390/ijms15034531 - 14 Mar 2014

Cited by 23 | Viewed by 11567

Abstract

Currently, adenosine 5'-triphosphate (ATP) is recognized as the extracellular messenger that acts through P2 receptors. P2 receptors are divided into two subtypes: P2Y metabotropic receptors and P2X ionotropic receptors, both of which are found in virtually all mammalian cell types studied. Due to [...] Read more.

Currently, adenosine 5'-triphosphate (ATP) is recognized as the extracellular messenger that acts through P2 receptors. P2 receptors are divided into two subtypes: P2Y metabotropic receptors and P2X ionotropic receptors, both of which are found in virtually all mammalian cell types studied. Due to the difficulty in studying membrane protein structures by X-ray crystallography or NMR techniques, there is little information about these structures available in the literature. Two structures of the P2X4 receptor in truncated form have been solved by crystallography. Molecular modeling has proven to be an excellent tool for studying ionotropic receptors. Recently, modeling studies carried out on P2X receptors have advanced our knowledge of the P2X receptor structure-function relationships. This review presents a brief history of ion channel structural studies and shows how modeling approaches can be used to address relevant questions about P2X receptors. Full article

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

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Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction

by Anna Mietelska-Porowska, Urszula Wasik, Marcelina Goras, Anna Filipek and Grazyna Niewiadomska

Int. J. Mol. Sci. 2014, 15(3), 4671-4713; https://doi.org/10.3390/ijms15034671 - 18 Mar 2014

Cited by 268 | Viewed by 17654

Abstract

Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and its [...] Read more.

Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and its interaction with several proteins play an important regulatory role in the physiology of tau. As a consequence of abnormal modifications and expression, tau is redistributed from neuronal processes to the soma and forms toxic oligomers or aggregated deposits. The accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementia disorders known as tauopathies. Dysfunction of tau protein may contribute to collapse of cytoskeleton, thereby causing improper anterograde and retrograde movement of motor proteins and their cargos on microtubules. These disturbances in intraneuronal signaling may compromise synaptic transmission as well as trophic support mechanisms in neurons. Full article

(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)

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Current Progress in Bioactive Ceramic Scaffolds for Bone Repair and Regeneration

by Chengde Gao, Youwen Deng, Pei Feng, Zhongzheng Mao, Pengjian Li, Bo Yang, Junjie Deng, Yiyuan Cao, Cijun Shuai and Shuping Peng

Int. J. Mol. Sci. 2014, 15(3), 4714-4732; https://doi.org/10.3390/ijms15034714 - 18 Mar 2014

Cited by 242 | Viewed by 15714

Abstract

Bioactive ceramics have received great attention in the past decades owing to their success in stimulating cell proliferation, differentiation and bone tissue regeneration. They can react and form chemical bonds with cells and tissues in human body. This paper provides a comprehensive review [...] Read more.

Bioactive ceramics have received great attention in the past decades owing to their success in stimulating cell proliferation, differentiation and bone tissue regeneration. They can react and form chemical bonds with cells and tissues in human body. This paper provides a comprehensive review of the application of bioactive ceramics for bone repair and regeneration. The review systematically summarizes the types and characters of bioactive ceramics, the fabrication methods for nanostructure and hierarchically porous structure, typical toughness methods for ceramic scaffold and corresponding mechanisms such as fiber toughness, whisker toughness and particle toughness. Moreover, greater insights into the mechanisms of interaction between ceramics and cells are provided, as well as the development of ceramic-based composite materials. The development and challenges of bioactive ceramics are also discussed from the perspective of bone repair and regeneration. Full article

(This article belongs to the Section Materials Science)

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The Role of Chemokines in Hepatitis C Virus-Mediated Liver Disease

by Anette Brass and Erwin Daniel Brenndörfer

Int. J. Mol. Sci. 2014, 15(3), 4747-4779; https://doi.org/10.3390/ijms15034747 - 18 Mar 2014

Cited by 25 | Viewed by 9925

Abstract

The hepatitis C virus (HCV) is a global health problem affecting more than 170 million people. A chronic HCV infection is associated with liver fibrosis, liver cirrhosis and hepatocellular carcinoma. To enable viral persistence, HCV has developed mechanisms to modulate both innate and [...] Read more.

The hepatitis C virus (HCV) is a global health problem affecting more than 170 million people. A chronic HCV infection is associated with liver fibrosis, liver cirrhosis and hepatocellular carcinoma. To enable viral persistence, HCV has developed mechanisms to modulate both innate and adaptive immunity. The recruitment of antiviral immune cells in the liver is mainly dependent on the release of specific chemokines. Thus, the modulation of their expression could represent an efficient viral escape mechanism to hamper specific immune cell migration to the liver during the acute phase of the infection. HCV-mediated changes in hepatic immune cell chemotaxis during the chronic phase of the infection are significantly affecting antiviral immunity and tissue damage and thus influence survival of both the host and the virus. This review summarizes our current understanding of the HCV-mediated modulation of chemokine expression and of its impact on the development of liver disease. A profound knowledge of the strategies used by HCV to interfere with the host’s immune response and the pro-fibrotic and pro-carcinogenic activities of HCV is essential to be able to design effective immunotherapies against HCV and HCV-mediated liver diseases. Full article

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

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Toxicological Assessment of Inhaled Nanoparticles: Role of in Vivo, ex Vivo, in Vitro, and in Silico Studies

by Eleonore Fröhlich and Sharareh Salar-Behzadi

Int. J. Mol. Sci. 2014, 15(3), 4795-4822; https://doi.org/10.3390/ijms15034795 - 18 Mar 2014

Cited by 185 | Viewed by 17656

Abstract

The alveolar epithelium of the lung is by far the most permeable epithelial barrier of the human body. The risk for adverse effects by inhaled nanoparticles (NPs) depends on their hazard (negative action on cells and organism) and on exposure (concentration in the [...] Read more.

The alveolar epithelium of the lung is by far the most permeable epithelial barrier of the human body. The risk for adverse effects by inhaled nanoparticles (NPs) depends on their hazard (negative action on cells and organism) and on exposure (concentration in the inhaled air and pattern of deposition in the lung). With the development of advanced in vitro models, not only in vivo, but also cellular studies can be used for toxicological testing. Advanced in vitro studies use combinations of cells cultured in the air-liquid interface. These cultures are useful for particle uptake and mechanistic studies. Whole-body, nose-only, and lung-only exposures of animals could help to determine retention of NPs in the body. Both approaches also have their limitations; cellular studies cannot mimic the entire organism and data obtained by inhalation exposure of rodents have limitations due to differences in the respiratory system from that of humans. Simulation programs for lung deposition in humans could help to determine the relevance of the biological findings. Combination of biological data generated in different biological models and in silico modeling appears suitable for a realistic estimation of potential risks by inhalation exposure to NPs. Full article

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

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Open AccessReview

The Growth Hormone Secretagogue Receptor: Its Intracellular Signaling and Regulation

by Yue Yin, Yin Li and Weizhen Zhang

Int. J. Mol. Sci. 2014, 15(3), 4837-4855; https://doi.org/10.3390/ijms15034837 - 19 Mar 2014

Cited by 108 | Viewed by 12473

Abstract

The growth hormone secretagogue receptor (GHSR), also known as the ghrelin receptor, is involved in mediating a wide variety of biological effects of ghrelin, including: stimulation of growth hormone release, increase of food intake and body weight, modulation of glucose and lipid metabolism, [...] Read more.

The growth hormone secretagogue receptor (GHSR), also known as the ghrelin receptor, is involved in mediating a wide variety of biological effects of ghrelin, including: stimulation of growth hormone release, increase of food intake and body weight, modulation of glucose and lipid metabolism, regulation of gastrointestinal motility and secretion, protection of neuronal and cardiovascular cells, and regulation of immune function. Dependent on the tissues and cells, activation of GHSR may trigger a diversity of signaling mechanisms and subsequent distinct physiological responses. Distinct regulation of GHSR occurs at levels of transcription, receptor interaction and internalization. Here we review the current understanding on the intracellular signaling pathways of GHSR and its modulation. An overview of the molecular structure of GHSR is presented first, followed by the discussion on its signaling mechanisms. Finally, potential mechanisms regulating GHSR are reviewed. Full article

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

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Open AccessReview

P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases

by Andrea Picchianti-Diamanti, Maria Manuela Rosado, Marco Scarsella, Bruno Laganà and Raffaele D'Amelio

Int. J. Mol. Sci. 2014, 15(3), 4965-4976; https://doi.org/10.3390/ijms15034965 - 20 Mar 2014

Cited by 43 | Viewed by 7384

Abstract

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as [...] Read more.

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins)

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Open AccessReview

The Multiple Mechanisms of Cell Death Triggered by Resveratrol in Lymphoma and Leukemia

by Raffaele Frazzi and Marco Tigano

Int. J. Mol. Sci. 2014, 15(3), 4977-4993; https://doi.org/10.3390/ijms15034977 - 20 Mar 2014

Cited by 26 | Viewed by 8926

Abstract

Lymphoma and leukemia represent a serious threat to human health and life expectancy. Resveratrol is, among the natural-derived chemopreventive molecules, one of the most effective and better studied. In this paper the main mechanisms of cell death triggered by- or linked to- resveratrol [...] Read more.

Lymphoma and leukemia represent a serious threat to human health and life expectancy. Resveratrol is, among the natural-derived chemopreventive molecules, one of the most effective and better studied. In this paper the main mechanisms of cell death triggered by- or linked to- resveratrol are reviewed and discussed. The main focus is on lymphoma and leukemia experimental models where resveratrol has been tested and investigated at the cellular, molecular or physiological levels. The most relevant in vivo challenges involving resveratrol are also reported and analyzed in order to define the key features of this polyphenol and the potential for the treatment of hematologic tumors. Full article

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

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Open AccessReview

No Stress! Relax! Mechanisms Governing Growth and Shape in Plant Cells

by Gea Guerriero, Jean-Francois Hausman and Giampiero Cai

Int. J. Mol. Sci. 2014, 15(3), 5094-5114; https://doi.org/10.3390/ijms15035094 - 21 Mar 2014

Cited by 51 | Viewed by 14012

Abstract

The mechanisms through which plant cells control growth and shape are the result of the coordinated action of many events, notably cell wall stress relaxation and turgor-driven expansion. The scalar nature of turgor pressure would drive plant cells to assume spherical shapes; however, [...] Read more.

The mechanisms through which plant cells control growth and shape are the result of the coordinated action of many events, notably cell wall stress relaxation and turgor-driven expansion. The scalar nature of turgor pressure would drive plant cells to assume spherical shapes; however, this is not the case, as plant cells show an amazing variety of morphologies. Plant cell walls are dynamic structures that can display alterations in matrix polysaccharide composition and concentration, which ultimately affect the wall deformation rate. The wide varieties of plant cell shapes, spanning from elongated cylinders (as pollen tubes) and jigsaw puzzle-like epidermal cells, to very long fibres and branched stellate leaf trichomes, can be understood if the underlying mechanisms regulating wall biosynthesis and cytoskeletal dynamics are addressed. This review aims at gathering the available knowledge on the fundamental mechanisms regulating expansion, growth and shape in plant cells by putting a special emphasis on the cell wall-cytoskeleton system continuum. In particular, we discuss from a molecular point of view the growth mechanisms characterizing cell types with strikingly different geometries and describe their relationship with primary walls. The purpose, here, is to provide the reader with a comprehensive overview of the multitude of events through which plant cells manage to expand and control their final shapes. Full article

(This article belongs to the Special Issue Plant Cell Compartmentation and Volume Control)

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267 KiB

Open AccessTechnical Note

PseAAC-General: Fast Building Various Modes of General Form of Chou’s Pseudo-Amino Acid Composition for Large-Scale Protein Datasets

by Pufeng Du, Shuwang Gu and Yasen Jiao

Int. J. Mol. Sci. 2014, 15(3), 3495-3506; https://doi.org/10.3390/ijms15033495 - 26 Feb 2014

Cited by 249 | Viewed by 9603

Abstract

The general form pseudo-amino acid composition (PseAAC) has been widely used to represent protein sequences in predicting protein structural and functional attributes. We developed the program PseAAC-General to generate various different modes of Chou’s general PseAAC, such as the gene ontology mode, the [...] Read more.

The general form pseudo-amino acid composition (PseAAC) has been widely used to represent protein sequences in predicting protein structural and functional attributes. We developed the program PseAAC-General to generate various different modes of Chou’s general PseAAC, such as the gene ontology mode, the functional domain mode, and the sequential evolution mode. This program allows the users to define their own desired modes. In every mode, 544 physicochemical properties of the amino acids are available for choosing. The computing efficiency is at least 100 times that of existing programs, which makes it able to facilitate the extensive studies on proteins and peptides. The PseAAC-General is freely available via SourceForge. It runs on both Linux and Windows. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine)

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Open AccessCorrection

Correction: Zainalabdeen, N., et al., Synthesis and Characterization of Naphthalenediimide-Functionalized Flavin Derivatives. Int. J. Mol. Sci. 2013, 14, 7468–7479.

by Nada Zainalabdeen, Brian Fitzpatrick, Mohanad Mousa Kareem, Vikas Nandwana, Graeme Cooke and Vincent M. Rotello

Int. J. Mol. Sci. 2014, 15(3), 4255-4256; https://doi.org/10.3390/ijms15034255 - 10 Mar 2014

Viewed by 4576

Abstract

In the original version of the manuscript [1] some of the analytical data for compounds 1 and 2 were incorrect. The correct NMR data are presented below. [...] Full article

248 KiB

Open AccessComment

Calcium and Vitamin D in the Regulation of Energy Balance: Where Do We Stand?

by Mario J. Soares, Kaveri Pathak and Emily K. Calton

Int. J. Mol. Sci. 2014, 15(3), 4938-4945; https://doi.org/10.3390/ijms15034938 - 20 Mar 2014

Cited by 39 | Viewed by 8832

Abstract

There is a pandemic of obesity and associated chronic diseases. Dietary calcium and vitamin D have many extra-skeletal roles in human health. In this review we have summarized the current understanding of their influence on human energy balance by examining the epidemiological, clinical, [...] Read more.

There is a pandemic of obesity and associated chronic diseases. Dietary calcium and vitamin D have many extra-skeletal roles in human health. In this review we have summarized the current understanding of their influence on human energy balance by examining the epidemiological, clinical, animal, cellular and molecular evidence. We opine that while calcium and vitamin D are functional nutrients in the battle against obesity, there is a need for prospective human trials to tilt the balance of evidence in favour of these nutrients. Full article

(This article belongs to the Special Issue Nutritional Control of Metabolism)

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Int. J. Mol. Sci., Volume 15, Issue 3 (March 2014) – 106 articles , Pages 3356-5192

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