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Int. J. Mol. Sci., Volume 15, Issue 8 (August 2014), Pages 13135-14908

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Open AccessArticle Overexpression of Shox2 Leads to Congenital Dysplasia of the Temporomandibular Joint in Mice
Int. J. Mol. Sci. 2014, 15(8), 13135-13150; doi:10.3390/ijms150813135
Received: 3 April 2014 / Revised: 18 May 2014 / Accepted: 26 June 2014 / Published: 24 July 2014
Cited by 3 | PDF Full-text (6958 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Our previous study reported that inactivation of Shox2 led to dysplasia and ankylosis of the temporomandibular joint (TMJ), and that replacing Shox2 with human Shox partially rescued the phenotype with a prematurely worn out articular disc. However, the mechanisms of Shox2 activity [...] Read more.
Our previous study reported that inactivation of Shox2 led to dysplasia and ankylosis of the temporomandibular joint (TMJ), and that replacing Shox2 with human Shox partially rescued the phenotype with a prematurely worn out articular disc. However, the mechanisms of Shox2 activity in TMJ development remain to be elucidated. In this study, we investigated the molecular and cellular basis for the congenital dysplasia of TMJ in Wnt1-Cre; pMes-stop Shox2 mice. We found that condyle and glenoid fossa dysplasia occurs primarily in the second week after the birth. The dysplastic TMJ of Wnt1-Cre; pMes-stop Shox2 mice exhibits a loss of Collagen type I, Collagen type II, Ihh and Gli2. In situ zymography and immunohistochemistry further demonstrate an up-regulation of matrix metalloproteinases (MMPs), MMP9 and MMP13, accompanied by a significantly increased cell apoptosis. In addition, the cell proliferation and expressions of Sox9, Runx2 and Ihh are no different in the embryonic TMJ between the wild type and mutant mice. Our results show that overexpression of Shox2 leads to the loss of extracellular matrix and the increase of cell apoptosis in TMJ dysplasia by up-regulating MMPs and down-regulating the Ihh signaling pathway. Full article
(This article belongs to the Special Issue Signal Transduction of Tissue Repair)
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Open AccessArticle Potential Spermatogenesis Recovery with Bone Marrow Mesenchymal Stem Cells in an Azoospermic Rat Model
Int. J. Mol. Sci. 2014, 15(8), 13151-13165; doi:10.3390/ijms150813151
Received: 15 June 2014 / Revised: 15 July 2014 / Accepted: 16 July 2014 / Published: 24 July 2014
Cited by 5 | PDF Full-text (4712 KB) | HTML Full-text | XML Full-text
Abstract
Non-obstructive azoospermia is the most challenging type of male infertility. Stem cell based therapy provides the potential to enhance the recovery of spermatogenesis following cancer therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) possess the potential to differentiate or trans-differentiate into multi-lineage cells, [...] Read more.
Non-obstructive azoospermia is the most challenging type of male infertility. Stem cell based therapy provides the potential to enhance the recovery of spermatogenesis following cancer therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) possess the potential to differentiate or trans-differentiate into multi-lineage cells, secrete paracrine factors to recruit the resident stem cells to participate in tissue regeneration, or fuse with the local cells in the affected region. In this study, we tested whether spermatogenically-induced BMSCs can restore spermatogenesis after administration of an anticancer drug. Allogeneic BMSCs were co-cultured in conditioned media derived from cultured testicular Sertoli cells in vitro, and then induced stem cells were transplanted into the seminiferous tubules of a busulfan-induced azoospermatic rat model for 8 weeks. The in vitro induced BMSCs exhibited specific spermatogonic gene and protein markers, and after implantation the donor cells survived and located at the basement membranes of the recipient seminiferous tubules, in accordance with what are considered the unique biological characteristics of spermatogenic stem cells. Molecular markers of spermatogonial stem cells and spermatogonia (Vasa, Stella, SMAD1, Dazl, GCNF, HSP90α, integrinβ1, and c-kit) were expressed in the recipient testis tissue. No tumor mass, immune response, or inflammatory reaction developed. In conclusion, BMSCs might provide the potential to trans-differentiate into spermatogenic-like-cells, enhancing endogenous fertility recovery. The present study indicates that BMSCs might offer alternative treatment for the patients with azoospermatic infertility after cancer chemotherapy. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
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Open AccessArticle Distinct Roles of Soluble and Transmembrane Adenylyl Cyclases in the Regulation of Flagellar Motility in Ciona Sperm
Int. J. Mol. Sci. 2014, 15(8), 13192-13208; doi:10.3390/ijms150813192
Received: 22 April 2014 / Revised: 6 May 2014 / Accepted: 11 July 2014 / Published: 28 July 2014
Cited by 4 | PDF Full-text (4007 KB) | HTML Full-text | XML Full-text
Abstract
Adenylyl cyclase (AC) is a key enzyme that synthesizes cyclic AMP (cAMP) at the onset of the signaling pathway to activate sperm motility. Here, we showed that both transmembrane AC (tmAC) and soluble AC (sAC) are distinctly involved in the regulation of [...] Read more.
Adenylyl cyclase (AC) is a key enzyme that synthesizes cyclic AMP (cAMP) at the onset of the signaling pathway to activate sperm motility. Here, we showed that both transmembrane AC (tmAC) and soluble AC (sAC) are distinctly involved in the regulation of sperm motility in the ascidian Ciona intestinalis. A tmAC inhibitor blocked both cAMP synthesis and the activation of sperm motility induced by the egg factor sperm activating and attracting factor (SAAF), as well as those induced by theophylline, an inhibitor of phoshodiesterase. It also significantly inhibited cAMP-dependent phosphorylation of a set of proteins at motility activation. On the other hand, a sAC inhibitor does not affect on SAAF-induced transient increase of cAMP, motility activation or protein phosphorylation, but it reduced swimming velocity to half in theophylline-induced sperm. A sAC inhibitor KH-7 induced circular swimming trajectory with smaller diameter and significantly suppressed chemotaxis of sperm to SAAF. These results suggest that tmAC is involved in the basic mechanism for motility activation through cAMP-dependent protein phosphorylation, whereas sAC plays distinct roles in increase of flagellar beat frequency and in the Ca2+-dependent chemotactic movement of sperm. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Sperm-Egg Interaction)
Open AccessArticle Chikusetsu Saponin V Attenuates MPP+-Induced Neurotoxicity in SH-SY5Y Cells via Regulation of Sirt1/Mn-SOD and GRP78/Caspase-12 Pathways
Int. J. Mol. Sci. 2014, 15(8), 13209-13222; doi:10.3390/ijms150813209
Received: 20 April 2014 / Revised: 5 June 2014 / Accepted: 16 June 2014 / Published: 28 July 2014
PDF Full-text (5586 KB) | HTML Full-text | XML Full-text
Abstract
Studies have shown that saponins from Panax japonicus (SPJ) possess neuroprotective effects. However, whether Chikusetsu saponin V (CsV), the most abundant member of SPJ, can exert neuroprotective effects against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity is not known. In this study, we [...] Read more.
Studies have shown that saponins from Panax japonicus (SPJ) possess neuroprotective effects. However, whether Chikusetsu saponin V (CsV), the most abundant member of SPJ, can exert neuroprotective effects against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity is not known. In this study, we aimed to investigate the neuroprotective effects of CsV on MPP+-induced cytotoxicity in human neuroblastoma SH-SY5Y cells and explore its possible mechanisms. Our results show that CsV attenuates MPP+-induced cytotoxicity, inhibits ROS accumulation, and increases mitochondrial membrane potential dose-dependently. We also found that levels of Sirt1 protein and Mn-SOD mRNA significantly decreased in MPP+-treated group but were restored with CsV treatment in a dose-dependent manner. Furthermore, GRP78 protein and Caspase-12 mRNA levels were elevated by MPP+ exposure but reversed by CsV treatment. CsV inhibited the MPP+-induced downregulation of Bcl-2 and up-regulation of Bax in a dose-dependent manner and, thus, increased the ratio of Bcl-2/Bax. Overall, these results suggest that Sirt1/Mn-SOD and GRP78/Caspase-12 pathways might be involved in the CsV-mediated neuroprotective effects. Full article
(This article belongs to the Section Molecular Toxicology)
Open AccessArticle Effects of Antidepressants on IP-10 Production in LPS-Activated THP-1 Human Monocytes
Int. J. Mol. Sci. 2014, 15(8), 13223-13235; doi:10.3390/ijms150813223
Received: 1 April 2014 / Revised: 12 June 2014 / Accepted: 7 July 2014 / Published: 28 July 2014
Cited by 3 | PDF Full-text (3818 KB) | HTML Full-text | XML Full-text
Abstract
Major depressive disorder and cardiovascular disease are common serious illnesses worldwide. Selective serotonin reuptake inhibitors and norepinephrine-dopamine reuptake inhibitors may reduce the mortality of cardiovascular disease patients with comorbid depression. Interferon-γ-inducible protein 10 (IP-10), a type 1 T helper cell (Th1)-related chemokine, [...] Read more.
Major depressive disorder and cardiovascular disease are common serious illnesses worldwide. Selective serotonin reuptake inhibitors and norepinephrine-dopamine reuptake inhibitors may reduce the mortality of cardiovascular disease patients with comorbid depression. Interferon-γ-inducible protein 10 (IP-10), a type 1 T helper cell (Th1)-related chemokine, contributes to manifestations of atherosclerosis during cardiovascular inflammations; however, the pathophysiological mechanisms linking cardiovascular disease and effective antidepressants have remained elusive. We investigated the in vitro effects of six different classes of antidepressants on the IP-10 chemokine expression in lipopolysaccharide (LPS)-stimulated monocytes, and their detailed intracellular mechanisms. The human monocytes were pretreated with antidepressants (10−8–10−5 M) before LPS-stimulation. IP-10 was measured by enzyme-linked immunosorbent assay (ELISA) and then intracellular signaling was investigated using Western blotting and chromatin immunoprecipitation. Fluoxetine and bupropion suppressed LPS-induced IP-10 expression in monocytes, and they had no cytotoxic effects. Furthermore, fluoxetine inhibited LPS-induced IP-10 expression via the mitogen-activated protein kinase (MAPK)-p38 pathway. Fluoxetine and bupropion could not only treat depression but also reduce Th1-related chemokine IP-10 production in human monocytes. Our results may indicate a possible mechanism related to how particular antidepressants reduce the risk of cardiovascular disease. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Disruption of Phosphoinositide-Specific Phospholipases Cγ1 Contributes to Extracellular Matrix Synthesis of Human Osteoarthritis Chondrocytes
Int. J. Mol. Sci. 2014, 15(8), 13236-13246; doi:10.3390/ijms150813236
Received: 23 May 2014 / Revised: 26 June 2014 / Accepted: 21 July 2014 / Published: 28 July 2014
Cited by 5 | PDF Full-text (2925 KB) | HTML Full-text | XML Full-text
Abstract
Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation including extracellular matrix (ECM) degradation and cell loss. It is known that phosphoinositide-specific phospholipase γ1 (PLCγ1) can trigger several signaling pathways to regulate cell metabolism. However, whether this kinase is [...] Read more.
Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation including extracellular matrix (ECM) degradation and cell loss. It is known that phosphoinositide-specific phospholipase γ1 (PLCγ1) can trigger several signaling pathways to regulate cell metabolism. However, whether this kinase is expressive and active in human OA chondrocytes and its role in the pathological progression of OA have not been investigated. The current study was designed to investigate the PLCγ1 expression in human OA cartilage, and whether PLCγ1 was involved in the ECM synthesis had been further explored using cultured human OA chondrocytes. Our results indicated that PLCγ1 was highly expressed in human OA chondrocytes. In our further study using the cultured human OA chondrocytes, the results demonstrated that the disruption of PLCγ1 by its inhibitor, U73122, and siRNA contributed to the ECM synthesis of human OA chondrocytes through regulating the expression of ECM-related signaling molecules, including MMP-13, Col II, TIMP1, Sox-9, and AGG. Furthermore, PLCγ1/IP3/Ca(2+)/CaMK II signaling axis regulated the ECM synthesis of human chondrocytes through triggering mTOR/P70S6K/S6 pathway. In summary, our results suggested that PLC-γ1 activities played an important role in the ECM synthesis of human OA chondrocytes, and may serve as a therapeutic target for treating OA. Full article
(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)
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Open AccessArticle Synthesis and Properties of Poly(l-lactide)-b-poly (l-phenylalanine) Hybrid Copolymers
Int. J. Mol. Sci. 2014, 15(8), 13247-13266; doi:10.3390/ijms150813247
Received: 19 May 2014 / Revised: 28 June 2014 / Accepted: 14 July 2014 / Published: 29 July 2014
Cited by 2 | PDF Full-text (3074 KB) | HTML Full-text | XML Full-text
Abstract
Hybrid materials constituted by peptides and synthetic polymers have nowadays a great interest since they can combine the properties and functions of each constitutive block, being also possible to modify the final characteristics by using different topologies. Poly(l-lactide-b-l-phenylalanine) copolymers with [...] Read more.
Hybrid materials constituted by peptides and synthetic polymers have nowadays a great interest since they can combine the properties and functions of each constitutive block, being also possible to modify the final characteristics by using different topologies. Poly(l-lactide-b-l-phenylalanine) copolymers with various block lengths were synthesized by sequential ring-opening polymerization of l-lactide and the N-carboxyanhydride of l-phenylalanine. The resulting block copolymers were characterized by NMR spectrometry, IR spectroscopy, gel permeation chromatography, MALDI-TOF and UV-vis, revealing the successful incorporation of the polyphenylalanine (PPhe) peptide into the previously formed poly(l-lactide) (PLLA) polymer chain. X-ray diffraction and DSC data also suggested that the copolymers were phase-separated in domains containing either crystalline PLLA or PPhe phases. A peculiar thermal behavior was also found by thermogravimetric analysis when polyphenylalanine blocks were incorporated into polylactide. Full article
(This article belongs to the Special Issue Biodegradable Materials)
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Open AccessArticle The First Mutation Identified in a Chinese Acrodysostosis Patient Confirms a p.G289E Variation of PRKAR1A Causes Acrodysostosis
Int. J. Mol. Sci. 2014, 15(8), 13267-13274; doi:10.3390/ijms150813267
Received: 14 May 2014 / Revised: 28 May 2014 / Accepted: 11 June 2014 / Published: 29 July 2014
Cited by 2 | PDF Full-text (4144 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Acrodysostosis is a rare skeletal dysplasia, which has not been reported previously in patients of Chinese origin. The PRKAR1A gene and PDE4D gene have been found to be causative genes of acrodysostosis. A Chinese girl with acrodysostosis and concomitant multiple hormone resistance [...] Read more.
Acrodysostosis is a rare skeletal dysplasia, which has not been reported previously in patients of Chinese origin. The PRKAR1A gene and PDE4D gene have been found to be causative genes of acrodysostosis. A Chinese girl with acrodysostosis and concomitant multiple hormone resistance was recruited for our study. Clinical and biochemical characters were analyzed. DNA was extracted from leukocytes and was sequenced for GNAS, PDE4D and PRKAR1A gene mutations. A de novo heterozygous missense mutation (c.866G>A/p.G289E) was identified in the PRKAR1A gene. This mutation coincided with a mutation that had been found in a patient from another ethnic group. Our findings further suggest that the c.866G>A/p.G289E mutation in the PRKAR1A gene may be the cause of acrodysostosis with concomitant multiple hormone resistance. Moreover, it is the first report of acrodysostosis genetic analysis of Chinese origin. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs
Int. J. Mol. Sci. 2014, 15(8), 13275-13298; doi:10.3390/ijms150813275
Received: 10 June 2014 / Revised: 23 July 2014 / Accepted: 24 July 2014 / Published: 29 July 2014
Cited by 2 | PDF Full-text (4027 KB) | HTML Full-text | XML Full-text
Abstract
p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely [...] Read more.
p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely mutated in human cancer, using a bioinformatics approaches, we examined the phosphorylation site and its nearby flanking residues, focusing on the consensus phosphorylation motif pattern, amino-acid correlations within the phosphorylation motifs, the propensity of structural disorder of the phosphorylation motifs, and cancer mutations observed within the phosphorylation motifs. Many p53 phosphorylation sites are targets for several kinases. The phosphorylation sites match 17 consensus sequence motifs out of the 29 classified. In addition to proline, which is common in kinase specificity-determining sites, we found high propensity of acidic residues to be adjacent to phosphorylation sites. Analysis of human cancer mutations in the phosphorylation motifs revealed that motifs with adjacent acidic residues generally have fewer mutations, in contrast to phosphorylation sites near proline residues. p53 phosphorylation motifs are mostly disordered. However, human cancer mutations within phosphorylation motifs tend to decrease the disorder propensity. Our results suggest that combination of acidic residues Asp and Glu with phosphorylation sites provide charge redundancy which may safe guard against loss-of-function mutations, and that the natively disordered nature of p53 phosphorylation motifs may help reduce mutational damage. Our results further suggest that engineering acidic amino acids adjacent to potential phosphorylation sites could be a p53 gene therapy strategy. Full article
(This article belongs to the collection Human Single Nucleotide Polymorphisms and Disease Diagnostics)
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Open AccessArticle Comparative Evaluation of Urinary PCA3 and TMPRSS2: ERG Scores and Serum PHI in Predicting Prostate Cancer Aggressiveness
Int. J. Mol. Sci. 2014, 15(8), 13299-13316; doi:10.3390/ijms150813299
Received: 20 June 2014 / Revised: 15 July 2014 / Accepted: 18 July 2014 / Published: 30 July 2014
Cited by 17 | PDF Full-text (731 KB) | HTML Full-text | XML Full-text
Abstract
It has been suggested that urinary PCA3 and TMPRSS2:ERG fusion tests and serum PHI correlate to cancer aggressiveness-related pathological criteria at prostatectomy. To evaluate and compare their ability in predicting prostate cancer aggressiveness, PHI and urinary PCA3 and TMPRSS2:ERG (T2) scores were [...] Read more.
It has been suggested that urinary PCA3 and TMPRSS2:ERG fusion tests and serum PHI correlate to cancer aggressiveness-related pathological criteria at prostatectomy. To evaluate and compare their ability in predicting prostate cancer aggressiveness, PHI and urinary PCA3 and TMPRSS2:ERG (T2) scores were assessed in 154 patients who underwent radical prostatectomy for biopsy-proven prostate cancer. Univariate and multivariate analyses using logistic regression and decision curve analyses were performed. All three markers were predictors of a tumor volume ≥0.5 mL. Only PHI predicted Gleason score ≥7. T2 score and PHI were both independent predictors of extracapsular extension (≥pT3), while multifocality was only predicted by PCA3 score. Moreover, when compared to a base model (age, digital rectal examination, serum PSA, and Gleason sum at biopsy), the addition of both PCA3 score and PHI to the base model induced a significant increase (+12%) when predicting tumor volume >0.5 mL. PHI and urinary PCA3 and T2 scores can be considered as complementary predictors of cancer aggressiveness at prostatectomy. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessArticle TCF2 Attenuates FFA-Induced Damage in Islet β-Cells by Regulating Production of Insulin and ROS
Int. J. Mol. Sci. 2014, 15(8), 13317-13332; doi:10.3390/ijms150813317
Received: 20 April 2014 / Revised: 5 June 2014 / Accepted: 18 June 2014 / Published: 30 July 2014
Cited by 2 | PDF Full-text (4010 KB) | HTML Full-text | XML Full-text
Abstract
Free fatty acids (FFAs) are cytotoxic to pancreatic islet β-cells and play a crucial role in the diabetes disease process. A recent study revealed a down-regulation of transcription factor 2 (TCF2) levels during FFA-mediated cytotoxicity in pancreatic β-cells. However, its function during [...] Read more.
Free fatty acids (FFAs) are cytotoxic to pancreatic islet β-cells and play a crucial role in the diabetes disease process. A recent study revealed a down-regulation of transcription factor 2 (TCF2) levels during FFA-mediated cytotoxicity in pancreatic β-cells. However, its function during this process and the underlying mechanism remains unclear. In this study, treatment with palmitic acid (PA) at high levels (400 and 800 μM) decreased β-cell viability and TCF2 protein expression, along with the glucose-stimulated insulin secretion (GSIS). Western and RT-PCR analysis confirmed the positive regulatory effect of TCF2 on GSIS through promotion of the key regulators pancreatic duodenal homeobox-1 (PDX1) and glucose transporter 2 (GLUT2) in β-cells. In addition, both PI3K/AKT and MEK/ERK showed decreased expression in PA (800 μM)-treated β-cells. Overexpression of TCF2 could effectively restore the inhibitory effect of PA on the activation of PI3K/AKT and MEK/ERK as well as β-cell viability, simultaneously, inhibited PA-induced reactive oxygen species (ROS) generation. After blocking the PI3K/AKT and MAPK/ERK signals with their specific inhibitor, the effect of overexpressed TCF2 on β-cell viability and ROS production was obviously attenuated. Furthermore, a protective effect of TCF2 on GSIS by positive modulation of JNK-PDX1/GLUT2 signaling was also confirmed. Accordingly, our study has confirmed that TCF2 positively modulates insulin secretion and further inhibits ROS generation via the PI3K/AKT and MEK/ERK signaling pathways. Our work may provide a new therapeutic target to achieve prevention and treatment of diabetes. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle β-Defensin 2 Ameliorates Lung Injury Caused by Pseudomonas Infection and Regulates Proinflammatory and Anti-Inflammatory Cytokines in Rat
Int. J. Mol. Sci. 2014, 15(8), 13372-13387; doi:10.3390/ijms150813372
Received: 7 February 2014 / Revised: 13 June 2014 / Accepted: 17 June 2014 / Published: 30 July 2014
Cited by 2 | PDF Full-text (2593 KB) | HTML Full-text | XML Full-text
Abstract
An important member of the defensin family, β-defensin 2, is believed to play an important role in defense against foreign pathogens. In the present study, we constructed lentiviral vectors to express and knockdown β-defensin 2 in rat lungs. The results showed [...] Read more.
An important member of the defensin family, β-defensin 2, is believed to play an important role in defense against foreign pathogens. In the present study, we constructed lentiviral vectors to express and knockdown β-defensin 2 in rat lungs. The results showed that the infection of β-defensin 2 overexpression lentivirus and β-defensin 2 shRNA effectively increased and suppressed the expression of β-defensin 2 in rat lung, respectively. The overexpression of β-defensin 2 mediated by the lentiviral vector protected lung from infection of Pseudomonas aeruginosa, but shRNA targeting β-defensin 2 aggregated the damage of lung. In addition, we also found that β-defensin 2 overexpression increased basal expression of anti-inflammatory cytokine such as IL-4, IL-10 and IL-13 and decreased levels of proinflammatory cytokines which include IL-1α, IL-1β, IL-5, IL-6, IL-8, IL-18, and TNF-α. Moreover, in the process of cytokine regulation, NF-κB pathway may be involved. Taken together, these data suggest that β-defensin 2 has protective effects against infection of Pseudomonas aeruginosa in rat and plays a role in inflammatory regulation by adjusting cytokine levels. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Water-Soluble Coenzyme Q10 Inhibits Nuclear Translocation of Apoptosis Inducing Factor and Cell Death Caused by Mitochondrial Complex I Inhibition
Int. J. Mol. Sci. 2014, 15(8), 13388-13400; doi:10.3390/ijms150813388
Received: 20 May 2014 / Revised: 23 June 2014 / Accepted: 1 July 2014 / Published: 31 July 2014
Cited by 3 | PDF Full-text (2036 KB) | HTML Full-text | XML Full-text
Abstract
The objectives of the study were to explore the mechanism of rotenone-induced cell damage and to examine the protective effects of water-soluble Coenzyme Q10 (CoQ10) on the toxic effects of rotenone. Murine hippocampal HT22 cells were cultured with mitochondrial complex I inhibitor [...] Read more.
The objectives of the study were to explore the mechanism of rotenone-induced cell damage and to examine the protective effects of water-soluble Coenzyme Q10 (CoQ10) on the toxic effects of rotenone. Murine hippocampal HT22 cells were cultured with mitochondrial complex I inhibitor rotenone. Water-soluble CoQ10 was added to the culture media 3 h prior to the rotenone incubation. Cell viability was determined by alamar blue, reactive oxygen species (ROS) production by dihydroethidine (DHE) and mitochondrial membrane potential by tetramethyl rhodamine methyl ester (TMRM). Cytochrome c, caspase-9 and apoptosis-inducing factor (AIF) were measured using Western blotting after 24 h rotenone incubation. Rotenone caused more than 50% of cell death, increased ROS production, AIF nuclear translocation and reduction in mitochondrial membrane potential, but failed to cause mitochondrial cytochrome c release and caspase-9 activation. Pretreatment with water-soluble CoQ10 enhanced cell viability, decreased ROS production, maintained mitochondrial membrane potential and prevented AIF nuclear translocation. The results suggest that rotenone activates a mitochondria-initiated, caspase-independent cell death pathway. Water-soluble CoQ10 reduces ROS accumulation, prevents the fall of mitochondrial membrane potential, and inhibits AIF translocation and subsequent cell death. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2014)
Open AccessArticle Effects of Lead on the Morphology and Structure of the Nucleolus in the Root Tip Meristematic Cells of Allium cepa L.
Int. J. Mol. Sci. 2014, 15(8), 13406-13423; doi:10.3390/ijms150813406
Received: 20 June 2014 / Revised: 15 July 2014 / Accepted: 24 July 2014 / Published: 31 July 2014
Cited by 5 | PDF Full-text (9714 KB) | HTML Full-text | XML Full-text
Abstract
To study the toxic mechanisms of lead (Pb) in plants, the effects of Pb on the morphology and structure of the nucleolus in root tip meristematic cells of Allium cepa var. agrogarum L. were investigated. Fluorescence labeling, silver-stained indirect immunofluorescent microscopy and [...] Read more.
To study the toxic mechanisms of lead (Pb) in plants, the effects of Pb on the morphology and structure of the nucleolus in root tip meristematic cells of Allium cepa var. agrogarum L. were investigated. Fluorescence labeling, silver-stained indirect immunofluorescent microscopy and western blotting were used. Fluorescence labeling showed that Pb ions were localized in the meristematic cells and the uptake and accumulation of Pb increased with treatment time. At low concentrations of Pb (1–10 μM) there were persistent nucleoli in some cells during mitosis, and at high concentration (100 μM) many of the nucleolar organizing regions were localized on sticky chromosomes in metaphase and anaphase cells. Pb induced the release of particles containing argyrophilic proteins to be released from the nucleus into the cytoplasm. These proteins contained nucleophosmin and nucleolin. Pb also caused the extrusion of fibrillarin from the nucleus into the cytoplasm. Western blotting demonstrated the increased expression of these three major nucleolar proteins under Pb stress. Full article
(This article belongs to the Section Molecular Toxicology)
Open AccessArticle The Constituents of Roots and Stems of Illigera luzonensis and Their Anti-Platelet Aggregation Effects
Int. J. Mol. Sci. 2014, 15(8), 13424-13436; doi:10.3390/ijms150813424
Received: 31 May 2014 / Revised: 21 July 2014 / Accepted: 22 July 2014 / Published: 31 July 2014
Cited by 2 | PDF Full-text (727 KB) | HTML Full-text | XML Full-text
Abstract
Phytochemical investigation of the roots and stems of Illigera luzonensis afforded two new aporphine alkaloids (1) and (2), one new bisdehydroaporphine alkaloid (3), and one new benzenoid (4), along with 28 known structures. The [...] Read more.
Phytochemical investigation of the roots and stems of Illigera luzonensis afforded two new aporphine alkaloids (1) and (2), one new bisdehydroaporphine alkaloid (3), and one new benzenoid (4), along with 28 known structures. The structures of new compounds were elucidated by spectral and MS analysis. Among the isolated compounds, (1) and (413) were subjected into the examination for their inhibitory effects on the aggregation of washed rabbit platelets. Full article
(This article belongs to the Section Green Chemistry)
Open AccessArticle Hip Osteoarthritis in Dogs: A Randomized Study Using Mesenchymal Stem Cells from Adipose Tissue and Plasma Rich in Growth Factors
Int. J. Mol. Sci. 2014, 15(8), 13437-13460; doi:10.3390/ijms150813437
Received: 27 June 2014 / Revised: 18 July 2014 / Accepted: 21 July 2014 / Published: 31 July 2014
Cited by 7 | PDF Full-text (1254 KB) | HTML Full-text | XML Full-text
Abstract
Purpose: The aim of this study was to compare the efficacy and safety of a single intra-articular injection of adipose mesenchymal stem cells (aMSCs) versus plasma rich in growth factors (PRGF) as a treatment for reducing symptoms in dogs with hip osteoarthritis [...] Read more.
Purpose: The aim of this study was to compare the efficacy and safety of a single intra-articular injection of adipose mesenchymal stem cells (aMSCs) versus plasma rich in growth factors (PRGF) as a treatment for reducing symptoms in dogs with hip osteoarthritis (OA). Methods: This was a randomized, multicenter, blinded, parallel group. Thirty-nine dogs with symptomatic hip OA were assigned to one of the two groups, to receive aMSCs or PRGF. The primary outcome measures were pain and function subscales, including radiologic assessment, functional limitation and joint mobility. The secondary outcome measures were owners’ satisfaction questionnaire, rescue analgesic requirement and overall safety. Data was collected at baseline, then, 1, 3 and 6 months post-treatment. Results: OA degree did not vary within groups. Functional limitation, range of motion (ROM), owner’s and veterinary investigator visual analogue scale (VAS), and patient’s quality of life improved from the first month up to six months. The aMSCs group obtained better results at 6 months. There were no adverse effects during the study. Our findings show that aMSCs and PRGF are safe and effective in the functional analysis at 1, 3 and 6 months; provide a significant improvement, reducing dog’s pain, and improving physical function. With respect to basal levels for every parameter in patients with hip OA, aMSCs showed better results at 6 months. Full article
(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)
Open AccessArticle The Mitochondrion-Located Protein OsB12D1 Enhances Flooding Tolerance during Seed Germination and Early Seedling Growth in Rice
Int. J. Mol. Sci. 2014, 15(8), 13461-13481; doi:10.3390/ijms150813461
Received: 25 May 2014 / Revised: 22 June 2014 / Accepted: 21 July 2014 / Published: 31 July 2014
Cited by 1 | PDF Full-text (11284 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
B12D belongs to a function unknown subgroup of the Balem (Barley aleurone and embryo) proteins. In our previous work on rice seed germination, we identified a B12D-like protein encoded by LOC_Os7g41350 (named OsB12D1). OsB12D1 pertains to an ancient protein family with [...] Read more.
B12D belongs to a function unknown subgroup of the Balem (Barley aleurone and embryo) proteins. In our previous work on rice seed germination, we identified a B12D-like protein encoded by LOC_Os7g41350 (named OsB12D1). OsB12D1 pertains to an ancient protein family with an amino acid sequence highly conserved from moss to angiosperms. Among the six OsB12Ds, OsB12D1 is one of the major transcripts and is primarily expressed in germinating seed and root. Bioinformatics analyses indicated that OsB12D1 is an anoxic or submergence resistance-related gene. RT-PCR results showed OsB12D1 is induced remarkably in the coleoptiles or roots by flooding during seed germination and early seedling growth. The OsB12D1-overexpressed rice seeds could protrude radicles in 8 cm deep water, further exhibiting significant flooding tolerance compared to the wild type. Moreover, this tolerance was not affected by the gibberellin biosynthesis inhibitor paclobutrazol. OsB12D1 was identified in the mitochondrion by subcellular localization analysis and possibly enhances electron transport through mediating Fe and oxygen availability under flooded conditions. This work indicated that OsB12D1 is a promising gene that can help to enhance rice seedling establishment in farming practices, especially for direct seeding. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Population Structure of the Greenhouse Whitefly, Trialeurodes vaporariorum (Westwood), an Invasive Species from the Americas, 60 Years after Invading China
Int. J. Mol. Sci. 2014, 15(8), 13514-13528; doi:10.3390/ijms150813514
Received: 18 May 2014 / Revised: 16 June 2014 / Accepted: 21 July 2014 / Published: 4 August 2014
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Abstract
Though the greenhouse whitefly, Trialeurodes vaporariorum (Westwood) (Hemiptera: Aleyrodidae) was introduced into China more than 60 years ago, the genetic diversity and structure of this exotic insect pest and virus vector have not been studied. To investigate the population genetic characteristics of [...] Read more.
Though the greenhouse whitefly, Trialeurodes vaporariorum (Westwood) (Hemiptera: Aleyrodidae) was introduced into China more than 60 years ago, the genetic diversity and structure of this exotic insect pest and virus vector have not been studied. To investigate the population genetic characteristics of this invasive species and to identify potential invasion routes, the genetic diversity and population structure of 17 collections of T. vaporariorum from nine provinces in China were analyzed using seven microsatellite loci. The results of the analyses indicated that the genetic diversity for the populations examined from the four provinces: Jilin, Ningxia, Guizhou and Qinghai, was lower than the genetic diversity of populations from the five provinces: Yunnan, Shandong, Shanxi, Liaoning, and Gansu. The T. vaporariorum populations analyzed in this study grouped as two distinct genetic clusters based on the analysis using STRUCTURE, whereas, 8 clusters were identified based on the BAPS analysis. Of the 136 genetic distance (Fst) values, 128 (94%) were associated with a significant exact test. However, there was no significant relationship between Fst and geographical distance. These results demonstrate that populations of T. vaporariorum in China exhibit significant genetic differentiation, indicating the likelihood that multiple introductions of T. vaporariorum into China have occurred. Also, the populations collected from the provinces of Jilin, Ningxia, Guizhou and Qinghai appear to represent secondary introductions originating from other Chinese provinces. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Dose-Dependent Protective Effect of Lithium Chloride on Retinal Ganglion Cells Is Interrelated with an Upregulated Intraretinal BDNF after Optic Nerve Transection in Adult Rats
Int. J. Mol. Sci. 2014, 15(8), 13550-13563; doi:10.3390/ijms150813550
Received: 30 January 2014 / Revised: 7 July 2014 / Accepted: 22 July 2014 / Published: 5 August 2014
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Abstract
Neuroprotection of lithium for axotomized retinal ganglion cells (RGCs) is attributed to upregulated intraretinal Bcl-2. As lithium also upregulates brain-derived neurotrophic factor (BDNF) which can rescue axotomized RGCs, it is hypothesized that lithium could protect RGCs through BDNF. This study investigated this [...] Read more.
Neuroprotection of lithium for axotomized retinal ganglion cells (RGCs) is attributed to upregulated intraretinal Bcl-2. As lithium also upregulates brain-derived neurotrophic factor (BDNF) which can rescue axotomized RGCs, it is hypothesized that lithium could protect RGCs through BDNF. This study investigated this hypothesis and a possible relationship between the dose and protection of lithium. All adult experimental rats received daily intraperitoneal injections of lithium chloride (LiCl) at 30, 60 or 85 mg/kg·bw until they were euthanized 2, 7 or 14 days after left intraorbital optic nerve (ON) transection. Our results revealed that RGC densities promoted and declined with increased dose of LiCl and the highest RGC densities were always in the 60 mg/kg·bw LiCl group at both 7 and 14 day points. Similar promotion and decline in the mRNA and protein levels of intraretinal BDNF were also found at the 14 day point, while such BDNF levels increased in the 30 mg/kg·bw LiCl group but peaked in the 60 and 85 mg/kg·bw LiCl groups at the 7 day point. These findings suggested that lithium can delay the death of axotomized RGCs in a dose-dependent manner within a certain period after ON injury and such beneficial effect is interrelated with an upregulated level of intraretinal BDNF. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Phylogeography of the Chinese Beard Eel, Cirrhimuraena chinensis Kaup, Inferred from Mitochondrial DNA: A Range Expansion after the Last Glacial Maximum
Int. J. Mol. Sci. 2014, 15(8), 13564-13577; doi:10.3390/ijms150813564
Received: 29 March 2014 / Revised: 10 June 2014 / Accepted: 10 July 2014 / Published: 5 August 2014
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Abstract
The Chinese beard eel (Cirrhimuraena chinensis Kaup) is an intertidal fish and a model organism for the study of impacts caused by topological fluctuations during the Pleistocene and current intricate hydrological conditions on fauna living in the coastal areas of China. [...] Read more.
The Chinese beard eel (Cirrhimuraena chinensis Kaup) is an intertidal fish and a model organism for the study of impacts caused by topological fluctuations during the Pleistocene and current intricate hydrological conditions on fauna living in the coastal areas of China. In this study, we examined the phylogeographical pattern, population genetic profile and demographical history of C. chinensis using mitochondrial DNA (cytochrome b (cyt b) and control region (CR)) from 266 individuals sampled in seven localities across the coastal area of southeastern China. The combined data indicated high levels of haplotype diversity and low levels of nucleotide diversity. Analyses of molecular variance (AMOVA) and FST statistics suggested the absence of a significant population structure across the Chinese coast. Neutrality tests, mismatch distributions and Bayesian skyline plots uniformly indicated a recent population expansion. The phylogeographic structure of C. chinensis may be attributed to past population expansion and long-distance pelagic larval dispersal facilitated by present-day ocean currents. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Age Dependent Changes in Cartilage Matrix, Subchondral Bone Mass, and Estradiol Levels in Blood Serum, in Naturally Occurring Osteoarthritis in Guinea Pigs
Int. J. Mol. Sci. 2014, 15(8), 13578-13595; doi:10.3390/ijms150813578
Received: 12 May 2014 / Revised: 17 June 2014 / Accepted: 27 June 2014 / Published: 5 August 2014
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Abstract
The Dunkin Hartley (DH) guinea pig is a widely used naturally occurring osteoarthritis model. The aim of this study was to provide detailed evidence of age-related changes in articular cartilage, subchondral bone mineral density, and estradiol levels. We studied the female Dunkin [...] Read more.
The Dunkin Hartley (DH) guinea pig is a widely used naturally occurring osteoarthritis model. The aim of this study was to provide detailed evidence of age-related changes in articular cartilage, subchondral bone mineral density, and estradiol levels. We studied the female Dunkin Hartley guinea pigs at 1, 3, 6, 9, and 12 months of age (eight animals in each group). Histological analysis were used to identify degenerative cartilage and electron microscopy was performed to further observe the ultrastructure. Estradiol expression levels in serum were assessed, and matrix metalloproteinase 3 and glycosaminoglycan expression in cartilage was performed by immunohistochemistry. Bone mineral density of the tibia subchondral bone was measured using dual X-ray absorptiometry. Histological analysis showed that the degeneration of articular cartilage grew more severe with increasing age starting at 3 months, coupled with the loss of normal cells and an increase in degenerated cells. Serum estradiol levels increased with age from 1 to 6 months and thereafter remained stable from 6 to 12 months. Matrix metalloproteinase 3 expression in cartilage increased with age, but no significant difference was found in glycosaminoglycan expression between 1- and 3-month old animals. The bone mineral density of the tibia subchondral bone increased with age before reaching a stable value at 9 months of age. Age-related articular cartilage degeneration occurred in Dunkin Hartley guinea pigs beginning at 3 months of age, while no directly positive or negative correlation between osteoarthritis progression and estradiol serum level or subchondral bone mineral density was discovered. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Identification of Cold-Responsive miRNAs and Their Target Genes in Nitrogen-Fixing Nodules of Soybean
Int. J. Mol. Sci. 2014, 15(8), 13596-13614; doi:10.3390/ijms150813596
Received: 29 May 2014 / Revised: 14 July 2014 / Accepted: 17 July 2014 / Published: 5 August 2014
Cited by 4 | PDF Full-text (1385 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
As a warm climate species, soybean is highly sensitive to chilling temperatures. Exposure to chilling temperatures causes a significant reduction in the nitrogen fixation rate in soybean plants and subsequent yield loss. However, the molecular basis for the sensitivity of soybean to [...] Read more.
As a warm climate species, soybean is highly sensitive to chilling temperatures. Exposure to chilling temperatures causes a significant reduction in the nitrogen fixation rate in soybean plants and subsequent yield loss. However, the molecular basis for the sensitivity of soybean to chilling is poorly understood. In this study, we identified cold-responsive miRNAs in nitrogen-fixing nodules of soybean. Upon chilling, the expression of gma-miR397a, gma-miR166u and gma-miR171p was greatly upregulated, whereas the expression of gma-miR169c, gma-miR159b, gma-miR319a/b and gma-miR5559 was significantly decreased. The target genes of these miRNAs were predicted and validated using 5' complementary DNA ends (5'-RACE) experiments, and qPCR analysis identified putative genes targeted by the cold-responsive miRNAs in response to chilling temperatures. Taken together, our results reveal that miRNAs may be involved in the protective mechanism against chilling injury in mature nodules of soybean. Full article
Open AccessArticle Role of Serum Cholesterol and Statin Use in the Risk of Prostate Cancer Detection and Tumor Aggressiveness
Int. J. Mol. Sci. 2014, 15(8), 13615-13623; doi:10.3390/ijms150813615
Received: 6 May 2014 / Revised: 11 July 2014 / Accepted: 11 July 2014 / Published: 6 August 2014
Cited by 10 | PDF Full-text (696 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The aim of this study was to analyze the relationship between statin use along with serum cholesterol levels and prostate cancer (PCa) detection and aggressiveness. Statin users of three years or more and serum cholesterol levels (SC) were assessed in 2408 men [...] Read more.
The aim of this study was to analyze the relationship between statin use along with serum cholesterol levels and prostate cancer (PCa) detection and aggressiveness. Statin users of three years or more and serum cholesterol levels (SC) were assessed in 2408 men scheduled for prostate biopsy. SC was classified as normal (NSC: <200 mg/dL) or high (HSC: >200 mg/dL). High-grade PCa (HGPCa) was considered if the Gleason score was greater than 7. Statin users comprised 30.9% of those studied. The PCa detection rate was 31.2% of men on statins and 37% of non-statin users (p < 0.006). The PCa detection rate was 26.3% in men with NSC and 40.6% in those with HSC (p < 0.001). In the subset of NSC men, the PCa rate was 26.5% for statin users and 26.2% for non-users (p = 0.939), while in men with HSC, the PCa rate was 36.4% for statin users and 42.0% for non-statin users (p = 0.063). The HGPCa rate was 41.8% for statin users and 32.5% for non-users (p = 0.012). NSC men had a 53.8% rate of HGPCa, while the rate was only 27.6% in HSC men (p < 0.001). NSC men on statins had an HGPCa rate of 70.2%, while non-statin users had a rate of 41.2% (p < 0.001). The HGPCa rate for HSC men on statins was 18.8%, while the rate was 30.0% (p = 0.011) for non-users. Logistic regression analysis suggested that serum cholesterol levels could serve as an independent predictor of PCa risk, OR 1.87 (95% CI 1.56–2.24) and HGPCa risk, OR 0.31 (95% CI 0.23–0.44), while statin usage could not. Statin treatment may prevent PCa detection through serum cholesterol-mediated mechanisms. A disturbing increase in the HGPCa rate was observed in statin users who normalized their serum cholesterol. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessArticle TNF-α Blocker Effect of Naringenin-Loaded Sericin Microparticles that Are Potentially Useful in the Treatment of Psoriasis
Int. J. Mol. Sci. 2014, 15(8), 13624-13636; doi:10.3390/ijms150813624
Received: 19 May 2014 / Revised: 22 July 2014 / Accepted: 25 July 2014 / Published: 6 August 2014
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Abstract
This study aims to evaluate the effect of combined use of the racemic flavanone Naringenin (NRG) and the protein sericin as TNF-α blockers. Sericin (SMs) and (R/S) NRG-loaded Sericin (SNRGMs) microparticles were prepared by spray-drying, characterized in terms [...] Read more.
This study aims to evaluate the effect of combined use of the racemic flavanone Naringenin (NRG) and the protein sericin as TNF-α blockers. Sericin (SMs) and (R/S) NRG-loaded Sericin (SNRGMs) microparticles were prepared by spray-drying, characterized in terms of morphology and particle size distribution, and encapsulation efficiency was determined. Concerning morphology and particle size distribution of microparticles, results indicated that they were not affected by the presence of NRG. The encapsulation efficiency was almost quantitative (93%), thus proving that sericin can be advantageously loaded with (R/S) NRG. Biological evaluation of (R/S) NRG, SMs and SNRGMs was then performed in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (hPBMC). SNRGMs resulted cytotoxic at the higher dose used (200 μg/mL) and the effect was greater than (R/S) NRG alone. Moreover, even if sericin alone was not effective in suppressing LPS-induced serum TNF-α levels, SNRGMs loaded with 9.3% of (R/S) NRG were significantly more potent than (R/S) NRG alone. In summary, this study provides the proof of concept that sericin-based microspheres loaded with TNF-α-blockers could contribute to the down regulation of the cytokine and represents the starting point for the development of new topical formulations for the treatment of middle-stage psoriasis. Full article
(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols)
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Open AccessArticle Celastrol Attenuates Inflammatory and Neuropathic Pain Mediated by Cannabinoid Receptor Type 2
Int. J. Mol. Sci. 2014, 15(8), 13637-13648; doi:10.3390/ijms150813637
Received: 9 May 2014 / Revised: 9 June 2014 / Accepted: 16 June 2014 / Published: 6 August 2014
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Abstract
Celastrol, a major active ingredient of Chinese herb Tripterygium wilfordii Hook. f. (thunder god vine), has exhibited a broad spectrum of pharmacological activities, including anti-inflammation, anti-cancer and immunosuppression. In the present study, we used animal models of inflammatory pain and neuropathic pain, [...] Read more.
Celastrol, a major active ingredient of Chinese herb Tripterygium wilfordii Hook. f. (thunder god vine), has exhibited a broad spectrum of pharmacological activities, including anti-inflammation, anti-cancer and immunosuppression. In the present study, we used animal models of inflammatory pain and neuropathic pain, generated by carrageenan injection and spared nerve injury (SNI), respectively, to evaluate the effect of celastrol and to address the mechanisms underlying pain processing. Intraperitoneal (i.p.) injection of celastrol produced a dose-dependent inhibition of carrageenan-induced edema and allodynia. Real-time PCR analysis showed that celastrol (0.3 mg/kg, i.p.) significantly reduced mRNA expressions of inflammatory cytokines, TNF-α, IL-6, IL-1β, in carrageenan-injected mice. In SNI mice, pain behavior studies showed that celastrol (1 mg/kg, i.p.) effectively prevented the hypersensitivity of mechanical nociceptive response on the third day post-surgery and the seventh day post-surgery. Furthermore, the anti-hyperalgesic effects of celastrol in carrageenan-injected mice and SNI mice were reversed by SR144528 (1 mg/kg, i.p.), a specific cannabinoid receptor-2 (CB2) receptor antagonist, but not by SR141716 (1 mg/kg, i.p.), a specific cannabinoid receptor-1 (CB1) receptor antagonist. Taken together, our results demonstrate the analgesia effects of celastrol through CB2 signaling and propose the potential of exploiting celastrol as a novel candidate for pain relief. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle In Vivo Immunotoxicity of SiO2@(Y0.5Gd0.45Eu0.05)2O3 as Dual-Modality Nanoprobes
Int. J. Mol. Sci. 2014, 15(8), 13649-13662; doi:10.3390/ijms150813649
Received: 29 April 2014 / Revised: 22 May 2014 / Accepted: 4 July 2014 / Published: 7 August 2014
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Abstract
We have successfully synthesized SiO2@(Y0.5Gd0.45Eu0.05)2O3 nanocomposites as a potential dual-modality nanoprobe for molecular imaging in vitro. However, their immunotoxicity assessment in vivo remains unknown. In this article, the in [...] Read more.
We have successfully synthesized SiO2@(Y0.5Gd0.45Eu0.05)2O3 nanocomposites as a potential dual-modality nanoprobe for molecular imaging in vitro. However, their immunotoxicity assessment in vivo remains unknown. In this article, the in vitro biocompatibility of our dual-modality nanoprobes was assayed in terms of cell viability and apoptosis. In vivo immunotoxicity was investigated by monitoring the generation of reactive oxygen species (ROS), cluster of differentiation (CD) markers and cytokines in Balb/c mice. The data show that the in vitro biocompatibility was satisfactory. In addition, the immunotoxicity data revealed there are no significant changes in the expression levels of CD11b and CD71 between the nanoprobe group and the Gd in a diethylenetriaminepentaacetic acid (DTPA) chelator (Gd-DTPA) group 24 h after injection in Balb/c mice (p > 0.05). Importantly, there are significant differences in the expression levels of CD206 and CD25 as well as the secretion of IL-4 and the generation of ROS 24 h after injection (p < 0.05). Transmission electron microscopy (TEM) images showed that few nanoprobes were localized in the phagosomes of liver and lung. In conclusion, the toxic effects of our nanoprobes may mainly result from the aggregation of particles in phagosomes. This accumulation may damage the microstructure of the cells and generate oxidative stress reactions that further stimulate the immune response. Therefore, it is important to evaluate the in vivo immunotoxicity of these rare earth-based biomaterials at the molecular level before molecular imaging in vivo. Full article
(This article belongs to the Special Issue Bioactive Nanoparticles 2014)
Open AccessArticle Identification of Bacterial Community Composition in Freshwater Aquaculture System Farming of Litopenaeus vannamei Reveals Distinct Temperature-Driven Patterns
Int. J. Mol. Sci. 2014, 15(8), 13663-13680; doi:10.3390/ijms150813663
Received: 31 March 2014 / Revised: 1 July 2014 / Accepted: 16 July 2014 / Published: 7 August 2014
Cited by 7 | PDF Full-text (3467 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Change in temperature is often a major environmental factor in triggering waterborne disease outbreaks. Previous research has revealed temporal and spatial patterns of bacterial population in several aquatic ecosystems. To date, very little information is available on aquaculture environment. Here, we assessed [...] Read more.
Change in temperature is often a major environmental factor in triggering waterborne disease outbreaks. Previous research has revealed temporal and spatial patterns of bacterial population in several aquatic ecosystems. To date, very little information is available on aquaculture environment. Here, we assessed environmental temperature effects on bacterial community composition in freshwater aquaculture system farming of Litopenaeus vannamei (FASFL). Water samples were collected over a one-year period, and aquatic bacteria were characterized by polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and 16S rDNA pyrosequencing. Resulting DGGE fingerprints revealed a specific and dynamic bacterial population structure with considerable variation over the seasonal change, suggesting that environmental temperature was a key driver of bacterial population in the FASFL. Pyrosequencing data further demonstrated substantial difference in bacterial community composition between the water at higher (WHT) and at lower (WLT) temperatures in the FASFL. Actinobacteria, Proteobacteria and Bacteroidetes were the highest abundant phyla in the FASFL, however, a large number of unclassified bacteria contributed the most to the observed variation in phylogenetic diversity. The WHT harbored remarkably higher diversity and richness in bacterial composition at genus and species levels when compared to the WLT. Some potential pathogenenic species were identified in both WHT and WLT, providing data in support of aquatic animal health management in the aquaculture industry. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Robust Non-Wetting PTFE Surfaces by Femtosecond Laser Machining
Int. J. Mol. Sci. 2014, 15(8), 13681-13696; doi:10.3390/ijms150813681
Received: 18 June 2014 / Revised: 18 July 2014 / Accepted: 25 July 2014 / Published: 8 August 2014
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Abstract
Nature shows many examples of surfaces with extraordinary wettability, which can often be associated with particular air-trapping surface patterns. Here, robust non-wetting surfaces have been created by femtosecond laser ablation of polytetrafluoroethylene (PTFE). The laser-created surface structure resembles a forest of entangled [...] Read more.
Nature shows many examples of surfaces with extraordinary wettability, which can often be associated with particular air-trapping surface patterns. Here, robust non-wetting surfaces have been created by femtosecond laser ablation of polytetrafluoroethylene (PTFE). The laser-created surface structure resembles a forest of entangled fibers, which support structural superhydrophobicity even when the surface chemistry is changed by gold coating. SEM analysis showed that the degree of entanglement of hairs and the depth of the forest pattern correlates positively with accumulated laser fluence and can thus be influenced by altering various laser process parameters. The resulting fibrous surfaces exhibit a tremendous decrease in wettability compared to smooth PTFE surfaces; droplets impacting the virgin or gold coated PTFE forest do not wet the surface but bounce off. Exploratory bioadhesion experiments showed that the surfaces are truly air-trapping and do not support cell adhesion. Therewith, the created surfaces successfully mimic biological surfaces such as insect wings with robust anti-wetting behavior and potential for antiadhesive applications. In addition, the fabrication can be carried out in one process step, and our results clearly show the insensitivity of the resulting non-wetting behavior to variations in the process parameters, both of which make it a strong candidate for industrial applications. Full article
(This article belongs to the Special Issue Biomimetic and Functional Materials)
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Open AccessArticle A Sensitive and Effective Proteomic Approach to Identify She-Donkey’s and Goat’s Milk Adulterations by MALDI-TOF MS Fingerprinting
Int. J. Mol. Sci. 2014, 15(8), 13697-13719; doi:10.3390/ijms150813697
Received: 23 April 2014 / Revised: 25 June 2014 / Accepted: 18 July 2014 / Published: 8 August 2014
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Abstract
She-donkey’s milk (DM) and goat’s milk (GM) are commonly used in newborn and infant feeding because they are less allergenic than other milk types. It is, therefore, mandatory to avoid adulteration and contamination by other milk allergens, developing fast and efficient analytical [...] Read more.
She-donkey’s milk (DM) and goat’s milk (GM) are commonly used in newborn and infant feeding because they are less allergenic than other milk types. It is, therefore, mandatory to avoid adulteration and contamination by other milk allergens, developing fast and efficient analytical methods to assess the authenticity of these precious nutrients. In this experimental work, a sensitive and robust matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling was designed to assess the genuineness of DM and GM milks. This workflow allows the identification of DM and GM adulteration at levels of 0.5%, thus, representing a sensitive tool for milk adulteration analysis, if compared with other laborious and time-consuming analytical procedures. Full article
(This article belongs to the Special Issue Advances in Proteomic Research)
Open AccessArticle BMP4 Protects Rat Pulmonary Arterial Smooth Muscle Cells from Apoptosis by PI3K/AKT/Smad1/5/8 Signaling
Int. J. Mol. Sci. 2014, 15(8), 13738-13754; doi:10.3390/ijms150813738
Received: 8 June 2014 / Revised: 21 July 2014 / Accepted: 1 August 2014 / Published: 8 August 2014
Cited by 7 | PDF Full-text (4995 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bone morphogenetic protein-4 (BMP4), a member of the transforming growth factor β (TGF-β) family of growth factors, is activated and increased under hypoxic conditions, which plays an important role in the progression of pulmonary arterial hypertension (PAH). Previous studies have shown that [...] Read more.
Bone morphogenetic protein-4 (BMP4), a member of the transforming growth factor β (TGF-β) family of growth factors, is activated and increased under hypoxic conditions, which plays an important role in the progression of pulmonary arterial hypertension (PAH). Previous studies have shown that BMP4 is involved in the regulation of proliferation, differentiation, migration and apoptosis of various cell types. However, the precise mechanisms involved in the regulation of pulmonary artery smooth muscle cells (PASMCs) in PAH are still incompletely understood. It has been reported that AKT is a critical regulator of cell survival and vascular remodeling. Therefore, there may be crosstalk between BMP4 anti-apoptotic processes and PI3K/AKT survival effect in rat PASMCs. To test this hypothesis, we performed confocal, cell viability measurement, mitochondrial potential, real-time polymerase chain reaction (PCR), and Western blot analysis to determine the role of BMP4 on cell survival and apoptosis. We found that hypoxia up-regulated the expression of BMP4. BMP4 promoted cell survival, reduced mitochondrial depolarization, and increased the expression of Bcl-2 and procaspase-3 in PASMCs under serum-deprived condition. These effects were reversed by PI3K/AKT inhibitors (LY294002 and wortmannin). Thus, these findings indicate that BMP4 protects PASMCs from apoptosis at least in part, mediated via the PI3K/AKT pathway. Full article
(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)
Open AccessArticle Lutein Inhibits the Migration of Retinal Pigment Epithelial Cells via Cytosolic and Mitochondrial Akt Pathways (Lutein Inhibits RPE Cells Migration)
Int. J. Mol. Sci. 2014, 15(8), 13755-13767; doi:10.3390/ijms150813755
Received: 11 May 2014 / Revised: 16 July 2014 / Accepted: 25 July 2014 / Published: 8 August 2014
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Abstract
During the course of proliferative vitreoretinopathy (PVR), the retinal pigment epithelium (RPE) cells will de-differentiate, proliferate, and migrate onto the surfaces of the sensory retina. Several studies have shown that platelet-derived growth factor (PDGF) can induce migration of RPE cells via an [...] Read more.
During the course of proliferative vitreoretinopathy (PVR), the retinal pigment epithelium (RPE) cells will de-differentiate, proliferate, and migrate onto the surfaces of the sensory retina. Several studies have shown that platelet-derived growth factor (PDGF) can induce migration of RPE cells via an Akt-related pathway. In this study, the effect of lutein on PDGF-BB-induced RPE cells migration was examined using transwell migration assays and Western blot analyses. We found that both phosphorylation of Akt and mitochondrial translocation of Akt in RPE cells induced by PDGF-BB stimulation were suppressed by lutein. Furthermore, the increased migration observed in RPE cells with overexpressed mitochondrial Akt could also be suppressed by lutein. Our results demonstrate that lutein can inhibit PDGF-BB induced RPE cells migration through the inhibition of both cytoplasmic and mitochondrial Akt activation. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle The Inflammation-Related Gene S100A12 Is Positively Regulated by C/EBPβ and AP-1 in Pigs
Int. J. Mol. Sci. 2014, 15(8), 13802-13816; doi:10.3390/ijms150813802
Received: 10 June 2014 / Revised: 7 July 2014 / Accepted: 23 July 2014 / Published: 8 August 2014
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Abstract
S100A12 is involved in the inflammatory response and is considered an important marker for many inflammatory diseases in humans. Our previous studies indicated that the S100A12 gene was abundant in the immune tissues of pigs and was significantly upregulated during infection with [...] Read more.
S100A12 is involved in the inflammatory response and is considered an important marker for many inflammatory diseases in humans. Our previous studies indicated that the S100A12 gene was abundant in the immune tissues of pigs and was significantly upregulated during infection with Haemophilus parasuis (HPS) or porcine circovirus type 2 (PCV2). In this study, the mechanism of transcriptional regulation of S100A12 was investigated in pigs. Our results showed that S100A12, CCAAT/enhancer-binding protein beta (C/EBPβ) and activator protein-1 (AP-1) genes were up-regulated in PK-15 (ATCC, CCL-33) cells when treated with LPS or Poly I: C. Additionally, the promoter activity and expression level of the S100A12 gene were significantly upregulated when C/EBPβ or AP-1 were overexpressed. We utilized electromobility shift assays (EMSA) to confirm that C/EBPβ and AP-1 could directly bind the S100A12 gene promoter. We also found that the transcriptional activity and expression levels of C/EBPβ and AP-1 could positively regulate each other. Furthermore, the promoter activity of the S100A12 gene was higher when C/EBPβ and AP-1 were cotransfected than when they were transfected individually. We concluded that the S100A12 gene was cooperatively and positively regulated by C/EBPβ and AP-1 in pigs. Our study offers new insight into the transcriptional regulation of the S100A12 gene. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Theoretical Study of the Transpore Velocity Control of Single-Stranded DNA
Int. J. Mol. Sci. 2014, 15(8), 13817-13832; doi:10.3390/ijms150813817
Received: 10 June 2014 / Revised: 15 July 2014 / Accepted: 22 July 2014 / Published: 11 August 2014
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Abstract
The electrokinetic transport dynamics of deoxyribonucleic acid (DNA) molecules have recently attracted significant attention in various fields of research. Our group is interested in the detailed examination of the behavior of DNA when confined in micro/nanofluidic channels. In the present study, the [...] Read more.
The electrokinetic transport dynamics of deoxyribonucleic acid (DNA) molecules have recently attracted significant attention in various fields of research. Our group is interested in the detailed examination of the behavior of DNA when confined in micro/nanofluidic channels. In the present study, the translocation mechanism of a DNA-like polymer chain in a nanofluidic channel was investigated using Langevin dynamics simulations. A coarse-grained bead-spring model was developed to simulate the dynamics of a long polymer chain passing through a rectangular cross-section nanopore embedded in a nanochannel, under the influence of a nonuniform electric field. Varying the cross-sectional area of the nanopore was found to allow optimization of the translocation process through modification of the electric field in the flow channel, since a drastic drop in the electric potential at the nanopore was induced by changing the cross-section. Furthermore, the configuration of the polymer chain in the nanopore was observed to determine its translocation velocity. The competition between the strength of the electric field and confinement in the small pore produces various transport mechanisms and the results of this study thus represent a means of optimizing the design of nanofluidic devices for single molecule detection. Full article
(This article belongs to the Special Issue Identification and Roles of the Structure of DNA)
Open AccessArticle Rapamycin-Induced Apoptosis in HGF-Stimulated Lens Epithelial Cells by AKT/mTOR, ERK and JAK2/STAT3 Pathways
Int. J. Mol. Sci. 2014, 15(8), 13833-13848; doi:10.3390/ijms150813833
Received: 12 May 2014 / Revised: 25 July 2014 / Accepted: 26 July 2014 / Published: 11 August 2014
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Abstract
Hepatocyte growth factor (HGF) induced the proliferation of lens epithelial cells (LECs) and may be a major cause of posterior capsule opacification (PCO), which is the most frequent postoperative complication of cataract surgery. To date, several agents that can block LECs proliferation [...] Read more.
Hepatocyte growth factor (HGF) induced the proliferation of lens epithelial cells (LECs) and may be a major cause of posterior capsule opacification (PCO), which is the most frequent postoperative complication of cataract surgery. To date, several agents that can block LECs proliferation have been studied, but none have been used in clinic. Recently, accumulating evidence has suggested rapamycin, the inhibitor of mTOR (mammalian target of Rapamycin), was associated with the induction of apoptosis in LECs. The purpose of our study was to investigate the potential effects of rapamycin on HGF-induced LECs and the underlying mechanisms by which rapamycin exerted its actions. Using cell proliferation, cell viability and flow cytometric apoptosis assays, we found that rapamycin potently not only suppressed proliferation but also induced the apoptosis of LECs in a dose-dependent manner under HGF administration. Further investigation of the underlying mechanism using siRNA transfection revealed that rapamycin could promote apoptosis of LECs via inhibiting HGF-induced phosphorylation of AKT/mTOR, ERK and JAK2/STAT3 signaling molecules. Moreover, the forced expression of AKT, ERK and STAT3 could induce a significant suppression of apoptosis in these cells after treatment of rapamycin. Together, these findings suggested that rapamycin-induced apoptosis in HGF-stimulated LECs is accompanied by inhibition of AKT/mTOR, ERK and JAK2/STAT3 pathways, which supports its use to inhibit PCO in preclinical studies and provides theoretical foundation for future possible practice. Full article
(This article belongs to the collection Programmed Cell Death and Apoptosis)
Open AccessArticle Effect of β-Glucan Supplementation on Acute Postprandial Changes in Fatty Acid Profile of Lymph and Serum in Pigs
Int. J. Mol. Sci. 2014, 15(8), 13881-13891; doi:10.3390/ijms150813881
Received: 1 July 2014 / Revised: 29 July 2014 / Accepted: 31 July 2014 / Published: 11 August 2014
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Abstract
Triglycerides are absorbed by the lymphatic system and have various functions in the body. It has been shown that some types of β-glucans have a positive effect on the systemic concentrations of cholesterol and lipid, presumably through interference with the absorption of [...] Read more.
Triglycerides are absorbed by the lymphatic system and have various functions in the body. It has been shown that some types of β-glucans have a positive effect on the systemic concentrations of cholesterol and lipid, presumably through interference with the absorption of lipid and/or reabsorption of bile acids. In the current study we investigated the acute effects of ingesting 2 g of β-glucan concentrates derived from barley β-(1→3)(1→4)-d-glucan or yeast β-(1→3)(1→6)-d-glucan on fatty acid content and composition in lymph and serum of 10 female pigs (initial weight 34.7 ± 1.1 kg) fitted with a permanent catheter in the jejunal lymphatic trunk in a cross-over design. Lymph was collected continuously for 8 h followed by a spot sample taken 24 h after. A significant effect of time after feeding was observed for all fatty acids in serum and for 18:0, 18:2ω6 and 18:3ω3 in lymph, but a significant effect of β-glucan was only observed for 14:0 (p = 0.049) and 22:6ω3 (p = 0.048) in lymph and 18:0 (p = 0.019) in serum. While the concentration of dietary fatty acids increased postprandially in lymph, the concentration of arachidonic and docahexanoic acid tended to decrease. Furthermore, there was a drop in concentration of all fatty acid in serum 1 h after the meal. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Heterosis in Early Maize Ear Inflorescence Development: A Genome-Wide Transcription Analysis for Two Maize Inbred Lines and Their Hybrid
Int. J. Mol. Sci. 2014, 15(8), 13892-13915; doi:10.3390/ijms150813892
Received: 10 May 2014 / Revised: 1 July 2014 / Accepted: 2 July 2014 / Published: 11 August 2014
Cited by 6 | PDF Full-text (2306 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Heterosis, or hybrid vigor, contributes to superior agronomic performance of hybrids compared to their inbred parents. Despite its importance, little is known about the genetic and molecular basis of heterosis. Early maize ear inflorescences formation affects grain yield, and are thus an [...] Read more.
Heterosis, or hybrid vigor, contributes to superior agronomic performance of hybrids compared to their inbred parents. Despite its importance, little is known about the genetic and molecular basis of heterosis. Early maize ear inflorescences formation affects grain yield, and are thus an excellent model for molecular mechanisms involved in heterosis. To determine the parental contributions and their regulation during maize ear-development-genesis, we analyzed genome-wide digital gene expression profiles in two maize elite inbred lines (B73 and Mo17) and their F1 hybrid using deep sequencing technology. Our analysis revealed 17,128 genes expressed in these three genotypes and 22,789 genes expressed collectively in the present study. Approximately 38% of the genes were differentially expressed in early maize ear inflorescences from heterotic cross, including many transcription factor genes and some presence/absence variations (PAVs) genes, and exhibited multiple modes of gene action. These different genes showing differential expression patterns were mainly enriched in five cellular component categories (organelle, cell, cell part, organelle part and macromolecular complex), five molecular function categories (structural molecule activity, binding, transporter activity, nucleic acid binding transcription factor activity and catalytic activity), and eight biological process categories (cellular process, metabolic process, biological regulation, regulation of biological process, establishment of localization, cellular component organization or biogenesis, response to stimulus and localization). Additionally, a significant number of genes were expressed in only one inbred line or absent in both inbred lines. Comparison of the differences of modes of gene action between previous studies and the present study revealed only a small number of different genes had the same modes of gene action in both maize seedlings and ear inflorescences. This might be an indication that in different tissues or developmental stages, different global expression patterns prevail, which might nevertheless be related to heterosis. Our results support the hypotheses that multiple molecular mechanisms (dominance and overdominance modes) contribute to heterosis. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Epigenetic Determinants of CYP1A1 Induction by the Aryl Hydrocarbon Receptor Agonist 3,3',4,4',5-Pentachlorobiphenyl (PCB 126)
Int. J. Mol. Sci. 2014, 15(8), 13916-13931; doi:10.3390/ijms150813916
Received: 4 June 2014 / Revised: 6 August 2014 / Accepted: 7 August 2014 / Published: 11 August 2014
Cited by 2 | PDF Full-text (1069 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Many enzymes involved in xenobiotic metabolism, including cytochrome P450 (CYP) 1A1, are regulated by the aryl hydrocarbon receptor (AhR). 3,3',4,4',5-Penta chlorobiphenyl (PCB 126) is a potent ligand for AhR and can thus induce the expression of CYP1A1. Interestingly, we observed that [...] Read more.
Many enzymes involved in xenobiotic metabolism, including cytochrome P450 (CYP) 1A1, are regulated by the aryl hydrocarbon receptor (AhR). 3,3',4,4',5-Penta chlorobiphenyl (PCB 126) is a potent ligand for AhR and can thus induce the expression of CYP1A1. Interestingly, we observed that human carcinoma cell lines derived from different types of epithelial cells displayed divergent degrees of CYP1A1 induction after exposure to PCB 126. Since epigenetic mechanisms are known to be involved in cell type-specific gene expression, we sought to assess the epigenetic determinants of CYP1A1 induction in these carcinoma cell lines. In contrast to HepG2 hepatocarcinoma cells, HeLa cervical carcinoma cells showed significantly lower levels of CYP1A1 mRNA expression following PCB 126 exposure. Our results show that the two cell lines maintained differences in the chromatin architecture along the CYP1A1 promoter region. Furthermore, treatment with the epigenetic modifiers, trichostatin A (TSA) and 5-aza-2'-deoxycytidine (5-Aza-dC), significantly increased the expression of CYP1A1 after PCB 126 treatment in HeLa cells. However, we did not observe apparent differences in methylation levels or specific location of CpG DNA methylation between the two cell lines in the analyzed CYP1A1 promoter region. Taken together, our findings suggest that the differences in CYP1A1 expression between HepG2 and HeLa cells are due to differences in the chromatin architecture of the CYP1A1 promoter and thus establish a role of epigenetic regulation in cell-specific CYP1A1 expression. Full article
(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)
Open AccessCommunication Localization of MLH3 at the Centrosomes
Int. J. Mol. Sci. 2014, 15(8), 13932-13937; doi:10.3390/ijms150813932
Received: 10 June 2014 / Revised: 7 July 2014 / Accepted: 4 August 2014 / Published: 11 August 2014
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Abstract
Mutations in human DNA mismatch repair (MMR) genes are commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC). MLH1 protein heterodimerizes with PMS2, PMS1, and MLH3 to form MutLα, MutLβ, and MutLγ, respectively. We reported recently stable expression of GFP-linked MLH3 in human [...] Read more.
Mutations in human DNA mismatch repair (MMR) genes are commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC). MLH1 protein heterodimerizes with PMS2, PMS1, and MLH3 to form MutLα, MutLβ, and MutLγ, respectively. We reported recently stable expression of GFP-linked MLH3 in human cell lines. Monitoring these cell lines during the cell cycle using live cell imaging combined with confocal microscopy, we detected accumulation of MLH3 at the centrosomes. Fluorescence recovery after photobleaching (FRAP) revealed high mobility and fast exchange rates at the centrosomes as it has been reported for other DNA repair proteins. MLH3 may have a role in combination with other repair proteins in the control of centrosome numbers. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessArticle Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Hormones of Energy Balance in a TCDD-Sensitive and a TCDD-Resistant Rat Strain
Int. J. Mol. Sci. 2014, 15(8), 13938-13966; doi:10.3390/ijms150813938
Received: 14 May 2014 / Revised: 24 July 2014 / Accepted: 29 July 2014 / Published: 12 August 2014
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Abstract
One of the hallmarks of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a drastically reduced feed intake by an unknown mechanism. To further elucidate this wasting syndrome, we followed the effects of a single large dose (100 μg/kg) of TCDD [...] Read more.
One of the hallmarks of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a drastically reduced feed intake by an unknown mechanism. To further elucidate this wasting syndrome, we followed the effects of a single large dose (100 μg/kg) of TCDD on the serum levels of several energy balance-influencing hormones, clinical chemistry variables, and hepatic aryl hydrocarbon receptor (AHR) expression in two rat strains that differ widely in their TCDD sensitivities, for up to 10 days. TCDD affected most of the analytes in sensitive Long-Evans rats, while there were few alterations in the resistant Han/Wistar strain. However, analyses of feed-restricted unexposed Long-Evans rats indicated several of the perturbations to be secondary to energy deficiency. Notable increases in ghrelin and glucagon occurred in TCDD-treated Long-Evans rats alone, which links these hormones to the wasting syndrome. The newly found energy balance regulators, insulin-like growth factor 1 and fibroblast growth factor 21 (FGF-21), appeared to function in concert in body weight loss-induced metabolic state, and FGF-21 was putatively linked to increased lipolysis induced by TCDD. Finally, we demonstrate a reverse set of changes in the AHR protein and mRNA response to TCDD and feed restriction, suggesting that AHR might function also as a physiological regulator, possibly involved in the maintenance of energy balance. Full article
(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)
Open AccessArticle Silver Nanoparticles/Ibuprofen-Loaded Poly(l-lactide) Fibrous Membrane: Anti-Infection and Anti-Adhesion Effects
Int. J. Mol. Sci. 2014, 15(8), 14014-14025; doi:10.3390/ijms150814014
Received: 10 June 2014 / Revised: 14 July 2014 / Accepted: 24 July 2014 / Published: 12 August 2014
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Abstract
Infection caused by bacteria is one of the crucial risk factors for tendon adhesion formation. Silver nanoparticles (AgNP)-loaded physical barriers were reported to be effective in anti-infection and anti-adhesion. However, high silver load may lead to kidney and liver damages. This study [...] Read more.
Infection caused by bacteria is one of the crucial risk factors for tendon adhesion formation. Silver nanoparticles (AgNP)-loaded physical barriers were reported to be effective in anti-infection and anti-adhesion. However, high silver load may lead to kidney and liver damages. This study was designed for Ibuprofen (IBU)-loaded poly(l-lactide) (PLLA) electrospun fibrous membranes containing a low dosage of Ag to evaluate its potential in maintaining suitable anti-infection and good anti-adhesion effects. The in vitro drug release study showed a sustained release of Ag ions and IBU from the membrane. Inferior adherence and proliferation of fibroblasts were found on the Ag4%–IBU4%-loaded PLLA electrospun fibrous membranes in comparison with pure PLLA and 4% Ag-loaded PLLA membranes. In the antibacterial test, all Ag-loaded PLLA electrospun fibrous membranes prevented the adhesion of Staphylococcus aureus and Staphylococcus epidermidis. Taken together, these results demonstrate that Ibuprofen is effective in enhancing the anti-adhesion and anti-proliferation effects of 4% Ag-loaded PLLA fibrous membrane. The medical potential of infection reduction and adhesion prevention of Ag4%–IBU4%-loaded PLLA electrospun fibrous membrane deserves to be further studied. Full article
(This article belongs to the Special Issue Antimicrobial Polymers)
Open AccessArticle The Effects of Synthetic Oligopeptide Derived from Enamel Matrix Derivative on Cell Proliferation and Osteoblastic Differentiation of Human Mesenchymal Stem Cells
Int. J. Mol. Sci. 2014, 15(8), 14026-14043; doi:10.3390/ijms150814026
Received: 15 May 2014 / Revised: 6 June 2014 / Accepted: 9 July 2014 / Published: 13 August 2014
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Abstract
Enamel matrix derivative (EMD) is widely used in periodontal tissue regeneration therapy. However, because the bioactivity of EMD varies from batch to batch, and the use of a synthetic peptide could avoid use from an animal source, a completely synthetic peptide (SP) [...] Read more.
Enamel matrix derivative (EMD) is widely used in periodontal tissue regeneration therapy. However, because the bioactivity of EMD varies from batch to batch, and the use of a synthetic peptide could avoid use from an animal source, a completely synthetic peptide (SP) containing the active component of EMD would be useful. In this study an oligopeptide synthesized derived from EMD was evaluated for whether it contributes to periodontal tissue regeneration. We investigated the effects of the SP on cell proliferation and osteoblast differentiation of human mesenchymal stem cells (MSCs), which are involved in tissue regeneration. MSCs were treated with SP (0 to 1000 ng/mL), to determine the optimal concentration. We examined the effects of SP on cell proliferation and osteoblastic differentiation indicators such as alkaline phosphatase activity, the production of procollagen type 1 C-peptide and osteocalcin, and on mineralization. Additionally, we investigated the role of extracellular signal-related kinases (ERK) in cell proliferation and osteoblastic differentiation induced by SP. Our results suggest that SP promotes these processes in human MSCs, and that ERK inhibitors suppress these effects. In conclusion, SP promotes cell proliferation and osteoblastic differentiation of human MSCs, probably through the ERK pathway. Full article
(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)
Open AccessArticle Association between Phosphatase Related Gene Variants and Coronary Artery Disease: Case-Control Study and Meta-Analysis
Int. J. Mol. Sci. 2014, 15(8), 14058-14076; doi:10.3390/ijms150814058
Received: 5 June 2014 / Revised: 21 July 2014 / Accepted: 30 July 2014 / Published: 13 August 2014
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Abstract
Recent studies showed that the serum alkaline phosphatase is an independent predictor of the coronary artery disease (CAD). In this work, we aimed to summarize the association between three phosphatase related single nucleotide polymorphisms (rs12526453, rs11066301 and rs3828329) and the risk of [...] Read more.
Recent studies showed that the serum alkaline phosphatase is an independent predictor of the coronary artery disease (CAD). In this work, we aimed to summarize the association between three phosphatase related single nucleotide polymorphisms (rs12526453, rs11066301 and rs3828329) and the risk of CAD in Han Chinese. Our results showed that the rs3828329 of the ACP1 gene was closely related to the risk of CAD in Han Chinese (OR = 1.45, p = 0.0006). This significant association of rs3828329 with CAD was only found in the females (Additive model: OR = 1.80, p = 0.001; dominant model: OR = 1.69, p = 0.03; recessive model: OR = 1.96, p = 0.0008). Moreover, rs3828329 was likely to exert its effect in females aged 65 years and older (OR = 2.27, p = 0.001). Further meta-analyses showed that the rs12526453 of PHACTR11 gene (OR = 1.14, p < 0.0001, random-effect method) and the rs11066301 of PTPN11 gene (OR = 1.15, p < 0.0001, fixed-effects method) were associated with CAD risk in multiple populations. Our results showed that the polymorphisms rs12526453 and rs11066301 are significantly associated with the CAD risk in multiple populations. The rs3828329 of ACP1 gene is also a risk factor of CAD in Han Chinese females aged 65 years and older. Full article
(This article belongs to the Section Molecular Diagnostics)
Open AccessArticle Angiotensin I-Converting Enzyme (ACE) Inhibitory Activity and ACE Inhibitory Peptides of Salmon (Salmo salar) Protein Hydrolysates Obtained by Human and Porcine Gastrointestinal Enzymes
Int. J. Mol. Sci. 2014, 15(8), 14077-14101; doi:10.3390/ijms150814077
Received: 21 May 2014 / Revised: 24 June 2014 / Accepted: 16 July 2014 / Published: 13 August 2014
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Abstract
The objectives of the present study were two-fold: first, to detect whether salmon protein fractions possess angiotensin I-converting enzyme (ACE) inhibitory properties and whether salmon proteins can release ACE inhibitory peptides during a sequential in vitro hydrolysis (with commercial porcine enzymes) and [...] Read more.
The objectives of the present study were two-fold: first, to detect whether salmon protein fractions possess angiotensin I-converting enzyme (ACE) inhibitory properties and whether salmon proteins can release ACE inhibitory peptides during a sequential in vitro hydrolysis (with commercial porcine enzymes) and ex vivo digestion (with human gastrointestinal enzymes). Secondly, to evaluate the ACE inhibitory activity of generated hydrolysates. A two-step ex vivo and in vitro model digestion was performed to simulate the human digestion process. Salmon proteins were degraded more efficiently by porcine enzymes than by human gastrointestinal juices and sarcoplasmic proteins were digested/hydrolyzed more easily than myofibrillar proteins. The ex vivo digested myofibrillar and sarcoplasmic duodenal samples showed IC50 values (concentration required to decrease the ACE activity by 50%) of 1.06 and 2.16 mg/mL, respectively. The in vitro hydrolyzed myofibrillar and sarcoplasmic samples showed IC50 values of 0.91 and 1.04 mg/mL, respectively. Based on the results of in silico studies, it was possible to identify 9 peptides of the ex vivo hydrolysates and 7 peptides of the in vitro hydrolysates of salmon proteins of 11 selected peptides. In both types of salmon hydrolysates, ACE-inhibitory peptides IW, IY, TVY and VW were identified. In the in vitro salmon protein hydrolysates an ACE-inhibitory peptides VPW and VY were also detected, while ACE-inhibitory peptides ALPHA, IVY and IWHHT were identified in the hydrolysates generated with ex vivo digestion. In our studies, we documented ACE inhibitory in vitro effects of salmon protein hydrolysates obtained by human and as well as porcine gastrointestinal enzymes. Full article
(This article belongs to the Special Issue Bioactive Proteins and Peptides Derived from Food)
Open AccessArticle Melatonin Suppresses Hypoxia-Induced Migration of HUVECs via Inhibition of ERK/Rac1 Activation
Int. J. Mol. Sci. 2014, 15(8), 14102-14121; doi:10.3390/ijms150814102
Received: 5 April 2014 / Revised: 31 July 2014 / Accepted: 7 August 2014 / Published: 13 August 2014
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Abstract
Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK/Rac1 signaling is involved [...] Read more.
Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK/Rac1 signaling is involved in this process. Here, we found that melatonin inhibited hypoxia-stimulated hypoxia-inducible factor-1α (HIF-1α) expression and cell migration in a dose-dependent manner. Mechanistically, melatonin inhibited Rac1 activation and suppressed the co-localized Rac1 and F-actin on the membrane of HUVECs under hypoxic condition. In addition, the blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1-T17N suppressed HIF-1α expression and cell migration in response to hypoxia, as well, but constitutive activation of Rac1 mutant Rac1-V12 restored HIF-1α expression, preventing the inhibition of melatonin on cell migration. Furthermore, the anti-Rac1 effect of melatonin in HUVECs appeared to be associated with its inhibition of ERK phosphorylation, but not that of the PI3k/Akt signaling pathway. Taken together, our work indicates that melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK/Rac1 activation and subsequent HIF-1α upregulation. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Kinetics and Quantitative Structure—Activity Relationship Study on the Degradation Reaction from Perfluorooctanoic Acid to Trifluoroacetic Acid
Int. J. Mol. Sci. 2014, 15(8), 14153-14165; doi:10.3390/ijms150814153
Received: 1 March 2014 / Revised: 5 June 2014 / Accepted: 19 July 2014 / Published: 14 August 2014
Cited by 2 | PDF Full-text (1032 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Investigation of the degradation kinetics of perfluorooctanoic acid (PFOA) has been carried out to calculate rate constants of the main elementary reactions using the multichannel Rice-Ramsperger-Kassel-Marcus theory and canonical variational transition state theory with small-curvature tunneling correction over a temperature range of [...] Read more.
Investigation of the degradation kinetics of perfluorooctanoic acid (PFOA) has been carried out to calculate rate constants of the main elementary reactions using the multichannel Rice-Ramsperger-Kassel-Marcus theory and canonical variational transition state theory with small-curvature tunneling correction over a temperature range of 200~500 K. The Arrhenius equations of rate constants of elementary reactions are fitted. The decarboxylation is role step in the degradation mechanism of PFOA. For the perfluorinated carboxylic acids from perfluorooctanoic acid to trifluoroacetic acid, the quantitative structure–activity relationship of the decarboxylation was analyzed with the genetic function approximation method and the structure–activity model was constructed. The main parameters governing rate constants of the decarboxylation reaction from the eight-carbon chain to the two-carbon chain were obtained. As the structure–activity model shows, the bond length and energy of C1–C2 (RC1–C2 and EC1–C2) are positively correlated to rate constants, while the volume (V), the energy difference between EHOMO and ELUMOE), and the net atomic charges on atom C2 (QC2) are negatively correlated. Full article
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Open AccessArticle Modulation of Nitrosative Stress via Glutathione-Dependent Formaldehyde Dehydrogenase and S-Nitrosoglutathione Reductase
Int. J. Mol. Sci. 2014, 15(8), 14166-14179; doi:10.3390/ijms150814166
Received: 17 June 2014 / Revised: 28 July 2014 / Accepted: 8 August 2014 / Published: 14 August 2014
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Abstract
Glutathione-dependent formaldehyde dehydrogenase (GFD) from Taiwanofungus camphorata plays important roles in formaldehyde detoxification and antioxidation. The enzyme is bifunctional. In addition to the GFD activity, it also functions as an effective S-nitrosoglutathione reductase (GSNOR) against nitrosative stress. We investigated the modulation [...] Read more.
Glutathione-dependent formaldehyde dehydrogenase (GFD) from Taiwanofungus camphorata plays important roles in formaldehyde detoxification and antioxidation. The enzyme is bifunctional. In addition to the GFD activity, it also functions as an effective S-nitrosoglutathione reductase (GSNOR) against nitrosative stress. We investigated the modulation of HEK (human embryonic kidney) 293T cells under nitrosative stress by transfecting a codon optimized GFD cDNA from Taiwanofungus camphorata (Tc-GFD-O) to these cells. The parental and transfected HEK 293T cells were then subjected to S-nitrosoglutathione treatment to induce nitrosative stress. The results showed that in Tc-GFD-O-transfected 293T cells, the expression and activity of GFD increased. Additionally, these cells under the nitrosative stress induced by S-nitrosoglutathione showed both higher viability and less apoptosis than the parental 293T cells. This finding suggests that the Tc-GFD-O in HEK 293T cells may provide a protective function under nitrosative stress. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Effects of Pulsed Electromagnetic Field on Differentiation of HUES-17 Human Embryonic Stem Cell Line
Int. J. Mol. Sci. 2014, 15(8), 14180-14190; doi:10.3390/ijms150814180
Received: 11 June 2014 / Revised: 14 July 2014 / Accepted: 25 July 2014 / Published: 14 August 2014
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Abstract
Electromagnetic fields are considered to potentially affect embryonic development, but the mechanism is still unknown. In this study, human embryonic stem cell (hESC) line HUES-17 was applied to explore the mechanism of exposure on embryonic development to pulsed electromagnetic field (PEMF) for [...] Read more.
Electromagnetic fields are considered to potentially affect embryonic development, but the mechanism is still unknown. In this study, human embryonic stem cell (hESC) line HUES-17 was applied to explore the mechanism of exposure on embryonic development to pulsed electromagnetic field (PEMF) for 400 pulses at different electric field intensities and the differentiation of HUES-17 cells was observed after PEMF exposure. The expression of alkaline phosphatase (AP), stage-specific embryonic antigen-3 (SSEA-3), SSEA-4 and the mRNA level and protein level of Oct4, Sox2 and Nanog in HUES-17 cells remained unchanged after PEMF exposure at the electric field intensities of 50, 100, 200 or 400 kV/m. Four hundred pulses PEMF exposure at the electric field intensities of 50, 100, 200 or 400 kV/m did not affect the differentiation of HUES-17 cells. The reason why electromagnetic fields affect embryonic development may be due to other mechanisms rather than affecting the differentiation of embryonic stem cells. Full article
(This article belongs to the Section Molecular Diagnostics)
Open AccessArticle Complete Proteome of a Quinolone-Resistant Salmonella Typhimurium Phage Type DT104B Clinical Strain
Int. J. Mol. Sci. 2014, 15(8), 14191-14219; doi:10.3390/ijms150814191
Received: 8 June 2014 / Revised: 27 June 2014 / Accepted: 25 July 2014 / Published: 15 August 2014
Cited by 3 | PDF Full-text (1752 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Salmonellosis is one of the most common and widely distributed foodborne diseases. The emergence of Salmonella strains that are resistant to a variety of antimicrobials is a serious global public health concern. Salmonella enterica serovar Typhimurium definitive phage type 104 (DT104) is [...] Read more.
Salmonellosis is one of the most common and widely distributed foodborne diseases. The emergence of Salmonella strains that are resistant to a variety of antimicrobials is a serious global public health concern. Salmonella enterica serovar Typhimurium definitive phage type 104 (DT104) is one of these emerging epidemic multidrug resistant strains. Here we collate information from the diverse and comprehensive range of experiments on Salmonella proteomes that have been published. We then present a new study of the proteome of the quinolone-resistant Se20 strain (phage type DT104B), recovered after ciprofloxacin treatment and compared it to the proteome of reference strain SL1344. A total of 186 and 219 protein spots were recovered from Se20 and SL1344 protein extracts, respectively, after two-dimensional gel electrophoresis. The signatures of 94% of the protein spots were successfully identified through matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS). Three antimicrobial resistance related proteins, whose genes were previously detected by polymerase chain reaction (PCR), were identified in the clinical strain. The presence of these proteins, dihydropteroate synthase type-2 (sul2 gene), aminoglycoside resistance protein A (strA gene) and aminoglycoside 6'-N-acetyltransferase type Ib-cr4 (aac(6')-Ib-cr4 gene), was confirmed in the DT104B clinical strain. The aac(6')-Ib-cr4 gene is responsible for plasmid-mediated aminoglycoside and quinolone resistance. This is a preliminary analysis of the proteome of these two S. Typhimurium strains and further work is being developed to better understand how antimicrobial resistance is developing in this pathogen. Full article
(This article belongs to the collection Advances in Proteomic Research)
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Open AccessArticle Functional Cross-Talk between the α1- and β1-Adrenergic Receptors Modulates the Rapidly Activating Delayed Rectifier Potassium Current in Guinea Pig Ventricular Myocytes
Int. J. Mol. Sci. 2014, 15(8), 14220-14233; doi:10.3390/ijms150814220
Received: 19 May 2014 / Revised: 1 August 2014 / Accepted: 5 August 2014 / Published: 15 August 2014
PDF Full-text (3294 KB) | HTML Full-text | XML Full-text | Correction
Abstract
The rapidly activating delayed rectifier potassium current (IKr) plays a critical role in cardiac repolarization. Although IKr is known to be regulated by both α1- and β1-adrenergic receptors (ARs), the cross-talk and feedback mechanisms [...] Read more.
The rapidly activating delayed rectifier potassium current (IKr) plays a critical role in cardiac repolarization. Although IKr is known to be regulated by both α1- and β1-adrenergic receptors (ARs), the cross-talk and feedback mechanisms that dictate its response to α1- and β1-AR activation are not known. In the present study, IKr was recorded using the whole-cell patch-clamp technique. IKr amplitude was measured before and after the sequential application of selective adrenergic agonists targeting α1- and β1-ARs. Stimulation of either receptor alone (α1-ARs using 1 μM phenylephrine (PE) or β1-ARs using 10 μM xamoterol (Xamo)) reduced IKr by 0.22 ± 0.03 and 0.28 ± 0.01, respectively. The voltage-dependent activation curve of IKr shifted in the negative direction. The half-maximal activation voltage (V0.5) was altered by −6.35 ± 1.53 and −1.95 ± 2.22 mV, respectively, with no major change in the slope factor (k). When myocytes were pretreated with Xamo, PE-induced reduction in IKr was markedly blunted and the corresponding change in V0.5 was significantly altered. Similarly, when cells were pretreated with PE, Xamo-induced reduction of IKr was significantly attenuated. The present results demonstrate that functional cross-talk between α1- and β1-AR signaling regulates IKr. Such non-linear regulation may form a protective mechanism under excessive adrenergic stimulation. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Identification of Diversity-Generating Retroelements in Human Microbiomes
Int. J. Mol. Sci. 2014, 15(8), 14234-14246; doi:10.3390/ijms150814234
Received: 21 June 2014 / Revised: 2 August 2014 / Accepted: 6 August 2014 / Published: 15 August 2014
Cited by 3 | PDF Full-text (2950 KB) | HTML Full-text | XML Full-text
Abstract
Diversity-generating retroelements (DGRs) are a unique family of retroelements that confer selective advantages to their hosts by accelerating the evolution of target genes through a specialized, error-prone, reverse transcription process. First identified in a Bordetella phage (BPP-1), which mediates the phage tropism [...] Read more.
Diversity-generating retroelements (DGRs) are a unique family of retroelements that confer selective advantages to their hosts by accelerating the evolution of target genes through a specialized, error-prone, reverse transcription process. First identified in a Bordetella phage (BPP-1), which mediates the phage tropism specificity by generating variability in an involved gene, DGRs were predicted to be present in a larger collection of viral and bacterial species. A minimal DGR system is comprised of a reverse transcriptase (RTase) gene, a template sequence (TR) and a variable region (VR) within a target gene. We developed a computational tool, DGRscan, to allow either de novo identification (based on the prediction of potential template-variable region pairs) or similarity-based searches of DGR systems using known template sequences as the reference. The application of DGRscan to the human microbiome project (HMP) datasets resulted in the identification of 271 non-redundant DGR systems, doubling the size of the collection of known DGR systems. We further identified a large number of putative target genes (651, which share no more than 90% sequence identity at the amino acid level) that are potentially under diversification by the DGR systems. Our study provides the first survey of the DGR systems in the human microbiome, showing that the DGR systems are frequently found in human-associated bacterial communities, although they are of low incidence in individual genomes. Our study also provides functional clues for a large number of genes (reverse transcriptases and target genes) that were previously annotated as proteins of unknown functions or nonspecific functions. Full article
(This article belongs to the Special Issue Metagenomics: a Powerful Lens Viewing the Microbial World)
Figures

Open AccessArticle The Influence of Fatty Acids on the GpA Dimer Interface by Coarse-Grained Molecular Dynamics Simulation
Int. J. Mol. Sci. 2014, 15(8), 14247-14268; doi:10.3390/ijms150814247
Received: 22 May 2014 / Revised: 14 July 2014 / Accepted: 6 August 2014 / Published: 15 August 2014
PDF Full-text (2508 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The hydrophobic thickness of membranes, which is manly defined by fatty acids, influences the packing of transmembrane domains of proteins and thus can modulate the activity of these proteins. We analyzed the dynamics of the dimerization of Glycophorin A (GpA) by molecular [...] Read more.
The hydrophobic thickness of membranes, which is manly defined by fatty acids, influences the packing of transmembrane domains of proteins and thus can modulate the activity of these proteins. We analyzed the dynamics of the dimerization of Glycophorin A (GpA) by molecular dynamics simulations to describe the fatty acid dependence of the transmembrane region assembly. GpA represents a well-established model for dimerization of single transmembrane helices containing a GxxxG motif in vitro and in silico. We performed simulations of the dynamics of the NMR-derived dimer as well as self-assembly simulations of monomers in membranes composed of different fatty acid chains and monitored the formed interfaces and their transitions. The observed dimeric interfaces, which also include the one known from NMR, are highly dynamic and converted into each other. The frequency of interface formation and the preferred transitions between interfaces similar to the interface observed by NMR analysis strongly depend on the fatty acid used to build the membrane. Molecular dynamic simulations after adaptation of the helix topology parameters to better represent NMR derived structures of single transmembrane helices yielded an enhanced occurrence of the interface determined by NMR in molecular dynamics simulations. Taken together we give insights into the influence of fatty acids and helix conformation on the dynamics of the transmembrane domain of GpA. Full article
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
Open AccessArticle Artesunate Induces Apoptosis of Bladder Cancer Cells by miR-16 Regulation of COX-2 Expression
Int. J. Mol. Sci. 2014, 15(8), 14298-14312; doi:10.3390/ijms150814298
Received: 31 May 2014 / Revised: 14 July 2014 / Accepted: 23 July 2014 / Published: 15 August 2014
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Abstract
Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide. In this study, we investigated the effect and mechanism of Artesunate (ART), a traditional Chinese medicine, on inducing apoptosis [...] Read more.
Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide. In this study, we investigated the effect and mechanism of Artesunate (ART), a traditional Chinese medicine, on inducing apoptosis of human bladder cancer cells. In vivo antitumor activity was investigated in bladder cancer in rat by subcutaneous injection of different concentration of ART. The effect of ART on growth inhibition and apoptosis of bladder cancer cells was evaluated using dimethylthiazoly-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. Cyclooxygenase-2 (COX-2) and miR-16 expression levels were determined with real-time PCR. The concentrations of prostaglandin E2 (PGE2) in the supernatants of bladder cancer cells were measured with an ELISA kit. The miR-16 inhibitor or mimic were transfected into cells to up- or down-regulate miR-16 expression. ART efficiently inhibited orthotopic tumor growth in the bladder cancer rat, which is accompanied with an increase of miR-16 expression and a decrease of COX-2 expression. In vitro, ART could induce cytotoxicity and apoptosis in bladder cancer cells, but presented a much lighter toxicity effect against normal human urothelial cells. ART significantly increased miR-16 expression and decreased the expression of COX-2 and the production of PGE2. More importantly, down-regulation of miR-16 expression could reverse the effect of ART on apoptosis and COX-2 expression in bladder cells. Moreover, exogenous PGE2 could inhibit apoptosis of bladder cancer cells treated with ART. In conclusion, ART can elicit an anti-tumor effect against bladder cancer by up-regulation of miR-16 expression, which resulted in the decrease of COX-2 expression and PGE2 production. Hence, ART might be an effective drug for the treatment of bladder cancer. Full article
(This article belongs to the collection Programmed Cell Death and Apoptosis)
Open AccessArticle Data Mining of Atherosclerotic Plaque Transcriptomes Predicts STAT1-Dependent Inflammatory Signal Integration in Vascular Disease
Int. J. Mol. Sci. 2014, 15(8), 14313-14331; doi:10.3390/ijms150814313
Received: 12 June 2014 / Revised: 29 July 2014 / Accepted: 1 August 2014 / Published: 18 August 2014
Cited by 4 | PDF Full-text (3887 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Atherosclerotic plaque development involves multiple extra- and intra-cellular signals engaging cells from the immune system and from the vasculature. Pro-inflammatory pathways activated by interferon gamma (IFNγ) and toll-like receptor 4 (TLR4) ligands are profoundly involved in plaque formation and have been shown [...] Read more.
Atherosclerotic plaque development involves multiple extra- and intra-cellular signals engaging cells from the immune system and from the vasculature. Pro-inflammatory pathways activated by interferon gamma (IFNγ) and toll-like receptor 4 (TLR4) ligands are profoundly involved in plaque formation and have been shown to involve cross-talk in all atheroma-interacting cell types leading to increased activation of signal transducer and activator of transcription-1 (STAT1) and elevated expression of pro-inflammatory mediators. Here we demonstrate that in Gene Expression Omnibus repository (GEO) deposited microarray datasets, obtained from human coronary and carotid atherosclerotic plaques, a significant increase in expression of pro-inflammatory and immunomodulatory genes can be detected. Moreover, increased expression of multiple chemokines, adhesion molecules and matrix-remodeling molecules was commonly detected in both plaque types and correlated with the presence of putative STAT1 binding sites in their promoters, suggesting strong involvement of STAT1 in plaque development. We also provide evidence to suggest that STAT1-nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) or STAT1-interferon-regulated factor (IRF) regulatory modules are over-represented in the promoters of these inflammatory genes, which points to a possible contribution of IFNγ and TLR4 cross-talk in the process of atherogenesis. Finally, a subset of these genes encodes for secreted proteins that could serve as a basis of a non-invasive diagnostic assay. The results of our in silico analysis in vitro provide potential evidence that STAT1-dependent IFNγ-TLR4 cross-talk plays a crucial role in coronary and carotid artery plaque development and identifies a STAT1-dependent gene signature that could represent a novel diagnostic tool to monitor and diagnose plaque progression in human atherosclerosis. Full article
(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)
Open AccessArticle In Vitro Selection of a Single-Stranded DNA Molecular Recognition Element against Atrazine
Int. J. Mol. Sci. 2014, 15(8), 14332-14347; doi:10.3390/ijms150814332
Received: 5 June 2014 / Revised: 11 July 2014 / Accepted: 8 August 2014 / Published: 18 August 2014
Cited by 9 | PDF Full-text (1068 KB) | HTML Full-text | XML Full-text
Abstract
Widespread use of the chlorotriazine herbicide, atrazine, has led to serious environmental and human health consequences. Current methods of detecting atrazine contamination are neither rapid nor cost-effective. In this work, atrazine-specific single-stranded DNA (ssDNA) molecular recognition elements (MRE) were isolated. We utilized [...] Read more.
Widespread use of the chlorotriazine herbicide, atrazine, has led to serious environmental and human health consequences. Current methods of detecting atrazine contamination are neither rapid nor cost-effective. In this work, atrazine-specific single-stranded DNA (ssDNA) molecular recognition elements (MRE) were isolated. We utilized a stringent Systematic Evolution of Ligands by Exponential Enrichment (SELEX) methodology that placed the greatest emphasis on what the MRE should not bind to. After twelve rounds of SELEX, an atrazine-specific MRE with high affinity was obtained. The equilibrium dissociation constant (Kd) of the ssDNA sequence is 0.62 ± 0.21 nM. It also has significant selectivity for atrazine over atrazine metabolites and other pesticides found in environmentally similar locations and concentrations. Furthermore, we have detected environmentally relevant atrazine concentrations in river water using this MRE. The strong affinity and selectivity of the selected atrazine-specific ssDNA validated the stringent SELEX methodology and identified a MRE that will be useful for rapid atrazine detection in environmental samples. Full article
(This article belongs to the Section Molecular Recognition)
Open AccessArticle Cross-Species, Amplifiable Microsatellite Markers for Neoverrucid Barnacles from Deep-Sea Hydrothermal Vents Developed Using Next-Generation Sequencing
Int. J. Mol. Sci. 2014, 15(8), 14364-14371; doi:10.3390/ijms150814364
Received: 19 June 2014 / Revised: 16 July 2014 / Accepted: 12 August 2014 / Published: 18 August 2014
Cited by 1 | PDF Full-text (2196 KB) | HTML Full-text | XML Full-text
Abstract
Barnacles of the genus Neoverruca are abundant near deep-sea hydrothermal vents of the northwestern Pacific Ocean, and are useful for understanding processes of population formation and maintenance of deep-sea vent faunas. Using next-generation sequencing, we isolated 12 polymorphic microsatellite loci from Neoverruca [...] Read more.
Barnacles of the genus Neoverruca are abundant near deep-sea hydrothermal vents of the northwestern Pacific Ocean, and are useful for understanding processes of population formation and maintenance of deep-sea vent faunas. Using next-generation sequencing, we isolated 12 polymorphic microsatellite loci from Neoverruca sp., collected in the Okinawa Trough. These microsatellite loci revealed 2–19 alleles per locus. The expected and observed heterozygosities ranged from 0.286 to 1.000 and 0.349 to 0.935, respectively. Cross-species amplification showed that 9 of the 12 loci were successfully amplified for Neoverruca brachylepadoformis in the Mariana Trough. A pairwise FST value calculated using nine loci showed significant genetic differentiation between the two species. Consequently, the microsatellite markers we developed will be useful for further population genetic studies to elucidate genetic diversity, differentiation, classification, and evolutionary processes in the genus Neoverruca. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Beclin 1 Expression is Closely Linked to Colorectal Carcinogenesis and Distant Metastasis of Colorectal Carcinoma
Int. J. Mol. Sci. 2014, 15(8), 14372-14385; doi:10.3390/ijms150814372
Received: 14 June 2014 / Revised: 29 July 2014 / Accepted: 11 August 2014 / Published: 18 August 2014
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Abstract
Beclin 1 participates in development, autophagy, differentiation, anti- apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal [...] Read more.
Beclin 1 participates in development, autophagy, differentiation, anti- apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal carcinoma and matched mucosa by Reverse transcriptase-polymerase chain reaction and Western blot. Immunohistochemistry and in situ hybridization (ISH) were performed on tissue microarryer with colorectal carcinoma, adenoma and mucosa. The expression of Beclin 1 mRNA and protein was found to be higher in colorectal carcinoma than matched mucosa by real-time PCR and Western blot (p < 0.05). According to the ISH data, Beclin 1 expression was lower in colorectal non-neoplastic mucosa (NNM) than adenoma and carcinoma (p < 0.05). Immunohistochemically, primary carcinoma showed stronger Beclin 1 expression than NNM and metastatic carcinoma in the liver (p < 0.05). Beclin 1 protein expression was negatively related to liver and distant metastasis (p < 0.05), but not correlated with age, sex, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumor-node-metastasis (TNM) staging, differentiation or serum carcinoembryonic antigen (CEA) concentration (p > 0.05). Survival analysis indicated that Beclin 1 expression was not linked to favorable prognosis of the patients with colorectal carcinoma (p > 0.05). Cox’s model indicated that depth of invasion and distant metastasis were independent prognostic factors for colorectal carcinomas (p < 0.05). It was suggested that Beclin 1 expression is closely linked to colorectal carcinogenesis and distant metastasis of colorectal carcinoma. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Quantitative Proteomic Analysis of Serum Proteins from Oral Cancer Patients: Comparison of Two Analytical Methods
Int. J. Mol. Sci. 2014, 15(8), 14386-14395; doi:10.3390/ijms150814386
Received: 10 March 2014 / Revised: 16 July 2014 / Accepted: 17 July 2014 / Published: 18 August 2014
Cited by 1 | PDF Full-text (3059 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Serum proteomic analysis can be a valuable approach for the discovery of protein biomarkers for early detection or monitoring of a disease. In this study, two analytical methods were compared for quantification of serum proteins in patients with oral cancer. In the [...] Read more.
Serum proteomic analysis can be a valuable approach for the discovery of protein biomarkers for early detection or monitoring of a disease. In this study, two analytical methods were compared for quantification of serum proteins in patients with oral cancer. In the first approach, we quantified serum proteins between oral squamous cell carcinoma (OSCC) and healthy control subjects by performing in-solution digestion of serum proteins, isobaric tags for relative and absolute quantification (iTRAQ) labeling of the resulting peptides, strong cation exchange (SCX) fractionation of labeled peptides and finally capillary liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of the peptides. In the second approach, we first separated serum proteins with SDS-PAGE. The gel-separated proteins were then digested with trypsin and the resulting peptides were labeled with iTRAQ and analyzed with LC-MS/MS for protein quantification. A total of 319 serum proteins were quantified with the first proteomic approach whereas a total of 281 proteins were quantified by the second proteomic approach. Most of the proteins were identified and quantified by both approaches, suggesting that these methods are similarly effective for serum proteome analysis. This study provides compelling evidence that quantitative serum proteomic analysis of OSCC is a valuable approach for identifying differentially expressed proteins in cancer patients’ circulation systems that may be used as potential biomarkers for disease detection. Further validation in large oral cancer patient populations may lead to a simple and low invasive clinical tool for OSCC diagnosis or monitoring. Full article
(This article belongs to the collection Advances in Proteomic Research)
Open AccessArticle Neuroprotective Effects of Sulforaphane on Cholinergic Neurons in Mice with Alzheimer’s Disease-Like Lesions
Int. J. Mol. Sci. 2014, 15(8), 14396-14410; doi:10.3390/ijms150814396
Received: 4 July 2014 / Revised: 5 August 2014 / Accepted: 11 August 2014 / Published: 18 August 2014
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Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration [...] Read more.
Alzheimer’s disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and d-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle MiRNA-548ah, a Potential Molecule Associated with Transition from Immune Tolerance to Immune Activation of Chronic Hepatitis B
Int. J. Mol. Sci. 2014, 15(8), 14411-14426; doi:10.3390/ijms150814411
Received: 17 June 2014 / Revised: 24 July 2014 / Accepted: 31 July 2014 / Published: 19 August 2014
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Abstract
Objective: The present study aims to identify the differently expressed microRNA (miRNA) molecules and target genes of miRNA in the immune tolerance (IT) and immune activation (IA) stages of chronic hepatitis B (CHB). Methods: miRNA expression profiles of peripheral blood mononuclear cells [...] Read more.
Objective: The present study aims to identify the differently expressed microRNA (miRNA) molecules and target genes of miRNA in the immune tolerance (IT) and immune activation (IA) stages of chronic hepatitis B (CHB). Methods: miRNA expression profiles of peripheral blood mononuclear cells (PBMCs) at the IT and IA stages of CHB were screened using miRNA microarrays and authenticated using a quantitative real-time polymerase chain reaction (RT-PCR). Gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) were used to analyze the significant functions and pathways of possible target genes of miRNAs. Assays of the gain and loss of function of the miRNAs were performed to verify the target genes in THP-1 cell lines. The luciferase reporter test was used on 293T cells as direct targets. Results: Significantly upregulated miR-548 and miR-4804 were observed in the miRNA microarrays and confirmed by RT-PCR in PBMCs at the IT and IA stages of CHB. GO and KEGG analysis revealed that MiR-548 and miR-4804 could be involved in numerous signaling pathways and protein binding activity. IFNγR1 was predicted as a target gene and validated as the direct gene of MiR-548. Significant negative correlation was found between the miR-548ah and mRNA levels of IFN-γR1 in CHB patients. Conclusions: The abnormal expression profiles of miRNA in PBMCs could be closely associated with immune activation of chronic HBV infection. miR-548, by targeting IFN-γR1, may represent a mechanism that can facilitate viral pathogenesis and help determine new therapeutic molecular targets. Full article
(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)
Open AccessArticle Low-Frequency High-Magnitude Mechanical Strain of Articular Chondrocytes Activates p38 MAPK and Induces Phenotypic Changes Associated with Osteoarthritis and Pain
Int. J. Mol. Sci. 2014, 15(8), 14427-14441; doi:10.3390/ijms150814427
Received: 14 April 2014 / Revised: 12 August 2014 / Accepted: 14 August 2014 / Published: 19 August 2014
Cited by 7 | PDF Full-text (3922 KB) | HTML Full-text | XML Full-text
Abstract
Osteoarthritis (OA) is a debilitating joint disorder resulting from an incompletely understood combination of mechanical, biological, and biochemical processes. OA is often accompanied by inflammation and pain, whereby cytokines associated with chronic OA can up-regulate expression of neurotrophic factors such as nerve [...] Read more.
Osteoarthritis (OA) is a debilitating joint disorder resulting from an incompletely understood combination of mechanical, biological, and biochemical processes. OA is often accompanied by inflammation and pain, whereby cytokines associated with chronic OA can up-regulate expression of neurotrophic factors such as nerve growth factor (NGF). Several studies suggest a role for cytokines and NGF in OA pain, however the effects of changing mechanical properties in OA tissue on chondrocyte metabolism remain unclear. Here, we used high-extension silicone rubber membranes to examine if high mechanical strain (HMS) of primary articular chondrocytes increases inflammatory gene expression and promotes neurotrophic factor release. HMS cultured chondrocytes displayed up-regulated NGF, TNFα and ADAMTS4 gene expression while decreasing TLR2 expression, as compared to static controls. HMS culture increased p38 MAPK activity compared to static controls. Conditioned medium from HMS dynamic cultures, but not static cultures, induced significant neurite sprouting in PC12 cells. The increased neurite sprouting was accompanied by consistent increases in PC12 cell death. Low-frequency high-magnitude mechanical strain of primary articular chondrocytes in vitro drives factor secretion associated with degenerative joint disease and joint pain. This study provides evidence for a direct link between cellular strain, secretory factors, neo-innervation, and pain in OA pathology. Full article
(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)
Open AccessArticle Phylogenetic and Transcription Analysis of Chrysanthemum WRKY Transcription Factors
Int. J. Mol. Sci. 2014, 15(8), 14442-14455; doi:10.3390/ijms150814442
Received: 7 July 2014 / Revised: 30 July 2014 / Accepted: 12 August 2014 / Published: 19 August 2014
Cited by 15 | PDF Full-text (1701 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
WRKY transcription factors are known to function in a number of plant processes. Here we have characterized 15 WRKY family genes of the important ornamental species chrysanthemum (Chrysanthemum morifolium). A total of 15 distinct sequences were isolated; initially internal fragments [...] Read more.
WRKY transcription factors are known to function in a number of plant processes. Here we have characterized 15 WRKY family genes of the important ornamental species chrysanthemum (Chrysanthemum morifolium). A total of 15 distinct sequences were isolated; initially internal fragments were amplified based on transcriptomic sequence, and then the full length cDNAs were obtained using RACE (rapid amplification of cDNA ends) PCR. The transcription of these 15 genes in response to a variety of phytohormone treatments and both biotic and abiotic stresses was characterized. Some of the genes behaved as would be predicted based on their homology with Arabidopsis thaliana WRKY genes, but others showed divergent behavior. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Immunoproteome of Aspergillus fumigatus Using Sera of Patients with Invasive Aspergillosis
Int. J. Mol. Sci. 2014, 15(8), 14505-14530; doi:10.3390/ijms150814505
Received: 13 May 2014 / Revised: 24 July 2014 / Accepted: 8 August 2014 / Published: 20 August 2014
Cited by 4 | PDF Full-text (1474 KB) | HTML Full-text | XML Full-text
Abstract
Invasive aspergillosis is a life-threatening lung or systemic infection caused by the opportunistic mold Aspergillus fumigatus. The disease affects mainly immunocompromised hosts, and patients with hematological malignances or who have been submitted to stem cell transplantation are at high risk. Despite the [...] Read more.
Invasive aspergillosis is a life-threatening lung or systemic infection caused by the opportunistic mold Aspergillus fumigatus. The disease affects mainly immunocompromised hosts, and patients with hematological malignances or who have been submitted to stem cell transplantation are at high risk. Despite the current use of Platelia Aspergillus as a diagnostic test, the early diagnosis of invasive aspergillosis remains a major challenge in improving the prognosis of the disease. In this study, we used an immunoproteomic approach to identify proteins that could be putative candidates for the early diagnosis of invasive aspergillosis. Antigenic proteins expressed in the first steps of A. fumigatus germination occurring in a human host were revealed using 2-D Western immunoblots with the serum of patients who had previously been classified as probable and proven for invasive aspergillosis. Forty antigenic proteins were identified using mass spectrometry (MS/MS). A BLAST analysis revealed that two of these proteins showed low homology with proteins of either the human host or etiological agents of other invasive fungal infections. To our knowledge, this is the first report describing specific antigenic proteins of A. fumigatus germlings that are recognized by sera of patients with confirmed invasive aspergillosis who were from two separate hospital units. Full article
(This article belongs to the collection Advances in Proteomic Research)
Open AccessArticle New Milk Protein-Derived Peptides with Potential Antimicrobial Activity: An Approach Based on Bioinformatic Studies
Int. J. Mol. Sci. 2014, 15(8), 14531-14545; doi:10.3390/ijms150814531
Received: 6 June 2014 / Revised: 14 July 2014 / Accepted: 16 July 2014 / Published: 20 August 2014
Cited by 5 | PDF Full-text (715 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
New peptides with potential antimicrobial activity, encrypted in milk protein sequences, were searched for with the use of bioinformatic tools. The major milk proteins were hydrolyzed in silico by 28 enzymes. The obtained peptides were characterized by the following parameters: molecular weight, [...] Read more.
New peptides with potential antimicrobial activity, encrypted in milk protein sequences, were searched for with the use of bioinformatic tools. The major milk proteins were hydrolyzed in silico by 28 enzymes. The obtained peptides were characterized by the following parameters: molecular weight, isoelectric point, composition and number of amino acid residues, net charge at pH 7.0, aliphatic index, instability index, Boman index, and GRAVY index, and compared with those calculated for known 416 antimicrobial peptides including 59 antimicrobial peptides (AMPs) from milk proteins listed in the BIOPEP database. A simple analysis of physico-chemical properties and the values of biological activity indicators were insufficient to select potentially antimicrobial peptides released in silico from milk proteins by proteolytic enzymes. The final selection was made based on the results of multidimensional statistical analysis such as support vector machines (SVM), random forest (RF), artificial neural networks (ANN) and discriminant analysis (DA) available in the Collection of Anti-Microbial Peptides (CAMP database). Eleven new peptides with potential antimicrobial activity were selected from all peptides released during in silico proteolysis of milk proteins. Full article
(This article belongs to the Special Issue Bioactive Proteins and Peptides Derived from Food)
Open AccessArticle Matrilin-3 Chondrodysplasia Mutations Cause Attenuated Chondrogenesis, Premature Hypertrophy and Aberrant Response to TGF-β in Chondroprogenitor Cells
Int. J. Mol. Sci. 2014, 15(8), 14555-14573; doi:10.3390/ijms150814555
Received: 18 June 2014 / Revised: 24 July 2014 / Accepted: 8 August 2014 / Published: 21 August 2014
Cited by 5 | PDF Full-text (2213 KB) | HTML Full-text | XML Full-text
Abstract
Studies have shown that mutations in the matrilin-3 gene (MATN3) are associated with multiple epiphyseal dysplasia (MED) and spondyloepimetaphyseal dysplasia (SEMD). We tested whether MATN3 mutations affect the differentiation of chondroprogenitor and/or mesenchymal stem cells, which are precursors to chondrocytes. [...] Read more.
Studies have shown that mutations in the matrilin-3 gene (MATN3) are associated with multiple epiphyseal dysplasia (MED) and spondyloepimetaphyseal dysplasia (SEMD). We tested whether MATN3 mutations affect the differentiation of chondroprogenitor and/or mesenchymal stem cells, which are precursors to chondrocytes. ATDC5 chondroprogenitors stably expressing wild-type (WT) MATN3 underwent spontaneous chondrogenesis. Expression of chondrogenic markers collagen II and aggrecan was inhibited in chondroprogenitors carrying the MED or SEMD MATN3 mutations. Hypertrophic marker collagen X remained attenuated in WT MATN3 chondroprogenitors, whereas its expression was elevated in chondroprogenitors expressing the MED or SEMD mutant MATN3 gene suggesting that these mutations inhibit chondrogenesis but promote hypertrophy. TGF-β treatment failed to rescue chondrogenesis markers but dramatically increased collagen X mRNA expression in mutant MATN3 expressing chondroprogenitors. Synovium derived mesenchymal stem cells harboring the SEMD mutation exhibited lower glycosaminoglycan content than those of WT MATN3 in response to TGF-β. Our results suggest that the properties of progenitor cells harboring MATN3 chondrodysplasia mutations were altered, as evidenced by attenuated chondrogenesis and premature hypertrophy. TGF-β treatment failed to completely rescue chondrogenesis but instead induced hypertrophy in mutant MATN3 chondroprogenitors. Our data suggest that chondroprogenitor cells should be considered as a potential target of chondrodysplasia therapy. Full article
(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)
Open AccessArticle Liquid Phase Sintered Ceramic Bone Scaffolds by Combined Laser and Furnace
Int. J. Mol. Sci. 2014, 15(8), 14574-14590; doi:10.3390/ijms150814574
Received: 26 June 2014 / Revised: 29 July 2014 / Accepted: 14 August 2014 / Published: 21 August 2014
Cited by 7 | PDF Full-text (19359 KB) | HTML Full-text | XML Full-text
Abstract
Fabrication of mechanically competent bioactive scaffolds is a great challenge in bone tissue engineering. In this paper, β-tricalcium phosphate (β-TCP) scaffolds were successfully fabricated by selective laser sintering combined with furnace sintering. Bioglass 45S5 was introduced in the process as liquid phase [...] Read more.
Fabrication of mechanically competent bioactive scaffolds is a great challenge in bone tissue engineering. In this paper, β-tricalcium phosphate (β-TCP) scaffolds were successfully fabricated by selective laser sintering combined with furnace sintering. Bioglass 45S5 was introduced in the process as liquid phase in order to improve the mechanical and biological properties. The results showed that sintering of β-TCP with the bioglass revealed some features of liquid phase sintering. The optimum amount of 45S5 was 5 wt %. At this point, the scaffolds were densified without defects. The fracture toughness, compressive strength and stiffness were 1.67 MPam1/2, 21.32 MPa and 264.32 MPa, respectively. Bone like apatite layer was formed and the stimulation for apatite formation was increased with increase in 45S5 content after soaking in simulated body fluid, which indicated that 45S5 could improve the bioactivity. Furthermore, MG-63 cells adhered and spread well, and proliferated with increase in the culture time. Full article
(This article belongs to the Special Issue Artificial Organs)
Open AccessArticle Sirt3 Protects Cortical Neurons against Oxidative Stress via Regulating Mitochondrial Ca2+ and Mitochondrial Biogenesis
Int. J. Mol. Sci. 2014, 15(8), 14591-14609; doi:10.3390/ijms150814591
Received: 27 April 2014 / Revised: 13 July 2014 / Accepted: 22 July 2014 / Published: 21 August 2014
Cited by 19 | PDF Full-text (2300 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative stress is a well-established event in the pathology of several neurobiological diseases. Sirt3 is a nicotinamide adenine nucleotide (NAD+)-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. This study aims to investigate [...] Read more.
Oxidative stress is a well-established event in the pathology of several neurobiological diseases. Sirt3 is a nicotinamide adenine nucleotide (NAD+)-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. This study aims to investigate the role of Sirt3 in H2O2 induced oxidative neuronal injury in primary cultured rat cortical neurons. We found that H2O2 treatment significantly increased the expression of Sirt3 in a time-dependent manner at both mRNA and protein levels. Knockdown of Sirt3 with a specific small interfering RNA (siRNA) exacerbated H2O2-induced neuronal injury, whereas overexpression of Sirt3 by lentivirus transfection inhibited H2O2-induced neuronal damage reduced the generation of reactive oxygen species (ROS), and increased the activities of endogenous antioxidant enzymes. In addition, the intra-mitochondrial Ca2+ overload, but not cytosolic Ca2+ increase after H2O2 treatment, was strongly attenuated after Sirt3 overexpression. Overexpression of Sirt3 also increased the content of mitochondrial DNA (mtDNA) and the expression of mitochondrial biogenesis related transcription factors. All these results suggest that Sirt3 acts as a prosurvival factor playing an essential role to protect cortical neurons under H2O2 induced oxidative stress, possibly through regulating mitochondrial Ca2+ homeostasis and mitochondrial biogenesis. Full article
(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)
Open AccessArticle Mechanistic Studies of Anti-Hyperpigmentary Compounds: Elucidating Their Inhibitory and Regulatory Actions
Int. J. Mol. Sci. 2014, 15(8), 14649-14668; doi:10.3390/ijms150814649
Received: 29 June 2014 / Revised: 28 July 2014 / Accepted: 13 August 2014 / Published: 21 August 2014
Cited by 2 | PDF Full-text (1414 KB) | HTML Full-text | XML Full-text
Abstract
Searching for depigmenting agents from natural sources has become a new direction in the cosmetic industry as natural products are generally perceived as relatively safer. In our previous study, selected Chinese medicines traditionally used to treat hyperpigmentation were tested for anti-hyperpigmentary effects [...] Read more.
Searching for depigmenting agents from natural sources has become a new direction in the cosmetic industry as natural products are generally perceived as relatively safer. In our previous study, selected Chinese medicines traditionally used to treat hyperpigmentation were tested for anti-hyperpigmentary effects using a melan-a cell culture model. Among the tested chemical compounds, 4-ethylresorcinol, 4-ethylphenol and 1-tetradecanol were found to possess hypopigmentary effects. Western blot analysis, reverse transcriptase polymerase chain reaction (RT-PCR), cyclic adenosine monophosphate (cAMP) assay, protein kinase A (PKA) activity assay, tyrosinase inhibition assay and lipid peroxidation inhibition assay were performed to reveal the underlying cellular and molecular mechanisms of the hypopigmentary effects. 4-Ethylresorcinol and 4-ethylphenol attenuated mRNA and protein expression of tyrosinase-related protein (TRP)-2, and possessed antioxidative effect by inhibiting lipid peroxidation. 1-Tetradecanol was able to attenuate protein expression of tyrosinase. The hypopigmentary actions of 4-ethylresorcinol, 4-ethylphenol and 1-tetradecanol were associated with regulating downstream proteins along the PKA pathway. 4-Ethylresorcinol was more effective in inhibiting melanin synthesis when compared to 4-ethylphenol and 1-tetradecanol. Full article
Open AccessArticle Identification of Genes Related to Paulownia Witches’ Broom by AFLP and MSAP
Int. J. Mol. Sci. 2014, 15(8), 14669-14683; doi:10.3390/ijms150814669
Received: 7 April 2014 / Revised: 12 June 2014 / Accepted: 15 June 2014 / Published: 21 August 2014
Cited by 6 | PDF Full-text (8156 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
DNA methylation is believed to play important roles in regulating gene expression in plant growth and development. Paulownia witches’ broom (PaWB) infection has been reported to be related to gene expression changes in paulownia plantlets. To determine whether DNA methylation is associated [...] Read more.
DNA methylation is believed to play important roles in regulating gene expression in plant growth and development. Paulownia witches’ broom (PaWB) infection has been reported to be related to gene expression changes in paulownia plantlets. To determine whether DNA methylation is associated with gene expression changes in response to phytoplasma, we investigated variations in genomic DNA sequence and methylation in PaWB plantlets treated with methyl methane sulfonate (MMS) using amplified fragment length polymorphism (AFLP) and methylation-sensitive amplification polymorphism (MSAP) techniques, respectively. The results indicated that PaWB seedings recovered a normal morphology after treatment with more than 15 mg·L−1 MMS. PaWB infection did not cause changes of the paulownia DNA sequence at the AFLP level; However, DNA methylation levels and patterns were altered. Quantitative real-time PCR (qRT-PCR) showed that three of the methylated genes were up-regulated and three were down-regulated in the MMS-treated PaWB plantlets that had regained healthy morphology. These six genes might be involved in transcriptional regulation, plant defense, signal transduction and energy. The possible roles of these genes in PaWB are discussed. The results showed that changes of DNA methylation altered gene expression levels, and that MSAP might help identify genes related to PaWB. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Antibacterial Performance of Alginic Acid Coating on Polyethylene Film
Int. J. Mol. Sci. 2014, 15(8), 14684-14696; doi:10.3390/ijms150814684
Received: 9 June 2014 / Revised: 11 July 2014 / Accepted: 29 July 2014 / Published: 21 August 2014
Cited by 4 | PDF Full-text (1416 KB) | HTML Full-text | XML Full-text
Abstract
Alginic acid coated polyethylene films were examined in terms of surface properties and bacteriostatic performance against two most representative bacterial strains, that is, Escherichia coli and Staphylococcus aureus. Microwave plasma treatment followed by brush formation in vapor state from three distinguished [...] Read more.
Alginic acid coated polyethylene films were examined in terms of surface properties and bacteriostatic performance against two most representative bacterial strains, that is, Escherichia coli and Staphylococcus aureus. Microwave plasma treatment followed by brush formation in vapor state from three distinguished precursors (allylalcohol, allylamine, hydroxyethyl methacrylate) was carried out to deposit alginic acid on the substrate. Surface analyses via various techniques established that alginic acid was immobilized onto the surface where grafting (brush) chemistry influenced the amount of alginic acid coated. Moreover, alginic acid was found to be capable of bacterial growth inhibition which itself was significantly affected by the brush type. The polyanionic character of alginic acid as a carbohydrate polymer was assumed to play the pivotal role in antibacterial activity. The cell wall composition of two bacterial strains along with the substrates physicochemical properties accounted for different levels of bacteriostatic performance. Full article
(This article belongs to the Special Issue Antimicrobial Polymers)
Open AccessArticle Quantitative Analysis of Tau-Microtubule Interaction Using FRET
Int. J. Mol. Sci. 2014, 15(8), 14697-14714; doi:10.3390/ijms150814697
Received: 23 May 2014 / Revised: 30 June 2014 / Accepted: 14 July 2014 / Published: 21 August 2014
Cited by 1 | PDF Full-text (1494 KB) | HTML Full-text | XML Full-text
Abstract
The interaction between the microtubule associated protein, tau and the microtubules is investigated. A fluorescence resonance energy transfer (FRET) assay was used to determine the distance separating tau to the microtubule wall, as well as the binding parameters of the interaction. By [...] Read more.
The interaction between the microtubule associated protein, tau and the microtubules is investigated. A fluorescence resonance energy transfer (FRET) assay was used to determine the distance separating tau to the microtubule wall, as well as the binding parameters of the interaction. By using microtubules stabilized with Flutax-2 as donor and tau labeled with rhodamine as acceptor, a donor-to-acceptor distance of 54 ± 1 Å was found. A molecular model is proposed in which Flutax-2 is directly accessible to tau-rhodamine molecules for energy transfer. By titration, we calculated the stoichiometric dissociation constant to be equal to 1.0 ± 0.5 µM. The influence of the C-terminal tails of αβ-tubulin on the tau-microtubule interaction is presented once a procedure to form homogeneous solution of cleaved tubulin has been determined. The results indicate that the C-terminal tails of α- and β-tubulin by electrostatic effects and of recruitment seem to be involved in the binding mechanism of tau. Full article
(This article belongs to the Special Issue Förster Resonance Energy Transfer (FRET) 2015)
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Open AccessArticle Prediction of Radical Scavenging Activities of Anthocyanins Applying Adaptive Neuro-Fuzzy Inference System (ANFIS) with Quantum Chemical Descriptors
Int. J. Mol. Sci. 2014, 15(8), 14715-14727; doi:10.3390/ijms150814715
Received: 15 May 2014 / Revised: 24 July 2014 / Accepted: 11 August 2014 / Published: 22 August 2014
Cited by 5 | PDF Full-text (3185 KB) | HTML Full-text | XML Full-text
Abstract
Radical scavenging activity of anthocyanins is well known, but only a few studies have been conducted by quantum chemical approach. The adaptive neuro-fuzzy inference system (ANFIS) is an effective technique for solving problems with uncertainty. The purpose of this study was to [...] Read more.
Radical scavenging activity of anthocyanins is well known, but only a few studies have been conducted by quantum chemical approach. The adaptive neuro-fuzzy inference system (ANFIS) is an effective technique for solving problems with uncertainty. The purpose of this study was to construct and evaluate quantitative structure-activity relationship (QSAR) models for predicting radical scavenging activities of anthocyanins with good prediction efficiency. ANFIS-applied QSAR models were developed by using quantum chemical descriptors of anthocyanins calculated by semi-empirical PM6 and PM7 methods. Electron affinity (A) and electronegativity (χ) of flavylium cation, and ionization potential (I) of quinoidal base were significantly correlated with radical scavenging activities of anthocyanins. These descriptors were used as independent variables for QSAR models. ANFIS models with two triangular-shaped input fuzzy functions for each independent variable were constructed and optimized by 100 learning epochs. The constructed models using descriptors calculated by both PM6 and PM7 had good prediction efficiency with Q-square of 0.82 and 0.86, respectively. Full article
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
Open AccessArticle The Effect of Fiber Bleaching Treatment on the Properties of Poly(lactic acid)/Oil Palm Empty Fruit Bunch Fiber Composites
Int. J. Mol. Sci. 2014, 15(8), 14728-14742; doi:10.3390/ijms150814728
Received: 19 June 2014 / Revised: 31 July 2014 / Accepted: 13 August 2014 / Published: 22 August 2014
Cited by 6 | PDF Full-text (4934 KB) | HTML Full-text | XML Full-text
Abstract
In this work, biodegradable composites from poly(lactic acid) (PLA) and oil palm empty fruit bunch (OPEFB) fiber were prepared by melt blending method. Prior to mixing, the fiber was modified through bleaching treatment using hydrogen peroxide. Bleached fiber composite showed an improvement [...] Read more.
In this work, biodegradable composites from poly(lactic acid) (PLA) and oil palm empty fruit bunch (OPEFB) fiber were prepared by melt blending method. Prior to mixing, the fiber was modified through bleaching treatment using hydrogen peroxide. Bleached fiber composite showed an improvement in mechanical properties as compared to untreated fiber composite due to the enhanced fiber/matrix interfacial adhesion. Interestingly, fiber bleaching treatment also improved the physical appearance of the composite. The study was extended by blending the composites with commercially available masterbatch colorant. Full article
(This article belongs to the Special Issue Biodegradable Materials)
Open AccessArticle Enhancement of Chlorogenic Acid Production in Hairy Roots of Platycodon grandiflorum by Over-Expression of An Arabidopsis thaliana Transcription Factor AtPAP1
Int. J. Mol. Sci. 2014, 15(8), 14743-14752; doi:10.3390/ijms150814743
Received: 30 May 2014 / Revised: 17 July 2014 / Accepted: 22 July 2014 / Published: 22 August 2014
Cited by 1 | PDF Full-text (860 KB) | HTML Full-text | XML Full-text
Abstract
To improve the production of chlorogenic acid (CGA) in hairy roots of Platycodon grandiflorum, we induced over-expression of Arabidopsis thaliana transcription factor production of anthocyanin pigment (AtPAP1) using an Agrobacterium rhizogenes-mediated transformation system. Twelve hairy root lines showing over-expression of [...] Read more.
To improve the production of chlorogenic acid (CGA) in hairy roots of Platycodon grandiflorum, we induced over-expression of Arabidopsis thaliana transcription factor production of anthocyanin pigment (AtPAP1) using an Agrobacterium rhizogenes-mediated transformation system. Twelve hairy root lines showing over-expression of AtPAP1 were generated. In order to investigate the regulation of AtPAP1 on the activities of CGA biosynthetic genes, the expression levels of seven P. grandiflorum CGA biosynthetic genes were analyzed in the hairy root line that had the greatest accumulation of AtPAP1 transcript, OxPAP1-1. The introduction of AtPAP1 increased the mRNA levels of all examined CGA biosynthetic genes and resulted in a 900% up-regulation of CGA accumulation in OxPAP1-1 hairy roots relative to controls. This suggests that P. grandiflorum hairy roots that over-express the AtPAP1 gene are a potential alternative source of roots for the production of CGA. Full article
(This article belongs to the Special Issue Pharmaceuticals and Nutraceuticals by Molecular Farming)
Open AccessArticle Affinity Purification of Binding miRNAs for Messenger RNA Fused with a Common Tag
Int. J. Mol. Sci. 2014, 15(8), 14753-14765; doi:10.3390/ijms150814753
Received: 9 April 2014 / Revised: 9 June 2014 / Accepted: 1 August 2014 / Published: 22 August 2014
Cited by 2 | PDF Full-text (2992 KB) | HTML Full-text | XML Full-text
Abstract
Prediction of microRNA–mRNA interaction typically relies on bioinformatic methods, but these methods only suggest the possibility of microRNA binding and may miss important interactions as well as falsely predict others. A major obstacle to the miRNA research has been the lack of [...] Read more.
Prediction of microRNA–mRNA interaction typically relies on bioinformatic methods, but these methods only suggest the possibility of microRNA binding and may miss important interactions as well as falsely predict others. A major obstacle to the miRNA research has been the lack of experimental procedures for the identification of miRNA–mRNA interactions. Recently, a few studies have attempted to explore experimental methods to isolate and identify miRNA targets or miRNAs targeting a single gene. Here, we developed an more convenient experimental approach for the isolation and identification of miRNAs targeting a single gene by applying short biotinylated DNA anti-sense oligonucleotides mix to enhanced green fluorescent protein (EGFP) mRNA which was fused to target gene mRNA. This method does not require a design of different anti-sense oligonucleotides to any mRNA. This is a simple and an efficient method to potentially identify miRNAs targeting specific gene mRNA combined with chip screen. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Molecular Cloning and Functional Characterization of the Lycopene ε-Cyclase Gene via Virus-Induced Gene Silencing and Its Expression Pattern in Nicotiana tabacum
Int. J. Mol. Sci. 2014, 15(8), 14766-14785; doi:10.3390/ijms150814766
Received: 27 June 2014 / Revised: 11 August 2014 / Accepted: 12 August 2014 / Published: 22 August 2014
Cited by 5 | PDF Full-text (2100 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Lycopene ε-cyclase (ε-LCY) is a key enzyme that catalyzes the synthesis of α-branch carotenoids through the cyclization of lycopene. Two cDNA molecules encoding ε-LCY (designated Ntε-LCY1 and Ntε-LCY2) were cloned from Nicotiana tabacum. Ntε-LCY1 and Nt [...] Read more.
Lycopene ε-cyclase (ε-LCY) is a key enzyme that catalyzes the synthesis of α-branch carotenoids through the cyclization of lycopene. Two cDNA molecules encoding ε-LCY (designated Ntε-LCY1 and Ntε-LCY2) were cloned from Nicotiana tabacum. Ntε-LCY1 and Ntε-LCY2 are encoded by two distinct genes with different evolutionary origins, one originating from the tobacco progenitor, Nicotiana sylvestris, and the other originating from Nicotiana tomentosiformis. The two coding regions are 97% identical at the nucleotide level and 95% identical at the amino acid level. Transcripts of Ntε-LCY were detectable in both vegetative and reproductive organs, with a relatively higher level of expression in leaves than in other tissues. Subcellular localization experiments using an Ntε-LCY1-GFP fusion protein demonstrated that mature Ntε-LCY1 protein is localized within the chloroplast in Bright Yellow 2 suspension cells. Under low-temperature and low-irradiation stress, Ntε-LCY transcript levels substantially increased relative to control plants. Tobacco rattle virus (TRV)-mediated silencing of ε-LCY in Nicotiana benthamiana resulted in an increase of β-branch carotenoids and a reduction in the levels of α-branch carotenoids. Meanwhile, transcripts of related genes in the carotenoid biosynthetic pathway observably increased, with the exception of β-OHase in the TRV-ε-lcy line. Suppression of ε-LCY expression was also found to alleviate photoinhibition of Potosystem II in virus-induced gene silencing (VIGS) plants under low-temperature and low-irradiation stress. Our results provide insight into the regulatory role of ε-LCY in plant carotenoid biosynthesis and suggest a role for ε-LCY in positively modulating low temperature stress responses. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Polymorphism of the Flap Endonuclease 1 Gene in Keratoconus and Fuchs Endothelial Corneal Dystrophy
Int. J. Mol. Sci. 2014, 15(8), 14786-14802; doi:10.3390/ijms150814786
Received: 10 June 2014 / Revised: 9 July 2014 / Accepted: 16 July 2014 / Published: 22 August 2014
Cited by 2 | PDF Full-text (995 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative stress is implicated in the pathogenesis of many diseases, including serious ocular diseases, keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Flap endonuclease 1 (FEN1) plays an important role in the repair of oxidative DNA damage in the base excision repair [...] Read more.
Oxidative stress is implicated in the pathogenesis of many diseases, including serious ocular diseases, keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Flap endonuclease 1 (FEN1) plays an important role in the repair of oxidative DNA damage in the base excision repair pathway. We determined the association between two single nucleotide polymorphisms (SNPs), c.–441G>A (rs174538) and g.61564299G>T (rs4246215), in the FEN1 gene and the occurrence of KC and FECD. This study involved 279 patients with KC, 225 patients with FECD and 322 control individuals. Polymerase chain reaction (PCR) and length polymorphism restriction fragment analysis (RFLP) were applied. The T/T genotype of the g.61564299G>T polymorphism was associated with an increased occurrence of KC and FECD. There was no association between the c.–441G>A polymorphism and either disease. However, the GG haplotype of both polymorphisms was observed more frequently and the GT haplotype less frequently in the KC group than the control. The AG haplotype was associated with increased FECD occurrence. Our findings suggest that the g.61564299G>T and c.–441G>A polymorphisms in the FEN1 gene may modulate the risk of keratoconus and Fuchs endothelial corneal dystrophy. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Simvastatin Attenuates the Oxidative Stress, Endothelial Thrombogenicity and the Inducibility of Atrial Fibrillation in a Rat Model of Ischemic Heart Failure
Int. J. Mol. Sci. 2014, 15(8), 14803-14818; doi:10.3390/ijms150814803
Received: 13 May 2014 / Revised: 21 July 2014 / Accepted: 1 August 2014 / Published: 22 August 2014
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Abstract
Increased atrial oxidative stress has an important role in inducing and maintaining atrial fibrillation (AF), and the activation of the small GTPase Rac1 contributes to the oxidative stress. We investigated the relationship of Rac1, atrial endothelial thromboprotective markers and AF inducibility and [...] Read more.
Increased atrial oxidative stress has an important role in inducing and maintaining atrial fibrillation (AF), and the activation of the small GTPase Rac1 contributes to the oxidative stress. We investigated the relationship of Rac1, atrial endothelial thromboprotective markers and AF inducibility and if simvastatin has a potential beneficial effect on a myocardial infarction (MI)-induced heart failure (HF) rat model. Rats were randomized into three groups (shams, MI group and simvastatin treatment group) and underwent echocardiography, AF induction studies and left atrial (LA) fibrosis analysis. Atrial Rac 1, sodium calcium exchanger (INCX), sarcoplasmic reticulum calcium ATPase (SERCA), endothelial nitric oxide synthase (eNOS) and induced nitric oxide synthase (iNOS) were measured. AF inducibility, AF duration and LA fibrosis were significantly higher in the MI group (p < 0.001 vs. sham), which were significantly reduced by simvastatin (p < 0.05 vs. MI). The reduced expressions of atrial eNOS, SERCA, thrombomodulin, tissue factor pathway inhibitor and tissue plasminogen activator in the MI group were significantly improved by simvastatin. Furthermore, the increased expression of atrial iNOS, INCX and Rac1 activity were significantly decreased by the simvastatin. Oxidative stress, endothelial dysfunction and thrombogenicity are associated with the promotion of AF in a rat model of ischemic HF. These were associated with increased Rac1 activity, and simvastatin treatment prevents these changes. Full article
(This article belongs to the Special Issue Pathogenesis of Cardiac Arrhythmias and Heart Failure)
Open AccessArticle ZmCIPK21, A Maize CBL-Interacting Kinase, Enhances Salt Stress Tolerance in Arabidopsis thaliana
Int. J. Mol. Sci. 2014, 15(8), 14819-14834; doi:10.3390/ijms150814819
Received: 26 May 2014 / Revised: 7 August 2014 / Accepted: 11 August 2014 / Published: 22 August 2014
Cited by 5 | PDF Full-text (6693 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Salt stress represents an increasing threat to crop growth and yield in saline soil. In this study, we identified a maize calcineurin B-like protein-interacting protein kinase (CIPK), ZmCIPK21, which was primarily localized in the cytoplasm and the nucleus of cells and [...] Read more.
Salt stress represents an increasing threat to crop growth and yield in saline soil. In this study, we identified a maize calcineurin B-like protein-interacting protein kinase (CIPK), ZmCIPK21, which was primarily localized in the cytoplasm and the nucleus of cells and displayed enhanced expression under salt stress. Over-expression of ZmCIPK21 in wild-type Arabidopsis plants increased their tolerance to salt, as supported by the longer root lengths and improved growth. The downstream stress-response genes, including dehydration-responsive element-binding (DREB) genes were also activated in transgenic plants over-expressing ZmCIPK21. In addition, introduction of the transgenic ZmCIPK21 gene into the Arabidopsis mutant cipk1-2 rescued the salt-sensitive phenotype under high salt stress. Measurement of Na+ and K+ content in transgenic plants showed that over-expression of ZmCIPK21 decreased accumulation of Na+ and allowed retention of relatively high levels of K+, thereby enhancing plant tolerance to salt conditions. Full article
(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)
Open AccessArticle Influence of Gradual Elongation to the Patella Tendon Insertion in Rabbits
Int. J. Mol. Sci. 2014, 15(8), 14835-14847; doi:10.3390/ijms150814835
Received: 21 May 2014 / Revised: 13 August 2014 / Accepted: 18 August 2014 / Published: 22 August 2014
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Abstract
The purpose of this study was to examine the histological changes at the patella tendon (PT) insertion site under gradual elongation in rabbits. Gradual elongation of the PT was performed using external fixation for 4 weeks, with a lengthening speed of 0.5 [...] Read more.
The purpose of this study was to examine the histological changes at the patella tendon (PT) insertion site under gradual elongation in rabbits. Gradual elongation of the PT was performed using external fixation for 4 weeks, with a lengthening speed of 0.5 mm/day (elongation group; n = 24). Rabbits in the sham group underwent the same surgical procedure without gradual elongation (sham group; n = 24). Eight animals were sacrificed 1, 2 and 4 weeks after surgery in each group, respectively. Average thicknesses of stained glycosaminoglycan (GAGs) areas by Safranin-O staining in the total cartilage layer and the uncalcified fibrocartilage layer in the elongation group were significantly higher than that in the sham group at 4 weeks (p < 0.05) and that in the intact PT group (n = 6, p < 0.05). In the elongation group, the peak in the average thicknesses of the stained GAGs areas in the total cartilage layer and the uncalcified fibrocartilage layer were observed at 4 weeks. Gradual elongation of PT insertion significantly affected the increase in the average thicknesses of the stained GAGs areas in the cartilage layer especially in the uncalcified fibrocartilage layer at 4 weeks in rabbits. Clinically, insertions of tendon and ligament can extend during gradual elongation using external fixation more than 4 weeks after the operation. Full article
(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)
Open AccessArticle Multi-Step Pathogenesis and Induction of Local Immune Response by Systemic Candida Albicans Infection in an Intravenous Challenge Mouse Model
Int. J. Mol. Sci. 2014, 15(8), 14848-14867; doi:10.3390/ijms150814848
Received: 12 June 2014 / Revised: 11 July 2014 / Accepted: 25 July 2014 / Published: 22 August 2014
PDF Full-text (3053 KB) | HTML Full-text | XML Full-text
Abstract
Different murine species differ in their susceptibility to systemic infection with Candida albicans, giving rise to varied host immune responses, and this is compounded by variations in virulence of the different yeast strains used. Hence, this study was aimed at elucidating [...] Read more.
Different murine species differ in their susceptibility to systemic infection with Candida albicans, giving rise to varied host immune responses, and this is compounded by variations in virulence of the different yeast strains used. Hence, this study was aimed at elucidating the pathogenesis of a clinical C. albicans isolate (HVS6360) in a murine intravenous challenge model by examining the different parameters which included the counts of red blood cells and associated components as well as the organ-specific expression profiles of cytokines and chemokines. Kidneys and brains of infected mice have higher fungal recovery rates as compared to other organs and there were extensive yeast infiltration with moderate to severe inflammation seen in kidney and brain tissues. Red blood cells (RBCs) and haemoglobin (Hb) counts were reduced throughout the infection period. Pattern recognition receptors (PRRs), chemokines and cytokine transcription profiles were varied among the different organs (kidney, spleen and brain) over 72 h post infections. Transcription of most of the PRRs, cytokines and chemokines were suppressed at 72 h post infection in spleen while continuous expression of PRRs, cytokines and chemokines genes were seen in brain and kidney. Reduction in red blood cells and haemoglobin counts might be associated with the action of extracellular haemolysin enzyme and haeme oxygenase of C. albicans in conjunction with iron scavenging for the fungal growth. Renal cells responsible for erythropoietin production may be injured by the infection and hence the combined effect of haemolysis plus lack of erythropoietin-induced RBC replenishment leads to aggravated reduction in RBC numbers. The varied local host immune profiles among target organs during systemic C. albicans infection could be of importance for future work in designing targeted immunotherapy through immunomodulatory approaches. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessArticle Separators for Li-Ion and Li-Metal Battery Including Ionic Liquid Based Electrolytes Based on the TFSI and FSI Anions
Int. J. Mol. Sci. 2014, 15(8), 14868-14890; doi:10.3390/ijms150814868
Received: 24 May 2014 / Revised: 27 June 2014 / Accepted: 8 July 2014 / Published: 22 August 2014
Cited by 7 | PDF Full-text (12285 KB) | HTML Full-text | XML Full-text
Abstract
The characterization of separators for Li-ion or Li-metal batteries incorporating hydrophobic ionic liquid electrolytes is reported herein. Ionic liquids made of N-butyl-N-methylpyrrolidinium (PYR14+) or N-methoxyethyl-N-methylpyrrolidinium (PYR12O1+), paired with bis(trifluoromethanesulfonyl)imide (TFSI [...] Read more.
The characterization of separators for Li-ion or Li-metal batteries incorporating hydrophobic ionic liquid electrolytes is reported herein. Ionic liquids made of N-butyl-N-methylpyrrolidinium (PYR14+) or N-methoxyethyl-N-methylpyrrolidinium (PYR12O1+), paired with bis(trifluoromethanesulfonyl)imide (TFSI) or bis(fluorosulfonyl)imide (FSI) anions, were tested in combination with separators having different chemistries and morphologies in terms of wetting behavior, Gurley and McMullin number, as well as Li/(Separator + Electrolyte) interfacial properties. It is shown that non-functionalized microporous polyolefin separators are poorly wetted by FSI-based electrolytes (contrary to TFSI-based electrolytes), while the ceramic coated separator Separion® allows good wetting with all electrolytes. Furthermore, by comparing the lithium solid electrolyte interphase (SEI) resistance evolution at open circuit and during cycling, depending on separator morphologies and chemistries, it is possible to propose a scale for SEI forming properties in the order: PYR12O1FSI > PYR14FSI > PYR14TFSI > PYR12O1TFSI. Finally, the impact the separator morphology is evidenced by the SEI resistance evolution and by comparing Li electrodes cycled using separators with two different morphologies. Full article
(This article belongs to the Special Issue Ionic Liquids 2014 & Selected Papers from ILMAT 2013)
Open AccessArticle A Heavy Metal-Associated Protein (AcHMA1) from the Halophyte, Atriplex canescens (Pursh) Nutt., Confers Tolerance to Iron and Other Abiotic Stresses When Expressed in Saccharomyces cerevisiae
Int. J. Mol. Sci. 2014, 15(8), 14891-14906; doi:10.3390/ijms150814891
Received: 14 July 2014 / Revised: 15 August 2014 / Accepted: 18 August 2014 / Published: 22 August 2014
Cited by 7 | PDF Full-text (1622 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Many heavy metals are essential for metabolic processes, but are toxic at elevated levels. Metal tolerance proteins provide resistance to this toxicity. In this study, we identified and characterized a heavy metal-associated protein, AcHMA1, from the halophyte, Atriplex canescens. Sequence [...] Read more.
Many heavy metals are essential for metabolic processes, but are toxic at elevated levels. Metal tolerance proteins provide resistance to this toxicity. In this study, we identified and characterized a heavy metal-associated protein, AcHMA1, from the halophyte, Atriplex canescens. Sequence analysis has revealed that AcHMA1 contains two heavy metal binding domains. Treatments with metals (Fe, Cu, Ni, Cd or Pb), PEG6000 and NaHCO3 highly induced AcHMA1 expression in A. canescens, whereas NaCl and low temperature decreased its expression. The role of AcHMA1 in metal stress tolerance was examined using a yeast expression system. Expression of the AcHMA1 gene significantly increased the ability of yeast cells to adapt to and recover from exposure to excess iron. AcHMA1 expression also provided salt, alkaline, osmotic and oxidant stress tolerance in yeast cells. Finally, subcellular localization of an AcHMA1/GFP fusion protein expressed in tobacco cells showed that AcHMA1 was localized in the plasma membrane. Thus, our results suggest that AcHMA1 encodes a membrane-localized metal tolerance protein that mediates the detoxification of iron in eukaryotes. Furthermore, AcHMA1 also participates in the response to abiotic stress. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)

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Open AccessReview Receptor for Advanced Glycation End Products (RAGE) and Its Ligands: Focus on Spinal Cord Injury
Int. J. Mol. Sci. 2014, 15(8), 13172-13191; doi:10.3390/ijms150813172
Received: 5 June 2014 / Revised: 7 July 2014 / Accepted: 21 July 2014 / Published: 25 July 2014
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Abstract
Spinal cord injury (SCI) results in neuronal and glial death and the loss of axons at the injury site. Inflammation after SCI leads to the inhibition of tissue regeneration and reduced neuronal survival. In addition, the loss of axons after SCI results [...] Read more.
Spinal cord injury (SCI) results in neuronal and glial death and the loss of axons at the injury site. Inflammation after SCI leads to the inhibition of tissue regeneration and reduced neuronal survival. In addition, the loss of axons after SCI results in functional loss below the site of injury accompanied by neuronal cell body’s damage. Consequently, reducing inflammation and promoting axonal regeneration after SCI is a worthy therapeutic goal. The receptor for advanced glycation end products (RAGE) is a transmembrane protein and receptor of the immunoglobulin superfamily. RAGE is implicated in inflammation and neurodegeneration. Several recent studies demonstrated an association between RAGE and central nervous system disorders through various mechanisms. However, the relationship between RAGE and SCI has not been shown. It is imperative to elucidate the association between RAGE and SCI, considering that RAGE relates to inflammation and axonal degeneration following SCI. Hence, the present review highlights recent research regarding RAGE as a compelling target for the treatment of SCI. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2014)
Open AccessReview Non-Synonymous Single Nucleotide Polymorphisms in the P2X Receptor Genes: Association with Diseases, Impact on Receptor Functions and Potential Use as Diagnosis Biomarkers
Int. J. Mol. Sci. 2014, 15(8), 13344-13371; doi:10.3390/ijms150813344
Received: 6 June 2014 / Revised: 10 July 2014 / Accepted: 14 July 2014 / Published: 30 July 2014
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Abstract
P2X receptors are Ca2+-permeable cationic channels in the cell membranes, where they play an important role in mediating a diversity of physiological and pathophysiological functions of extracellular ATP. Mammalian cells express seven P2X receptor genes. Single nucleotide polymorphisms (SNPs) are [...] Read more.
P2X receptors are Ca2+-permeable cationic channels in the cell membranes, where they play an important role in mediating a diversity of physiological and pathophysiological functions of extracellular ATP. Mammalian cells express seven P2X receptor genes. Single nucleotide polymorphisms (SNPs) are widespread in the P2RX genes encoding the human P2X receptors, particularly the human P2X7 receptor. This article will provide an overview of the non-synonymous SNPs (NS-SNPs) that have been associated with or implicated in altering the susceptibility to pathologies or disease conditions, and discuss the consequences of the mutations resulting from such NS-SNPs on the receptor functions. Disease-associated NS-SNPs in the P2RX genes have been valuable in understanding the disease etiology and the receptor function, and are promising as biomarkers to be used for the diagnosis and development of stratified therapeutics. Full article
(This article belongs to the collection Human Single Nucleotide Polymorphisms and Disease Diagnostics)
Open AccessReview Melatonin and Atopy: Role in Atopic Dermatitis and Asthma
Int. J. Mol. Sci. 2014, 15(8), 13482-13493; doi:10.3390/ijms150813482
Received: 26 June 2014 / Revised: 22 July 2014 / Accepted: 22 July 2014 / Published: 4 August 2014
Cited by 8 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin may have important immunostimulatory actions in allergic diseases, in addition to its well-known antioxidant and cytoprotective effects in several inflammatory conditions. The activation of the immune system leads to free radical production associated with decreased melatonin levels and depressed antioxidant enzyme [...] Read more.
Melatonin may have important immunostimulatory actions in allergic diseases, in addition to its well-known antioxidant and cytoprotective effects in several inflammatory conditions. The activation of the immune system leads to free radical production associated with decreased melatonin levels and depressed antioxidant enzyme activities in several inflammatory diseases. Many skin disorders, including atopic dermatitis, are accompanied by infiltration and activation of mast cells, which release vasoactive and proinflammatory mediators. Experimental data suggest that melatonin inhibits development of atopic eczema and reduces serum total IgE and IL-4. Allergic asthma is a condition characterized by bronchial hyperresponsiveness and the presence of IgE antibodies in response to inhaled allergens; often there is also enhanced total serum IgE levels. Melatonin regulates smooth muscle tone and influences the immune response. Melatonin may, however, act as a pro-inflammatory agent in asthma leading to bronchial constriction. The safety of melatonin as a sleep-inducing agent has been confirmed in asthmatic subjects, but its routine use is not recommended in bronchial asthma. This review summarizes what is known about the role of melatonin as an immunomodulatory agent in asthma and atopic eczema. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Non-Coding RNAs and Lipid Metabolism
Int. J. Mol. Sci. 2014, 15(8), 13494-13513; doi:10.3390/ijms150813494
Received: 14 June 2014 / Revised: 14 July 2014 / Accepted: 28 July 2014 / Published: 4 August 2014
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Abstract
A high percentage of the mammalian genome consists of non-coding RNAs (ncRNAs). Among ncRNAs two main subgroups have been identified: long ncRNAs (lncRNAs) and micro RNAs (miRNAs). ncRNAs have been demonstrated to play a role in a vast variety of diseases, since [...] Read more.
A high percentage of the mammalian genome consists of non-coding RNAs (ncRNAs). Among ncRNAs two main subgroups have been identified: long ncRNAs (lncRNAs) and micro RNAs (miRNAs). ncRNAs have been demonstrated to play a role in a vast variety of diseases, since they regulate gene transcription and are involved in post-transcriptional regulation. They have the potential to function as molecular signals or as guides for transcription factors and to regulate epigenetic modifiers. In this literature review we have summarized data on miRNAs and lncRNAs and their involvement in dyslipidaemia, atherosclerosis, insulin resistance and adipogenesis. Outlining certain ncRNAs as disease biomarkers and/or therapeutic targets, and testing them in vivo, will be the next steps in future research. Full article
(This article belongs to the collection Regulation by Non-Coding RNAs) Print Edition available
Open AccessReview Cystic Fibrosis Related Liver Disease—Another Black Box in Hepatology
Int. J. Mol. Sci. 2014, 15(8), 13529-13549; doi:10.3390/ijms150813529
Received: 1 May 2014 / Revised: 10 July 2014 / Accepted: 16 July 2014 / Published: 4 August 2014
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Abstract
Due to improved medical care, life expectancy in patients with cystic fibrosis (CF) has veritably improved over the last decades. Importantly, cystic fibrosis related liver disease (CFLD) has become one of the leading causes of morbidity and mortality in CF patients. However, [...] Read more.
Due to improved medical care, life expectancy in patients with cystic fibrosis (CF) has veritably improved over the last decades. Importantly, cystic fibrosis related liver disease (CFLD) has become one of the leading causes of morbidity and mortality in CF patients. However, CFLD might be largely underdiagnosed and diagnostic criteria need to be refined. The underlying pathomechanisms are largely unknown, and treatment strategies with proven efficacy are lacking. This review focuses on current invasive and non-invasive diagnostic standards, the current knowledge on the pathophysiology of CFLD, treatment strategies, and possible future developments. Full article
(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)
Open AccessReview Biosurfactant Mediated Biosynthesis of Selected Metallic Nanoparticles
Int. J. Mol. Sci. 2014, 15(8), 13720-13737; doi:10.3390/ijms150813720
Received: 29 May 2014 / Revised: 27 June 2014 / Accepted: 7 July 2014 / Published: 8 August 2014
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Abstract
Developing a reliable experimental protocol for the synthesis of nanomaterials is one of the challenging topics in current nanotechnology particularly in the context of the recent drive to promote green technologies in their synthesis. The increasing need to develop clean, nontoxic and [...] Read more.
Developing a reliable experimental protocol for the synthesis of nanomaterials is one of the challenging topics in current nanotechnology particularly in the context of the recent drive to promote green technologies in their synthesis. The increasing need to develop clean, nontoxic and environmentally safe production processes for nanoparticles to reduce environmental impact, minimize waste and increase energy efficiency has become essential in this field. Consequently, recent studies on the use of microorganisms in the synthesis of selected nanoparticles are gaining increased interest as they represent an exciting area of research with considerable development potential. Microorganisms are known to be capable of synthesizing inorganic molecules that are deposited either intra- or extracellularly. This review presents a brief overview of current research on the use of biosurfactants in the biosynthesis of selected metallic nanoparticles and their potential importance. Full article
(This article belongs to the Special Issue Bioactive Nanoparticles 2014)
Open AccessReview Small-Molecule Inhibitors of the Receptor Tyrosine Kinases: Promising Tools for Targeted Cancer Therapies
Int. J. Mol. Sci. 2014, 15(8), 13768-13801; doi:10.3390/ijms150813768
Received: 3 July 2014 / Revised: 31 July 2014 / Accepted: 5 August 2014 / Published: 8 August 2014
Cited by 32 | PDF Full-text (1378 KB) | HTML Full-text | XML Full-text
Abstract
Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on [...] Read more.
Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK–TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK–TKIs have been developed for the treatment of cancer patients. Specific/selective RTK–TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK–TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs. Full article
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Open AccessReview Antibacterial Surface Treatment for Orthopaedic Implants
Int. J. Mol. Sci. 2014, 15(8), 13849-13880; doi:10.3390/ijms150813849
Received: 30 December 2013 / Revised: 6 June 2014 / Accepted: 13 June 2014 / Published: 11 August 2014
Cited by 19 | PDF Full-text (7922 KB) | HTML Full-text | XML Full-text
Abstract
It is expected that the projected increased usage of implantable devices in medicine will result in a natural rise in the number of infections related to these cases. Some patients are unable to autonomously prevent formation of biofilm on implant surfaces. Suppression [...] Read more.
It is expected that the projected increased usage of implantable devices in medicine will result in a natural rise in the number of infections related to these cases. Some patients are unable to autonomously prevent formation of biofilm on implant surfaces. Suppression of the local peri-implant immune response is an important contributory factor. Substantial avascular scar tissue encountered during revision joint replacement surgery places these cases at an especially high risk of periprosthetic joint infection. A critical pathogenic event in the process of biofilm formation is bacterial adhesion. Prevention of biomaterial-associated infections should be concurrently focused on at least two targets: inhibition of biofilm formation and minimizing local immune response suppression. Current knowledge of antimicrobial surface treatments suitable for prevention of prosthetic joint infection is reviewed. Several surface treatment modalities have been proposed. Minimizing bacterial adhesion, biofilm formation inhibition, and bactericidal approaches are discussed. The ultimate anti-infective surface should be “smart” and responsive to even the lowest bacterial load. While research in this field is promising, there appears to be a great discrepancy between proposed and clinically implemented strategies, and there is urgent need for translational science focusing on this topic. Full article
(This article belongs to the Special Issue Biologic Coatings for Orthopaedic Implant)
Open AccessReview Mechanistic Understanding of Toxicity from Nanocatalysts
Int. J. Mol. Sci. 2014, 15(8), 13967-13992; doi:10.3390/ijms150813967
Received: 16 June 2014 / Revised: 4 July 2014 / Accepted: 11 July 2014 / Published: 12 August 2014
Cited by 2 | PDF Full-text (1763 KB) | HTML Full-text | XML Full-text
Abstract
Nanoparticle-based catalysts, or nanocatalysts, have been applied in various industrial sectors, including refineries, petrochemical plants, the pharmaceutical industry, the chemical industry, food processing, and environmental remediation. As a result, there is an increasing risk of human exposure to nanocatalysts. This review evaluates [...] Read more.
Nanoparticle-based catalysts, or nanocatalysts, have been applied in various industrial sectors, including refineries, petrochemical plants, the pharmaceutical industry, the chemical industry, food processing, and environmental remediation. As a result, there is an increasing risk of human exposure to nanocatalysts. This review evaluates the toxicity of popular nanocatalysts applied in industrial processes in cell and animal models. The molecular mechanisms associated with such nanotoxicity are emphasized to reveal common toxicity-inducing pathways from various nanocatalysts and the uniqueness of each specific nanocatalyst. Full article
(This article belongs to the Special Issue Bioactive Nanoparticles 2014)
Open AccessReview Current Status of Long Non-Coding RNAs in Human Cancer with Specific Focus on Colorectal Cancer
Int. J. Mol. Sci. 2014, 15(8), 13993-14013; doi:10.3390/ijms150813993
Received: 30 June 2014 / Revised: 23 July 2014 / Accepted: 5 August 2014 / Published: 12 August 2014
Cited by 6 | PDF Full-text (1096 KB) | HTML Full-text | XML Full-text
Abstract
The latest investigations of long non-coding RNAs (lncRNAs) have revealed their important role in human cancers. LncRNAs are larger than 200 nucleotides in length and fulfill their cellular purpose without being translated into proteins. Though the molecular functions of some lncRNAs have [...] Read more.
The latest investigations of long non-coding RNAs (lncRNAs) have revealed their important role in human cancers. LncRNAs are larger than 200 nucleotides in length and fulfill their cellular purpose without being translated into proteins. Though the molecular functions of some lncRNAs have been elucidated, there is still a high number of lncRNAs with unknown or controversial functions. In this review, we provide an overview of different lncRNAs and their role in human cancers. In particular, we emphasize their importance in tumorigenesis of colorectal cancer, the third most common cancer worldwide. Full article
(This article belongs to the collection Regulation by Non-Coding RNAs) Print Edition available
Open AccessReview Mammalian Cytochrome P450-Dependent Metabolism of Polychlorinated Dibenzo-p-dioxins and Coplanar Polychlorinated Biphenyls
Int. J. Mol. Sci. 2014, 15(8), 14044-14057; doi:10.3390/ijms150814044
Received: 13 May 2014 / Revised: 8 July 2014 / Accepted: 16 July 2014 / Published: 13 August 2014
Cited by 5 | PDF Full-text (1429 KB) | HTML Full-text | XML Full-text
Abstract
Polychlorinated dibenzo-p-dioxins (PCDDs) and coplanar polychlorinated biphenyls (PCBs) contribute to dioxin toxicity in humans and wildlife after bioaccumulation through the food chain from the environment. The authors examined human and rat cytochrome P450 (CYP)-dependent metabolism of PCDDs and PCBs. A [...] Read more.
Polychlorinated dibenzo-p-dioxins (PCDDs) and coplanar polychlorinated biphenyls (PCBs) contribute to dioxin toxicity in humans and wildlife after bioaccumulation through the food chain from the environment. The authors examined human and rat cytochrome P450 (CYP)-dependent metabolism of PCDDs and PCBs. A number of human CYP isoforms belonging to the CYP1 and CYP2 families showed remarkable activities toward low-chlorinated PCDDs. In particular, human CYP1A1, CYP1A2, and CYP1B1 showed high activities toward monoCDDs, diCDDs, and triCDDs but no detectable activity toward 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetraCDD). Large amino acids located at putative substrate-recognition sites and the F-G loop in rat CYP1A1 contributed to the successful metabolism of 2,3,7,8-tetraCDD. Rat, but not human, CYP1A1 metabolized 3,3',4,4',5-pentachlorobiphenyl (CB126) to two hydroxylated metabolites. These metabolites are probably less toxic than is CB126, due to their higher solubility. Homology models of human and rat CYP1A1s and CB126 docking studies indicated that two amino acid differences in the CB126-binding cavity were important for CB126 metabolism. In this review, the importance of CYPs in the metabolism of dioxins and PCBs in mammals and the species-based differences between humans and rats are described. In addition, the authors reveal the molecular mechanism behind the binding modes of dioxins and PCBs in the heme pocket of CYPs. Full article
(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)
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Open AccessReview Genetic Breeding and Diversity of the Genus Passiflora: Progress and Perspectives in Molecular and Genetic Studies
Int. J. Mol. Sci. 2014, 15(8), 14122-14152; doi:10.3390/ijms150814122
Received: 23 March 2014 / Revised: 12 June 2014 / Accepted: 30 June 2014 / Published: 14 August 2014
Cited by 8 | PDF Full-text (1747 KB) | HTML Full-text | XML Full-text
Abstract
Despite the ecological and economic importance of passion fruit (Passiflora spp.), molecular markers have only recently been utilized in genetic studies of this genus. In addition, both basic genetic researches related to population studies and pre-breeding programs of passion fruit remain [...] Read more.
Despite the ecological and economic importance of passion fruit (Passiflora spp.), molecular markers have only recently been utilized in genetic studies of this genus. In addition, both basic genetic researches related to population studies and pre-breeding programs of passion fruit remain scarce for most Passiflora species. Considering the number of Passiflora species and the increasing use of these species as a resource for ornamental, medicinal, and food purposes, the aims of this review are the following: (i) to present the current condition of the passion fruit crop; (ii) to quantify the applications and effects of using molecular markers in studies of Passiflora; (iii) to present the contributions of genetic engineering for passion fruit culture; and (iv) to discuss the progress and perspectives of this research. Thus, the present review aims to summarize and discuss the relationship between historical and current progress on the culture, breeding, and molecular genetics of passion fruit. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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Open AccessReview Expert Panel Workshop Consensus Statement on the Role of the Environment in the Development of Autoimmune Disease
Int. J. Mol. Sci. 2014, 15(8), 14269-14297; doi:10.3390/ijms150814269
Received: 9 June 2014 / Revised: 31 July 2014 / Accepted: 4 August 2014 / Published: 15 August 2014
Cited by 11 | PDF Full-text (731 KB) | HTML Full-text | XML Full-text
Abstract
Autoimmune diseases include 80 or more complex disorders characterized by self-reactive, pathologic immune responses in which genetic susceptibility is largely insufficient to determine disease onset. In September 2010, the National Institute of Environmental Health Sciences (NIEHS) organized an expert panel workshop to [...] Read more.
Autoimmune diseases include 80 or more complex disorders characterized by self-reactive, pathologic immune responses in which genetic susceptibility is largely insufficient to determine disease onset. In September 2010, the National Institute of Environmental Health Sciences (NIEHS) organized an expert panel workshop to evaluate the role of environmental factors in autoimmune diseases, and the state of the science regarding relevant mechanisms, animal models, and human studies. The objective of the workshop was to analyze the existing data to identify conclusions that could be drawn regarding environmental exposures and autoimmunity and to identify critical knowledge gaps and areas of uncertainty for future study. This consensus document summarizes key findings from published workshop monographs on areas in which “confident” and “likely” assessments were made, with recommendations for further research. Transcribed notes and slides were reviewed to synthesize an overview on exposure assessment and questions addressed by interdisciplinary panels. Critical advances in the field of autoimmune disease research have been made in the past decade. Collaborative translational and interdisciplinary research is needed to elucidate the role of environmental factors in autoimmune diseases. A focus on exposure assessment methodology is needed to improve the effectiveness of human studies, and more experimental studies are needed to focus on causal mechanisms underlying observed associations of environmental factors with autoimmune disease in humans. Full article
(This article belongs to the Special Issue Environmental Toxicants and Autoimmune Disease)
Open AccessReview Mesenchymal Stem Cell-Derived Microparticles: A Promising Therapeutic Strategy
Int. J. Mol. Sci. 2014, 15(8), 14348-14363; doi:10.3390/ijms150814348
Received: 18 June 2014 / Revised: 25 July 2014 / Accepted: 4 August 2014 / Published: 18 August 2014
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Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that give rise to various cell types of the mesodermal germ layer. Because of their unique ability to home in on injured and cancerous tissues, MSCs are of great potential in regenerative medicine. MSCs [...] Read more.
Mesenchymal stem cells (MSCs) are multipotent stem cells that give rise to various cell types of the mesodermal germ layer. Because of their unique ability to home in on injured and cancerous tissues, MSCs are of great potential in regenerative medicine. MSCs also contribute to reparative processes in different pathological conditions, including cardiovascular diseases and cancer. However, many studies have shown that only a small proportion of transplanted MSCs can actually survive and be incorporated into host tissues. The effects of MSCs cannot be fully explained by their number. Recent discoveries suggest that microparticles (MPs) derived from MSCs may be important for the physiological functions of their parent. Though the physiological role of MSC-MPs is currently not well understood, inspiring results indicate that, in tissue repair and anti-cancer therapy, MSC-MPs have similar pro-regenerative and protective properties as their cellular counterparts. Thus, MSC-MPs represent a promising approach that may overcome the obstacles and risks associated with the use of native or engineered MSCs. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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Open AccessReview Recent Advances of Stem Cell Therapy for Retinitis Pigmentosa
Int. J. Mol. Sci. 2014, 15(8), 14456-14474; doi:10.3390/ijms150814456
Received: 24 April 2014 / Revised: 24 July 2014 / Accepted: 11 August 2014 / Published: 20 August 2014
Cited by 5 | PDF Full-text (703 KB) | HTML Full-text | XML Full-text
Abstract
Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive loss of photoreceptors and eventually leads to retina degeneration and atrophy. Until now, the exact pathogenesis and etiology of this disease has not been clear, and many approaches for [...] Read more.
Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive loss of photoreceptors and eventually leads to retina degeneration and atrophy. Until now, the exact pathogenesis and etiology of this disease has not been clear, and many approaches for RP therapies have been carried out in animals and in clinical trials. In recent years, stem cell transplantation-based attempts made some progress, especially the transplantation of bone marrow-derived mesenchymal stem cells (BMSCs). This review will provide an overview of stem cell-based treatment of RP and its main problems, to provide evidence for the safety and feasibility for further clinical treatment. Full article
Open AccessReview MicroRNAs, Genomic Instability and Cancer
Int. J. Mol. Sci. 2014, 15(8), 14475-14491; doi:10.3390/ijms150814475
Received: 2 July 2014 / Revised: 7 August 2014 / Accepted: 12 August 2014 / Published: 20 August 2014
Cited by 10 | PDF Full-text (657 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs) are small non-coding RNA transcripts approximately 20 nucleotides in length that regulate expression of protein-coding genes via complementary binding mechanisms. The last decade has seen an exponential increase of publications on miRNAs, ranging from every aspect of basic cancer biology [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNA transcripts approximately 20 nucleotides in length that regulate expression of protein-coding genes via complementary binding mechanisms. The last decade has seen an exponential increase of publications on miRNAs, ranging from every aspect of basic cancer biology to diagnostic and therapeutic explorations. In this review, we summarize findings of miRNA involvement in genomic instability, an interesting but largely neglected topic to date. We discuss the potential mechanisms by which miRNAs induce genomic instability, considered to be one of the most important driving forces of cancer initiation and progression, though its precise mechanisms remain elusive. We classify genomic instability mechanisms into defects in cell cycle regulation, DNA damage response, and mitotic separation, and review the findings demonstrating the participation of specific miRNAs in such mechanisms. Full article
(This article belongs to the collection Regulation by Non-Coding RNAs) Print Edition available
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Open AccessReview High-Resolution Imaging Reveals New Features of Nuclear Export of mRNA through the Nuclear Pore Complexes
Int. J. Mol. Sci. 2014, 15(8), 14492-14504; doi:10.3390/ijms150814492
Received: 10 July 2014 / Revised: 8 August 2014 / Accepted: 15 August 2014 / Published: 20 August 2014
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Abstract
The nuclear envelope (NE) of eukaryotic cells provides a physical barrier for messenger RNA (mRNA) and the associated proteins (mRNPs) traveling from sites of transcription in the nucleus to locations of translation processing in the cytoplasm. Nuclear pore complexes (NPCs) embedded in [...] Read more.
The nuclear envelope (NE) of eukaryotic cells provides a physical barrier for messenger RNA (mRNA) and the associated proteins (mRNPs) traveling from sites of transcription in the nucleus to locations of translation processing in the cytoplasm. Nuclear pore complexes (NPCs) embedded in the NE serve as a dominant gateway for nuclear export of mRNA. However, the fundamental characterization of export dynamics of mRNPs through the NPC has been hindered by several technical limits. First, the size of NPC that is barely below the diffraction limit of conventional light microscopy requires a super-resolution microscopy imaging approach. Next, the fast transit of mRNPs through the NPC further demands a high temporal resolution by the imaging approach. Finally, the inherent three-dimensional (3D) movements of mRNPs through the NPC demand the method to provide a 3D mapping of both transport kinetics and transport pathways of mRNPs. This review will highlight the recently developed super-resolution imaging techniques advanced from 1D to 3D for nuclear export of mRNPs and summarize the new features in the dynamic nuclear export process of mRNPs revealed from these technical advances. Full article
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Open AccessReview Salmonella as an Innovative Therapeutic Antitumor Agent
Int. J. Mol. Sci. 2014, 15(8), 14546-14554; doi:10.3390/ijms150814546
Received: 24 June 2014 / Revised: 28 July 2014 / Accepted: 18 August 2014 / Published: 21 August 2014
Cited by 5 | PDF Full-text (943 KB) | HTML Full-text | XML Full-text
Abstract
Lack of specificity of the therapeutic agent is a primary limitation in the treatment of a tumor. The use of preferentially replicating bacteria as therapeutic agents is an innovative approach to tumor treatment. This is based on the observation that certain obligate [...] Read more.
Lack of specificity of the therapeutic agent is a primary limitation in the treatment of a tumor. The use of preferentially replicating bacteria as therapeutic agents is an innovative approach to tumor treatment. This is based on the observation that certain obligate or facultative anaerobic bacteria are capable of multiplying selectively in tumors and inhibiting their growth. Bacteria have been employed as antitumor agents that are capable of preferentially amplifying within tumors and inhibiting their growth. Moreover, bacteria-derived factors have an immune-stimulation effect. Therefore, bacteria are able to transfer therapeutic genes into the tumor cells using their infective ability. Herein, we introduce the application of bacteria for tumor therapy and focus on Salmonella, which have been widely used for tumor therapy. Salmonella have mainly been applied as gene-delivery vectors, antitumor immune activators and tumor cell death inducers. This study will not only evaluate the therapeutic efficacy of Salmonella for the treatment of tumor but will also elucidate the mechanisms underlying the antitumor activities mediated by Salmonella, which involve host immune responses and cellular molecular responses. Full article
(This article belongs to the Special Issue Advances in Molecular Oncology 2014)
Open AccessReview The tRNA-Dependent Biosynthesis of Modified Cyclic Dipeptides
Int. J. Mol. Sci. 2014, 15(8), 14610-14631; doi:10.3390/ijms150814610
Received: 18 June 2014 / Revised: 1 August 2014 / Accepted: 18 August 2014 / Published: 21 August 2014
Cited by 5 | PDF Full-text (5955 KB) | HTML Full-text | XML Full-text
Abstract
In recent years it has become apparent that aminoacyl-tRNAs are not only crucial components involved in protein biosynthesis, but are also used as substrates and amino acid donors in a variety of other important cellular processes, ranging from bacterial cell wall biosynthesis [...] Read more.
In recent years it has become apparent that aminoacyl-tRNAs are not only crucial components involved in protein biosynthesis, but are also used as substrates and amino acid donors in a variety of other important cellular processes, ranging from bacterial cell wall biosynthesis and lipid modification to protein turnover and secondary metabolite assembly. In this review, we focus on tRNA-dependent biosynthetic pathways that generate modified cyclic dipeptides (CDPs). The essential peptide bond-forming catalysts responsible for the initial generation of a CDP-scaffold are referred to as cyclodipeptide synthases (CDPSs) and use loaded tRNAs as their substrates. After initially discussing the phylogenetic distribution and organization of CDPS gene clusters, we will focus on structural and catalytic properties of CDPSs before turning to two recently characterized CDPS-dependent pathways that assemble modified CDPs. Finally, possible applications of CDPSs in the rational design of structural diversity using combinatorial biosynthesis will be discussed before concluding with a short outlook. Full article
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Open AccessReview Adoptive Immunotherapy Strategies with Cytokine-Induced Killer (CIK) Cells in the Treatment of Hematological Malignancies
Int. J. Mol. Sci. 2014, 15(8), 14632-14648; doi:10.3390/ijms150814632
Received: 20 June 2014 / Revised: 14 July 2014 / Accepted: 11 August 2014 / Published: 21 August 2014
Cited by 9 | PDF Full-text (725 KB) | HTML Full-text | XML Full-text
Abstract
Cytokine-induced killer (CIK) cells are a heterogeneous population of immune effector cells that feature a mixed T- and Natural killer (NK) cell-like phenotype in their terminally-differentiated CD3+CD56+ subset. The easy availability, high proliferation rate and widely major histocompatibility complex [...] Read more.
Cytokine-induced killer (CIK) cells are a heterogeneous population of immune effector cells that feature a mixed T- and Natural killer (NK) cell-like phenotype in their terminally-differentiated CD3+CD56+ subset. The easy availability, high proliferation rate and widely major histocompatibility complex (MHC)-unrestricted antitumor activity of CIK cells contribute to their particularly advantageous profile, making them an attractive approach for adoptive immunotherapy. CIK cells have shown considerable cytotoxicity against both solid tumors and hematological malignancies in vitro and in animal studies. Recently, initial clinical experiences demonstrated the feasibility and efficacy of CIK cell immunotherapy in cancer patients, even at advanced disease stages. Likewise, the clinical application of CIK cells in combination with standard therapeutic procedures revealed synergistic antitumor effects. In this report, we will focus our consideration on CIK cells in the treatment of hematological malignancies. We will give insight into the latest advances and future perspectives and outline the most prominent results obtained in 17 clinical studies. Overall, CIK cells demonstrated a crucial impact on the treatment of patients with hematological malignancies, as evidenced by complete remissions, prolonged survival durations and improved quality of life. However, up to now, the optimal application schedule eventually favoring their integration into clinical practice has still to be developed. Full article
(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)

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Open AccessCase Report Coexistence of Granular Cell Tumor and Invasive Ductal Breast Cancer in Contralateral Breasts: A Case Report
Int. J. Mol. Sci. 2014, 15(8), 13166-13171; doi:10.3390/ijms150813166
Received: 25 March 2014 / Revised: 16 July 2014 / Accepted: 21 July 2014 / Published: 25 July 2014
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Abstract
Granular cell tumor (GCT) is a benign tumor of the breast that can mimic, on breast imaging, invasive carcinomas. Biological evolution of mammary GCT is unknown, especially if it is associated with an invasive carcinoma in the same or contralateral breast. This [...] Read more.
Granular cell tumor (GCT) is a benign tumor of the breast that can mimic, on breast imaging, invasive carcinomas. Biological evolution of mammary GCT is unknown, especially if it is associated with an invasive carcinoma in the same or contralateral breast. This report details the morphological features of these synchronous lesions highlighting their biological characteristics and suggesting an appropriate follow up. Full article
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Open AccessShort Note Discrepancies between VEGF −1154 G>A Polymorphism Analysis Performed in Peripheral Blood Samples and FFPE Tissue
Int. J. Mol. Sci. 2014, 15(8), 13333-13343; doi:10.3390/ijms150813333
Received: 29 May 2014 / Revised: 2 July 2014 / Accepted: 23 July 2014 / Published: 30 July 2014
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Abstract
Single nucleotide polymorphisms (SNPs) may be associated with the response or toxicity to different types of treatment. Although SNP analysis is usually performed on DNA from peripheral blood, formalin fixed paraffin-embedded (FFPE) tissue is often used for retrospective studies. We analyzed VEGF [...] Read more.
Single nucleotide polymorphisms (SNPs) may be associated with the response or toxicity to different types of treatment. Although SNP analysis is usually performed on DNA from peripheral blood, formalin fixed paraffin-embedded (FFPE) tissue is often used for retrospective studies. We analyzed VEGF (−2578C>A, −1498C>T, −1154G>A, −634C>G, +936C>T) and eNOS (+894G>T, −786T>C, VNTR (variable number of tandem repeats) 27bp intron 4) polymorphisms by direct sequencing or Real Time PCR in 237 patients with advanced colorectal cancer. Peripheral blood was used for 153 patients, whereas only FFPE tumor tissue was available for 84 patients. All SNP frequencies were in Hardy-Weinberg Equilibrium (HWE), with the exception of VEGF −1154, which was only in HWE in peripheral blood specimens. We therefore analyzed this SNP in DNA extracted from FFPE tumor tissue compared to FFPE healthy tissue and peripheral blood from 20 patients. Numerous heterozygous patients in peripheral blood DNA were homozygous for the A-allele in both tumor and healthy FFPE tissues. Our findings indicate that, although FFPE tissue might be a suitable specimen for genotyping, VEGF −1154 does not give reliable results on this type of material. As other SNPs may also have this limitation, genotype concordance should first be confirmed by comparing results obtained from FFPE and fresh sample analyses. Full article
(This article belongs to the Section Molecular Diagnostics)
Open AccessLetter Molecular Research in Urology 2014: Update on PET/MR Imaging of the Prostate
Int. J. Mol. Sci. 2014, 15(8), 13401-13405; doi:10.3390/ijms150813401
Received: 15 June 2014 / Revised: 23 July 2014 / Accepted: 28 July 2014 / Published: 31 July 2014
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Abstract This article gives an overview of recent publications and potential indications of Positron emission tomography/ Magnetic resonance (PET/MR) imaging of prostate cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
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Open AccessCorrection Xia, J.; et al., Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer. Int. J. Mol. Sci. 2012, 13, 9627–9641
Int. J. Mol. Sci. 2014, 15(8), 14907-14908; doi:10.3390/ijms150814907
Received: 25 July 2014 / Accepted: 11 August 2014 / Published: 22 August 2014
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Abstract
The authors wish to change Figure 5D of the paper published in IJMS [1]. In Figure 5D, the bands for NF-κB and Bcl-2 are similar with Notch-1 bands. The authors have carefully checked the original files and found that it is an [...] Read more.
The authors wish to change Figure 5D of the paper published in IJMS [1]. In Figure 5D, the bands for NF-κB and Bcl-2 are similar with Notch-1 bands. The authors have carefully checked the original files and found that it is an inadvertent mistake in the published version of Figure 5D. Figure 5 is revised as follows. The authors would like to apologize for any inconvenience caused to the readers by these changes.[...] Full article

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