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Int. J. Mol. Sci., Volume 16, Issue 9 (September 2015) – 165 articles , Pages 20100-23126

Cover Story: Photosensitizers (PS) are the main agents for Photodynamic therapy (PDT). Still, photosensitizers are usually considered simple singlet oxygen generators. By analyzing the molecular and biological processes taking place during and after photosensitization, we aim to suggest alternatives for achieving high-efficiency PDT protocols. We submit that PSs should be designed to induce specific mechanisms of cell death and researchers should first consider tissue and intracellular localization, instead of trying to maximize the generation of reactive species. View the article.
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1075 KiB  
Article
Multiple Factors Drive Replicating Strand Composition Bias in Bacterial Genomes
by Hai-Long Zhao, Zhong-Kui Xia, Fa-Zhan Zhang, Yuan-Nong Ye and Feng-Biao Guo
Int. J. Mol. Sci. 2015, 16(9), 23111-23126; https://doi.org/10.3390/ijms160923111 - 23 Sep 2015
Cited by 9 | Viewed by 5055
Abstract
Composition bias from Chargaff’s second parity rule (PR2) has long been found in sequenced genomes, and is believed to relate strongly with the replication process in microbial genomes. However, some disagreement on the underlying reason for strand composition bias remains. We performed an [...] Read more.
Composition bias from Chargaff’s second parity rule (PR2) has long been found in sequenced genomes, and is believed to relate strongly with the replication process in microbial genomes. However, some disagreement on the underlying reason for strand composition bias remains. We performed an integrative analysis of various genomic features that might influence composition bias using a large-scale dataset of 1111 genomes. Our results indicate (1) the bias was stronger in obligate intracellular bacteria than in other free-living species (p-value = 0.0305); (2) Fusobacteria and Firmicutes had the highest average bias among the 24 microbial phyla analyzed; (3) the strength of selected codon usage bias and generation times were not observably related to strand composition bias (p-value = 0.3247); (4) significant negative relationships were found between GC content, genome size, rearrangement frequency, Clusters of Orthologous Groups (COG) functional subcategories A, C, I, Q, and composition bias (p-values < 1.0 × 10−8); (5) gene density and COG functional subcategories D, F, J, L, and V were positively related with composition bias (p-value < 2.2 × 10−16); and (6) gene density made the most important contribution to composition bias, indicating transcriptional bias was associated strongly with strand composition bias. Therefore, strand composition bias was found to be influenced by multiple factors with varying weights. Full article
(This article belongs to the Special Issue Microbial Genomics and Metabolomics)
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840 KiB  
Review
Rational Protein Engineering Guided by Deep Mutational Scanning
by HyeonSeok Shin and Byung-Kwan Cho
Int. J. Mol. Sci. 2015, 16(9), 23094-23110; https://doi.org/10.3390/ijms160923094 - 23 Sep 2015
Cited by 12 | Viewed by 8886
Abstract
Sequence–function relationship in a protein is commonly determined by the three-dimensional protein structure followed by various biochemical experiments. However, with the explosive increase in the number of genome sequences, facilitated by recent advances in sequencing technology, the gap between protein sequences available and [...] Read more.
Sequence–function relationship in a protein is commonly determined by the three-dimensional protein structure followed by various biochemical experiments. However, with the explosive increase in the number of genome sequences, facilitated by recent advances in sequencing technology, the gap between protein sequences available and three-dimensional structures is rapidly widening. A recently developed method termed deep mutational scanning explores the functional phenotype of thousands of mutants via massive sequencing. Coupled with a highly efficient screening system, this approach assesses the phenotypic changes made by the substitution of each amino acid sequence that constitutes a protein. Such an informational resource provides the functional role of each amino acid sequence, thereby providing sufficient rationale for selecting target residues for protein engineering. Here, we discuss the current applications of deep mutational scanning and consider experimental design. Full article
(This article belongs to the Special Issue Protein Engineering)
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1087 KiB  
Review
Critical Issues in the Study of Magnesium Transport Systems and Magnesium Deficiency Symptoms in Plants
by Natsuko I. Kobayashi and Keitaro Tanoi
Int. J. Mol. Sci. 2015, 16(9), 23076-23093; https://doi.org/10.3390/ijms160923076 - 23 Sep 2015
Cited by 53 | Viewed by 11177
Abstract
Magnesium (Mg) is the second most abundant cation in living cells. Over 300 enzymes are known to be Mg-dependent, and changes in the Mg concentration significantly affects the membrane potential. As Mg becomes deficient, starch accumulation and chlorosis, bridged by the generation of [...] Read more.
Magnesium (Mg) is the second most abundant cation in living cells. Over 300 enzymes are known to be Mg-dependent, and changes in the Mg concentration significantly affects the membrane potential. As Mg becomes deficient, starch accumulation and chlorosis, bridged by the generation of reactive oxygen species, are commonly found in Mg-deficient young mature leaves. These defects further cause the inhibition of photosynthesis and finally decrease the biomass. Recently, transcriptome analysis has indicated the transcriptinal downregulation of chlorophyll apparatus at the earlier stages of Mg deficiency, and also the potential involvement of complicated networks relating to hormonal signaling and circadian oscillation. However, the processes of the common symptoms as well as the networks between Mg deficiency and signaling are not yet fully understood. Here, for the purpose of defining the missing pieces, several problems are considered and explained by providing an introduction to recent reports on physiological and transcriptional responses to Mg deficiency. In addition, it has long been unclear whether the Mg deficiency response involves the modulation of Mg2+ transport system. In this review, the current status of research on Mg2+ transport and the relating transporters are also summarized. Especially, the rapid progress in physiological characterization of the plant MRS2 gene family as well as the fundamental investigation about the molecular mechanism of the action of bacterial CorA proteins are described. Full article
(This article belongs to the Special Issue Regulation of Plant Mineral Nutrition: Transport, Sensing and Signalling)
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Article
Reference Genes in the Pathosystem Phakopsora pachyrhizi/ Soybean Suitable for Normalization in Transcript Profiling
by Daniela Hirschburger, Manuel Müller, Ralf T. Voegele and Tobias Link
Int. J. Mol. Sci. 2015, 16(9), 23057-23075; https://doi.org/10.3390/ijms160923057 - 23 Sep 2015
Cited by 16 | Viewed by 6705
Abstract
Phakopsora pachyrhizi is a devastating pathogen on soybean, endangering soybean production worldwide. Use of Host Induced Gene Silencing (HIGS) and the study of effector proteins could provide novel strategies for pathogen control. For both approaches quantification of transcript abundance by RT-qPCR is essential. [...] Read more.
Phakopsora pachyrhizi is a devastating pathogen on soybean, endangering soybean production worldwide. Use of Host Induced Gene Silencing (HIGS) and the study of effector proteins could provide novel strategies for pathogen control. For both approaches quantification of transcript abundance by RT-qPCR is essential. Suitable stable reference genes for normalization are indispensable to obtain accurate RT-qPCR results. According to the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines and using algorithms geNorm and NormFinder we tested candidate reference genes from P. pachyrhizi and Glycine max for their suitability in normalization of transcript levels throughout the infection process. For P. pachyrhizi we recommend a combination of CytB and PDK or GAPDH for in planta experiments. Gene expression during in vitro stages and over the whole infection process was found to be highly unstable. Here, RPS14 and UbcE2 are ranked best by geNorm and NormFinder. Alternatively CytB that has the smallest Cq range (Cq: quantification cycle) could be used. We recommend specification of gene expression relative to the germ tube stage rather than to the resting urediospore stage. For studies omitting the resting spore and the appressorium stages a combination of Elf3 and RPS9, or PKD and GAPDH should be used. For normalization of soybean genes during rust infection Ukn2 and cons7 are recommended. Full article
(This article belongs to the Special Issue Plant Microbe Interaction)
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Review
Early Pregnancy Biomarkers in Pre-Eclampsia: A Systematic Review and Meta-Analysis
by Pensée Wu, Caroline Van den Berg, Zarko Alfirevic, Shaughn O’Brien, Maria Röthlisberger, Philip Newton Baker, Louise C. Kenny, Karolina Kublickiene and Johannes J. Duvekot
Int. J. Mol. Sci. 2015, 16(9), 23035-23056; https://doi.org/10.3390/ijms160923035 - 23 Sep 2015
Cited by 91 | Viewed by 16227
Abstract
Pre-eclampsia (PE) complicates 2%–8% of all pregnancies and is an important cause of perinatal morbidity and mortality worldwide. In order to reduce these complications and to develop possible treatment modalities, it is important to identify women at risk of developing PE. The use [...] Read more.
Pre-eclampsia (PE) complicates 2%–8% of all pregnancies and is an important cause of perinatal morbidity and mortality worldwide. In order to reduce these complications and to develop possible treatment modalities, it is important to identify women at risk of developing PE. The use of biomarkers in early pregnancy would allow appropriate stratification into high and low risk pregnancies for the purpose of defining surveillance in pregnancy and to administer interventions. We used formal methods for a systematic review and meta-analyses to assess the accuracy of all biomarkers that have been evaluated so far during the first and early second trimester of pregnancy to predict PE. We found low predictive values using individual biomarkers which included a disintegrin and metalloprotease 12 (ADAM-12), inhibin-A, pregnancy associated plasma protein A (PAPP-A), placental growth factor (PlGF) and placental protein 13 (PP-13). The pooled sensitivity of all single biomarkers was 0.40 (95% CI 0.39–0.41) at a false positive rate of 10%. The area under the Summary of Receiver Operating Characteristics Curve (SROC) was 0.786 (SE 0.02). When a combination model was used, the predictive value improved to an area under the SROC of 0.893 (SE 0.03). In conclusion, although there are multiple potential biomarkers for PE their efficacy has been inconsistent and comparisons are difficult because of heterogeneity between different studies. Therefore, there is an urgent need for high quality, large-scale multicentre research in biomarkers for PE so that the best predictive marker(s) can be identified in order to improve the management of women destined to develop PE. Full article
(This article belongs to the Special Issue Prediction, Diagnostics and Prevention of Pregnancy Complications)
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Review
Quo Vadis Clozapine? A Bibliometric Study of 45 Years of Research in International Context
by Francisco López-Muñoz, Javier Sanz-Fuentenebro, Gabriel Rubio, Pilar García-García and Cecilio Álamo
Int. J. Mol. Sci. 2015, 16(9), 23012-23034; https://doi.org/10.3390/ijms160923012 - 23 Sep 2015
Cited by 19 | Viewed by 7872
Abstract
We have carried out a bibliometric study about the international scientific publications on clozapine. We have used the EMBASE and MEDLINE databases, and we applied bibliometric indicators of production, as Price’s Law on the increase of scientific literature. We also calculated the participation [...] Read more.
We have carried out a bibliometric study about the international scientific publications on clozapine. We have used the EMBASE and MEDLINE databases, and we applied bibliometric indicators of production, as Price’s Law on the increase of scientific literature. We also calculated the participation index (PI) of the different countries. The bibliometric data have also been correlated with some social and health data from the 12 most productive countries in biomedicine and health sciences. In addition, 5607 original documents dealing with clozapine, published between 1970 and 2013, were downloaded. Our results state non-fulfilment of Price’s Law, with scientific production on clozapine showing linear growth (r = 0.8691, vs. r = 0.8478 after exponential adjustment). Seven of the 12 journals with the highest numbers of publications on clozapine have an Impact Factor > 2. Among the countries generating clozapine research, the most prominent is the USA (PI = 24.32), followed by the UK (PI = 6.27) and Germany (PI = 5.40). The differences among countries on clozapine research are significantly related to economic variables linked to research. The scientific interest in clozapine remains remarkable, although after the application of bibliometric indicators of production, a saturation point is evident in the growth of scientific literature on this topic. Full article
(This article belongs to the Special Issue Antipsychotics)
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Article
Modulation of the PI3K/Akt Pathway and Bcl-2 Family Proteins Involved in Chicken’s Tubular Apoptosis Induced by Nickel Chloride (NiCl2)
by Hongrui Guo, Hengmin Cui, Xi Peng, Jing Fang, Zhicai Zuo, Junliang Deng, Xun Wang, Bangyuan Wu, Kejie Chen and Jie Deng
Int. J. Mol. Sci. 2015, 16(9), 22989-23011; https://doi.org/10.3390/ijms160922989 - 23 Sep 2015
Cited by 45 | Viewed by 7950
Abstract
Exposure of people and animals to environments highly polluted with nickel (Ni) can cause pathologic effects. Ni compounds can induce apoptosis, but the mechanism and the pathway of Ni compounds-induced apoptosis are unclear. We evaluated the alterations of apoptosis, mitochondrial membrane potential (MMP), [...] Read more.
Exposure of people and animals to environments highly polluted with nickel (Ni) can cause pathologic effects. Ni compounds can induce apoptosis, but the mechanism and the pathway of Ni compounds-induced apoptosis are unclear. We evaluated the alterations of apoptosis, mitochondrial membrane potential (MMP), phosphoinositide-3-kinase (PI3K)/serine-threonine kinase (Akt) pathway, and Bcl-2 family proteins induced by nickel chloride (NiCl2) in the kidneys of broiler chickens, using flow cytometry, terminal deoxynucleotidyl transferase 2ʹ-deoxyuridine 5ʹ-triphosphate dUTP nick end-labeling (TUNEL), immunohistochemstry and quantitative real-time polymerase chain reaction (qRT-PCR). We found that dietary NiCl2 in excess of 300 mg/kg resulted in a significant increase in apoptosis, which was associated with decrease in MMP, and increase in apoptosis inducing factor (AIF) and endonuclease G (EndoG) protein and mRNA expression. Concurrently, NiCl2 inhibited the PI3K/Akt pathway, which was characterized by decreasing PI3K, Akt1 and Akt2 mRNA expression levels. NiCl2 also reduced the protein and mRNA expression of anti-apoptotic Bcl-2 and Bcl-xL and increased the protein and mRNA expression of pro-apoptotic Bax and Bak. These results show that NiCl2 causes mitochondrial-mediated apoptosis by disruption of MMP and increased expression of AIF and EndoG mRNA and protein, and that the underlying mechanism of MMP loss involves the Bcl-2 family proteins modulation and PI3K/Akt pathway inhibition. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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1013 KiB  
Review
Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers
by Sally Temraz, Deborah Mukherji and Ali Shamseddine
Int. J. Mol. Sci. 2015, 16(9), 22976-22988; https://doi.org/10.3390/ijms160922976 - 23 Sep 2015
Cited by 87 | Viewed by 12397
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are frequently implicated in CRC. Targeting the downstream substrate MEK in these mutated tumors stands [...] Read more.
Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are frequently implicated in CRC. Targeting the downstream substrate MEK in these mutated tumors stands out as a potential target in CRC. Several selective inhibitors of MEK have entered clinical trial evaluation; however, clinical activity with single MEK inhibitors has been rarely observed and acquired resistance seems to be inevitable. Amplification of the driving oncogene KRAS(13D), which increases signaling through the ERK1/2 pathway, upregulation of the noncanonical wingless/calcium signaling pathway (Wnt), and coexisting PIK3CA mutations have all been implicated with resistance against MEK inhibitor therapy in KRAS mutated CRC. The Wnt pathway and amplification of the oncogene have also been associated with resistance to MEK inhibitors in CRCs harboring BRAF mutations. Thus, dual targeted inhibition of MEK and PI3K pathway effectors (mTOR, PI3K, AKT, IGF-1R or PI3K/mTOR inhibitors) presents a potential strategy to overcome resistance to MEK inhibitor therapy. Many clinical trials are underway to evaluate multiple combinations of these pathway inhibitors in solid tumors. Full article
(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)
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2896 KiB  
Article
Exogenous GA3 Application Enhances Xylem Development and Induces the Expression of Secondary Wall Biosynthesis Related Genes in Betula platyphylla
by Huiyan Guo, Yucheng Wang, Huizi Liu, Ping Hu, Yuanyuan Jia, Chunrui Zhang, Yanmin Wang, Shan Gu, Chuanping Yang and Chao Wang
Int. J. Mol. Sci. 2015, 16(9), 22960-22975; https://doi.org/10.3390/ijms160922960 - 23 Sep 2015
Cited by 44 | Viewed by 7299
Abstract
Gibberellin (GA) is a key signal molecule inducing differentiation of tracheary elements, fibers, and xylogenesis. However the molecular mechanisms underlying the effect of GA on xylem elongation and secondary wall development in tree species remain to be determined. In this study, Betula platyphylla [...] Read more.
Gibberellin (GA) is a key signal molecule inducing differentiation of tracheary elements, fibers, and xylogenesis. However the molecular mechanisms underlying the effect of GA on xylem elongation and secondary wall development in tree species remain to be determined. In this study, Betula platyphylla (birch) seeds were treated with 300 ppm GA3 and/or 300 ppm paclobutrazol (PAC), seed germination was recorded, and transverse sections of hypocotyls were stained with toluidine blue; the two-month-old seedlings were treated with 50 μM GA3 and/or 50 μM PAC, transverse sections of seedling stems were stained using phloroglucinol–HCl, and secondary wall biosynthesis related genes expression was analyzed by real-time quantitative PCR. Results indicated that germination percentage, energy and time of seeds, hypocotyl height and seedling fresh weight were enhanced by GA3, and reduced by PAC; the xylem development was wider in GA3-treated plants than in the control; the expression of NAC and MYB transcription factors, CESA, PAL, and GA oxidase was up-regulated during GA3 treatment, suggesting their role in GA3-induced xylem development in the birch. Our results suggest that GA3 induces the expression of secondary wall biosynthesis related genes to trigger xylogenesis in the birch plants. Full article
(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism 2015)
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1211 KiB  
Correction
Zhou, N., et al. Exposure of Tumor-Associated Macrophages to ApoptoticMCF-7 Cells Promotes Breast Cancer Growth and Metastasis. Int. J. Mol. Sci. 2015, 16, 11966–11982
by Na Zhou, Yizhuang Zhang, Xuehui Zhang, Zhen Lei, Ruobi Hu, Hui Li, Yiqing Mao, Xi Wang, David M. Irwin, Gang Niu and Huanran Tan
Int. J. Mol. Sci. 2015, 16(9), 22957-22959; https://doi.org/10.3390/ijms160922957 - 22 Sep 2015
Viewed by 3989
Abstract
The authors wish to change Figure 2 in Section 2 of their paper published in IJMS [1]. In Figure 2C, the tumor tissue of the Mac group was mixed up with that of the CoA group. [...] Full article
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Article
Phenotypic and Transcriptomic Analyses of Autotetraploid and Diploid Mulberry (Morus alba L.)
by Fanwei Dai, Zhenjiang Wang, Guoqing Luo and Cuiming Tang
Int. J. Mol. Sci. 2015, 16(9), 22938-22956; https://doi.org/10.3390/ijms160922938 - 22 Sep 2015
Cited by 53 | Viewed by 7695
Abstract
Autopolyploid plants and their organs are often larger than their diploid counterparts, which makes them attractive to plant breeders. Mulberry (Morus alba L.) is an important commercial woody plant in many tropical and subtropical areas. In this study, we obtained a series [...] Read more.
Autopolyploid plants and their organs are often larger than their diploid counterparts, which makes them attractive to plant breeders. Mulberry (Morus alba L.) is an important commercial woody plant in many tropical and subtropical areas. In this study, we obtained a series of autotetraploid mulberry plants resulting from a colchicine treatment. To evaluate the effects of genome duplications in mulberry, we compared the phenotypes and transcriptomes of autotetraploid and diploid mulberry trees. In the autotetraploids, the height, breast-height diameter, leaf size, and fruit size were larger than those of diploids. Transcriptome data revealed that of 21,229 expressed genes only 609 (2.87%) were differentially expressed between diploids and autotetraploids. Among them, 30 genes were associated with the biosynthesis and signal transduction of plant hormones, including cytokinin, gibberellins, ethylene, and auxin. In addition, 41 differentially expressed genes were involved in photosynthesis. These results enhance our understanding of the variations that occur in mulberry autotetraploids and will benefit future breeding work. Full article
(This article belongs to the Special Issue Plant Molecular Biology)
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229 KiB  
Article
Effects of Microcystin-LR Exposure on Spermiogenesis in Nematode Caenorhabditis elegans
by Yunhui Li, Minhui Zhang, Pan Chen, Ran Liu, Geyu Liang, Lihong Yin and Yuepu Pu
Int. J. Mol. Sci. 2015, 16(9), 22927-22937; https://doi.org/10.3390/ijms160922927 - 22 Sep 2015
Cited by 9 | Viewed by 5130
Abstract
Little is known about the effect on spermiogenesis induced by microcystin-leucine arginine (MC-LR), even though such data are very important to better elucidate reproductive health. In the current work, with the aid of nematode Caenorhabditis elegans (C. elegans) as an animal [...] Read more.
Little is known about the effect on spermiogenesis induced by microcystin-leucine arginine (MC-LR), even though such data are very important to better elucidate reproductive health. In the current work, with the aid of nematode Caenorhabditis elegans (C. elegans) as an animal model, we investigated the defects on spermiogenesis induced by MC-LR. Our results showed that MC-LR exposure induced sperm morphology abnormality and caused severe defects of sperm activation, trans-activation, sperm behavior and competition. Additionally, the expression levels of spe-15 were significantly decreased in C. elegans exposed to MC-LR lower than 16.0 μg/L, while the expression levels of spe-10 and fer-1 could be significantly lowered in C. elegans even exposed to 1.0 μg/L of MC-LR. Therefore, the present study reveals that MC-LR can induce adverse effects on spermiogenesis, and those defects of sperm functions may be induced by the decreases of spe-10, spe-15 and fer-1 gene expressions in C. elegans. Full article
(This article belongs to the Section Molecular Toxicology)
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Article
Transcriptome Analysis and Identification of Differentially Expressed Transcripts of Immune-Related Genes in Spleen of Gosling and Adult Goose
by Anqi Wang, Fei Liu, Shun Chen, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Kunfeng Sun, Ying Wu, Xiaoyue Chen and Anchun Cheng
Int. J. Mol. Sci. 2015, 16(9), 22904-22926; https://doi.org/10.3390/ijms160922904 - 22 Sep 2015
Cited by 19 | Viewed by 6717
Abstract
The goose (Anser cygnoides), having high nutritional value, high-quality feathers and high economic benefit, is an economically important poultry species. However, the molecular mechanisms underlying the higher susceptibility to pathogens in goslings than in adult geese remains poorly understood. In this [...] Read more.
The goose (Anser cygnoides), having high nutritional value, high-quality feathers and high economic benefit, is an economically important poultry species. However, the molecular mechanisms underlying the higher susceptibility to pathogens in goslings than in adult geese remains poorly understood. In this study, the histological sections of spleen tissue from a two-week-old gosling and an adult goose, respectively, were subjected to comparative analysis. The spleen of gosling was mainly composed of mesenchyma, accompanied by scattered lymphocytes, whereas the spleen parenchyma was well developed in the adult goose. To investigate goose immune-related genes, we performed deep transcriptome and gene expression analyses of the spleen samples using paired-end sequencing technology (Illumina). In total, 50,390 unigenes were assembled using Trinity software and TGICL software. Moreover, these assembled unigenes were annotated with gene descriptions and gene ontology (GO) analysis was performed. Through Kyoto encyclopedia of genes and genomes (KEGG) analysis, we investigated 558 important immune-relevant unigenes and 23 predicted cytokines. In addition, 22 immune-related genes with differential expression between gosling and adult goose were identified, among which the three genes showing largest differences in expression were immunoglobulin alpha heavy chain (IgH), mannan-binding lectin serine protease 1 isoform X1 (MASP1) and C–X–C chemokine receptor type 4 (CXCR4). Finally, of these 22 differentially expressed immune-related genes, seven genes, including tumor necrosis factor receptor superfamily member 13B (TNFRSF13B), C-C motif chemokine 4-like (CCL4), CXCR4, interleukin 2 receptor alpha (IL2RA), MHC class I heavy chain (MHCIα), transporter of antigen processing 2 (TAP2), IgH, were confirmed by quantitative real-time PCR (qRT-PCR). The expression levels of all the candidate unigenes were up-regulated in adult geese other than that of TNFRSF13B. The comparative analysis of the spleen transcriptomes of gosling and adult goose may promote better understanding of immune molecular development in goose. Full article
(This article belongs to the Section Biochemistry)
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Article
Roles of NlAKTIP in the Growth and Eclosion of the Rice Brown Planthopper, Nilaparvata lugens Stål, as Revealed by RNA Interference
by Peiying Hao, Chaofeng Lu, Yan Ma, Lingbo Xu, Jiajun Zhu and Xiaoping Yu
Int. J. Mol. Sci. 2015, 16(9), 22888-22903; https://doi.org/10.3390/ijms160922888 - 22 Sep 2015
Cited by 10 | Viewed by 5967
Abstract
AKT-interacting protein (AKTIP) interacts with serine/threonine protein kinase B (PKB)/AKT. AKTIP modulates AKT’s activity by enhancing the phosphorylation of the regulatory site and plays a crucial role in multiple biological processes. In this study, the full length cDNA of NlAKTIP, a novel [...] Read more.
AKT-interacting protein (AKTIP) interacts with serine/threonine protein kinase B (PKB)/AKT. AKTIP modulates AKT’s activity by enhancing the phosphorylation of the regulatory site and plays a crucial role in multiple biological processes. In this study, the full length cDNA of NlAKTIP, a novel AKTIP gene in the brown planthopper (BPH) Nilaparvata lugens, was cloned. The reverse transcription quantitive PCR (RT-qPCR) results showed that the NlAKTIP gene was strongly expressed in gravid female adults, but was relatively weakly expressed in nymphs and male adult BPH. In female BPH, treatment with dsAKTIP resulted in the efficient silencing of NlAKTIP, leading to a significant reduction of mRNA levels, about 50% of those of the untreated control group at day 7 of the study. BPH fed with dsAKTIP had reduced growth with lower body weights and smaller sizes, and the body weight of BPH treated with dsAKTIP at day 7 decreased to about 30% of that of the untreated control. Treatment of dsAKTIP significantly delayed the eclosion for over 7 days relative to the control group and restricted ovarian development to Grade I (transparent stage), whereas the controls developed to Grade IV (matured stage). These results indicated that NlAKTIP is crucial to the growth and development of female BPH. This study provided a valuable clue of a potential target NlAKTIP for inhibiting the BPH, and also provided a new point of view on the interaction between BPH and resistant rice. Full article
(This article belongs to the Section Biochemistry)
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Review
The Current Role of Omega-3 Fatty Acids in the Management of Atrial Fibrillation
by Georgios A. Christou, Konstantinos A. Christou, Panagiotis Korantzopoulos, Evangelos C. Rizos, Dimitrios N. Nikas and John A. Goudevenos
Int. J. Mol. Sci. 2015, 16(9), 22870-22887; https://doi.org/10.3390/ijms160922870 - 22 Sep 2015
Cited by 20 | Viewed by 6105
Abstract
Background: The main dietary source of omega-3 polyunsaturated fatty acids (n-3 PUFA) is fish, which contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In the present manuscript, we aimed to review the current evidence regarding the clinical role of n-3 PUFA in the [...] Read more.
Background: The main dietary source of omega-3 polyunsaturated fatty acids (n-3 PUFA) is fish, which contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In the present manuscript, we aimed to review the current evidence regarding the clinical role of n-3 PUFA in the prevention of atrial fibrillation (AF) and the possible underlying mechanisms. Methods: A literature search based on PubMed listings was performed using “Omega-3 fatty acids” and “atrial fibrilation” as key search terms. Results: n-3 PUFA have been shown to attenuate structural atrial remodeling, prolong atrial effective refractory period through the prevention of reentry and suppress ectopic firing from pulmonary veins. Dietary fish intake has been found to have no effect on the incidence of AF in the majority of studies. Circulating DHA has been consistently reported to be inversely associated with AF risk, whereas EPA has no such effect. The majority of studies investigating the impact of n-3 PUFA supplementation on the incidence of AF following cardiac surgery reported no benefit, though most of them did not use n-3 PUFA pretreatment for adequate duration. Studies using adequate four-week pretreatment with n-3 PUFA before cardioversion of AF showed a reduction of the AF incidence. Conclusions: Although n-3 PUFA have antiarrhythmogenic properties, their clinical efficacy on the prevention of AF is not consistently supported. Further well-designed studies are needed to overcome the limitations of the existing studies and provide robust conclusions. Full article
(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Diseases)
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Article
The Role of PTP1B O-GlcNAcylation in Hepatic Insulin Resistance
by Yun Zhao, Zhuqi Tang, Aiguo Shen, Tao Tao, Chunhua Wan, Xiaohui Zhu, Jieru Huang, Wanlu Zhang, Nana Xia, Suxin Wang, Shiwei Cui and Dongmei Zhang
Int. J. Mol. Sci. 2015, 16(9), 22856-22869; https://doi.org/10.3390/ijms160922856 - 22 Sep 2015
Cited by 24 | Viewed by 6693
Abstract
Protein tyrosine phosphatase 1B (PTP1B), which can directly dephosphorylate both the insulin receptor and insulin receptor substrate 1 (IRS-1), thereby terminating insulin signaling, reportedly plays an important role in insulin resistance. Accumulating evidence has demonstrated that O-GlcNAc modification regulates functions of several [...] Read more.
Protein tyrosine phosphatase 1B (PTP1B), which can directly dephosphorylate both the insulin receptor and insulin receptor substrate 1 (IRS-1), thereby terminating insulin signaling, reportedly plays an important role in insulin resistance. Accumulating evidence has demonstrated that O-GlcNAc modification regulates functions of several important components of insulin signal pathway. In this study, we identified that PTP1B is modified by O-GlcNAcylation at three O-GlcNAc sites (Ser104, Ser201, and Ser386). Palmitate acid (PA) impaired the insulin signaling, indicated by decreased phosphorylation of both serine/threonine-protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) following insulin administration, and upregulated PTP1B O-GlcNAcylation in HepG2 cells. Compared with the wild-type, intervention PTP1B O-GlcNAcylation by site-directed gene mutation inhibited PTP1B phosphatase activity, resulted in a higher level of phosphorylated Akt and GSK3β, recovered insulin sensitivity, and improved lipid deposition in HepG2 cells. Taken together, our research showed that O-GlcNAcylation of PTP1B can influence insulin signal transduction by modulating its own phosphatase activity, which participates in the process of hepatic insulin resistance. Full article
(This article belongs to the Special Issue Glycosylation and Glycoproteins)
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Review
Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach
by Lian Chen and Hengmin Cui
Int. J. Mol. Sci. 2015, 16(9), 22830-22855; https://doi.org/10.3390/ijms160922830 - 22 Sep 2015
Cited by 130 | Viewed by 21698
Abstract
Glutamine metabolism has been proved to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells, which makes glutamine an appealing target for cancer therapy. In order to be well used by cells, glutamine must be transported to [...] Read more.
Glutamine metabolism has been proved to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells, which makes glutamine an appealing target for cancer therapy. In order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase. There are currently several drugs that target glutaminase under development or clinical trials. Also, glutamine metabolism restriction has been proved to be effective in inhibiting tumor growth both in vivo and vitro through inducing apoptosis, growth arrest and/or autophagy. Here, we review recent researches about glutamine metabolism in cancer, and cell death induced by targeting glutamine, and their potential roles in cancer therapy. Full article
(This article belongs to the Collection Programmed Cell Death and Apoptosis)
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693 KiB  
Review
Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia
by Marialuisa Polillo, Sara Galimberti, Claudia Baratè, Mario Petrini, Romano Danesi and Antonello Di Paolo
Int. J. Mol. Sci. 2015, 16(9), 22811-22829; https://doi.org/10.3390/ijms160922811 - 21 Sep 2015
Cited by 33 | Viewed by 8513
Abstract
Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics [...] Read more.
Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics and pharmacodynamics of BCR-ABL1 tyrosine kinase activity inhibitors (TKIs). Transmembrane transporters seem to influence in a significant manner the disposition of TKIs, especially that of imatinib at both cellular and systemic levels. In particular, members of the ATP-binding cassette (ABC) family (namely ABCB1 and ABCG2) together with solute carrier (SLC) transporters (i.e., SLC22A1) are responsible for the differences in drug pharmacokinetics. In the case of the newer TKIs, such as nilotinib and dasatinib, the substrate affinity of these drugs for transporters is variable but lower than that measured for imatinib. In this scenario, the investigation of genetic variants as possible predictive markers has led to some discordant results. With the partial exception of imatinib, these discrepancies seem to limit the application of discovered biomarkers in the clinical settings. In order to overcome these issues, larger prospective confirmative trials are needed. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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Article
Chemically Bonding of Amantadine with Gardenamide A Enhances the Neuroprotective Effects against Corticosterone-Induced Insults in PC12 Cells
by Jiaqiang Zhao, Lizhi Peng, Wenhua Zheng, Rikang Wang, Lei Zhang, Jian Yang and Heru Chen
Int. J. Mol. Sci. 2015, 16(9), 22795-22810; https://doi.org/10.3390/ijms160922795 - 21 Sep 2015
Cited by 11 | Viewed by 5910
Abstract
Two amantadine (ATD)-gardenamide A (GA) ligands have been designed and synthesized. The bonding of ATD with GA through a methylene carbonyl brigde (L1) enhances the neuroprotective effect against corticosterone (CORT)-induced impairments in PC12 cells; while the bonding through a succinyl brigde [...] Read more.
Two amantadine (ATD)-gardenamide A (GA) ligands have been designed and synthesized. The bonding of ATD with GA through a methylene carbonyl brigde (L1) enhances the neuroprotective effect against corticosterone (CORT)-induced impairments in PC12 cells; while the bonding through a succinyl brigde (L2) does not. L1 reduces the level of reactive oxygen species (ROS) and cell apoptosis generated by CORT. It restores CORT-changed cell morphology to a state that is closed to normal PC12 cells. One mechanism of L1 to attenuate CORT-induced cell apoptosis is through the adjustment of both caspase-3 and Bcl-2 proteins. Like GA, both nNOS and eNOS might be involved in the neuroprotective mechanism of L1. All the evidences suggest that L1 may be a potential agent to treat depression. Full article
(This article belongs to the Section Biochemistry)
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Article
Enantioselective Pharmacokinetics of α-Lipoic Acid in Rats
by Ryota Uchida, Hinako Okamoto, Naoko Ikuta, Keiji Terao and Takashi Hirota
Int. J. Mol. Sci. 2015, 16(9), 22781-22794; https://doi.org/10.3390/ijms160922781 - 21 Sep 2015
Cited by 31 | Viewed by 6136
Abstract
α-Lipoic acid (LA) is widely used for nutritional supplements as a racemic mixture, even though the R enantiomer is biologically active. After oral administration of the racemic mixture (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA) mixed at the ratio of [...] Read more.
α-Lipoic acid (LA) is widely used for nutritional supplements as a racemic mixture, even though the R enantiomer is biologically active. After oral administration of the racemic mixture (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA) mixed at the ratio of 50:50) to rats, RLA showed higher plasma concentration than SLA, and its area under the plasma concentration-time curve from time zero to the last (AUC) was significantly about 1.26 times higher than that of SLA. However, after intravenous administration of the racemic mixture, the pharmacokinetic profiles, initial concentration (C0), AUC, and half-life (T1/2) of the enantiomers were not significantly different. After oral and intraduodenal administration of the racemic mixture to pyrolus-ligated rats, the AUCs of RLA were significantly about 1.24 and 1.32 times higher than that of SLA, respectively. In addition, after intraportal administration the AUC of RLA was significantly 1.16 times higher than that of SLA. In conclusion, the enantioselective pharmacokinetics of LA in rats arose from the fraction absorbed multiplied by gastrointestinal availability (FaFg) and hepatic availability (Fh), and not from the total clearance. Full article
(This article belongs to the Section Biochemistry)
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Review
Interaction of DNA with Simple and Mixed Ligand Copper(II) Complexes of 1,10-Phenanthrolines as Studied by DNA-Fiber EPR Spectroscopy
by Makoto Chikira, Chew Hee Ng and Mallayan Palaniandavar
Int. J. Mol. Sci. 2015, 16(9), 22754-22780; https://doi.org/10.3390/ijms160922754 - 21 Sep 2015
Cited by 47 | Viewed by 9672
Abstract
The interaction of simple and ternary Cu(II) complexes of 1,10-phenanthrolines with DNA has been studied extensively because of their various interesting and important functions such as DNA cleavage activity, cytotoxicity towards cancer cells, and DNA based asymmetric catalysis. Such functions are closely related [...] Read more.
The interaction of simple and ternary Cu(II) complexes of 1,10-phenanthrolines with DNA has been studied extensively because of their various interesting and important functions such as DNA cleavage activity, cytotoxicity towards cancer cells, and DNA based asymmetric catalysis. Such functions are closely related to the DNA binding modes of the complexes such as intercalation, groove binding, and electrostatic surface binding. A variety of spectroscopic methods have been used to study the DNA binding mode of the Cu(II) complexes. Of all these methods, DNA-fiber electron paramagnetic resonance (EPR) spectroscopy affords unique information on the DNA binding structures of the complexes. In this review we summarize the results of our DNA-fiber EPR studies on the DNA binding structure of the complexes and discuss them together with the data accumulated by using other measurements. Full article
(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)
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Article
Effects of Non-Natural Amino Acid Incorporation into the Enzyme Core Region on Enzyme Structure and Function
by H. Edward Wong and Inchan Kwon
Int. J. Mol. Sci. 2015, 16(9), 22735-22753; https://doi.org/10.3390/ijms160922735 - 21 Sep 2015
Cited by 6 | Viewed by 6635
Abstract
Techniques to incorporate non-natural amino acids (NNAAs) have enabled biosynthesis of proteins containing new building blocks with unique structures, chemistry, and reactivity that are not found in natural amino acids. It is crucial to understand how incorporation of NNAAs affects protein function because [...] Read more.
Techniques to incorporate non-natural amino acids (NNAAs) have enabled biosynthesis of proteins containing new building blocks with unique structures, chemistry, and reactivity that are not found in natural amino acids. It is crucial to understand how incorporation of NNAAs affects protein function because NNAA incorporation may perturb critical function of a target protein. This study investigates how the site-specific incorporation of NNAAs affects catalytic properties of an enzyme. A NNAA with a hydrophobic and bulky sidechain, 3-(2-naphthyl)-alanine (2Nal), was site-specifically incorporated at six different positions in the hydrophobic core of a model enzyme, murine dihydrofolate reductase (mDHFR). The mDHFR variants with a greater change in van der Waals volume upon 2Nal incorporation exhibited a greater reduction in the catalytic efficiency. Similarly, the steric incompatibility calculated using RosettaDesign, a protein stability calculation program, correlated with the changes in the catalytic efficiency. Full article
(This article belongs to the Special Issue Protein Engineering)
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Article
The Use of a Liposomal Formulation Incorporating an Antimicrobial Peptide from Tilapia as a New Adjuvant to Epirubicin in Human Squamous Cell Carcinoma and Pluripotent Testicular Embryonic Carcinoma Cells
by Yu-Li Lo, Hsin-Pin Lee and Wei-Chen Tu
Int. J. Mol. Sci. 2015, 16(9), 22711-22734; https://doi.org/10.3390/ijms160922711 - 18 Sep 2015
Cited by 12 | Viewed by 6203
Abstract
This study aims to explore the effects and mechanisms of hepcidin, a potential antimicrobial peptide from Tilapia, and epirubicin (Epi), an antineoplastic agent, on the generation of reactive oxygen species (ROS) and link the ROS levels to the reversal mechanisms of multidrug resistance [...] Read more.
This study aims to explore the effects and mechanisms of hepcidin, a potential antimicrobial peptide from Tilapia, and epirubicin (Epi), an antineoplastic agent, on the generation of reactive oxygen species (ROS) and link the ROS levels to the reversal mechanisms of multidrug resistance (MDR) by epirubicin and hepcidin in human squamous cell carcinoma SCC15 and human embryonal carcinoma NT2D1 cells. The cells, pretreated with hepcidin, epirubicin, or a combination of these compounds in PEGylated liposomes, were used to validate the molecular mechanisms involved in inhibiting efflux transporters and inducing apoptosis as evaluated by cytotoxicity, intracellular accumulation, mRNA levels, cell cycle distribution, and caspase activity of this combination. We found that hepcidin significantly enhanced the cytotoxicity of epirubicin in liposomes. The co-incubation of epirubicin with hepcidin in liposomes intensified the ROS production, including hydrogen peroxide and superoxide free radicals. Hepcidin significantly increased epirubicin intracellular uptake into NT2D1 and SCC15 cells, as supported by the diminished mRNA expressions of MDR1, MDR-associated protein (MRP) 1, and MRP2. Hepcidin and/or epirubicin in liposomes triggered apoptosis, as verified by the reduced mitochondrial membrane potential, increased sub-G1 phase of cell cycle, incremental populations of apoptosis using annexin V/PI assay, and chromatin condensation. As far as we know, this is the first example showing that PEGylated liposomal TH1-5 and epirubicin gives rise to cell death in human squamous carcinoma and testicular embryonic carcinoma cells through the reduced epirubicin efflux via ROS-mediated suppression of P-gp and MRPs and concomitant initiation of mitochondrial apoptosis pathway. Hence, hepcidin in PEGylated liposomes may function as an adjuvant to anticancer drugs, thus demonstrating a novel strategy for reversing MDR. Full article
(This article belongs to the Special Issue Bioactivity of Marine Natural Products)
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Article
Transcriptome Analysis Revealed the Embryo-Induced Gene Expression Patterns in the Endometrium from Meishan and Yorkshire Pigs
by Jiangnan Huang, Ruize Liu, Lijie Su, Qian Xiao and Mei Yu
Int. J. Mol. Sci. 2015, 16(9), 22692-22710; https://doi.org/10.3390/ijms160922692 - 18 Sep 2015
Cited by 15 | Viewed by 5709
Abstract
The expression patterns in Meishan- and Yorkshire-derived endometrium during early (gestational day 15) and mid-gestation (gestational days 26 and 50) were investigated, respectively. Totally, 689 and 1649 annotated genes were identified to be differentially expressed in Meishan and Yorkshire endometrium during the three [...] Read more.
The expression patterns in Meishan- and Yorkshire-derived endometrium during early (gestational day 15) and mid-gestation (gestational days 26 and 50) were investigated, respectively. Totally, 689 and 1649 annotated genes were identified to be differentially expressed in Meishan and Yorkshire endometrium during the three gestational stages, respectively. Hierarchical clustering analysis identified that, of the annotated differentially expressed genes (DEGs), 73 DEGs were unique to Meishan endometrium, 536 DEGs were unique to Yorkshire endometrium, and 228 DEGs were common in Meishan and Yorkshire endometriums. Subsequently, DEGs in each of the three types of expression patterns were grouped into four distinct categories according to the similarities in their temporal expression patterns. The expression patterns identified from the microarray analysis were validated by quantitative RT-PCR. The functional enrichment analysis revealed that the common DEGs were enriched in pathways of steroid metabolic process and regulation of retinoic acid receptor signaling. These unique DEGs in Meishan endometrium were involved in cell cycle and adherens junction. The DEGs unique to Yorkshire endometrium were associated with regulation of Rho protein signal transduction, maternal placenta development and cell proliferation. This study revealed the different gene expression patterns or pathways related to the endometrium remodeling in Meishan and Yorkshire pigs, respectively. These unique DEGs in either Meishan or Yorkshire endometriums may contribute to the divergence of the endometrium environment in the two pig breeds. Full article
(This article belongs to the Section Biochemistry)
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Article
Poncirin Induces Apoptosis in AGS Human Gastric Cancer Cells through Extrinsic Apoptotic Pathway by up-Regulation of Fas Ligand
by Venu Venkatarame Gowda Saralamma, Arulkumar Nagappan, Gyeong Eun Hong, Ho Jeong Lee, Silvia Yumnam, Suchismita Raha, Jeong Doo Heo, Sang Joon Lee, Won Sup Lee, Eun Hee Kim and Gon Sup Kim
Int. J. Mol. Sci. 2015, 16(9), 22676-22691; https://doi.org/10.3390/ijms160922676 - 18 Sep 2015
Cited by 35 | Viewed by 9352
Abstract
Poncirin, a natural bitter flavanone glycoside abundantly present in many species of citrus fruits, has various biological benefits such as anti-oxidant, anti-microbial, anti-inflammatory and anti-cancer activities. The anti-cancer mechanism of Poncirin remains elusive to date. In this study, we investigated the anti-cancer effects [...] Read more.
Poncirin, a natural bitter flavanone glycoside abundantly present in many species of citrus fruits, has various biological benefits such as anti-oxidant, anti-microbial, anti-inflammatory and anti-cancer activities. The anti-cancer mechanism of Poncirin remains elusive to date. In this study, we investigated the anti-cancer effects of Poncirin in AGS human gastric cancer cells (gastric adenocarcinoma). The results revealed that Poncirin could inhibit the proliferation of AGS cells in a dose-dependent manner. It was observed Poncirin induced accumulation of sub-G1 DNA content, apoptotic cell population, apoptotic bodies, chromatin condensation, and DNA fragmentation in a dose-dependent manner in AGS cells. The expression of Fas Ligand (FasL) protein was up-regulated dose dependently in Poncirin-treated AGS cells Moreover, Poncirin in AGS cells induced activation of Caspase-8 and -3, and subsequent cleavage of poly(ADP-ribose) polymerase (PARP). Inhibitor studies’ results confirm that the induction of caspase-dependent apoptotic cell death in Poncirin-treated AGS cells was led by the Fas death receptor. Interestingly, Poncirin did not show any effect on mitochondrial membrane potential (ΔΨm), pro-apoptotic proteins (Bax and Bak) and anti-apoptotic protein (Bcl-xL) in AGS-treated cells followed by no activation in the mitochondrial apoptotic protein caspase-9. This result suggests that the mitochondrial-mediated pathway is not involved in Poncirin-induced cell death in gastric cancer. These findings suggest that Poncirin has a potential anti-cancer effect via extrinsic pathway-mediated apoptosis, possibly making it a strong therapeutic agent for human gastric cancer. Full article
(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables)
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Article
SOCS3 Methylation Predicts a Poor Prognosis in HBV Infection-Related Hepatocellular Carcinoma
by Xin Zhang, Qingshan You, Xiaolei Zhang and Xiangmei Chen
Int. J. Mol. Sci. 2015, 16(9), 22662-22675; https://doi.org/10.3390/ijms160922662 - 18 Sep 2015
Cited by 26 | Viewed by 5463
Abstract
Suppressor of cytokine signaling 3 (SOCS3) plays crucial roles in JAK/STAT signaling pathway inhibition in hepatocellular carcinoma (HCC). However, the methylation status of SOCS3 in HBV infection-related HCC and the relationship between SOCS3 methylation and the clinical outcome remain unknown. Here, [...] Read more.
Suppressor of cytokine signaling 3 (SOCS3) plays crucial roles in JAK/STAT signaling pathway inhibition in hepatocellular carcinoma (HCC). However, the methylation status of SOCS3 in HBV infection-related HCC and the relationship between SOCS3 methylation and the clinical outcome remain unknown. Here, we reported that in HCC tumor tissues, two regions of the CpG island (CGI) in the SOCS3 promoter were subjected to methylation analysis and only the region close to the translational start site of SOCS3 was hypermethylated. In HCC tumor tissues, SOCS3 showed an increased methylation frequency and intensity compared with that in the adjacent non-tumor tissues. Moreover, SOCS3 expression was significantly down-regulated in HCC cell lines and tumor tissues, and this was inversely correlated with methylation. Kaplan–Meier curve analysis revealed that in patients with an hepatitis B virus (HBV) infection background, SOCS3 hypermethylation was significantly correlated with a poor clinical outcome of HCC patients. Our findings indicated that SOCS3 hypermethylation has already happened in non-tumor tissues and increased in both frequency and intensity in tumor tissues. This suggests that the methylation of SOCS3 could predict a poor prognosis in HBV infection-related HCC patients. Full article
(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)
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1149 KiB  
Review
ω-3 Fatty Acids and Cardiovascular Diseases: Effects, Mechanisms and Dietary Relevance
by Hanne K. Maehre, Ida-Johanne Jensen, Edel O. Elvevoll and Karl-Erik Eilertsen
Int. J. Mol. Sci. 2015, 16(9), 22636-22661; https://doi.org/10.3390/ijms160922636 - 18 Sep 2015
Cited by 87 | Viewed by 18086
Abstract
ω-3 fatty acids (n-3 FA) have, since the 1970s, been associated with beneficial health effects. They are, however, prone to lipid peroxidation due to their many double bonds. Lipid peroxidation is a process that may lead to increased oxidative stress, a [...] Read more.
ω-3 fatty acids (n-3 FA) have, since the 1970s, been associated with beneficial health effects. They are, however, prone to lipid peroxidation due to their many double bonds. Lipid peroxidation is a process that may lead to increased oxidative stress, a condition associated with adverse health effects. Recently, conflicting evidence regarding the health benefits of intake of n-3 from seafood or n-3 supplements has emerged. The aim of this review was thus to examine recent literature regarding health aspects of n-3 FA intake from fish or n-3 supplements, and to discuss possible reasons for the conflicting findings. There is a broad consensus that fish and seafood are the optimal sources of n-3 FA and consumption of approximately 2–3 servings per week is recommended. The scientific evidence of benefits from n-3 supplementation has diminished over time, probably due to a general increase in seafood consumption and better pharmacological intervention and acute treatment of patients with cardiovascular diseases (CVD). Full article
(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Diseases)
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Article
Biliverdin Reductase A (BVRA) Mediates Macrophage Expression of Interleukin-10 in Injured Kidney
by Zhizhi Hu, Guangchang Pei, Pengge Wang, Juan Yang, Fengmin Zhu, Yujiao Guo, Meng Wang, Ying Yao, Rui Zeng, Wenhui Liao and Gang Xu
Int. J. Mol. Sci. 2015, 16(9), 22621-22635; https://doi.org/10.3390/ijms160922621 - 18 Sep 2015
Cited by 17 | Viewed by 8317
Abstract
Biliverdin reductase A is an enzyme, with serine/threonine/tyrosine kinase activation, converting biliverdin (BV) to bilirubin (BR) in heme degradation pathway. It has been reported to have anti-inflammatory and antioxidant effect in monocytes and human glioblastoma. However, the function of BVRA in polarized macrophage [...] Read more.
Biliverdin reductase A is an enzyme, with serine/threonine/tyrosine kinase activation, converting biliverdin (BV) to bilirubin (BR) in heme degradation pathway. It has been reported to have anti-inflammatory and antioxidant effect in monocytes and human glioblastoma. However, the function of BVRA in polarized macrophage was unknown. This study aimed to investigate the effect of BVRA on macrophage activation and polarization in injured renal microenvironment. Classically activated macrophages (M1macrophages) and alternative activation of macrophages (M2 macrophages) polarization of murine bone marrow derived macrophage was induced by GM-CSF and M-CSF. M1 polarization was associated with a significant down-regulation of BVRA and Interleukin-10 (IL-10), and increased secretion of TNF-α. We also found IL-10 expression was increased in BVRA over-expressed macrophages, while it decreased in BVRA knockdown macrophages. In contrast, BVRA over-expressed or knockdown macrophages had no effect on TNF-α expression level, indicating BVRA mediated IL-10 expression in macrophages. Furthermore, we observed in macrophages infected with recombinant adenoviruses BVRA gene, which BVRA over-expressed enhanced both INOS and ARG-1 mRNA expression, resulting in a specific macrophage phenotype. Through in vivo study, we found BVRA positive macrophages largely existed in mice renal ischemia perfusion injury. With the treatment of the regular cytokines GM-CSF, M-CSF or LPS, excreted in the injured renal microenvironment, IL-10 secretion was significantly increased in BVRA over-expressed macrophages. In conclusion, the BVRA positive macrophage is a source of anti-inflammatory cytokine IL-10 in injured kidney, which may provide a potential target for treatment of kidney disease. Full article
(This article belongs to the Section Biochemistry)
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Article
Identification and Characterization of CYP9A40 from the Tobacco Cutworm Moth (Spodoptera litura), a Cytochrome P450 Gene Induced by Plant Allelochemicals and Insecticides
by Rui-Long Wang, Christian Staehelin, Qing-Qing Xia, Yi-Juan Su and Ren-Sen Zeng
Int. J. Mol. Sci. 2015, 16(9), 22606-22620; https://doi.org/10.3390/ijms160922606 - 18 Sep 2015
Cited by 54 | Viewed by 6212
Abstract
Cytochrome P450 monooxygenases (P450s) of insects play crucial roles in the metabolism of endogenous and dietary compounds. Tobacco cutworm moth (Spodoptera litura), an important agricultural pest, causes severe yield losses in many crops. In this study, we identified CYP9A40, a [...] Read more.
Cytochrome P450 monooxygenases (P450s) of insects play crucial roles in the metabolism of endogenous and dietary compounds. Tobacco cutworm moth (Spodoptera litura), an important agricultural pest, causes severe yield losses in many crops. In this study, we identified CYP9A40, a novel P450 gene of S. litura, and investigated its expression profile and potential role in detoxification of plant allelochemicals and insecticides. The cDNA contains an open reading frame encoding 529 amino acid residues. CYP9A40 transcripts were found to be accumulated during various development stages of S. litura and were highest in fifth and sixth instar larvae. CYP9A40 was mainly expressed in the midgut and fat body. Larval consumption of xenobiotics, namely plant allelochemicals (quercetin and cinnamic acid) and insecticides (deltamethrin and methoxyfenozide) induced accumulation of CYP9A40 transcripts in the midgut and fat body. Injection of dsCYP9A40 (silencing of CYP9A40 by RNA interference) significantly increased the susceptibility of S. litura larvae to the tested plant allelochemicals and insecticides. These results indicate that CYP9A40 expression in S. litura is related to consumption of xenobiotics and suggest that CYP9A40 is involved in detoxification of these compounds. Full article
(This article belongs to the Section Biochemistry)
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Article
Expression of PD-1 Molecule on Regulatory T Lymphocytes in Patients with Insulin-Dependent Diabetes Mellitus
by Valentina Perri, Benedetta Russo, Antonino Crinò, Riccardo Schiaffini, Ezio Giorda, Marco Cappa, Maria Manuela Rosado and Alessandra Fierabracci
Int. J. Mol. Sci. 2015, 16(9), 22584-22605; https://doi.org/10.3390/ijms160922584 - 18 Sep 2015
Cited by 40 | Viewed by 6694
Abstract
Type 1 diabetes is caused by autoreactive T cells that destroy pancreatic beta cells. Animal models suggested that a CD4+CD25+ population has a regulatory function capable of preventing activation and effector functions of autoreactive T cells. However, the role of [...] Read more.
Type 1 diabetes is caused by autoreactive T cells that destroy pancreatic beta cells. Animal models suggested that a CD4+CD25+ population has a regulatory function capable of preventing activation and effector functions of autoreactive T cells. However, the role of CD4+CD25high T cells in autoimmunity and their molecular mechanisms remain the subject of investigation. We therefore evaluated T regulatory cell frequencies and their PD-1 expression in the peripheral blood of long-standing diabetics under basal conditions and after CD3/CD28 stimulation. Under basal conditions, the percentages of T regulatory cells were significantly higher while that of T effector cells were significantly lower in patients than in controls. The ratio of regulatory to effector T cells was higher in patients than that in controls, suggesting that T regulatory cells were functional in patients. Percentages of total PD-1+, PD-1low and PD-1high expressing T regulatory cells did not change in patients and in controls. After stimulation, a defect in T regulatory cell proliferation was observed in diabetics and the percentages of total PD-1+, PD-1low and PD-1high expressing cells were lower in patients. Our data suggest a defective activation of T regulatory cells in long-standing diabetics due to a lower expression of PD-1 on their surface. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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