Maternal exercise represses Nox4 via SIRT1 to prevent vascular oxidative stress and endothelial dysfunction in SHR offspring

Maternal exercise during pregnancy has emerged as a potentially promising approach to protect offspring from cardiovascular disease, including hypertension. Although endothelial dysfunction is involved in the pathophysiology of hypertension, limited studies have characterized how maternal exercise influences endothelial function of hypertensive offspring. In this study, pregnant spontaneously hypertensive rats and Wistar-Kyoto rats were assigned either to a sedentary lifestyle or to swimming training daily, and fetal histone deacetylase-mediated epigenetic modification and offspring vascular function of mesenteric arteries were analyzed. Maternal exercise ameliorated the impairment of acetylcholine-induced vasodilation without affecting sodium nitroprusside-induced vasodilation in mesenteric arteries from the hypertensive offspring. In accordance, maternal exercise reduced NADPH oxidase-4 (Nox4) protein to prevent the loss of nitric oxide generation and increased reactive oxygen species production in mesenteric arteries of hypertensive offspring. We further found that maternal exercise during pregnancy upregulated vascular SIRT1 (sirtuin 1) expression, leading to a low level of H3K9ac (histone H3 lysine 9 acetylation), resulting in the transcriptional downregulation of Nox4 in mesenteric arteries of hypertensive fetuses. These findings show that maternal exercise alleviates oxidative stress and the impairment of endothelium-dependent vasodilatation via SIRT1-regulated deacetylation of Nox4, which might contribute to improved vascular function in hypertensive offspring

Regulation of Ferredoxin-NADP+ Oxidoreductase to Cyclic Electron Transport in High Salinity Stressed Pyropia yezoensis

Pyropia yezoensis can survive the severe water loss that occurs during low tide, making it an ideal species to investigate the acclimation mechanism of intertidal seaweed to special extreme environments. In this study, we determined the effects of high salinity on photosynthesis using increasing salinity around algal tissues. Both electron transport rates, ETR (I) and ETR (II), showed continuous decreases as the salinity increased. However, the difference between these factors remained relatively stable, similar to the control. Inhibitor experiments illustrated that there were at least three different cyclic electron transport pathways. Under conditions of severe salinity, NAD(P)H could be exploited as an endogenous electron donor to reduce the plastoquinone pool in Py. yezoensis. Based on these findings, we next examined how these different cyclic electron transport (CETs) pathways were coordinated by cloning the gene (HM370553) for ferredoxin-NADP+ oxidoreductase (FNR). A phylogenetic tree was constructed, and the evolutionary relationships among different FNRs were evaluated. The results indicated that the Py. yezoensis FNR showed a closer relationship with cyanobacterial FNR. The results of both real-time polymerase chain reaction and western blotting showed that the enzyme was upregulated under 90–120‰ salinity. Due to the structure-function correlations in organism, Py. yezoensis FNR was proposed to be involved in NAD(P)H-dependent Fd+ reduction under severe salinity conditions. Thus, through the connection between different donors bridged by FNR, electrons were channeled toward distinct routes according to the different metabolic demands. This was expected to make the electron transfer in the chloroplasts become more flexible and to contribute greatly to acclimation of Py. yezoensis to the extreme variable environments in the intertidal zone

A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population.

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.This work was conducted on behalf of the CHIPGECS and The PRACTICAL consortia (see Supplementary Consortia). We acknowledge the contribution of doctors, nurses and postgraduate research students at the CHIPGENCS sample collecting centers. We thank Orchid and Rosetrees for funding support. This work was also supported by National Natural Science foundation of China for funding support to H Zhang (Grant No: 30671793 and 81072377), N Feng (Grant No: 81272831), X Zhang (Grant No: 30572139, 30872924 and 81072095), S Zhao (Grant No: 81072092 and 81328017), Y Yu (Grant No: 81172448) and Program for New Century Excellent Talents in University from Department of Education of China (NCET-08-0223) and the National High Technology Research and Development Program of China (863 Program 2012AA021101) to X Zhang.This is the final version of the article. It first appeared from Impact Journals via http://dx.doi.org/10.18632/oncotarget.725

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

DL-Selenomethionine Alleviates Oxidative Stress Induced by Zearalenone via Nrf2/Keap1 Signaling Pathway in IPEC-J2 Cells

Zearalenone (ZEN) is a kind of nonsteroidal mycotoxin that is considered a risk affecting the safety of human food and livestock feed that causes oxidative damages in mammalian cells. Selenomethionine (SeMet) was indicated to have antioxidant activity and received great interest in investigating the role of SeMet as a therapeutic agent in oxidation. Therefore, the aim of this study was to investigate the hormetic role of DL-SeMet in porcine intestinal epithelial J2 (IPEC-J2) cells against ZEN-induced oxidative stress injury. As a result of this experiment, 30 μg/mL of ZEN was observed with significantly statistical effects in cell viability. Following the dose-dependent manner, 20 μg/mL was chosen for the subsequent experiments. Then, further results in the current study showed that the ZENinduced oxidative stress with subsequent suppression of the expression of antioxidant stress pathway-related genes species. Moreover, SeMet reversed the oxidative damage and cell death of ZEN toxins to some extent, by a Nrf2/Keap1-ARE pathway. The finding of this experiment provided a foundation for further research on the ZEN-caused cell oxidative damage and the cure technology

Structural characteristics and genetic mechanism of Gaoyang low uplift in Jizhong Depression, Bohai Bay Basin

As a secondary structural unit locating in the central Jizhong Depression of the Bohai Bay Basin, the formation and evolution of Gaoyang low uplift is closely related to the development of the adjacent Baoding and Raoyang sags. The understanding for the structural characteristics of the Gaoyang low uplift is valuable for the overall study of the extensional deformation system in the central Jizhong Depression. Based on abundant seismic data, the structural characteristics of the Gaoyang low uplift were determined by using structural analysis method. According to drilling data and regional stratigraphic correlation, the age of syndepositional formation and the time of tectonic activity were determined. By compiling balanced sections and analyzing regional tectonic evolution, the genetic mechanism of the Gaoyang low uplift was discussed in this paper. The Gaoyang low uplift is featured by a gentle anticline which narrows from the south to the north, and the west limb of the anticline is steeper than the east counnterpart. Several NW-SE trending faults with large heave and long plane extension distance developed in the east flank of the Gaoyang low uplift, while only a few small-scale faults were developed in the west flank. The age of the oldest syndepositional strata in the southern part of the studied area is the Late Mesozoic, while that in the north is Paleocene. The Gaoyang low uplift is a compound rollover anticline developed in the common hanging wall of the boundary faults on both sides of the central Jizhong Depression, and its formation was mainly controlled by the extension of the boundary faults. The southern Gaoyang low uplift began to develop earlier than the northern part