Notes

Research ethics committees throughout Okazaki, japan: Any viewpoint through many years of know-how with Tokushima College.
Traditionally, understanding potential developmental toxicity from pharmaceutical exposures has been based on the results of ICH guideline studies in two species. However, support is growing for the use of weight of evidence approaches when communicating the risk of developmental toxicity, where the intended pharmacologic mode of action affects fundamental pathways in developmental biology or phenotypic data from genetically modified animals may increasingly be included in the overall assessment. Since some concern surrounds the use of data from knockout (KO) mice to accurately predict the risk for pharmaceutical modulation of a target, a deeper understanding of the relevance and predictivity of adverse developmental effects in KO mice for pharmacological target modulation is needed. To this end, we compared the results of embryo-fetal development (EFD) studies for 86 drugs approved by the FDA from 2017 to 2019 that also had KO mouse data available in the public domain. These comparisons demonstrate that data from KO mouse models are overall highly predictive of malformations or embryo-fetal lethality (MEFL) from EFD studies, but less so of a negative outcome in EFD studies. This information supports the use of embryo-fetal toxicity data in KO models as part of weight of evidence approaches in the communication of developmental toxicity risk of pharmaceutical compounds.Exposure to dioxin, a known endocrine disruptor and carcinogen, is associated with poor reproductive outcomes. Yet, few studies have explored the role of DNA methylation in these relationships. Utilizing a publicly available dataset from 37 male Air Force Health Study participants exposed to dioxin-contaminated Agent Orange during the Vietnam war, we cross-sectionally examined the relationship of serum dioxin levels with a novel DNA methylation-based measure of sperm age (DNAm-agesperm). DNAm-agesperm was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. We estimated associations of dioxin levels with DNAm-agesperm using linear regression models adjusted for chronological age, body mass index, and smoking status. Chronological age was highly correlated with DNAmagesperm (r = 0.80). In fully-adjusted linear models, a one percent increase in serum dioxin levels was significantly associated with a 0.0126-year (i.e. 4.6-day) increase in DNAm-agesperm (95%CI 0.003, 0.022, p = 0.01). Further analyses demonstrated significant negative associations of dioxin levels (β = -0.0005, 95%CI -0.0010, 0.00004, P = 0.03) and DNAm-agesperm (β = -0.02, 95%CI -0.04, -0.001, P = 0.03) with methylation levels of FOXK2 - a gene previously reported to be hypomethylated in infertile men. In sum, we demonstrate associations of dioxin with increased methylation aging of sperm. DNAm-agesperm may provide utility for understanding how dioxin levels impact sperm health and potentially male reproductive capacity in human population studies. Moreover, our pilot study contributes further evidence that some environmental toxicants are associated with methylation aging. Additional studies are necessary to confirm these findings, and better characterize dioxin and sperm methylation relationships with male reproductive health.The gut-brain hormone glucagon-like peptide-1 (GLP-1) has received immense attention over the last couple of decades for its widespread metabolic effects. Notably, intestinal GLP-1 has been recognized as an endogenous satiation signal. Yet, the underlying mechanisms and the pathophysiological relevance of intestinal GLP-1 in obesity remain unclear. This review first recapitulates early findings indicating that intestinal GLP-1 is an endogenous satiation signal, whose eating effects are primarily mediated by vagal afferents. Second, on the basis of recent findings challenging a paracrine action of intestinal GLP-1, a new model for the mediation of GLP-1 effects on eating by two discrete vagal afferent subsets will be proposed. The central mechanisms processing the vagal anorexigenic signals need however to be further delineated. Finally, the idea that intestinal GLP-1 secretion and/or effects on eating are altered in obesity and play a pathophysiological role in the development of obesity will be discussed. In summary, despite the successful therapeutic use of GLP-1 receptor agonists as anti-obesity drugs, the eating effects of intestinal GLP-1 still remain to be elucidated. Specifically, the findings presented here call for a further evaluation of the vago-central neuronal substrates activated by intestinal GLP-1 and for further investigation of its pathophysiological role in obesity.Previous research has identified variation in cancer cell line response to high levels of extracellular H2O2 (eH2O2) exposure. This directly contributes to our understanding cellular efficacy of pharmacological ascorbate (P-AscH-) therapy. Here we investigate the factors contributing to latency of peroxisomal catalase of a cell and the importance of latency in evaluating cell exposure to eH2O2. First, we develop a mathematical framework for the latency of catalase in terms of an effectiveness factor, ηeff, to describe the catalase activity in the presence of high levels of eH2O2. A simplified relationship emerges, [Formula see text] when mprp/Dij≪1, where mp,rp, and [Formula see text] are the experimentally determined peroxisome permeability, average peroxisome radius, and the pseudo first-order reaction rate constant, respectively. [Formula see text] is the catalase concentration in the peroxisome and k2=1.7x107M-1s-1. Next, previously published parameters are used to determine the latency effect of the cell lines normal pancreatic cells (H6c7), pancreatic cancer cells (MIA PaCa-2), and glioblastoma cells (LN-229, T98G, and U-87), all which vary in their susceptibility to exposure to high eH2O2. Upadacitinib purchase The results show that effectiveness is not significantly different except for the most susceptible, MIA PaCa-2 cell line, which is higher when compared to all other cell lines. This result is counterintuitive and further implies that latency, as a single parameter, is ineffective in forecasting cell line susceptibility to P-AscH- therapy equivalent eH2O. Thus, further research remains necessary to identify why cancer cells vary in susceptibility to P-AscH- therapy.
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