The NAFLD-updated PBPK model accurately predicts in vivo metabolism of perc through oxidative and conjugative pathways in all tissues across disease states and strains, but underestimated parent compound concentrations in blood and liver of NAFLD mice. Conclusions We demonstrate the application of PBPK modeling to predict the effects of pre-existing disease conditions as a variability factor in perc metabolism. These results suggest that non-genetic factors such as diet and pre-existing disease can be as influential as genetic factors in altering toxicokinetics of perc, and thus are likely contribute substantially to population variation in its adverse effects.Volatile organic compounds (VOCs), such as vinyl chloride (VC), can be directly toxic at high concentrations. However, we have shown that 'nontoxic' exposures to VC and its metabolite chloroethanol (CE) enhances experimental non-alcoholic fatty liver disease (NAFLD), suggesting an unpredicted interaction. Importantly, VOC exposure has been identified as a potential risk factor for the development of obesity and its sequelae in humans. As there is a known axis between adipose and hepatic tissue in NAFLD, the impact of CE on white adipose tissue (WAT) inflammation and lipolysis was investigated. Mice were administered CE (or vehicle) once, after 10 weeks of being fed high-fat or low-fat diet (LFD). CE significantly enhanced hepatic steatosis and inflammation caused by HFD. HFD significantly increased the size of epididymal fat pads, which was enhanced by CE. The relative size of adipocyte lipid droplets increased by HFD + CE, which was also correlated with increased expression of lipid-associated proteins (e.g., PLINs). CE also enhanced HFD-induced indices of WAT inflammation, and ER stress. Hepatic-derived circulating FGF21, a major modulator of WAT lipolysis, which is hypothesized to thereby regulate hepatic steatosis, was significantly increased by CE in animals fed HFD. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH, involving the liver-adipose axis in this process. Specifically, CE enhances local inflammation and alters lipid metabolism and WAT-mediated hepatic steatosis due to changes in WAT lipolysis.The hippocampus is essential for some types of memory, but its specific role remains conjectural. While studies on place cells have supported the hypothesis that the hippocampus provides a spatial substrate for episodic memory, recent engram studies have shown that optogenetic activation of a subset of hippocampal neurons that lack a temporal structure of the spike sequences can also induce memory-associated behavior. In this short review, I discuss the various lines of research that have led to different views of the role of the hippocampus in memory and propose a plausible interpretation of the findings that incorporates two influential theories.Sulfur mustard (SM), a dermal vesicant that has been used in chemical warfare, causes inflammation, edema and epidermal erosions depending on the dose and time following exposure. Herein, a minipig model was used to characterize wound healing following dermal exposure to SM. Saturated SM vapor caps were placed on the dorsal flanks of 3-month-old male Gottingen minipigs for 30 min. After 48 h the control and SM wounded sites were debrided daily for 7 days with wet to wet saline gauze soaks. Animals were then euthanized, and full thickness skin biopsies prepared for histology and immunohistochemistry. Control skin contained a well differentiated epidermis with a prominent stratum corneum. A well-developed eschar covered the skin of SM treated animals, however, the epidermis beneath the eschar displayed significant wound healing with a hyperplastic epidermis. Stratum corneum shedding and a multilayered basal epithelium consisting of cuboidal and columnar cells were also evident in the neoepidermis. Nuclear exprermeasures.Objective To uncover the expression patterns of HOXB2 and FOXC1 in Wilms tumor samples, and their synergistical regulations on the development of Wilms tumor. Methods Expression levels of HOXB2 and FOXC1 in 58 cases of Wilms tumor tissues and paracancerous ones were detected. The influences of HOXB2 and FOXC1 on prognosis in Wilms tumor patients were analyzed. Their regulatory effects on proliferative and migratory abilities in WT-CLS1 and HFWT cells were examined by cell counting kit-8 (CCK-8) and Transwell assay, respectively. The interaction between HOXB2 and FOXC1, and their synergistical regulation on the development of Wilms tumor were finally explored. Results HOXB2 and FOXC1 were upregulated in Wilms tumor tissues. Higher levels of HOXB2 and FOXC1 indicated higher risks of advanced stage and lymphatic metastasis, as well as worse prognosis in Wilms tumor patients. Knockdown of HOXB2 or FOXC1 weakened proliferative and migratory abilities in WT-CLS1 and HFWT cells, while the opposite trends were observed in those overexpressing HOXB2 or FOXC1. The positive interaction between HOXB2 and FOXC1 was identified, which synergistically drove the malignant development of Wilms tumor. Conclusions HOXB2 and FOXC1 are upregulated in Wilms tumor samples, and they are closely linked to tumor staging and lymphatic metastasis in Wilms tumor patients. HOXB2 and FOXC1 synergistically drive the malignant development of Wilms tumor by stimulating proliferative and migratory potentials.Objective Exosomes originated from mesenchymal stem cells (MSCs) benefit wound healing. This study investigated effects of exosomes originated from human umbilical cord MSCs (hUC-MSCs) on dermal fibroblasts-myofibroblasts transition via the TGF-β1/Smad2/3 signaling pathway. Methods Firstly, hUC-MSCs were collected and identified. Alizarin red, oil red O staining and toluidine blue staining were used to determine the osteogenic, adipogenic and chondrogenic differentiation abilities of hUC-MSCs. Then exosomes from hUC-MSCs were extracted and identified.  https://www.selleckchem.com/products/ziritaxestat.html  To figure out the roles of exosomes and TGF-β1 in dermal fibroblasts-myofibroblasts transition, dermal fibroblasts were treated with TGF-β1 or/and exosomes at different concentrations. RT-qPCR, Western blot analyses were employed to examine levels of Collagen I, Collagen III, α-smooth muscle actin (α-SMA), and Smad2/3 phosphorylation, and immunofluorescence was employed to test α-SMA content and the localization and nucleation of Smad2/3 protein in cells. Results hUC-MSCs and exosomes were successfully cultured and extracted.