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Organophosphorus flame retardants (PFRs) are a class of flame retardants and environmental pollutants with various biological effects. Recentstudies have evidenced activation of some PFRs by human CYP enzymes (including CYP2E1) for genotoxic effects. However, the activity of CYPs in fish species toward PFR metabolism remains unclear. This study was aimed on comparing the metabolism of triphenyl phosphate (TPHP) and 4-OH-TPHP in human, rat, and common carp, and the involvement of human CYP2E1 and its orthologs in the metabolism, by using fomepizole (4-MP, CYP2E1 inhibitor) as a modulator, in silico molecular docking and dynamics analyses. The rate of TPHP metabolism was apparently faster with human and rat, microsomes than with fish microsomes, the major metabolites were phosphodiester and hydroxylated phosphate, with 30–80 % of TPHP forming unidentified metabolites in the system of each species. 4-OH-TPHP was readily metabolized by both human and rat microsomes, whereas it was hardly metabolized in carp assays. Meanwhile, with 4-MP the transformation of TPHP to 4-OH-TPHP was enhanced in the human/rat systems while suppressed in the carp system. Moreover, the formation of unidentified metabolites in human and rat systems was mostly inhibited by 4-MP. Through molecular dynamics analysis TPHP and its primary metabolites showed high affinity for human and rat CYP2E1, as well as the carp ortholog (CYP2G1-like enzyme), however, the 4-OH-TPHP bond to the latter was too far from the heme to permit a biochemical reaction. This study suggests that the metabolism/activation of TPHP might be favored in mammals rather than carp, a fish species. • The biotransformation rate of TPHP was faster in mammals than in carp. • 4-OH-TPHP can be metabolized in mammal, but it is hardly metabolized in carp. • The formation of 4-OH-TPHP from TPHP can be mediated by carp CYP2E1-orthologs. • Most unidentified metabolites in mammalian assays were mediated by CYP2E1. • TPHP and its products have a high affinity for CYP2E1/CYP2G1-like in silico. [ABSTRACT FROM AUTHOR]

While most studies assessed the acute toxicity of saxitoxin (STX), fewer studies focus on the long-term degenerative effects of STX on the central nervous system. We investigated the cognitive impairment and hippocampal damages of 6 months' exposure of low-dose STX to C57BL/6NJ mice with behavioral tests, H&E staining, and Western blots, and the possible mechanism (Ppp1C, YAP1, tau-phosphorylation) underlies the pathological changes. Furthermore, we discussed the specific localization of YAP1 in N2a cells induced by STX and the effect of inactivated Ppp1C on its downstream protein YAP1 in the Hippo signal pathway. We found STX intoxicated mice showed declined cognitive performance in both NOR test and MWM test, degenerations in the CA1 area of hippocampi. STX induced up-regulation expression of Ppp1C and YAP1 in hippocampus and N2a cells. Meanwhile, STX treatment induced cell apoptosis and Tau protein hyperphosphorylation. In addition, STX treatment promoted YAP1 cytoplasmic retention that indicates the activation of Hippo pathway, while depletion of Ppp1C inactivate YAP1 during the treatment of STX. Our results highlight the role of Ppp1C and YAP1 cytoplasmic retention in chronic low-dose STX intoxication. [Display omitted] • The effect of long-term low-dose exposure of STX on cognitive function was appraised in a mammalian model. • STX changes the expression of Ppp1C and YAP1 proteins in Hippo signaling pathway. • STX activates Hippo signaling pathway by YAP1 cytoplasmic retention. [ABSTRACT FROM AUTHOR]

Abstract: This paper considers the global stability and stabilization of more general stochastic nonlinear systems. Due to the absence of the conventional assumptions (e.g., Lipschitz condition), the stochastic nonlinear systems under investigation may have more than one weak solution. However, the most associated results are only applicable to the stochastic systems having a unique strong solution, and therefore, it is meaningful to refine and extend the relevant concepts and methods to the more general case. In this paper, the concepts of stochastic stability in the more general sense are first introduced to cover the stochastic nonlinear systems having more than one weak solution. Then, the generalized stochastic Barbashin–Krasovskii theorem and LaSalle theorem are established, which present the criterions of stochastic stability for more general stochastic nonlinear systems. As one of the main contributions in this paper, we rigorously prove the generalized stochastic Barbashin–Krasovskii theorem. Moreover, based on the generalized theorems, the output-feedback and state-feedback stabilization are accomplished respectively for two classes of high-order stochastic nonlinear systems under rather weaker assumptions comparing to the existing literature. [Copyright &y& Elsevier]

Obesity is one of the risk factors of metabolic diseases. Decreased sensitivity to insulin or impairment of the insulin signaling pathway may affect the metabolism of adipose tissue. Bisphenol F (BPF) has been widely used in various products as a substitute for bisphenol A (BPA). BPA has been defined as "obesogen". However, knowledge about the correlation between BPF and obesity is very limited. This study was aimed to explore the effects of BPF on glucose metabolism and insulin sensitivity in mammalian tissues, using a mouse 3T3-L1 adipocyte line as the model. Differentiated 3T3-L1 adipocytes were treated with BPF at various concentrations for 24 h or 48 h, followed by the measurement of cell viability, lipid accumulation, expression levels of adipocytokines, glucose consumption, and impairment of the insulin signaling pathway. The results indicated that BPF had no effect on the size of 3T3-L1 adipocytes, but the expression of leptin, adiponectin and apelin was decreased, while that of chemerin and resistin was increased after 48 h of BPF treatment. Moreover, BPF inhibited the glucose consumption, the expression of GLUT4, and its translocation to the plasma membranes in 3T3-L1 adipocytes. Western blot analysis indicated that the activation of IRS-1/PI3K/AKT signaling pathway was inhibited by BPF, which resulted in reduced GLUT4 translocation. In conclusion, our data suggest that exposure of adipocytes to BPF may alter the expression of calorie metabolism-related adipokines and suppress insulin-stimulated glucose metabolism by impairing the insulin signaling (IRS-1/PI3K/AKT) pathway. • Bisphenol F had no effect on the lipid accumulation of 3T3-L1 adipocytes. • Bisphenol F influenced the expression of adipokines in 3T3-L1 adipocytes. • Bisphenol F could inhibit glucose metabolism in 3T3-L1 adipocytes. • Bisphenol F could inhibit the glucose metabolism via glucose transporter type 4. • Bisphenol F could inhibit the IRS-1/PI3K/AKT pathway in insulin-treated adipocytes. [ABSTRACT FROM AUTHOR]

Abstract: Sphingosine kinases (SphKs) have been recognized as important proteins regulating cell proliferation and apoptosis. Of the two isoforms of SphK (SphK1 and SphK2), little is known about the functions of SphK2. Sodium butyrate (NaBT) has been established as a promising chemotherapeutic agent, but the precise mechanism for its effects is unknown. In this study, we investigated the role of SphK2 in NaBT-induced apoptosis of HCT116 colon cancer cells. The results indicated that following NaBT treatment SphK2 was translocated from the nucleus to the cytoplasm, leading to its accumulation in the cytoplasm; in the meantime, only mild apoptosis occurred. However, downregulation of SphK2 resulted in sensitized apoptosis, and overexpression of SphK2 led to even lighter apoptosis; these strongly indicate an inhibitory role of SphK2 in cell apoptosis induced by NaBT. After knocking down protein kinase D (PKD), another protein reported to be critical in cell proliferation/apoptosis process, by using siRNA, blockage of cytoplasmic accumulation of SphK2 and sensitized apoptosis following NaBT treatment were observed. The present study suggests that PKD and SphK2 may form a mechanism for the resistance of cancer cells to tumor chemotherapies, such as HCT116 colon cancer cells to NaBT, and these two proteins may become molecular targets for designation of new tumor-therapeutic drugs. [Copyright &y& Elsevier]

Doxorubicin (DOX) is a commonly used antitumor drug. However, it may cause severe cardiotoxicity, apoptosis being a major change. A recent report indicates that miR-147 expression is decreased in the myocardium of a myocardial infarction model, suggesting a potential role of this miRNA in DOX-induced cardiomyocyte toxicity. In this study, freshly isolated neonatal pig cardiomyocytes were used; following transfection of a miR-147-y mimic, the cell death induced by DOX was alleviated, represented by augmented mitophagy [indicated by a decrease in P62, and increases in LC3, PINK1, parkin mRNA, LC3Ⅱ/Ⅰ, beclin-1, PINK1, and parkin including p-parkin (Ser65) protein expression], prohibited cell apoptosis as determined by TUNEL staining, and the suppression of caspase-3 transcription and cleaved caspase-3 translation. In cells transfected with an miR-147-y inhibitor, DOX-induced mitophagy was decreased, while apoptosis was increased. Additionally, RAPTOR gene silencing in cardiomyocytes exposed to DOX increased the rate of mitophagy and decreased that of apoptosis as compared with the treatment with DOX alone. Moreover, RAPTOR overexpression downregulated the rate of mitophagy and increased that of apoptosis in cells exposed to DOX. RAPTOR was confirmed as the target gene of miR-147-y based on the results of luciferase reporter gene assays and the opposite effects of the miR-147-y mimic and miR-147-y inhibitor on RAPTOR expression. In summary, our study suggests that miR-147-y mediates DOX-induced cardiomyocyte mitophagy while suppresses apoptosis by targeting RAPTOR, thus playing a protective role in DOX-induced cardiomyocyte damage. • Doxorubicin (DOX)-induced cardiomyocyte death was alleviated by miR-147-y. • Mitophagy and apoptosis in DOX-treated cells were oppositely altered by miR-147-y. • The effect of miR-147-y on cardiomyocytes was attained by targeting on Raptor. [ABSTRACT FROM AUTHOR]