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ABSTRACT The environmental toxicant TCDD may elicit cytotoxic effects by inducing reactive oxygen species (ROS) generation. Autophagy is one of the first lines of defense against oxidative stress damage. Herein, we investigated whether autophagy played a regulatory role in TCDD-induced neurotoxicity. Here, we showed that TCDD exposure caused marked autophagy in SH-SY5Y cells, whose dose range was close to that inducing apoptosis. Electron microscopic and Western blot analyses revealed that TCDD induced autophagy at a starting dose of approximate 100 nM. Interestingly, 100-200 nM TCDD exposure resulted in obviously decreased cell viability and evident apoptotic phenotype. Furthermore, the levels of pro-apoptotic molecules, Bax and cleaved-PARP, increased significantly, whereas Bcl2 declined after exposed to 100 nM TCDD. In addition, the apoptosis was verified using flow cytometrical analysis. These data strongly suggested that TCDD induced both autophagy and apoptosis at a similar dose range in SH-SY5Y cells. Interestingly, pretreatment with ROS scavenger, N-acetyl-cysteine (NAC), could effectively block both TCDD-induced apoptosis and autophagy. More surprisingly, inhibition of autophagy with 3-methyladenine (3MA), remarkably augmented TCDD-induced apoptosis. The findings implicated that the onset of autophagy might serve as a protective mechanism to ameliorate ROS-triggered cytotoxic effects in human SH-SY5Y neuronal cells under TCDD exposure. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1068-1079, 2016. [ABSTRACT FROM AUTHOR]

2, 3, 7, 8-tetrachlorodibenzo- p-dioxin (TCDD) is a ubiquitous environmental contaminant that could exert significant neurotoxicity in the human nervous system. Nevertheless, the molecular mechanism underlying TCDD-mediated neurotoxicity has not been clarified clearly. Herein, we investigated the potential role of TCDD in facilitating premature senescence in astrocytes and the underlying molecular mechanisms. Using the senescence-associated β-galactosidase (SA-β-Gal) assay, we demonstrated that TCDD exposure triggered significant premature senescence of astrocyte cells, which was accompanied by a marked activation of the Wingless and int (WNT)/β-catenin signaling pathway. In addition, TCDD altered the expression of senescence marker proteins, such as p16, p21 and GFAP, which together have been reported to be upregulated in aging astrocytes, in both dose- and time-dependent manners. Further, TCDD led to cell-cycle arrest, F-actin reorganization and the accumulation of cellular reactive oxygen species (ROS). Moreover, the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and astrocyte senescence. Notably, the application of XAV939, an inhibitor of WNT/β-catenin signaling pathway, ameliorated the effect of TCDD on cellular β-catenin level, ROS production, cellular oxidative damage and premature senescence in astrocytes. In summary, our findings indicated that TCDD might induce astrocyte senescence via WNT/β-catenin and ROS-dependent mechanisms. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: (-)-Epigallocatechin-3-gallate (EGCG) has preventive effects on obesity-related precocious puberty, but its underlying mechanism remains unclear. The aim of this study was to integrate metabolomics and network pharmacology to reveal the mechanism of EGCG in the prevention of obesity-related precocious puberty., Materials and Methods: A high-performance liquid chromatography-electrospray ionization ion-trap tandem mass spectrometry (LC-ESI-MS/MS) was used to analyze the impact of EGCG on serum metabolomics and associated metabolic pathways in a randomized controlled trial. Twelve weeks of EGCG capsules were given to obese girls in this trail. Additionally, the targets and pathways of EGCG in preventing obesity-related precocious puberty network pharmacology were predicted using network pharmacology. Finally, the mechanism of EGCG prevention of obesity-related precocious puberty was elucidated through integrated metabolomics and network pharmacology., Results: Serum metabolomics screened 234 endogenous differential metabolites, and network pharmacology identified a total of 153 common targets. These metabolites and targets mainly enrichment pathways involving endocrine-related pathways (estrogen signaling pathway, insulin resistance, and insulin secretion), and signal transduction (PI3K-Akt, MAPK, and Jak-STAT signaling pathways). The integrated metabolomics and network pharmacology indicated that AKT1, EGFR, ESR1, STAT3, IGF1, and MAPK1 may be key targets for EGCG in preventing obesity-related precocious puberty., Conclusion: EGCG may contribute to preventing obesity-related precocious puberty through targets such as AKT1, EGFR, ESR1, STAT3, IGF1, and MAPK1 and multiple signaling pathways, including the estrogen, PI3K-Akt, MAPK, and Jak-STAT pathways. This study provided a theoretical foundation for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gu, Xia, Du, Shao, He, Wu, Liang and Shen.)