Glutathione Might Attenuate Arsenic-Induced Liver Injury by Modulating the Foxa2-XIAP Axis to Reduce Oxidative Stress and Mitochondrial Apoptosis.

Arsenic (AS) is a metalloid element that widely exists and can cause different degrees of liver damage. The molecular mechanism of arsenic-induced liver injury has yet to be fully elucidated. Clinically, glutathione (GSH) is often used as an antidote for heavy metal poisoning and hepatoprotective drugs. However, the hepatoprotective effect of glutathione remains unknown in arsenic-induced liver injury. The regulatory relationship between Foxa2 and XIAP may play an important role in mitochondrial survival and death. Therefore, we took Foxa2-XIAP as the axis to explore the protective mechanism of GSH. In this study, we first established a mouse model of chronic arsenic exposure and examined liver function as reflected by quantitative parameters such as aspartate aminotransferase and alanine aminotransferase. Also, redox parameters in the liver were measured, including malondialdehyde, superoxide dismutase, 8-hydroxy-2'-deoxyguanosin, and glutathione peroxidase. RT-qPCR and western-blotting were used to detect the levels of related genes and proteins, such as Foxa2, XIAP, Smac, Bax, Bcl2, Caspase9, and Caspase3. Subsequently, GSH was administered at the same time as high arsenic exposure, and changes in the above parameters were observed. After a comprehensive analysis of the above results, we demonstrate that GSH treatment alleviates arsenic-induced oxidative stress and inhibits the mitochondrial pathway of apoptosis, which can be regulated through the Foxa2 and XIAP axis. The present study would be helpful in elucidating the molecular mechanism of arsenic-induced liver injury and identifying a new potential therapeutic target. And we also provided new theoretical support for glutathione in the treatment of liver damage caused by arsenic.

Isolation and characterization of node/notochord-like cells from mouse embryonic stem cells.

The homeobox gene Noto is expressed in the node and its derivative the notochord. Here we use a targeted Noto-GFP reporter to isolate and characterize node/notochord-like cells derived from mouse embryonic stem cells. We find very few Noto-expressing cells after spontaneous differentiation. However, the number of Noto-expressing cells was increased when using Activin A to induce a Foxa2- and Brachyury-expressing progenitor population, whose further differentiation into Noto-expressing cells was improved by simultaneous inhibition of BMP, Wnt, and retinoic acid signaling. Noto-GFP(+) cells expressed the node/notochord markers Noto, Foxa2, Shh, Noggin, Chordin, Foxj1, and Brachyury; showed a vacuolarization characteristic of notochord cells; and can integrate into midline structures when grafted into Hensen's node of gastrulating chicken embryos. The ability to generate node/notochord-like cells in vitro will aid the biochemical characterization of these developmentally important structures.