Depletion of S-adenosylmethionine induced by arsenic exposure is involved in liver injury of rat through perturbing histone H3K36 trimethylation dependent bile acid metabolism.

Long-term exposure to arsenic, a common environmental pollutant, can induce various types of liver injury, but the mechanism and treatment measures remain unclear. This study constructed a rat model of arsenic-induced liver injury, with methyl group donor S-adenosylmethionine (SAM) supplementation and Rosa roxburghii Tratt juice intervention, to explore the epigenetic mechanism and intervention method of arsenic-induced liver injury from the perspective of hepatic bile acid metabolism. The results showed that arsenic exposure induced the accumulation of total bile acids (TBA) in the liver and serum of rats, and the abnormalities in liver function and liver histopathology. Arsenic reduced histone H3K36 trimethylation (H3K36me3) in the liver via consuming methyl group donor SAM. The reduction of H3K36me3 was involved in arsenic-induced bile acid accumulation by inhibiting the transcription of negative feedback regulators Fxr and Fgfr4 for hepatic bile acid synthesis. SAM supplementation reversed arsenic-induced bile acid accumulation and liver injury by reactivating H3k36me3-dependent transcription of Fxr and Fgfr4. Moreover, this study found that Rosa roxburghii Tratt juice could rescue arsenic-induced SAM consumption, recover H3K36me3-dependent negative feedback regulation of hepatic bile acid synthesis, and alleviate arsenic-induced bile acid accumulation and liver injury. In conclusion, arsenic exposure perturbed H3K36me3-dependent hepatic bile acid metabolism via depleting SAM, thereby inducing hepatic bile acid accumulation and liver injury, which was ameliorated by the supporting effect of Rosa roxburghii Tratt juice on SAM. This study contributes to understanding the mechanism of arsenic-induced liver injury from the perspective of SAM-dependent epigenetics, providing new insight into its prevention and treatment.

Omega-3 polyunsaturated fatty acid biomarkers and risk of type 2 diabetes, cardiovascular disease, cancer, and mortality.

BACKGROUND & AIMS: Considerable attention has focused on the role of omega-3 polyunsaturated fatty acids (PUFA) in the prevention of cardiometabolic diseases, which has led to dietary recommendations to increase omega-3 fatty acid intake. A meta-analysis was conducted to summarize evidence from prospective studies regarding associations between omega-3 PUFA biomarkers and risk of developing major chronic diseases. METHODS: Four electronic databases were searched for articles from inception to March 1, 2022. Random-effects model was used to estimate the pooled relative risk (RR) and 95% confidence intervals (CIs) for the association of omega-3 PUFAs, including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), with risk of developing type 2 diabetes (T2D), cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, cancer, and mortality. The Grades of Recommendation, Assessment, Development and Evaluation assessment tool was used to rates the confidence in estimates. RESULTS: A total of 67 prospective studies comprised of 310,955 participants were identified. Individual omega-3 PUFAs showed divergent associations with the study outcomes of interest. A significant inverse association with T2D risk was observed across categories of ALA (relative risk [RR]: 0.89, 95% confidence interval [CI]: 0.82-0.96), EPA (RR: 0.85, 95% CI: 0.72-0.99) and DPA (RR: 0.84, 95% CI: 0.73-0.96) biomarkers. The marine-origin omega-3 fatty acids biomarkers but not ALA was significantly associated with lower risks of total CVD, CHD, and overall mortality, with RRs ranging from 0.70 for DHA-CHD association to 0.85 for EPA-CHD association. A lower risk of colorectal cancer was observed at higher levels of DPA (RR: 0.76, 95% CI: 0.59-0.98) and DHA (RR: 0.80; 95% CI: 0.65-0.99), whereas no association was noted for other outcomes. In addition, a dose-response relationship was observed between an increasing level of EPA, DPA, or DHA biomarker and lower risk of CVD. CONCLUSIONS: Higher concentrations of marine-derived omega-3 PUFA biomarkers were associated with a significantly reduced risk of total CVD, CHD, and total mortality. Levels of ALA were inversely associated with a lower risk of T2D but not CVD-related outcomes. These data support the dietary recommendations advocating the role of omega-3 PUFAs in maintaining an overall lower risk of developing cardiovascular disease and premature deaths.

α-Cyperone inhibitory effects on tumor-derived DNA trigger microglia by STING pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Cyperus rotundus L. (Cyperaceae) is a widespread herbal in China and widely used in Traditional Chinese Medicine for multiple effects such as anti-arthritic, anti-genotoxic, anti-mutagenic, anti-bacterial effects, and analgesic. α-Cyperone is an active compound in Cyperus rotundus and has analgesic effects, but the exact molecular mechanisms require further investigations. MATERIALS AND METHODS: Tumor-derived DNA isolated from Lewis cell lines was transfected into microglia, and analyzed for stimulator of interferon genes (STING) effects. The downstream protein, such as interferon regulatory factor 3 (IRF3) and p65 nuclear factor-κB (NF-κB) were treated with STING siRNA and 5,6-dimethyllxanthenone-4-acetic acid (DMXAA) in microglia. The α-Cyperone effect on microglia was also investigated. RESULTS: Tumor-derived DNA activate microglia by upregulation of STING and downstream proteins. STING siRNA was reduced to its downstream expression and neuroinflammation inhibition was caused by tumor-derived DNA. However, DMXAA reversed the STING siRNA effect and increased neuroinflammation. α-Cyperone takes inhibitory effects on tumor-derived DNA that trigger microglia by STING pathway. CONCLUSIONS: α-Cyperone inhibition by tumor-derived DNA activated microglial to neuroinflammation in STING signaling pathway.