An integrated network pharmacology approach reveals that Ampelopsis grossedentata improves alcoholic liver disease via TLR4/NF-κB/MLKL pathway.

BACKGROUND: Alcohol-related liver damage is the most prevalent chronic liver disease, which creates a heavy public health burden worldwide. The leaves of Ampelopsis grossedentata have been considered a popular tea and traditional herbal medicine in China for more than one thousand years, and possess anti-inflammatory, antioxidative, hepatoprotective, and antiviral activities. PURPOSE: We explored the protective effects of Ampelopsis grossedentata extract (AGE) against chronic alcohol-induced hepatic injury (alcoholic liver disease, ALD), aiming to elucidate its underlying mechanisms. METHODS: Firstly, UPLC-Q/TOF-MS analysis and network pharmacology were used to identify the constituents and elucidate the potential mechanisms of AGE against ALD. Secondly, C57BL/6 mice were pair-fed the Lieber-DeCarli diet containing either isocaloric maltodextrin or ethanol, AGE (150 and 300 mg/kg/d) and silymarin (200 mg/kg) were administered to chronic ethanol-fed mice for 7 weeks to evaluate the hepatoprotective effects. Serum biochemical parameters were determined, hepatic and ileum sections were used for histologic examination, and levels of inflammatory cytokines and oxidative stress in the liver were examined. The potential molecular mechanisms of AGE in improving ALD were demonstrated by RNA-seq, Western blotting analysis, and immunofluorescence staining. RESULTS: Ten main constituents of AGE were identified using UPLC-Q/TOF-MS and 274 potential ALD-related targets were identified. The enriched KEGG pathways included Toll-like receptor signaling pathway, NF-κB signaling pathway, and necroptosis. Moreover, in vivo experimental studies demonstrated that AGE significantly reduced serum aminotransferase levels and improved pathological abnormalities after chronic ethanol intake. Meanwhile, AGE improved ALD in mice by down-regulating oxidative stress and inflammatory cytokines. Furthermore, AGE notably repaired damaged intestinal epithelial barrier and suppressed the production of gut-derived lipopolysaccharide by elevating intestinal tight junction protein expression. Subsequent RNA-seq and experimental validation indicated that AGE inhibited NF-κB nuclear translocation, suppressed IκB-α, RIPK3 and MLKL phosphorylation and alleviated hepatic necroptosis in mice. CONCLUSION: In this study, we have demonstrated for the first time that AGE protects against alcoholic liver disease by regulating the gut-liver axis and inhibiting the TLR4/NF-κB/MLKL-mediated necroptosis pathway. Therefore, our present work provides important experimental evidence for AGE as a promising candidate for protection against ALD.

Depression and hepatobiliary diseases: a bidirectional Mendelian randomization study.

Background: More and more evidence suggests a close association between depression and hepatobiliary diseases, but its causal relationship is not yet clear. Method: Using genome-wide association studies (GWAS) to summarize data, independent genetic variations associated with depression were selected as instrumental variables. Firstly, we designed a univariate Mendelian randomization (UVMR) analysis with two samples and simultaneously conducted reverse validation to evaluate the potential bidirectional causal relationship between depression and various hepatobiliary diseases. Secondly, we conducted a multivariate Mendelian randomization (MVMR) analysis on diseases closely related to depression, exploring the mediating effects of waist to hip ratio, hypertension, and daytime nap. The mediating effects were obtained through MVMR. For UVMR and MVMR, inverse variance weighted method (IVW) is considered the most important analytical method. Sensitivity analysis was conducted using Cochran'Q, MR Egger, and Leave-one-out methods. Results: UVMR analysis showed that depression may increase the risk of non-alcoholic fatty liver disease (OR, 1.22; 95% CI, 1.03-1.46; p=0.0248) in liver diseases, while depression does not increase the risk of other liver diseases; In biliary and pancreatic related diseases, depression may increase the risk of cholelithiasis (OR, 1.26; 95% CI, 1.05-1.50; p=0.0120), chronic pancreatitis (OR, 1.61; 95% CI, 1.10-2.35; p=0.0140), and cholecystitis (OR, 1.23; 95% CI, 1.03-1.48; p=0.0250). In addition, through reverse validation, we found that non-alcoholic fatty liver disease, cholelithiasis, chronic pancreatitis, cholecystitis, or the inability to increase the risk of depression (p>0.05). The waist to hip ratio, hypertension, and daytime nap play a certain role in the process of depression leading to non-alcoholic fatty liver disease, with a mediating effect of 35.8%. Conclusion: Depression is a susceptibility factor for non-alcoholic fatty liver disease, and the causal effect of genetic susceptibility to depression on non-alcoholic fatty liver disease is mediated by waist-hip ratio, hypertension, and daytime nap.

The Impact of Income Inequality on Health Levels: Empirical Evidence from China:2002-2016.

Income inequality had been one of the important manifestations of social inequality, which can affect the health level by affecting savings, health care and living standards. Existing researches about the relationship between income inequality and health ignored the comprehensive characteristic of health concept, and did not consider the intrinsic relationship between health and income inequality. This paper attempts to re-shed light on the relationship. Firstly, this paper constructs a new health level evaluation system from three aspects: health basis, health environment and behavior, and health security. By means of the combination evaluation method, the health levels can be obtained. Then, considering the interaction between health and income inequality, a simultaneous equation group model is constructed to empirically test the relationship between income inequality and health levels in China. The results reveal that health level is negatively correlated with income inequality. Reducing income inequality plays an important role in improving health levels in China.

The efficacy and safety of adding anlotinib in gradual progression on third-generation EGFR-TKIs for EGFR-mutant advanced nonsmall cell lung cancer.

Acquired resistance is unavoidable with the approval of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for first-line therapy of advanced non small cell lung cancer (NSCLC). Some studies have found that combining antiangiogenesis medicines with EGFR-TKI may benefit clinical outcomes in EGFR-mutant NSCLC. However, it is unclear whether EGFR-TKI paired with antiangiogenesis therapy could further improve survival for patients with gradual progression. Thus, we comprised the clinical effectiveness and safety of continuous EGFR-TKI in combination with anlotinib and EGFR-TKI alone in patients who had gradual progression on third-generation EGFR-TKI treatment. The comparison of progression-free survival (PFS) and overall survival(OS) between two groups used the Kaplan-Meier method. Our study comprised 121 eligible patients in total. The objective response rates were 25.0% and 0%, and the disease response rate was 91.7% and 86.9% in the combination group and EGFR-TKIs monotherapy group. The median PFS of combined anlotinib and EGFR-TKI treatment was 6.7 months and the median PFS was 3.6 months in the EGFR-TKI monotherapy group ( P  < 0.001). There were no significant differences between the two groups in OS. The common adverse reactions were diarrhea (21.7%), hypertension (21.6%) and proteinuria (20.0%) in the combination group. Seven patients experienced a grade 3 or higher adverse event, no patients discounted the treatment or died due to the toxicity. Our study indicated that, when combined with anlotinib following gradual progression on EGFR-TKIs, it was more efficacious for EGFR-mutant NSCLC patients than EGFR-TKI monotherapy. And the toxicity was clinically manageable.