The Integrated Analysis of Transcriptomics and Metabolomics Unveils the Therapeutical Effect of Asiatic Acid on Alcoholic Hepatitis in Rats

The present study was to investigate the therapeutical effects and mechanisms of Asiatic acid from Potentilla Chinensis against alcoholic hepatitis. Rats were intragastrically fed with alcohol for 12 weeks to induce alcoholic hepatitis and then treated with various drugs for further 12 weeks. The results showed that Asiatic acid significantly alleviated liver injury caused by alcohol in rats, as evidenced by the improved histological changes and the lower levels of AST, ALT, and TBIL. Besides, Asiatic acid significantly enhanced the activity of ADH and ALDH, promoting alcohol metabolism. Asiatic acid suppressed CYP2E1 activity and NADP+/NADPH ratio, resulting in low ROS production. Further study revealed that Asiatic acid markedly reduced hepatocyte apoptosis by regulating the expression levels of the caspase and Bcl-2 families. Moreover, Asiatic acid could regulate the Keap1/Nrf2 and NF-κB signaling pathway, attenuating oxidative stress and inflammation as a result. Interestingly, the comprehensive analysis of transcriptomics and metabolomics indicated that Asiatic acid regulated the gene expression of Gpat4 and thereby affected the biosynthesis of the metabolites (1-acyl-Sn-glycerol-3-phosphocholine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine), regulating the glycerophospholipid metabolism pathway and ultimately ameliorating hepatocyte damage. In conclusion, this study demonstrates that Asiatic acid can ameliorate alcoholic hepatitis by modulating the NF-κB and Keap1/Nrf2 signaling pathways and the glycerophospholipid metabolism pathway, which may be developed as a potential medicine for the treatment of alcoholic hepatitis.

Combined Metabolomics and Network Toxicology to Explore the Molecular Mechanism of Phytolacca acinose Roxb-Induced Hepatotoxicity in Zebrafish Larvae in Vivo

Phytolacca acinosa Roxb (PAR), a traditional Chinese medicine, has been widely used as a diuretic drug for a long period of time for the treatment edema, swelling, and sores. However, it has been reported that PAR might induce hepatotoxicity, while the mechanisms of its toxic effect are still unclear. In this study, network toxicology and metabolomic technique were applied to explore PAR-induced hepatotoxicity on zebrafish larvae. We evaluated the effect of PAR on the ultrastructure and the function of the liver, predictive targets, and pathways in network toxicology, apoptosis of liver cells by PCR and western blot, and metabolic profile by GC-MS. PAR causes liver injury, abnormal liver function, and apoptosis in zebrafish. The level of arachidonic acid in endogenous metabolites treated with PAR was significantly increased, leading to oxidative stress in vivo. Excessive ROS further activated the p53 signal pathway and caspase family, which were obtained from KEGG enrichment analysis of network toxicology. The gene levels of caspase-3, caspase-8, and caspase-9 were significantly increased by RT-PCR, and the level of Caps3 protein was also significantly up-regulated through western blot. PAR exposure results in the liver function abnormal amino acid metabolism disturbance and motivates hepatocyte apoptosis, furthermore leading to liver injury.

PinX1 Depletion Improves Liver Injury in a Mouse Model of Nonalcoholic Fatty Liver Disease via Increasing Telomerase Activity and Inhibiting Apoptosis

PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) can inhibit tumor growth by inhibiting telomerase activity. However, only few studies investigated the expression and function of PinX1 in nonalcoholic fatty liver disease (NAFLD). Thus, here we aimed to explore the roles of PinX1 in high-fat diet (HFD)-induced NAFLD in mice and in isolated hepatocytes. The mRNA expression of PinX1 and mTERT as well as telomere length were analyzed by RT-PCR. Pathological changes were detected by HE staining and oil red O staining. Triglyceride, cholesterol, alanine aminotransferase, aspartic aminotransferase, and telomerase activity were detected by ELISA. Hepatocyte apoptosis was determined by TUNEL and flow cytometry, and protein expression was analyzed by western blotting. We found that the expression of PinX1 was upregulated in the HFD group compared with the WT group. <i>PinX1</i> knockout improved HFD-induced liver injury in mice and exhibited less lipid accumulation in hepatocytes. Moreover, telomere length, telomerase activity, and mTERT expression were significantly reduced in liver tissues of HFD-induced mice and palmitic acid-induced hepatocytes, while <i>PinX1</i> knockout attenuated the effect. Furthermore, HFD-induced <i>PinX1</i>^−/− mice exhibited less hepatocyte apoptosis than HFD-induced WT mice. Besides, <i>PinX1</i> knockout inhibited the increase of cleaved caspase-3 and cleaved PARP expression in vivo and in vitro. Moreover, inhibition of mTERT reversed the effect of <i>PinX1</i> knockout in hepatocytes. Taken together, our findings indicate that PinX1 promotes hepatocyte apoptosis and lipid accumulation by decreasing telomere length and telomerase activity in the development of NAFLD. PinX1 might be a target for the treatment of NAFLD.

Chronic Xiao-chai-hu Decoction Therapy Slows the Progression of Acute-on-chronic Liver Failure via Prokinetic Effects on Gastrointestinal Motility

BackgroundAcute-on-chronic liver failure (ACLF) has a high risk of mortality in liver diseases without effective treatment. Xiao Chai Hu decoction (XCHD) is a traditional herbal formula, widely administered for liver disease, including anti-hepatic fibrosis and anti-inflammatory. MethodsTo investigate whether XCHD prevents the progression of ACLF and the underlying mechanisms. Methods: Sprague–Dawley rats with compound factors were randomly divided into model control group with 30 rats and four treatment groups with 20 rats in each group: Polyene phosphatidylcholine (100 mg/kg; PP) group; high dose (44.5 g/kg; HXCHD), middle dose (26.5 g/kg; MXCHD), and low dose (8.5 g/kg; LXCHD). Firstly, liver disease progression after XCHD treatment was measured by detecting: 1) the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), and albumin, prothrombin time (PT); 2) the survival rate and rat-adapted model for end-stage liver disease (MELD) score; 3) the hepatic hyperplastic collagen fibers with Masson’s trichrome staining; 4) the serum level of TNF-α and endotoxin induced hepatocyte apoptosis expression; 5) the ileum slow waves, gastric emptying, and small intestinal transit after XCHD treatment. ResultsThe XCHD groups showed improved serum biochemical hepatic parameters, histological liver changes, and survival rate. In addition, the XCHD treatment decreased the serum level of TNF-α and endotoxin and reduced hepatocyte apoptosis. XCHD decreased the normal percentage ileum slow waves, prolonged gastric emptying, and increased the small intestinal transit of ACLF. ConclusionsXCHD prevented the progression of ACLF partially via the prokinetic effects on gastrointestinal motility to reduce TNF-α, endotoxin, and hepatocyte apoptosis.