phenanthrenes and Non-alcoholic-Fatty-Liver-Disease

Triptolide is naturally isolated from Tripterygium wilfordii Hook F., possessing multiple biological activities. Hepatotoxicity is one of the main side effects of triptolide. However, the effect of triptolide on nonalcoholic fatty liver disease remains unknown (NAFLD).. This study aimed to observe the amelioration of triptolide against NAFLD and investigate the engaged mechanism.. Two typical animal models of NAFLD, obese db/db mice and methionine/choline-deficient (MCD) diet-fed mice, were used. Hepatic steatosis, inflammation, and fibrosis were evaluated by H&E and Masson staining. Oil red O staining and lipid extraction analysis were used to detect fat content in mice livers. Expression of lipid metabolism, inflammatory and fibrogenic genes was also detected by Real-time PCR and Western blotting, respectively. Phosphoproteomics, molecular docking, and TR-FRET assay were performed to provide further insight into how triptolide improved NAFLD.. This study demonstrates that dose-related triptolide as an allosteric AMPK agonist has the potential to alleviate NAFLD without hepatotoxicity.

Topics: AMP-Activated Protein Kinases; Animals; Diterpenes; Epoxy Compounds; Inflammation; Lipid Metabolism; Lipids; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Non-alcoholic Fatty Liver Disease; Phenanthrenes

NLRP3 inflammasome activation is implicated in the pathogenesis of a wide range of inflammatory diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. Here, we demonstrate that cryptotanshinone (CTS), a major component derived from the traditional medicinal herb Salvia miltiorrhiza Bunge, is a specific inhibitor for the NLRP3 inflammasome. Cryptotanshinone inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanistically, cryptotanshinone blocks Ca

Topics: Animals; Cells, Cultured; Female; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; Liver; Macrophages; Male; Mice, Inbred C57BL; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Phenanthrenes; Reactive Oxygen Species; Shock, Septic; T-Lymphocytes, Regulatory; Th17 Cells; Tumor Necrosis Factor-alpha

Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic disease in adults and children worldwide. Importantly, there are currently no approved treatments available for NAFLD. This study aims to investigate the potential applications of sodium tanshinone IIA sulfonate (STS) on improving the NAFLD condition using both in vitro and in vivo approaches. The results showed that STS markedly inhibited lipid accumulation in oleic acid (OA) and palmitic acid (PA) treated HepG2 and primary immortalized human hepatic (PIH) cells. STS suppressed lipogenesis by inhibiting expression of sterol regulatory element binding transcription factor 1 (SREBF1), fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD). In addition, STS reduced inflammation in cells treated with OA-PA, shown by decreased transcriptional levels of tumor necrosis factor (TNF), transforming growth factor beta 1 (TGFB1) and interleukin 1 beta (IL1B). Consistently, protective effects on hepatic steatosis in db/db mice were observed after STS administration, demonstrated by decreased lipid accumulation in mouse hepatocytes. This protective effect might be associated with STS induced activation of sirtuin 1 (SIRT1)/protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1) pathways. Our findings suggest a potential therapeutic role for STS in the treatment of NAFLD.

Topics: Animals; Dose-Response Relationship, Drug; Hep G2 Cells; Humans; Inflammation; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phenanthrenes; Random Allocation

More and more evidence indicates that persistent organic pollutants (POPs) are a risk factor for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Phenanthrene (Phe) is a kind of POP which existed extensively in the environment, but whose toxicity on mammals has so far received less focus. Subcutaneously injection of Phe (0.5, 5, 50 μg/kg) for 21 days induced significant NAFLD/NASH symptoms in new born rats. Exposure to environmental levels of Phe decreased body weight and liver-somatic index; impaired histology of liver; influenced the peroxisome proliferator-activated receptor gamma (PPARγ) signaling and lipid metabolism in liver; stimulated oxidative stress in the rats' liver; induced the variation of NFκB pathway and liver inflammatory response; and caused liver fibrosis via transforming growth factor β1 (tgfβ1). We speculated that the subcutaneously injected Phe was transferred to the liver through blood circulation, which may have induced the elevation of PPARγ directly or indirectly, leading to liver steatosis. Excess lipid, acting as the first hit, stimulated the second hit factors - oxidative stress, inflammatory response and lipid peroxidation, and finally resulted in steatohepatitis and liver fibrosis.

Topics: Animals; Environmental Pollutants; Lipid Metabolism; Lipid Peroxidation; Liver; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phenanthrenes; Phenotype; Rats; Signal Transduction

Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH).. We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice.. Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer.. Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Fatty Liver, Alcoholic; Humans; Kupffer Cells; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD; Nitrosative Stress; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phenanthrenes; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Quinolines; Sirtuin 1