MitoQ protects against carbon tetrachloride-induced hepatocyte ferroptosis and acute liver injury by suppressing mtROS-mediated ACSL4 upregulation.

Ferroptosis has been shown to be involved in carbon tetrachloride (CCl4)-induced acute liver injury (ALI). The mitochondrion-targeted antioxidant MitoQ can eliminate the production of mitochondrial reactive oxygen species (mtROS). This study investigated the role of MitoQ in CCl4-induced hepatocytic ferroptosis and ALI. MDA and 4HNE were elevated in CCl4-induced mice. In vitro, CCl4 exposure elevated the levels of oxidized lipids in HepG2 cells. Alterations in the mitochondrial ultrastructure of hepatocytes were observed in the livers of CCl4-evoked mice. Ferrostatin-1 (Fer-1) attenuated CCl4-induced hepatic lipid peroxidation, mitochondrial ultrastructure alterations and ALI. Mechanistically, acyl-CoA synthetase long-chain family member 4 (ACSL4) was upregulated in CCl4-exposed human hepatocytes and mouse livers. The ACSL4 inhibitor rosiglitazone alleviated CCl4-induced hepatic lipid peroxidation and ALI. ACSL4 knockdown inhibited oxidized lipids in CCl4-exposed human hepatocytes. Moreover, CCl4 exposure decreased the mitochondrial membrane potential and OXPHOS subunit levels and increased the mtROS level in HepG2 cells. Correspondingly, MitoQ pretreatment inhibited the upregulation of ACSL4 in CCl4-evoked mouse livers and HepG2 cells. MitoQ attenuated lipid peroxidation in vivo and in vitro after CCl4 exposure. Finally, MitoQ pretreatment alleviated CCl4-induced hepatocytic ferroptosis and ALI. These findings suggest that MitoQ protects against hepatocyte ferroptosis in CCl4-induced ALI via the mtROS-ACSL4 pathway.

1,25(OH)2D3 alleviates oxidative stress and inflammation through up-regulating HMGCS2 in DSS-induced colitis.

BACKGROUND: Previous study found that supplements with active vitamin D3 alleviated experimental colitis. The objective of this study was to investigate the possible role of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a ketone synthase, on vitamin D3 protecting against experimental colitis. METHODS: HMGCS2 and vitamin D receptor (VDR) were measured in UC patients. The effects of vitamin D deficiency (VDD) and exogenous 1,25(OH)2D3 supplementation on experimental colitis were investigated in dextran sulfate sodium (DSS)-treated mice. DSS-induced oxidative stress and inflammation were analyzed in HT-29 cells. HMGCS2 was detected in 1,25(OH)2D3-pretreated HT-29 cells and mouse intestines. HMGCS2 was silenced to investigate the role of HMGCS2 in 1,25(OH)2D3 protecting against experimental colitis. RESULTS: Intestinal HMGCS2 downregulation was positively correlated with VDR reduction in UC patients. The in vivo experiments showed that VDD exacerbated DSS-induced colitis. By contrast, 1,25(OH)2D3 supplementation ameliorated DSS-induced colon damage, oxidative stress and inflammation. HMGCS2 was up-regulated after 1,25(OH)2D3 supplementation both in vivo and in vitro. Transfection with HMGCS2-siRNA inhibited antioxidant and anti-inflammatory effects of 1,25(OH)2D3 in DSS-treated HT-29 cells. CONCLUSION: 1,25(OH)2D3 supplementation up-regulates HMGCS2, which is responsible for 1,25(OH)2D3-mediated protection against oxidative stress and inflammation in DSS-induced colitis. These findings provide a potential therapeutic strategy for alleviating colitis-associated oxidative stress and inflammation.

Risk factors of recurrent choledocholithiasis following therapeutic endoscopic retrograde cholangiopancreatography.

BACKGROUND: The risk factors for the recurrent choledocholithiasis after endoscopic retrograde cholangiopancreatography (ERCP) have not been well studied. The aim of this study was to explore the risk factors of recurrent choledocholithiasis. METHODS: We carried out a retrospective analysis of data collected between January 1, 2010 and January 1, 2020. Univariate analysis and multivariate analysis were used to explore the independent risk factors of recurrent choledocholithiasis following therapeutic ERCP. RESULTS: In total, 598 patients were eventually selected for analysis, 299 patients in the recurrent choledocholithiasis group and 299 patients in the control group. The overall rate of recurrent choledocholithiasis was 6.91%. Multivariate analysis showed that diabetes [odds ratio (OR) = 3.677, 95% confidence interval (CI): 1.875-7.209; P < 0.001], fatty liver (OR = 4.741, 95% CI: 1.205-18.653; P = 0.026), liver cirrhosis (OR = 3.900, 95% CI: 1.358-11.201; P = 0.011), history of smoking (OR = 3.773, 95% CI: 2.060-6.908; P < 0.001), intrahepatic bile duct stone (OR = 4.208, 95% CI: 2.220-7.976; P < 0.001), biliary stent (OR = 2.996, 95% CI: 1.870-4.800; P < 0.001), and endoscopic papillary balloon dilation (EPBD) (OR = 3.009, 95% CI: 1.921-4.715; P < 0.001) were independent risk factors of recurrent choledocholithiasis. However, history of drinking (OR = 0.183, 95% CI: 0.099-0.337; P < 0.001), eating light food frequently (OR = 0.511, 95% CI: 0.343-0.760; P = 0.001), and antibiotic use before ERCP (OR = 0.315, 95% CI: 0.200-0.497; P < 0.001) were independent protective factors of recurrent choledocholithiasis. CONCLUSIONS: Patients with the abovementioned risk factors are more likely to have recurrent CBD stones. Patients who eat light food frequently and have a history of drinking are less likely to present with recurrent CBD calculi.