Ginsenoside Rd Inhibited Ferroptosis to Alleviate CCl4-Induced Acute Liver Injury in Mice via cGAS/STING Pathway.

Carbon tetrachloride (CCl4)-induced lipid peroxidation associated with hepatic oxidative stress and cell death is an important mechanism of acute liver injury (ALI). Ginsenoside Rd is considered an active ingredient of ginseng. Evidence suggests that ginsenoside Rd may improve ischaemic stroke, nerve damage, cancer and other diseases involving apoptosis, inflammation, oxidative stress, mitochondrial injury and autophagy. However, the effects of ginsenoside Rd on CCl4-induced ALI and its underlying mechanisms are still unclear. In this study, 0.25% CCl4 was injected intraperitoneally in mice to establish a CCl4-induced ALI model. In the Rd treatment group, Rd (10, 20[Formula: see text]mg/kg) doses were injected intraperitoneally 1[Formula: see text]h before and 23[Formula: see text]h after CCl4 administration. Ferroptosis inducer imidazole ketone erastin (IKE) was injected intraperitoneally 4[Formula: see text]h before CCl4 administration to explore the mechanism. The blood and liver were collected 24[Formula: see text]h after CCl4 administration to investigate the effect and mechanism of ginsenoside Rd on CCl4-induced ALI. Our results showed that ginsenoside Rd inhibited CCl4-induced ALI in mice. Ginsenoside Rd also downregulated CCl4-induced serum and liver iron, 4-hydroxynonenal, and 8-hydroxy-2 deoxyguanosine levels. Furthermore, it upregulated glutathione and glutathione peroxidase 4 levels. In addition, ginsenoside Rd downregulated the expression of cGAS and STING. Subsequently, the ferroptosis inducer imidazole ketone erastin significantly reversed the hepatoprotective effect and influence of ginsenoside Rd with regard to the indicators mentioned above. Our study confirmed that ginsenoside Rd ameliorated CCl4-induced ALI in mice, which was related to the reduction of ferroptosis. Simultaneously, the ginsenoside Rd-mediated inhibition of the cGAS/STING pathway contributed to its antiferroptosis effect. In conclusion, our results suggested that ginsenoside Rd inhibited ferroptosis via the cGAS/STING pathway, thereby protecting mice from CCl4-induced ALI. These results suggested ginsenoside Rd may be used as a potential intervention treatment against CCl4-induced ALI.

Inonotus obliquus extract alleviates myocardial ischemia/reperfusion injury by suppressing endoplasmic reticulum stress.

Inonotus obliquus (IO) is an edible fungus that exerts various biological functions, including anti­inflammatory, antitumor and immunomodulatory effects. The present study was designed to investigate the role of IO extract (IOE) in myocardial ischemia/reperfusion (MI/R) and determine the exact molecular mechanisms. The left anterior descending coronary artery was ligated to establish the MI/R injury model in rats. IOE exhibited a novel cardioprotective effect, as shown by improvement in cardiac function and decrease in infarct size. Pretreatment with IOE activated antioxidant enzymes in cardiomyocytes, including glutathione peroxidase, superoxide dismutase and catalase. IOE pretreatment also induced the upregulation of NAD­dependent protein deacetylase sirtuin­1 (SIRT1) and downregulation of glucose­regulated protein 78, phosphorylated (p­) protein kinase R­like endoplasmic reticulum kinase, p­eukaryotic translation initiation factor 2 subunit α, C/EBP homologous protein and caspase­12. Furthermore, IOE alleviated endoplasmic reticulum (ER) stress­induced apoptosis in cardiomyocytes by decreasing the mRNA levels of caspase­12. IOE inhibited apoptosis induced by overexpression of pro­caspase­9 and pro­caspase­3. In summary, IOE pretreatment protects the heart against MI/R injury through attenuating oxidative damage and suppressing ER stress­induced apoptosis, which may be primarily due to SIRT1 activation.