S-Acetyl-Glutathione Attenuates Carbon Tetrachloride-Induced Liver Injury by Modulating Oxidative Imbalance and Inflammation

International Journal of Molecular Sciences

Maria Laura Ontario¹  Angela Trovato Salinaro¹  Vittorio Calabrese¹  Sergio Modafferi¹  Marika Cordaro²  Rosalba Siracusa³  Livia Interdonato³  Salvatore Cuzzocrea³  Ramona D’Amico³  Daniela Impellizzeri³  Roberta Fusco⁴  Rosanna Di Paola⁵ 

[1] Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy;Department of Biomedical, Dental and Morphological and Functional Imaging, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy;Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy;

关键词: liver fibrosis;    antioxidant;    inflammation;   

DOI  :  10.3390/ijms23084429

来源: DOAJ

【 摘 要 】

Liver fibrosis, depending on the stage of the disease, could lead to organ dysfunction and cirrhosis, and no effective treatment is actually available. Emergent proof supports a link between oxidative stress, liver fibrogenesis and mitochondrial dysfunction as molecular bases of the pathology. A valid approach to protect against the disease would be to replenish the endogenous antioxidants; thus, we investigated the protective mechanisms of the S-acetyl-glutathione (SAG), a glutathione (GSH) prodrug. Preliminary in vitro analyses were conducted on primary hepatic cells. SAG pre-treatment significantly protected against cytotoxicity induced by CCl4. Additionally, CCl4 induced a marked increase in AST and ALT levels, whereas SAG significantly reduced these levels, reaching values found in the control group. For the in vivo analyses, mice were administered twice a week with eight consecutive intraperitoneal injections of 1 mL/kg CCl4 (diluted at 1:10 in olive oil) to induce oxidative imbalance and liver inflammation. SAG (30 mg/kg) was administered orally for 8 weeks. SAG significantly restored SOD activity, GSH levels and GPx activity, while it strongly reduced GSSG levels, lipid peroxidation and H₂O₂ and ROS levels in the liver. Additionally, CCl4 induced a decrease in anti-oxidants, including Nrf2, HO-1 and NQO-1, which were restored by treatment with SAG. The increased oxidative stress characteristic on liver disfunction causes the impairment of mitophagy and accumulation of dysfunctional and damaged mitochondria. Our results showed the protective effect of SAG administration in restoring mitophagy, as shown by the increased PINK1 and Parkin expressions in livers exposed to CCl4 intoxication. Thus, the SAG administration showed anti-inflammatory effects decreasing pro-inflammatory cytokines TNF-α, IL-6, MCP-1 and IL-1β in both serum and liver, and suppressing the TLR4/NFkB pathway. SAG attenuated reduced fibrosis, collagen deposition, hepatocellular damage and organ dysfunction. In conclusion, our results suggest that SAG administration protects the liver from CCl4 intoxication by restoring the oxidative balance, ameliorating the impairment of mitophagy and leading to reduced inflammation.

【 授权许可】

Unknown