Hydrogen Sulfide Protects against Paraquat-Induced Acute Liver Injury in Rats by Regulating Oxidative Stress, Mitochondrial Function, and Inflammation

Abstract

In addition to the lung, the liver is considered another major target for paraquat (PQ) poisoning. Hydrogen sulfide (H2S) has been demonstrated to be effective in the inhibition of oxidative stress and inflammation. The aim of this study was to investigate the protective effect of exogenous H2S against PQ-induced acute liver injury. The acute liver injury model was established by a single intraperitoneal injection of PQ, evidenced by histological alteration and elevated serum aminotransferase levels. Different doses of NaHS were administered intraperitoneally one hour before exposure to PQ. Analysis of the data shows that exogenous H2S attenuated the PQ-induced liver injury and oxidative stress in a dose-dependent manner. H2S significantly suppressed reactive oxygen species (ROS) generation and the elevation of malondialdehyde content while it increased the ratio of GSH/GSSG and levels of antioxidant enzymes including SOD, GSH-Px, HO-1, and NQO-1. When hepatocytes were subjected to PQ-induced oxidative stress, H2S markedly enhanced nuclear translocation of Nrf2 via S-sulfhydration of Keap1 and resulted in the increase in IDH2 activity by regulating S-sulfhydration of SIRT3. In addition, H2S significantly suppressed NLRP3 inflammasome activation and subsequent IL-1β excretion in PQ-induced acute liver injury. Moreover, H2S cannot reverse the decrease in SIRT3 and activation of the NLRP3 inflammasome caused by PQ in Nrf2-knockdown hepatocytes. In summary, H2S attenuated the PQ-induced acute liver injury by enhancing antioxidative capability, regulating mitochondrial function, and suppressing ROS-induced NLRP3 inflammasome activation. The antioxidative effect of H2S in PQ-induced liver injury can at least partly be attributed to the promotion of Nrf2-driven antioxidant enzymes via Keap1 S-sulfhydration and regulation of SIRT3/IDH2 signaling via Nrf2-dependent SIRT3 gene transcription as well as SIRT3 S-sulfhydration. Thus, H2S supplementation can form the basis for a promising novel therapeutic strategy for PQ-induced acute liver injury.

Intraarticular Administration Effect of Hydrogen Sulfide on an In Vivo Rat Model of Osteoarthritis

“…Wu et al (2016) observed that S-propargyl-cysteine, an endogenous inductor of H 2 S synthesis, activates Nrf-2 signaling in adjuvant-induced arthritis rats and inhibits inflammatory response, ameliorating the severity of the arthritis model [ 46 ]. Hence, a growing number of evidences suggest that the Nrf-2 activation induced by H 2 S is also responsible for its anti-inflammatory effects [ 46 , 63 , 64 ]. In our study, we observed for the first time that the administration of a slow-releasing H 2 S donor in the joint induces the expression of Nrf-2 in the cartilage and that this event could contribute to the attenuation of the expression of pro-inflammatory markers detected in our model and subsequently to its pathogenesis.…”

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review

“…The reports display that 5–15 ml of 20% concentration of paraquat can result in moderate or severe poisoning ( Wesseling et al, 2001 ; Baltazar et al, 2013 ). Several studies have shown that exposing to paraquat can induce liver injury by decreasing antioxidant capacity and stimulation of inflammation ( Gao et al, 2020a ; Liu et al, 2020c ). Although studies have put much emphasis on the involvement of oxidative stress and inflammation in paraquat-mediated toxicity, the role of TGF-β signaling pathway is uncertain in liver toxicity.…”

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

“…Nonenzymatic scavengers mainly include thioredoxin (Trx), glutathione (GSH), as well as low-molecular-weight antioxidants like cytochrome c and coenzyme Q. The process that GSH is oxidized to GSH disulfide (GSSG) through the interaction with GSH S-transferase directly or via a reaction catalyzed by GSH-Px could alleviate oxidative damage through decreasing disulfide bonds of cytoplasmic proteins to cysteines [ 54 ]. Excessive ROS can induce an oxidized Trx form, which is subsequently converted to a functionally reductive form by thioredoxin reductase (TrxR) to maintain redox homeostasis in cells [ 55 ] ( Figure 1 ).…”