Abstract
Objective: Hepatic encephalopathy (HE) characterized by neuropsychiatric abnormalities is a major complication of cirrhosis with high mortality. However, the pathogenesis of HE has not been fully elucidated. This study aimed to determine endogenous hydrogen sulfide (H2S) in the blood of HE patients and investigate the role of H2S in an astrocytic model of HE.Methods: Patients with and without HE were recruited to determine plasma H2S levels and blood microbial 16S rRNA gene. Rat astrocytes were employed as a model of HE by treatment of NH4Cl. Exogenous H2S was preadded. Cell viability was measured by Cell Counting Kit-8 (CCK-8) assay, and cell death was evaluated by lactate dehydrogenase (LDH) release. Apoptosis was determined by Hoechst 33342/Propidium Iodide (PI) Double Staining and Western blot analysis of apoptosis-related protein expression. Intracellular reactive oxygen species (ROS) levels were assessed by flow cytometer. Expressions of Nrf2 and its downstream regulated genes were examined by immunofluorescence staining and Western blot, respectively. Nrf2 gene knockdown was performed by antisense shRNA of Nrf2 gene.Results: There was a significant decrease in H2S levels in cirrhotic patients with HE compared with without HE. Blood microbiota analyses revealed that certain strains associated with H2S production were negatively correlated with HE. In vitro, H2S markedly attenuated NH4Cl-induced cytotoxicity, oxidative stress, and apoptosis. This effect was mediated by Nrf2/ARE signaling, and knockdown of Nrf2 expression abolished the antagonistic effect of H2S on NH4Cl-induced neurotoxicity in astrocytes.Conclusion: Levels of H2S and bacteria associated with H2S production are decreased in HE, and H2S functions as the neuroprotector against NH4Cl-induced HE by activating Nrf2/ARE signaling of astrocytes.
Highlights
Hepatic encephalopathy (HE) is a common complication of cirrhosis, leading to low quality of life and high mortality (Vilstrup et al, 2014)
The results of the current study reveal the decrease of endogenous H2S and the effective protective role of H2S in HE astrocyte model
Our results suggest that: (i) there is a decrease in H2S production and bacteria associated with H2S production in the blood of HE patients; (ii) H2S attenuates NH4Cl-induced cytotoxicity, Oxidative stress (OxS), and apoptosis in primary rat astrocytes; and (iii) the Nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway mediates the cytoprotection of H2S against NH4Cl-induced neurotoxicity
Summary
Hepatic encephalopathy (HE) is a common complication of cirrhosis, leading to low quality of life and high mortality (Vilstrup et al, 2014). Hydrogen sulfide (H2S), a well-known cytotoxic gas, has recently been regarded as an important endogenous gasotransmitter, which contributes to physiological and pathological responses of various organs through antioxidant defense, energy production, and cell cycle regulation (Kadota and Ishida, 1972; Ortenberg and Beckwith, 2003; Kimura and Kimura, 2004; Poole, 2005; Lloyd, 2006; Yin et al, 2009; Henderson et al, 2010). H2S is kept in a range of concentrations to maintain physiological processes (Kamoun, 2004). Of note is the antioxidative stress effect of H2S in diseases (Hu et al, 2010; Yin et al, 2013; Yang et al, 2018); the role of H2S in the prevention of HE remains unclear
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