Hydrogen Sulfide Protects Against Ammonia-Induced Neurotoxicity Through Activation of Nrf2/ARE Signaling in Astrocytic Model of Hepatic Encephalopathy

Frontiers in Cellular Neuroscience

Dazhi Chen¹  Lanman Xu³  Yu Huang⁴  Yongping Chen⁴  Zhuo Lin⁴  Lei Zhang⁴  Xiaozhi Jin⁴  Xiaodong Wang⁴  Rui Wang⁴  Faling Wu⁴ 

[1] Department of Gastroenterology, The First Hospital of Peking University, Beijing, China;Department of Infectious Diseases and Liver Diseases, Ningbo Medical Center Lihuili Hospital, Ningbo, China;Department of Infectious Diseases and Liver Diseases, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China;Department of Infectious Diseases, Wenzhou Key Laboratory of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Hepatology Institute of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou, China;

关键词: hepatic encephalopathy;    primary astrocytes;    H2S;    blood microbiota;    Nrf2;   

DOI  :  10.3389/fncel.2020.573422

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown