PMID- 33192318 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201117 IS - 1662-5102 (Print) IS - 1662-5102 (Electronic) IS - 1662-5102 (Linking) VI - 14 DP - 2020 TI - Hydrogen Sulfide Protects Against Ammonia-Induced Neurotoxicity Through Activation of Nrf2/ARE Signaling in Astrocytic Model of Hepatic Encephalopathy. PG - 573422 LID - 10.3389/fncel.2020.573422 [doi] LID - 573422 AB - 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 (H(2)S) in the blood of HE patients and investigate the role of H(2)S in an astrocytic model of HE. Methods: Patients with and without HE were recruited to determine plasma H(2)S levels and blood microbial 16S rRNA gene. Rat astrocytes were employed as a model of HE by treatment of NH(4)Cl. Exogenous H(2)S 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 H(2)S levels in cirrhotic patients with HE compared with without HE. Blood microbiota analyses revealed that certain strains associated with H(2)S production were negatively correlated with HE. In vitro, H(2)S markedly attenuated NH(4)Cl-induced cytotoxicity, oxidative stress, and apoptosis. This effect was mediated by Nrf2/ARE signaling, and knockdown of Nrf2 expression abolished the antagonistic effect of H(2)S on NH(4)Cl-induced neurotoxicity in astrocytes. Conclusion: Levels of H(2)S and bacteria associated with H(2)S production are decreased in HE, and H(2)S functions as the neuroprotector against NH(4)Cl-induced HE by activating Nrf2/ARE signaling of astrocytes. CI - Copyright (c) 2020 Jin, Chen, Wu, Zhang, Huang, Lin, Wang, Wang, Xu and Chen. FAU - Jin, Xiaozhi AU - Jin X AD - 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. FAU - Chen, Dazhi AU - Chen D AD - Department of Gastroenterology, The First Hospital of Peking University, Beijing, China. FAU - Wu, Faling AU - Wu F AD - 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. FAU - Zhang, Lei AU - Zhang L AD - 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. FAU - Huang, Yu AU - Huang Y AD - 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. FAU - Lin, Zhuo AU - Lin Z AD - 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. FAU - Wang, Xiaodong AU - Wang X AD - 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. FAU - Wang, Rui AU - Wang R AD - 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. FAU - Xu, Lanman AU - Xu L AD - Department of Infectious Diseases and Liver Diseases, Ningbo Medical Center Lihuili Hospital, Ningbo, China. AD - Department of Infectious Diseases and Liver Diseases, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China. FAU - Chen, Yongping AU - Chen Y AD - 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. LA - eng PT - Journal Article DEP - 20201022 PL - Switzerland TA - Front Cell Neurosci JT - Frontiers in cellular neuroscience JID - 101477935 PMC - PMC7642620 OTO - NOTNLM OT - H2S OT - Nrf2 OT - blood microbiota OT - hepatic encephalopathy OT - primary astrocytes EDAT- 2020/11/17 06:00 MHDA- 2020/11/17 06:01 PMCR- 2020/01/01 CRDT- 2020/11/16 08:44 PHST- 2020/06/17 00:00 [received] PHST- 2020/09/15 00:00 [accepted] PHST- 2020/11/16 08:44 [entrez] PHST- 2020/11/17 06:00 [pubmed] PHST- 2020/11/17 06:01 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fncel.2020.573422 [doi] PST - epublish SO - Front Cell Neurosci. 2020 Oct 22;14:573422. doi: 10.3389/fncel.2020.573422. eCollection 2020.