Molecular Mechanisms for Alcoholic Hepatitis Based on Analysis of Gene Expression Profile

Abstract

Background:Alcoholic hepatitis (AH) is an acute manifestation of alcoholic liver disease with high mortality rates.Objectives:Our aim was to study the molecular mechanisms of AH.Materials and Methods:The differentially expressed genes (DEGs) in liver between AH and control cases were identified by analyzing the GSE28619 microarray data using t-test. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) enrichment analyses were performed using DAVID online tool. The protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes (STRING) and the subnetwork was identified by BioNet. Both PPI network and subnetwork were visualized using the Cytoscape software.Results:Total 908 DEGs (551 up- and 357 down-regulated DEGs) were obtained. The up-regulated DEGs were significantly enriched in 15 pathways and 112 GO biological processes. The down-regulated DEGs were significantly enriched in 22 pathways and 84 GO biological processes. The PPI network with 608 nodes and 2878 interactions was constructed and the subnetwork with 53 nodes and 131 interactions was also identified. The hub DEGs (TSPO, PPIB, NME1 and NME2) were extracted in this subnetwork.Conclusions:TSPO might contribute to the liver damage and AH progression induced by mitochondrial dysfunction through oxidative stress of liver. TSPO interacted with PPIB might play important roles in liver damage in AH. The interaction between NME1 and NME2 might contribute to the transformation from AH to hepatocellular carcinoma.

Hyperoxidized albumin modulates neutrophils to induce oxidative stress and inflammation in severe alcoholic hepatitis

“…Further, the enhanced expression of intracellular antioxidant genes in SAH neutrophils and in SAH‐albumin‐treated healthy neutrophils demonstrates the compensatory protective mechanism of cells against oxidative stress–mediated damage. Additionally, the enhanced transcript profile for apoptosis, ER stress, and autophagy in SAH neutrophils were not observed in SAH‐albumin‐treated healthy neutrophils, suggesting roles for other pathological mechanisms in SAH patients, which have been well documented in other studies . Interestingly, our study shows that SAH‐albumin treatment of healthy neutrophils caused up‐regulation of the BAD, BAX, CASP8, and TNFα genes, indicating that SAH‐albumin may induce mitochondrial dislocation in neutrophils, though this warrants further investigation.…”

“…Additionally, the enhanced transcript profile for apoptosis, ER stress, and autophagy in SAH neutrophils were not observed in SAH-albumin-treated healthy neutrophils, suggesting roles for other pathological mechanisms in SAH patients, which have been well documented in other studies. (8) Interestingly, our study shows that SAH-albumin treatment of healthy neutrophils caused up-regulation of the BAD, BAX, CASP8, and TNFa genes, indicating that SAH-albumin may induce mitochondrial dislocation in neutrophils, though this warrants further investigation. Thus, our study demonstrates that besides other known mechanisms, the modified circulatory albumin (majorly oxidized) serves as a substantial source for activation and priming of neutrophils in SAH patients and may contribute to the vascular complications (36) in these patients.…”

“…The primary reason behind the development of SAH is prolonged injury to the liver cells by the metabolic products of ethanol . Recent data have demonstrated a complex association between ethanol metabolism, inflammation, and innate immunity in the development and progression of SAH . The immunopathological events of SAH involve the activation of innate as well as adaptive immune mechanisms .…”

“…(8) The immunopathological events of SAH involve the activation of innate as well as adaptive immune mechanisms. (3,8) Studies have demonstrated that neutrophils act as primary inflammatory agents through production of proinflammatory mediators and release of reactive oxygen species (ROS) and various cytokines. (9) In alcohol-induced liver disease, neutrophils are known to infiltrate the liver and reduce the alcohol-induced hepatocellular damage.…”

Association between the expression of carbonic anhydrase�II and clinicopathological features of hepatocellular carcinoma

“…Gene analysis based on interaction between genes can effectively produce biological information, providing valid scientific reference for the diagnosis, treatment and improvement of prognosis. Following the rapid development of genomic science, a large quantity of genomic data and gene expression data have provided a novel basis for the investigation of gene-gene and gene-environment interactions (23)(24)(25). By analyzing the existing data through systems biology approaches, it is possible to investigate the association between gene function, protein interaction and the occurrence of diseases, and construct a detailed network of the occurrence and progression of diseases.…”