Celastrol Alleviates Autoimmune Hepatitis Through the PI3K/AKT Signaling Pathway Based on Network Pharmacology and Experiments

Abstract

Objective: This work aims to explore the potential targets and underlying therapeutic mechanisms of celastrol in autoimmune hepatitis (AIH) through network pharmacology and experiments on Laboratory Animals.Methods: A drug-target interaction network was constructed to predict the possible targets of celastrol and their potential relationship with the drug; docking studies were also performed for validation. This study used both acute and chronic rodent models of autoimmune hepatitis. Gross appearance of liver and spleen were obtained from murine models, hematoxylin-eosin staining and Sirius red staining were performed to examine hepatic inflammation and fibrosis respectively. By combining molecular docking and enrichment analysis results, the most prominent signaling pathway was selected and further confirmed by Western blot in AIH models administered with celastrol.Results: In total, 82 common targets of celastrol and AIH were obtained from databases, identified by network pharmacology, and adequately enriched. Among them, PIK3R1, SRC, MAPK1, AKT1, and HRAS were selected as the top 5 closely related targets to celastrol. They all performed effectively in molecular docking, with AKT1 and PIK3R1 exhibiting more-prominent binding energy. Subsequently, celastrol administration significantly ameliorated hepatitis and liver fibrosis by reducing AKT1 and PI3K phosphorylation in both acute liver injury and chronic models of autoimmune hepatitis.Conclusion: In summary, celastrol significantly attenuates autoimmune hepatitis by suppressing the PI3K/AKT signaling pathway, confirmed by validated animal models. These findings may help identify the mechanism involved in the anti-inflammatory action of celastrol in autoimmune hepatitis and provide ideas for future comprehensive studies.

MFGE-8 identified in fetal mesenchymal-stromal-cell-derived exosomes ameliorates acute hepatic failure pathology

“…Thus, both MFGE-8-containing EXO and rMFGE-8 downregulate Akt and its target Foxo1 , upregulate the expression of Pten , and reduce the levels of the phosphorylated, active form of AKT. Given that inhibition of the PI3K/AKT/mTOR signaling pathway protects against acute hepatic injury induced by Concanavalin-A or LPS/D-galactosamine, 55 , 56 the aforementioned observations provide a mechanistic framework linking MFGE-8 to hepatoprotection.…”

Case Report: Activating PIK3CD Mutation in a Patient with Refractory Ascites

“…Autoimmune presentations are features of APDS1 in up to 42% of cases [9]. Among these, were the most frequent manifestations, followed by Evans syndrome, type 1 diabetes mellitus, enteropathy, arthritis, SLE, autoimmune thyroiditis, sclerosing cholangitis, Sjogren syndrome, and autoimmune hepatitis [10,11].…”

Two cases of successful sirolimus treatment for patients with activated phosphoinositide 3-kinase δ syndrome 1

“…Autoimmune presentations are the features of APDS1 in 28 to 42% of cases [ 16 ]. Among these, autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) were the most frequent manifestations, followed by Evans syndrome, type 1 diabetes mellitus, enteropathy, arthritis, SLE, autoimmune thyroiditis, sclerosing cholangitis, sjogren syndrome, and autoimmune hepatitis also have been previously reported [ 17 – 21 ]. To date, only a few cases of SLE phenotype have been described in patients with APDS1 [ 8 , 22 ].…”