Siming Dai1, Hui Wang1, Meng Wang2, Yue Zhang1, Zhiyi Zhang3, Zhiguo Lin4. 1. Department of Rheumatology and Immunology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, China. 2. Key Laboratory of Basic and Applied Research in North Medicine, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China. 3. Department of Rheumatology and Immunology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, China. zhangzhiyi2014@163.com. 4. Department of Rheumatology and Immunology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, China. 1977linzhiguo@163.com.
Abstract
INTRODUCTION: Celastrol is a promising therapeutic agent for the treatment of osteoarthritis (OA). However, the mechanism of action of celastrol is unclear. This study was aiming to identify the potential function of celastrol on OA and determine its underlying mechanism. METHOD: Celastrol targets were collected from web database searches and literature review, while pathogenic OA targets were obtained from Online Mendelian Inheritance in Man (OMIM) and GeneCards databases. Transcriptomics data was sequenced using an Illumina HiSeq 4000 platform. Celastrol-OA overlapping genes were then identified followed by prediction of the potential function and signaling pathways associated with celastrol using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A celastrol-target network was constructed to identify the candidate core targets of celastrol. The predictions were then validated by performing molecular docking and molecular dynamics simulation studies. RESULTS: In total, 96 genes were identified as the putative celastrol targets for treatment of OA. These genes were possibly involved in cell phenotype changes including response to lipopolysaccharide and oxidative stress as well as in cell apoptosis and aging. The genes also induced the mTOR pathway and AGE-RAGE signaling pathway at the intracellular level. Additionally, results indicated that 13 core targets including mTOR, TP53, MMP9, EGFR, CCND1, MAPK1, STAT3, VEGFA, CASP3, TNF, MYC, ESR1, and PTEN were likely direct targets of celastrol in OA. Finally, mTOR was determined as the most likely therapeutic target of celastrol in OA. CONCLUSION: This study provides a basic understanding and novel insight into the potential mechanism of celastrol against OA. Key Points • Our study provides a strong indication that further study of celastrol therapy in OA is required. • mTOR is the most likely therapeutic target of celastrol in OA.
INTRODUCTION:Celastrol is a promising therapeutic agent for the treatment of osteoarthritis (OA). However, the mechanism of action of celastrol is unclear. This study was aiming to identify the potential function of celastrol on OA and determine its underlying mechanism. METHOD:Celastrol targets were collected from web database searches and literature review, while pathogenic OA targets were obtained from Online Mendelian Inheritance in Man (OMIM) and GeneCards databases. Transcriptomics data was sequenced using an Illumina HiSeq 4000 platform. Celastrol-OA overlapping genes were then identified followed by prediction of the potential function and signaling pathways associated with celastrol using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A celastrol-target network was constructed to identify the candidate core targets of celastrol. The predictions were then validated by performing molecular docking and molecular dynamics simulation studies. RESULTS: In total, 96 genes were identified as the putative celastrol targets for treatment of OA. These genes were possibly involved in cell phenotype changes including response to lipopolysaccharide and oxidative stress as well as in cell apoptosis and aging. The genes also induced the mTOR pathway and AGE-RAGE signaling pathway at the intracellular level. Additionally, results indicated that 13 core targets including mTOR, TP53, MMP9, EGFR, CCND1, MAPK1, STAT3, VEGFA, CASP3, TNF, MYC, ESR1, and PTEN were likely direct targets of celastrol in OA. Finally, mTOR was determined as the most likely therapeutic target of celastrol in OA. CONCLUSION: This study provides a basic understanding and novel insight into the potential mechanism of celastrol against OA. Key Points • Our study provides a strong indication that further study of celastrol therapy in OA is required. • mTOR is the most likely therapeutic target of celastrol in OA.
Entities:
Keywords:
Celastrol; Computer-aided drug design; Mechanism; Network pharmacology; Osteoarthritis; Transcriptomics
Authors: Win Min Oo; Shirley Pei-Chun Yu; Matthew Sean Daniel; David John Hunter Journal: Expert Opin Emerg Drugs Date: 2018-12-03 Impact factor: 4.191