Investigating Celastrol’s Anti-DCM Targets and Mechanisms via Network Pharmacology and Experimental Validation

Abstract

Background and Purpose. DCM (diabetic cardiomyopathy), which may lead to significant complications including cardiovascular lesions, arrhythmia, and even heart failure, has a beginning element now known to be myocardial energy rebuilding. There are limited research on Celastrol’s ability to guard against this in the United States and elsewhere. Since it has not been known, whether Celastrol could reverse the early energy remodeling process, thus, it was hypothesized that triptolide Celastrol is suitable for the reversal of early myocardial energy remodeling in DCM. And our aim is to predict the targets and underlying mechanism of Celastrol in reversing the early energy remodeling for DCM. Methods. Data from TCMSP and GEO databases were utilized to identify targets for Celastrol on DCM. The relationship between the major targets and conventional glycolipid metabolism was obtained with Spearman correlation analysis. Experiments on animals were conducted utilizing healthy control (HC), low-dose Celastrol interventions (CL), and no intervention groups (NC), all of which had 8 SD rats in each group. To study alterations in signaling molecules, RT-PCR was performed. Results. There were 76 common targets and 5 major targets for Celastrol-DCM. Celastrol have been found to regulate AGE-RAGE, TNF, MAPK, TOLL-like receptors, insulin resistance, and other signaling pathways, and they are closely linked to adipocytokines, fatty acid metabolism, glycolipid biosynthesis, and glycosylphosphati-dylinositol biosynthesis on DCM. These five major targets have been found to regulate these pathways. Experiments on rats indicated that P38 MAPK was considerably elevated in the cardiac tissue from rats in the CL and NC groups compared to the HC group, and the difference was statistically significant ( P < 0.01 ). Significant differences were seen between the CL and NC groups in P38 MAPK levels, with a statistical significance level of less than 0.05. Conclusion. Celastrol may play a role in reversing energy remodeling, anti-inflammation, and oxidative stress via modulating p38 protein expression in the MAPK pathway, which have been shown in the treatment of DCM.