Sanhuang Jiangtang tablet protects type 2 diabetes osteoporosis via AKT-GSK3β-NFATc1 signaling pathway by integrating bioinformatics analysis and experimental validation

Authors: He Q, Yang J, Zhang G, Chen D, Zhang M, Pan Z, Wang Z, Su L, Zeng J, Wang B, Wang H, Chen P
Publication: J Ethnopharmacol
Keywords: AKT-GSK3β-NFATc1 signaling pathway, bioinformatics, diabetes, osteoporosis, Sanhuang jiangtang tablet, Type 2 diabetes
Software: ADMET Predictor®

Abstract

Abstract
Ethnopharmacological relevance
Sanhuang Jiangtang tablet (SHJTT), has been widely used to treat type 2 diabetes mellitus (T2DM). However, the potential and mechanism of SHJTT in treating type 2 diabetes osteoporosis (T2DOP) has not been reported.

Aim of the study
The aim of this work was to investigate the role and the underlying molecular mechanism of SHJTT in managing type 2 diabetes osteoporosis.

Materials and methods
The target genes of each component consisting of SHJTT were obtained by searching the ETCM database. The target genes of osteoporosis and diabetes were individually acquired by analyzing the DisGeNET and OMIM disease databases. Then the potential therapeutic genes were obtained from the intersection of the herbal medicine targets and the disease targets which were imported into the R and STRING platform for the analysis of GO terms, KEGG pathways and PPI network. The key modules of PPI network were constructed by Cytoscape software. Finally, leptin receptor deficiency (db/db) mice were confirmed as an animal model of type 2 diabetic osteoporosis (T2DOP) through phenotype assessment and the key genes of SHJTT against T2DOP were validated by quantitative real-time PCR (qRT-PCR).

Results
A total of 786 target genes of SHJTT were obtained from ETCM. Simultaneously, a total of 3906 osteoporosis and type 2 diabetes associated targets were acquired from DisGeNET and OMIM databases. Then, 97 common targets were found by overlapping them. On the basis of the GO and KEGG enrichment analysis and PPI network, we found that the related pathway of SHJTT in type 2 diabetes osteoporosis was AKT-GSK3β-NFATc1 pathway which is tightly associated with osteoclast differentiation. The expression of key genes including Akt1, Mapk3, Gsk3β, Mmp9, Nfkb1 were significantly down-regulated by SHJTT in T2DOP mice (p < 0.05).

Conclusions
SHJTT had a protective effect on T2DOP via regulating AKT-GSK3β-NFATc1 signaling pathway. This study might provide a theoretical basis for the application of SHJTT for the treatment of type 2 diabetic osteoporosis.

By Qi He, Junzheng Yang, Gangyu Zhang, Delong Chen, Meng Zhang, Zhaofeng Pan, Zihao Wang, Lijun Su, Jiaxu Zeng, Baohua Wang, Haibin Wang, Peng Chen