三黄降糖片通过整合生物信息学分析和实验验证通过 AKT-GSK3β-NFATc1 信号通路保护 2 型糖尿病骨质疏松症。
Sanhuang Jiangtang tablet protects type 2 diabetes osteoporosis via AKT-GSK3β-NFATc1 signaling pathway by integrating bioinformatics analysis and experimental validation.
机构信息
1(st) School of Medicine, Guangzhou University of Chinese Medicine, 12 Jichang Road, Baiyun Area, Guangzhou, 510405, PR China; The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China.
Department of Orthopaedic Surgery, Clifford Hospital, Jinan University, Guangzhou, 510006, PR China.
出版信息
J Ethnopharmacol. 2021 Jun 12;273:113946. doi: 10.1016/j.jep.2021.113946. Epub 2021 Feb 26.
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.
民族药理学相关性
三黄降糖片（SHJTT）已广泛用于治疗 2 型糖尿病（T2DM）。然而，SHJTT 治疗 2 型糖尿病骨质疏松症（T2DOP）的潜力和机制尚未报道。
研究目的
本研究旨在探讨 SHJTT 在治疗 2 型糖尿病骨质疏松症中的作用及其潜在的分子机制。
材料和方法
通过搜索 ETCM 数据库获得 SHJTT 各组成成分的靶基因。分别通过分析 DisGeNET 和 OMIM 疾病数据库获得骨质疏松症和糖尿病的靶基因。然后，将草药靶基因与疾病靶基因的交集导入 R 和 STRING 平台，进行 GO 术语、KEGG 通路和 PPI 网络分析，获得潜在的治疗靶基因。利用 Cytoscape 软件构建 PPI 网络的关键模块。最后，通过表型评估确认瘦素受体缺失（db/db）小鼠为 2 型糖尿病骨质疏松症（T2DOP）动物模型，并通过定量实时 PCR（qRT-PCR）验证 SHJTT 治疗 T2DOP 的关键基因。
结果
从 ETCM 中获得了 786 个 SHJTT 的靶基因。同时，从 DisGeNET 和 OMIM 数据库中获得了 3906 个骨质疏松症和 2 型糖尿病相关靶基因。然后，通过重叠获得了 97 个共同靶基因。基于 GO 和 KEGG 富集分析和 PPI 网络，我们发现 SHJTT 在 2 型糖尿病骨质疏松症中的相关途径是 AKT-GSK3β-NFATc1 途径，该途径与破骨细胞分化密切相关。在 T2DOP 小鼠中，SHJTT 显著下调关键基因包括 Akt1、Mapk3、Gsk3β、Mmp9、Nfkb1 的表达（p < 0.05）。
结论
SHJTT 通过调节 AKT-GSK3β-NFATc1 信号通路对 T2DOP 具有保护作用。本研究为 SHJTT 治疗 2 型糖尿病骨质疏松症提供了理论依据。
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