The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
J Ethnopharmacol. 2021 Jan 10;264:113289. doi: 10.1016/j.jep.2020.113289. Epub 2020 Aug 23.
GegenQinlian Decoction (GQD), a classical formula in traditional Chinese medicine, is widely used in the treatment of diabetes. While studies have demonstrated that GQD is an efficacious treatment for insulin resistance (IR) in type 2 diabetes mellitus (T2DM), the potential bioactive compounds and mechanisms remain unclear.
To further investigate the potential bioactive compounds, targets, and pathways of GQD on improving IR in T2DM for adipose, liver, and muscle tissue using an integrated strategy of system pharmacology and bioinformatics analysis.
We screened the candidate compounds and targets of GQD and identified IR-associated differentially expressed genes (DEGs) of adipose, liver, and muscle tissue, respectively. Then the intersecting target genes between candidate targets and DEGs were used for "GQD-compounds-targets-tissue" network construction in each type of tissue. The top 10 bioactive compounds acting on each type of tissue were intersected and consequently identified as potential bioactive compounds of GQD. Furthermore, pathway enrichment, protein-protein interaction (PPI) network construction, and hub target identification were performed based on the targets of GQD and the targets of quercetin in each type of tissue, respectively. Finally, to further confirm the role of quercetin, we intersected the hub targets of quercetin and the hub targets of GQD, and the pathways were intersected as well.
132 compounds and 119 potential targets of these compounds were obtained. 1,765, 3,206, and 3594 DEGs were identified between IR and insulin sensitivity (IS) tissue in adipose, liver, and muscle, respectively. There were 21, 23, 45 targets and 103, 73, 123 compounds in the "GQD-compounds-targets-tissue" network of adipose, liver, and muscle tissue, respectively. Then compounds such as quercetin, kaempferol, baicalein, wogonin, isorhamnetin, beta-sitosterol and licochalcone A, were identified as the potential bioactive compounds of GQD, and quercetin had the highest degree among the compounds. Moreover, based on the targets of GQD, hub targets like PPARG, RELA, EGFR, CASP3, VEGFA, AR, ESR1 and CCND1, and signaling pathways such as insulin signaling pathway, endocrine resistance, TNF signaling pathway, PI3K-Akt signaling pathway, AMPK signaling pathway, MAPK signaling pathway, NF-κB signaling pathway, HIF-1 signaling pathway, apoptosis, and VEGF signaling pathway, were filtered out as the underlying mechanisms of GQD on improving diabetic IR. In addition, the hub targets and pathways of quercetin coincided with most of the hub targets and pathways of GQD in each type of tissue, respectively, suggesting that quercetin may be a potential representative compound of GQD.
Our analysis identifies the potential bioactive compounds, targets, and pathways of GQD on improving IR in T2DM for adipose, liver, and muscle tissue, which shows the characteristics of multi-compounds, multi-targets, multi-pathways, and multi-mechanisms of GQD and lays a solid foundation for further experimental research and clinical application.
葛根芩连汤（GQD）是一种经典的中药方剂，广泛用于治疗糖尿病。虽然已有研究表明 GQD 是治疗 2 型糖尿病胰岛素抵抗（IR）的有效方法，但潜在的生物活性化合物和机制仍不清楚。
本研究采用系统药理学和生物信息学分析相结合的策略，进一步探讨 GQD 改善 T2DM 脂肪、肝和肌肉组织中 IR 的潜在生物活性化合物、靶点和途径。
我们筛选了 GQD 的候选化合物和靶点，并分别鉴定了脂肪、肝和肌肉组织中与 IR 相关的差异表达基因（DEGs）。然后，将候选靶点和 DEGs 之间的交集靶点用于每种组织类型的“GQD-化合物-靶点-组织”网络构建。将作用于每种组织的前 10 种生物活性化合物进行交集，进而确定 GQD 的潜在生物活性化合物。此外，还基于每种组织类型的 GQD 靶点和槲皮素靶点进行了通路富集、蛋白质-蛋白质相互作用（PPI）网络构建和枢纽靶点鉴定。最后，为了进一步验证槲皮素的作用，我们对槲皮素的枢纽靶点和 GQD 的枢纽靶点进行了交集，并对通路进行了交集。
得到了 132 种化合物和 119 种潜在化合物靶点。在脂肪、肝和肌肉组织中，IR 与胰岛素敏感性（IS）组织之间分别鉴定出 1765、3206 和 3594 个 DEGs。在脂肪、肝和肌肉组织的“GQD-化合物-靶点-组织”网络中分别有 21、23、45 个靶点和 103、73、123 种化合物。然后，鉴定出槲皮素、山奈酚、白杨素、汉黄芩素、异鼠李素、β-谷甾醇和甘草素 A 等化合物为 GQD 的潜在生物活性化合物，其中槲皮素的程度最高。此外，基于 GQD 的靶点，筛选出了如 PPARG、RELA、EGFR、CASP3、VEGFA、AR、ESR1 和 CCND1 等枢纽靶点，以及胰岛素信号通路、内分泌抵抗、TNF 信号通路、PI3K-Akt 信号通路、AMPK 信号通路、MAPK 信号通路、NF-κB 信号通路、HIF-1 信号通路、细胞凋亡和 VEGF 信号通路等信号通路，作为 GQD 改善糖尿病 IR 的潜在机制。此外，槲皮素的枢纽靶点和通路与每种组织类型的 GQD 的大部分枢纽靶点和通路相吻合，这表明槲皮素可能是 GQD 的潜在代表性化合物。
本研究确定了 GQD 改善 T2DM 脂肪、肝和肌肉组织中 IR 的潜在生物活性化合物、靶点和途径，显示了 GQD 多化合物、多靶点、多途径和多机制的特点，为进一步的实验研究和临床应用奠定了基础。
