AUTHOR=Li Qi , Zhao Chengcheng , Zhang Yunsen , Du Huan , Xu Tong , Xu Xinmei , Zhang Jing , Kuang Tingting , Lai Xianrong , Fan Gang , Zhang Yi 

TITLE=1H NMR-Based Metabolomics Coupled With Molecular Docking Reveal the Anti-Diabetic Effects and Potential Active Components of Berberis vernae on Type 2 Diabetic Rats

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00932

DOI=10.3389/fphar.2020.00932

ISSN=1663-9812

ABSTRACT=<p>The dried stem bark of <italic>Berberis vernae</italic> C.K.Schneid., known as “Xiao-bo-pi” in Chinese, is a representative anti-diabetic herb in traditional Tibetan medical system. However, its anti-diabetic mechanisms and active components remain unclear. In this study, <sup>1</sup>H NMR-based metabolomics, biochemistry assay, molecular docking, and network analysis were integrated to evaluate the anti-diabetic effects of <italic>B. vernae</italic> extract on type 2 diabetic rats, and to explore its active components and underlying mechanisms. Diabetes was induced by high-fat diet and streptozotocin. After 30 days of treatment, <italic>B. vernae</italic> extract significantly decreased the serum levels of fasting blood glucose, insulin, insulin resistance index, glycated serum protein, TNF-α, IL-1β, and IL-6, whereas significantly increased the serum levels of insulin sensitivity index in type 2 diabetic rats. A total of 28 endogenous metabolites were identified by <sup>1</sup>H NMR-based metabolomics, of which 9 metabolites that were changed by diabetes were significantly reversed by <italic>B. vernae</italic> extract. The constructed compound-protein-metabolite-disease (CPMD) interaction network revealed the correlation between chemical constituents, target proteins, differential metabolites, and type 2 diabetes. Ferulic acid 4-<italic>O</italic>-<italic>β</italic>-D-glucopyranoside, bufotenidine, jatrorrhizine, and berberine showed good hit rates for both the 30 disease-related proteins and 14 differential metabolites-related proteins, indicating that these four compounds might be the active ingredients of <italic>B. vernae</italic> against type 2 diabetes. Moreover, pathway analysis revealed that the anti-diabetic mechanisms of <italic>B. vernae</italic> might be related to its regulation of several metabolic pathways (e.g., butanoate metabolism) and disease-related signal pathways (e.g., adipocytokine signaling pathway). In summary, <italic>B. vernae</italic> exerts a significant anti-diabetic effect and has potential as a drug candidate for the treatment of type 2 diabetes.</p>