BACKGROUND Flavonoids from plant medicines are supposed to be viable alternatives for the treatment of type 2 diabetes (T2D) as less toxicity and side effects. Radix scutellariae (RS) is a widely used traditional medicine in Asia. It has shown great potential in the research of T2D. However, the pharmacological actions remain obscured due to the complex chemical nature of plant medicines. METHODS In the present study, a systematic method combining ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology was developed to screen α-glucosidase inhibitors from flavonoids of RS, and explore the underlying mechanism for the treatment of T2D. RESULTS The n-butanol part of ethanol extract from RS showed a strong α-glucosidase inhibition activity (90.55%, IC50 0.551 mg/mL) against positive control acarbose (90.59%, IC50 1.079 mg/mL). A total of 32 kinds of flavonoids were identified from the extract, and their ESI-MS/MS behaviors were elucidated. Thirteen compounds were screened as α-glucosidase inhibitors, including viscidulin III, 2',3,5,6',7-pentahydroxyflavanone, and so on. A compound-target-pathway (CTP) network was constructed by integrating these α-glucosidase inhibitors, target proteins, and related pathways. This network exhibited an uneven distribution and approximate scale-free property. Chrysin (k = 87), 5,8,2'-trihydroxy-7-methoxyflavone (k = 21) and wogonin (k = 20) were selected as the main active constituents with much higher degree values. A protein-protein interaction (PPI) weighted network was built for target proteins of these α-glucosidase inhibitors and drug targets of T2D. PPARG (Cd = 0.165, Cb = 0.232, Cc = 0.401), ACACB (Cd = 0.155, Cb = 0.184, Cc = 0.318), NFKB1 (Cd = 0.233, Cb = 0.161, Cc = 0.431), and PGH2 (Cd = 0.194, Cb = 0.157, Cc = 0.427) exhibited as key targets with the highest scores of centrality indices. Furthermore, a core subnetwork was extracted from the CTP and PPI weighted network. Type II diabetes mellitus (hsa04930) and PPAR signaling pathway (hsa03320) were confirmed as the critical pathways. CONCLUSIONS These results improved current understanding of natural flavonoids on the treatment of T2D. The combination of ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology provides a novel strategy for the research of plant medicines and complex diseases.

中文翻译：

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使用超滤UPLC-TripleTOF-MS / MS和网络药理学系统分析了黄Rad中黄酮类化合物中的天然α-葡萄糖苷酶抑制剂。

背景技术来自植物药的类黄酮被认为是治疗2型糖尿病（T2D）的可行替代品，因为毒性和副作用较小。黄（RS）是亚洲广泛使用的传统药物。在T2D的研究中显示出巨大的潜力。然而，由于植物药的复杂化学性质，其药理作用仍然被掩盖。方法在本研究中，开发了一种结合超滤UPLC-TripleTOF-MS / MS和网络药理学的系统方法，以从RS的黄酮中筛选α-葡萄糖苷酶抑制剂，并探索治疗T2D的潜在机制。结果RS乙醇提取物中的正丁醇部分对阳性对照阿卡波糖（90.59％，IC50 1.079 mg / mL）表现出很强的α-葡萄糖苷酶抑制活性（90.55％，IC50 0.551 mg / mL）。提取物中共鉴定出32种黄酮类化合物，并阐明了它们的ESI-MS / MS行为。筛选了13种化合物作为α-葡萄糖苷酶抑制剂，包括粘蛋白III，2'，3、5、6'，7-五羟基黄酮等。通过整合这些α-葡萄糖苷酶抑制剂，靶蛋白和相关途径，构建了复合靶通路（CTP）网络。该网络表现出不均匀的分布和近似的无鳞性质。选择了菊花蛋白（k = 87），5,8,2'-三羟基-7-甲氧基黄酮（k = 21）和沃戈宁（k = 20）作为主要的活性成分，其程度值更高。为这些α-葡萄糖苷酶抑制剂的靶蛋白和T2D的药物靶标建立了蛋白-蛋白相互作用（PPI）加权网络。PPARG（Cd = 0.165，Cb = 0.232，Cc = 0.401），ACACB（Cd = 0.155，Cb = 0。184，Cc = 0.318），NFKB1（Cd = 0.233，Cb = 0.161，Cc = 0.431）和PGH2（Cd = 0.194，Cb = 0.157，Cc = 0.427）被显示为中心指数最高得分的关键指标。此外，从CTP和PPI加权网络中提取了一个核心子网。II型糖尿病（hsa04930）和PPAR信号通路（hsa03320）被确认为关键途径。结论这些结果改善了目前对天然黄酮类药物治疗T2D的认识。超滤UPLC-TripleTOF-MS / MS和网络药理学的结合为植物药和复杂疾病的研究提供了新的策略。从CTP和PPI加权网络中提取了一个核心子网。II型糖尿病（hsa04930）和PPAR信号通路（hsa03320）被确认为关键途径。结论这些结果改善了目前对天然黄酮类药物治疗T2D的认识。超滤UPLC-TripleTOF-MS / MS与网络药理学的结合为植物药和复杂疾病的研究提供了新的策略。从CTP和PPI加权网络中提取了一个核心子网。II型糖尿病（hsa04930）和PPAR信号通路（hsa03320）被确认为关键途径。结论这些结果改善了目前对天然黄酮类药物治疗T2D的认识。超滤UPLC-TripleTOF-MS / MS和网络药理学的结合为植物药和复杂疾病的研究提供了新的策略。