Integrating pharmacological evaluation and computational identification for deciphering the action mechanism of Yunpi-Huoxue-Sanjie formula alleviates diabetic cardiomyopathy.
Integrating pharmacological evaluation and computational identification for deciphering the action mechanism of Yunpi-Huoxue-Sanjie formula alleviates diabetic cardiomyopathy.
复制标题
药理评价与计算鉴定相结合，破解运脾活血散结方缓解糖尿病心肌病的作用机制
DOI：
10.3389/fphar.2022.957829
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发表时间：
2022
影响因子：
5.6
通讯作者：
Mao, Zhu-Jun
中科院分区：
文献类型：
--
作者：
Zhang, Xin;You, Li-Yan;Zhang, Ze-Yu;Jiang, Dong-Xiao;Qiu, Yu;Ruan, Ye-Ping;Mao, Zhu-Jun
关键词：
背景：云脾活血散戒方是治疗糖尿病性心肌病（DCM）等心血管并发症具有独特优势的中药方剂。然而，潜在的靶点和分子机制尚不清楚。因此，我们的研究旨在通过对大鼠心肌形态、脂肪代谢和氧化应激的评价来验证YP-SJ方在体内对心肌的保护作用。然后通过网络药理学和体内外实验，探索并验证其可能的机制。方法：将DCM大鼠随机分为5组：对照组、模型组和YP-SJ方低、中、高3个剂量组。实验大鼠分别以6 g/kg/d、12 g/kg/d、24 g/kg/d的YP-SJ方灌胃10周。采用高分辨率小动物成像系统测定大鼠心功能。将细胞分为对照组、高糖组、高糖+对照血清组、高糖+给药血清组、高糖+ NC-siRNA组、高糖+ sirna - fox01组。流式细胞术、免疫荧光、western blotting检测细胞自噬程度。结果：YP-SJ方能有效改善DCM大鼠心脏收缩功能。我们确定了46个与DCM进展密切相关的主要候选YP-SJ配方靶点。富集分析揭示了YP-SJ分子式的关键靶点与环境信息处理、有机系统和活性氧的代谢发生有关。同时，我们在体外和体内验证了YP-SJ配方可以增加叉头盒蛋白O1 （FoxO1）、自噬相关蛋白7 （Atg7）、Beclin 1和轻链3 （LC3）的表达，降低磷酸化FoxO1的表达。结果表明，YP-SJ方可激活DCM大鼠fox01信号通路。进一步实验表明，YP-SJ方可通过调节自噬来改善心功能。结论：YP-SJ方通过多组分、多层次、多靶点、多途径、多机制的作用，通过调节自噬关键靶点，改善心肌功能，治疗DCM。
Background: Yunpi-Huoxue-Sanjie (YP-SJ) formula is a Chinese herbal formula with unique advantages for the treatment of diabetic cardiovascular complications, such as Diabetic cardiomyopathy (DCM). However, potential targets and molecular mechanisms remain unclear. Therefore, our research was designed to evaluate rat myocardial morphology, fat metabolism and oxidative stress to verify myocardial protective effect of YP-SJ formula in vivo. And then to explore and validate its probable mechanism through network pharmacology and experiments in vitro and in vivo. Methods: In this study, DCM rats were randomly divided into five groups: control group, model group, and three YP-SJ formula groups (low-dose, middle-dose, and high-dose groups). Experimental rats were treated with 6 g/kg/d, 12 g/kg/d and 24 g/kg/d YP-SJ formula by gavage for 10 weeks, respectively. Cardiac function of rats was measured by high-resolution small-animal imaging system. The cells were divided into control group, high glucose group, high glucose + control serum group, high glucose + dosed serum group, high glucose + NC-siRNA group, high glucose + siRNA-FoxO1 group. The extent of autophagy was measured by flow cytometry, immunofluorescence, and western blotting. Results: It was found that YP-SJ formula could effectively improve cardiac systolic function in DCM rats. We identified 46 major candidate YP-SJ formula targets that are closely related to the progression of DCM. Enrichment analysis revealed key targets of YP-SJ formula related to environmental information processing, organic systems, and the metabolic occurrence of reactive oxygen species. Meanwhile, we verified that YP-SJ formula can increase the expression of forkhead box protein O1 (FoxO1), autophagy-related protein 7 (Atg7), Beclin 1, and light chain 3 (LC3), and decrease the expression of phosphorylated FoxO1 in vitro and in vivo. The results showed that YP-SJ formula could activate the FoxO1 signaling pathway associated with DCM rats. Further experiments showed that YP-SJ formula could improve cardiac function by regulating autophagy. Conclusion: YP-SJ formula treats DCM by modulating targets that play a key role in autophagy, improving myocardial function through a multi-component, multi-level, multi-target, multi-pathway, and multi-mechanism approach.
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影响因子：
4.3
作者：
Erukainure, Ochuko L.;Msomi, Nontokozo Z.;Islam, Md Shahidul
通讯作者：
Islam, Md Shahidul
影响因子：
2.1
作者：
Hintz, KK;Ren, J
通讯作者：
Ren, J
影响因子：
39.3
作者：
Maack C;Lehrke M;Backs J;Heinzel FR;Hulot JS;Marx N;Paulus WJ;Rossignol P;Taegtmeyer H;Bauersachs J;Bayes-Genis A;Brutsaert D;Bugger H;Clarke K;Cosentino F;De Keulenaer G;Dei Cas A;González A;Huelsmann M;Iaccarino G;Lunde IG;Lyon AR;Pollesello P;Rena G;Riksen NP;Rosano G;Staels B;van Laake LW;Wanner C;Farmakis D;Filippatos G;Ruschitzka F;Seferovic P;de Boer RA;Heymans S
通讯作者：
Heymans S
影响因子：
13.3
作者：
Li, Yuan;Zong, Wei-Xing;Ding, Wen-Xing
通讯作者：
Ding, Wen-Xing
影响因子：
7.7
作者：
Kihara, A;Kabeya, Y;Yoshimori, T
通讯作者：
Yoshimori, T