Mixture design optimization of salvianolic acid B, tanshinone IIA, butein, and formononetin from Salvia miltiorrhiza and Dalbergia odorifera for myocardial infarction.
Salvia miltiorrhiza-Dalbergia odorifera (SM-DO) is a commonly used herb pair for treating cardiovascular diseases. It can treat myocardial infarction (MI) by regulating glycolysis and angiogenesis, but the optimal proportion of its active components remains unclear.
Based on the enhanced simplex-centroid mixture design using Minitab 19 software, 19 proportions of salvianolic acid B (Sal-B), butein (But), tanshinone IIA (Tan IIA), and formononetin (For) were applied to an oxygen-glucose deprivation (OGD)-treated human cardiac microvascular endothelial cells (HCMVECs)-AC16 cells co-culture system. The proportions were independent variables, and viability, lactic acid, vascular endothelial growth factor (VEGF) of HCMVECs, and cardiac troponin I (cTnI) of AC16 cells were dependent variables. Regression equations were fitted and multi-objective optimization was performed to determine the OP, and experimental verification was conducted.
Stepwise regression analysis yielded regression equations for the four response indicators. The R 2 and adjusted R 2 of each model were at reasonable levels, and the predicted R 2 showed no significant decay. Multi-objective simultaneous optimization revealed OP of 60% Sal-B, 5% But, 5% Tan IIA, and 30% For. Experimental validation results showed that OP could promote lactic acid and VEGF production in OGD HCMVECs, enhance HCMVEC viability, and inhibit cTnI release in OGD AC16 cells. In vivo, OP increased levels of lactic acid, total protein lactylation (Pan-Kla), and VEGF in the myocardium of MI mice, and decreased levels of cTnI, creatine kinase-myocardial band (CK-MB), and myoglobin (Myo) in serum, alleviated pathological injury and fibrosis in myocardial tissues, and enhanced cardiac function in mice.
This study preliminarily clarifies the OP composed of Sal-B, But, Tan IIA, and For that improves glycolysis and angiogenesis-related indicators and exerts cardioprotective effects, providing a new strategy for studies on active component formulations of traditional Chinese medicines. It is expected to lay a methodological foundation for the clinical application of SM-DO and the development of new drugs.
Based on the enhanced simplex-centroid mixture design using Minitab 19 software, 19 proportions of salvianolic acid B (Sal-B), butein (But), tanshinone IIA (Tan IIA), and formononetin (For) were applied to an oxygen-glucose deprivation (OGD)-treated human cardiac microvascular endothelial cells (HCMVECs)-AC16 cells co-culture system. The proportions were independent variables, and viability, lactic acid, vascular endothelial growth factor (VEGF) of HCMVECs, and cardiac troponin I (cTnI) of AC16 cells were dependent variables. Regression equations were fitted and multi-objective optimization was performed to determine the OP, and experimental verification was conducted.
Stepwise regression analysis yielded regression equations for the four response indicators. The R 2 and adjusted R 2 of each model were at reasonable levels, and the predicted R 2 showed no significant decay. Multi-objective simultaneous optimization revealed OP of 60% Sal-B, 5% But, 5% Tan IIA, and 30% For. Experimental validation results showed that OP could promote lactic acid and VEGF production in OGD HCMVECs, enhance HCMVEC viability, and inhibit cTnI release in OGD AC16 cells. In vivo, OP increased levels of lactic acid, total protein lactylation (Pan-Kla), and VEGF in the myocardium of MI mice, and decreased levels of cTnI, creatine kinase-myocardial band (CK-MB), and myoglobin (Myo) in serum, alleviated pathological injury and fibrosis in myocardial tissues, and enhanced cardiac function in mice.
This study preliminarily clarifies the OP composed of Sal-B, But, Tan IIA, and For that improves glycolysis and angiogenesis-related indicators and exerts cardioprotective effects, providing a new strategy for studies on active component formulations of traditional Chinese medicines. It is expected to lay a methodological foundation for the clinical application of SM-DO and the development of new drugs.
Authors
Li Li, Liu Liu, Liu Liu, Dai Dai, Yao Yao, Wang Wang, Ding Ding, Cao Cao, Wei Wei, Xi Xi, Zhang Zhang
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