ruscogenin and Myocardial-Ischemia

Chronic heart failure (CHF) as a long-term disease is highly prevalent in elder people worldwide. Early diagnosis and treatments are crucial for preventing the development of CHF. Herein, we aimed to identify novel diagnostic biomarker, therapeutic target and drug for CHF. Untargeted metabolomic analysis has been used to characterize the different metabolomic profile between CHF patients and healthy people. Meanwhile, the targeted metabolomic study demonstrated the elevation of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) in the serum of CHF patients and coronary artery ligation-induced CHF mice. Subsequently, we firstly observed that elevation of CMPF impaired cardiac function and aggravated myocardial injury by enhancing fatty acid oxidation (FAO). Interestingly, inhibition of responsible transporters organic anion transporter 1/3 (OAT1/3) has been found to decrease the CMPF level, and suppress FAO-related key protein expressions including peroxisome proliferator-activated receptor alpha, peroxisome proliferative activated receptor-α, carnitine palmitoyl transferase 1, and malonyl CoA decarboxylase in coronary artery ligation-induced CHF mice. Meanwhile, the inhibitor of OAT1/3 presented an excellent improvement in cardiac function and histological injury. Based on the above findings, molecular docking was adopted to screen the potential therapeutic drug targeting OAT1/3, and ruscogenin (RUS) exhibited a great binding affinity with OAT1 and OAT3. Next, it was verified that RUS could remarkedly decrease the expression of OAT1/3 and CMPF levels in heart tissue of CHF mice, as well as suppress the expression of FAO-related proteins. What's more, RUS can effectively improve cardiac function, myocardial fibrosis and morphological damage. Collectively, this study provided a potential metabolic marker CMPF and novel target OAT1/3 for CHF, which were demonstrated to be involved in FAO. And RUS was identified as a potential anti-FAO drug for CHF by regulating OAT1/3.

Topics: Aged; Animals; Chronic Disease; Coronary Artery Disease; Fatty Acids; Heart Failure; Humans; Mice; Molecular Docking Simulation; Myocardial Ischemia

Ruscogenin (RUS), a major effective steroidal sapogenin derived from

Topics: Apoptosis; Humans; Mitochondrial Dynamics; Myocardial Ischemia; Nonmuscle Myosin Type IIA; Spirostans

Traditional Chinese medicine (TCM) has been used in clinical practice for thousands of years and has accumulated considerable knowledge concerning the in vivo efficacy of targeting complicated diseases. TCM formulae are a mixture of hundreds of chemical components with multiple potential targets, essentially acting as a combination therapy of multi-component drugs. However, the obscure substances and the unclear molecular mechanisms are obstacles to their further development and internationalization. Therefore, it is necessary to develop new modern drugs based on the combination of effective components in TCM with exact clinical efficacy. In present study, we aimed to detect optimal ratio of the combination of effective components based on Sheng-Mai-San for myocardial ischemia.. On the basis of preliminary studies and references of relevant literature about Sheng-Mai-San for myocardial ischemia, we chose three representative components (ginsenoside Rb1 (G), ruscogenin (R) and schisandrin (S)) for the optimization design studies. First, the proper proportion of the combination was explored in different myocardial ischemia mice induced by isoproterenol and pituitrin based on orthogonal design. Then, the different proportion combinations were further optimized through uniform design in a multi-model and multi-index mode. Finally, the protective effect of combination was verified in three models of myocardial ischemia injured by ischemia/reperfusion, chronic intermittent hypoxia and acute infarction.. The optimized combination GRS (G: 6 mg/kg, R: 0.75 mg/kg, S: 6 mg/kg) obtained by experimental screening exhibited a significant protective effect on myocardial ischemia injury, as evidenced by decreased myocardium infarct size, ameliorated histological features, decreased myocardial myeloperoxidase (MPO) and malondiadehyde (MDA), calcium overload, and decreased serum lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), cardiac troponin I (cTn-I) activity. In addition, the interactions of three components in combination GRS were also investigated. The combination, compared to G, R and S, could significantly reduce the concentration of serum CK-MB and cTn-I, and decrease myocardial infarct size, which demonstrated the advantages of this combination for myocardial ischemia.. Our results demonstrated that the optimized combination GRS could exert significant cardioprotection against myocardial ischemia injury with similar effect compared to Sheng Mai preparations, which might provide some pharmacological evidences for further development of new modern Chinese drug for cardiovascular diseases basing on traditional Chinese formula with affirmative therapeutic effect.

Topics: Animals; Creatine Kinase, MB Form; Cyclooctanes; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Ginsenosides; Heart; Isoproterenol; L-Lactate Dehydrogenase; Lignans; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Pituitary Hormones, Posterior; Polycyclic Compounds; Spirostans; Troponin I