## 6 Therapeutic Actions of Madecassoside and Other Major Compounds in _C. asiatica_
### Cardiovascular Diseases  
Acute myocardial infarction (MI) produces irreversible myocardial injury, resulting in necrosis of a significant portion of the myocardium. Acute MI may be either the nonperfusion type, where the obstruction to blood flow is permanent, or the reperfusion type, in which the obstruction or lack of blood flow is long enough in duration but can be reversed or restored after myocardial cell death occurs. There is a direct correlation between infarct size and prognosis [159]. Since reperfusion is the keystone of treatment for acute MI, there is a need for the advancement of adjunct therapies, which may possibly diminish reperfusion injury and thereby intensify the benefits of reperfusion [160]. Madecassoside showed anti-ischemic effects in vitro and protected rabbit isolated hearts and cardiomyocytes against reperfusion injury [161]. It also protected against vascular endothelial cell injury and increased the coronary flow in the rat isolated heart. The protective effect of madecassoside against myocardial ischemia-reperfusion injury was investigated further in vivo in rats. Madecassoside significantly reduced infarct size in rats subjected to coronary artery ligation followed by reperfusion. The serum levels of CK and LDH, indicators of myocardial injury, were significantly reduced in madecassoside-treated rats, suggesting a protective effect of madecassoside on myocardial cells. There was also improved post-ischemic ventricular function in rats receiving a high dose of madecassoside. Moreover, madecassoside-treated animals exhibited significantly lower MDA levels, increased SOD activity and lower serum CRP levels compared to the control group [162]. These findings are exactly in accordance with those in a rabbit model of ischemia-reperfusion [161]. Myocardial TNF-\(\alpha\) is an autocrine contributor to myocardial contractile dysfunction and cardiomyocyte death in sepsis [163]. Pre-treatment of neonatal rat cardiomyocytes with madecassoside inhibited LPS-induced TNF-\(\alpha\) production in a concentration-dependent manner, and, in vivo, significantly reduced the elevation of plasma TNF-\(\alpha\) induced by LPS in rats. Investigation of the underlying mechanism showed that madecassoside prevented LPS-induced NF-\(\kappa\)B translocation from cytoplasm into nucleus, and inhibited LPS-induced phosphorylation of ERK1/2 and p38. In vivo studies showed that madecassoside pre-treatment delayed the reduction in mean arterial blood pressure, and attenuated the tachycardia induced by LPS [163]. Asiatic acid was also reported to protect against myocardial ischemia/reperfusion injury in an H9c2 cell model, partly via the Akt/GSK-3B/HIF-1\(\alpha\) pathway [164]. Asiatic acid, among two other triterpenes, protected H9c2 cardiomyocyteset against high glucose-induced injury by obliterating oxidative stress and apoptosis [165]. Other studies also reported that the antioxidant and anti-inflammatory properties of asiatic acid were responsible for attenuation of isoproterenol-induced cardiotoxicity [166] and lactate-induced cardiomyocyte apoptosis [167]. Furthermore, asiatic acid augmented survival of AC16 cardiomyocytes against hypoxia-induced apoptosis by regulation of miR-1290/HIF3A/HIF-1\(\alpha\) axis [168]. In a model of heart failure, treatment with asiatic acid preserved cardiac function and inhibited left ventricular remodeling, alleviated cardiomyocyte apoptosis, and reduced interstitial fibrosis and inflammatory responses by inhibiting the mitochondria-dependent apoptotic pathway [169]; it also inhibited phosphorylation of p38 MAPK and ERK 1/2 [170] and reduced NF-kB binding activity [171]. A role for AMPK in asiatic acid-mediated protection against cardiac hypertrophy and fibrosis was suggested by the loss of this protective effect following the depletion of AMPK\(\alpha\)[172]. A study also highlighted the efficacy of asiatic acid in blocking IL-1\(\beta\) activated NF-kB signaling in in vitro and in vivo models [173].