## 6 Therapeutic Actions of Madecassoside and Other Major Compounds in _C. asiatica_
### Liver Diseases  
Acute liver failure (ALF) is a life-threatening condition with a high mortality rate worldwide. It is manifested by hepatic dysfunction, abnormal liver biochemical parameters and coagulopathy [205]. The onset of ALF is an inflammation mediated by hepatocellular injury process that closely resembles the innate immune response induced by exposure to LPS (endotoxin). LPS combined with D-GaN acts as a hepatotoxic or liver damaging agent that is typically used to induce ALF in experimental models [206]. Pre-treatment of mice with mac accesssoide markedly suppressed the LPS/DGalN-induced increases in the serum concentrations of ALT and AST, and preserved hepatic integrity, protecting against hemorrhage and cellular necrosis. Madecassoside pre-treatment significantly reduced the LPS/DGalN-mediated increase in the hepatic levels of the inflammatory cytokines IL-\(\beta\), IL-6 and TNF-\(\alpha\), while increasing levels of the antioxidant enzymes SOD, catalase and glutathione peroxidase. These effects were associated with inhibition by mac accesssoide of the phosphorylation of p38 MAPK and NF-\(\kappa\)B [207]. The effects of asiaticoside on ALF were also tested in a similar model. Treatment with asiaticoside improved liver function, alleviated liver injury and attenuated apoptosis induced by LPS/DGalN, possibly via the inhibition of the expression of TNF-\(\alpha\) and MAPKs [208]. The protective effects of asiaticacid against LPS/DGalN-induced injury was associated with the inhibition of the cellular redox-regulated LTC4S expression pathway [209].  
Liver fibrosis occurs when excessive collagen and extracellular matrix deposit in the liver. Liver fibrosis can advance to liver cirrhosis, eventually causing liver failure and ultimately death [210]. Asiatic acid was discovered to protect against carbon tetrachloride (CCI4)-induced liver fibrosis via multiple mechanisms; these include the inhibition of TGF-\(\beta\)/Smad signaling pathways in in vivo and in vitro models [211], regulation of the PI3K/AKT/mTOR and Bcl-2/Bax signaling pathways [212] and suppression of NF-\(\kappa\)B/1 kB\(\alpha\) and JAK1/STAT3 signaling [213].  
Intragastric administration of asiatic acid was shown to protect the liver against ethanol-induced hepatotoxicityicity by ameliorating oxidative stress and inhibiting Kupffer cell activation, via diminishing the expression of TLR4, CD14 and MyD88 [214]. In addition, supplementation with asiatic acid improved insulin resistance and attenuated hepatic oxidative and inflammatory injury in mice fed a high-fat diet [215]. Pre-treatment with asiatic acid reportedly can protect against I/R-induced liver injury in rats and anoxia/reoxygenation (A/R)-induced injury in isolated rat liver mitochondria [216]. This is in agreement with a previous study demonstrating that treatment with asiatic acid induced partial uncoupling of mitochondria and thus protected mitochondrial function [217]. Moreover, asiatic acid may alleviate hepatic I/R injury through mitigation of Kupffer cells activation via the PPAR\(\gamma\)/NLRP3 inflammasome signaling pathway [218]. On the other hand, asiatic acid demonstrated a protective effect against DOX-induced liver toxicity in a rat model in a dose-dependent manner through the modulation of Nrf2 translocation, suggesting its use as an organ-protective adjuvant in DOX treatment [219].