## 6 Therapeutic Actions of Madecassoside and Other Major Compounds in _C. asiatica_
### Skin Related Disease or Wound
Asiaticoside has also showed potential in accelerating wound healing in a fish model via increased cellular proliferation and suppressed apoptosis [85]. Skin aging is a multifaceted biological process molded by a combination of endogenous or intrinsic (genetics, cellular metabolism, hormone and metabolic processes) and exogenous or extrinsic (chronic light exposure, pollution, ionizing radiation, chemicals, toxins) factors. It is characterized by features, such as wrinkling, loss of elasticity, laxity and a rough textured appearance. Madecassoside showed protective effects against oxidative stress and UVB radiation. It significantly inhibited UV-induced melanin synthesis and melanosome transfer in a co-culture system of keratinocytes and melanocytes, by suppressing PAR-2 expression and its signaling pathway involving COX-2, PGE2 and PGF2\(\alpha\) in keratinocytes [86]. Several traditional Chinese medicine practitioners have shown a therapeutic effect of madecassoside in the re-pigmentation of vitiligo and post-inflammatory hyperpigmentation. For example, madecassoside showed an anti-oxidative effect in human melanocytes exposed to hydrogen peroxide; here, it attenuated mitochondrial damage and promoted autophagy [87]. Madecassoside was also reported to impede the proliferation of SVK-14 keratinocytes, a cell line useful for investigating psoriasis [88]. In an in vivo mouse model of psoriasis-like inflammation induced by the immune response modifier imiquimod (IMQ), topically applied madecassoside decreased dermal inflammation and reduced keratinocyte proliferation. These effects were associated with a reduction in the elevated expression of IL-22, IL-17 and IL-23, and a reduction in the number of Th17 cells in the spleen and cervical lymph nodes [89]. Such observations suggest that madecassoside could be a novel treatment for psoriasis. Skin aging is primarily associated with reduction in type I collagen levels. As mentioned above, asiaticoside was reported to induce type I collagen; thus, it was hypothesized that asiaticoside induces an anti-wrinkle effect by elevating type I collagen levels through T\(\beta\)RI kinase-independent Smad signaling pathway [90]. Microphalmia-associated transcription factor (MITF) regulates key enzymes in melanocytes, which is important for hyper- or hypopigmentation diseases. Asiaticoside was shown to be a novel candidate for melanogenesis inhibition through repression of DNA binding to MITF [91]. Advanced glycation end-products (AGEs) accumulate in skin and cause overproduction of free radicals and inflammatory cytokines that enhance skin aging. Pre-treatment with asiatic acid protected HaCaT cells against AGE-induced injury. Asiatic acid exhibited antioxidative, anti-inflammatory and antiapoptotic effects by reducing ROS production and decreasing caspase activity [92]. Moreover, asiatic acid also prevented UVA irradiation-induced ROS production, lipid peroxidation and induction of MMP-2, as well as preventing UVA-enhanced expression of p53 in HaCaT cells [93]. Keloids result from an anomalous wound healing process: they are regarded as benign dermal tumors, as they proliferate beyond the boundaries of the original wound without regressing spontaneously [94]. Keloids cause substantial cosmetic defects and deformities, and can sometimes limit joint mobility. Although there are no reports of keloids transforming into malignant tumors, the invasion activity of keloid fibroblasts (KF) is comparable to some extent to that of malignant cells [94]. Treatment of human keloid-derived fibroblasts with madecassoside (10, 30 and 100 \(\upmu\)M) for 48 h inhibited their proliferation and migration in a time- and concentration-dependent manner, while inducing KF to undergo apoptosis [94]. Additionally, madecassoside depolarized the mitochondrial membrane, activated caspase-9 and caspase-3 and regulated the expression of Bcl-2 family members in KFs, implying that madecassoside induced KF apoptosis through a mitochondrial-dependent pathway.