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1 Current Updates on Centella asiatica: Phytochemistry, Pharmacology and Traditional uses 2 Dipankar Chandra Roy, Shital Kumar Barman, Md. Munan Shaik* 3 Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia-7003, 4 Bangladesh. 5 *Corresponding author, [email protected] and [email protected] 6 Md. Munan Shaik, Ph. D 7 ABSTRACT 8 Plants have been demonstrated extraordinary source of medicine, and recently focus on 9 medicinal plant research has increased. Centella asiatica is well known for its traditional uses 10 and medicinal properties for the treatment of many diseases. The published literatures mention 11 the use of this plant as whole and bioactive compounds isolated are widely used in the treatment 12 of various human ailments. C. asiatica reported to possess various pharmacological activities: 13 antimicrobial activity, anticancer activity, wound healing activity, neuroprotechtive activity, 14 immunomodulatory activity, anti-inflammatory activity, hepatoprotective activity, insecticidal 15 activity, and antioxidant activity. C. asiatica is also rich in flavonoids and terpenoids compounds 16 among them asiatic acid, asiaticoside, madecassoside is well characterized for its 17 pharmacological value. The present review summarized widespread information on 18 phytochemistry, isolated and characterized bioactive compounds, pharmacological properties, in 19 vitro propagation and traditional uses of the important medicinal plant C. asiatica. 20 Keywords: Centella asiatica, Medicinal Plants, Triterpenes, Terpenoids Phytochemistry, 21 Pharmacology, Neuroprotechtive activity, Wound Healing actitivty, Anti-inflammatory activity, 22 Anticancer activity. 23 Introduction 24 Medicinal plants are an important episode in the medical sector. Around 5000 species have 25 specific therapeutic value among 2,50,000 higher plant species on earth (Joy et al., 1998). 26 Centella asiatica has a long history in ancient Ayurvedic remedy, used in wound healing, 27 cleansing for skin problem and digestive disorders (Chevallier, 2001) and effective in treatment 1 28 of stomach ulcers, mental fatigue, diarrhea, epilepsy, hepatitis, syphilis and asthma (Goldstein 29 and Goldstein, 2012). Such traditional uses and reputation of this species cross over the boundary 30 limit of Bangladesh, India, and Srilanka and now extensively used in the West (Chevallier, 2001; 31 Meulenbeld and Wujastyk, 2001). C. asiatica and Hydrocotyle asiatica, belongs to family 32 Apiaceae (Umbelliferae) are used synonymously and commonly known as Thankuni (Bengali), 33 Bemgsag/ Brahma-Manduki/Gotukola/Khulakhudi/Mandookaparni (Hindi), Indian Pennywort/ 34 Marsh Pennywort/ Gotu kola (English) (Singh et al., 2010). C. asiatica is creeping, perennial 35 herb with up to 2m long slender and tender horizontal reddish prostrate stolons, characterized by 36 long rooting internodes (Jamil et al., 2007; Koh et al., 2009). Glabrous leaves, 1-3 arising from 37 each node of the stems, are green, fan-shaped or round renifrom, 1.4 cm by 1.7 cm with crenate 38 or dentate margin (Jamil et al., 2007; Koh et al., 2009). Flowers occurring in July-September are 39 umbels with 3-4 white or light purple-to-pink petals bearing 4mm long oval to globular shaped 40 fruit (Chauhan, 1999; Jamil et al., 2007; Koh et al., 2009). The most used part for medicinal 41 purposes is dried whole plant, leaves and stems. C. asiatica plant is indigenous to Bangladesh, 42 India, West Pakistan, China, Japan, America and the pacific (Koh et al., 2009). This plant is 43 commonly seen in moist, sandy or clayey soils waste places (Jamil et al., 2007). 44 Phytochemistry 45 C. asiatica is a rich source of amino acids, flavonoids, terpenoids, essential oils, alkaloids etc. 46 (Table 1). Most of the phytochemical studies concentrated on leaves and the constituents vary 47 depending upon the geographical distribution (Chong NJ and Aziz, 2011). 48 Table 1: Chemical constituents of C. asiatica Main groups Constituents References Amino acids Alanine and serine (major components), aminobutyrate, aspartate, glutamate, (Barnes et histidine, lysine, threonine, arginine, leucine, iso-leucine, valine, methionine, al., 2007; tyrosine, phenylalanine, proline, cystine, glycine. Chong NJ and Aziz, 2011), Carbohydrates Glucose, mesoinositol, centellose, pectin, arabinogalactan (Chong NJ and Aziz, 2011) 2 Phenols Flavonoids: Kaempferol, kaempferol-3-o-β-d-glucuronide, castilliferol, (Bhandari quercetin, quercetin-3-o-β-d-glucuronide, castillicetin, apigenin, rutin, luteolin, et al., 2007; naringin Zheng and Qin, 2007; Chong NJ and Aziz, 2011) Phenylpropanoids: Rosmarinic acid, chlorogenic acid, 3,4-di-o-caffeoyl quinic (Chong NJ acid, 1,5-di-o-caffeoyl quinic acid, 3,5-di-o-caffeoyl quinic acid, 4,5-di-o- and Aziz, caffeoyl quinic acid, isochlorogenic acid 2011) Tannin: Tannin, phlobatannin (Chong NJ and Aziz, 2011) Terpenoids Triterpenes, asiaticoside, centelloside, madecassoside, brahmoside, (Barnes et brahminoside (saponin glycosides), asiaticentoic acid, centellic acid, centoic al., 2007; acid, madecassic acid, terminolic acid and betulic acid. Jamil et al., 2007) Volatile oils Various terpenoids: β-caryophyllene, trans β-farnesene and germacrene D (Barnes et and fatty oils (sesquiterpenes), α-pinene and β-pinene. al., 2007; Fatty acids: linoleic acid, linolenic acid, lignocene, oleic acid, palmitic acid, Jamil et al., stearic acid. 2007) Ascorbic acid, nicotinic acid, β-carotene (Chong NJ Vitamins and Aziz, 2011) Mineral Calcium, phosphorus, iron, potassium, magnesium, manganese, zinc, sodium, (Chong NJ copper and Aziz, 2011) Other Hydrocotylin (an alkaloid), vallerine (a bitter principle), phytosterols (e.g. (Barnes et constituents campesterol, sitosterol, stigmasterol), resin. ~14 different polyacetylenes (8- al., 2007; acetoxycentellynol, cadiyenol, dotriacont-8-en-1-oic acid, 11-oxoheneicosanyl Chong NJ cyclohexane). and Aziz, 2011) 49 Bioactive compounds 3 50 C. asiatica is being used as a natural source of medicine for long time. The main active 51 constitients of C. asitica are pentacyclic triterpenes (asiatic acid, madecassic acid, asiaticoside, 52 and madecassoside, etc.) (Puttarak and Panichayupakaranant, 2012b). Two new dammarane 53 monodesmosides centellosides A (1) and B (2), and two new natural products ginsenosides Mc 54 (10) and Y (11), were reported recently (Weng et al., 2011; Han et al., 2012). An efficient 55 microwave-assisted extraction method was developed for asiatic acid and a sensitive method for 56 quantification of it and madecassoside in rat plasma also reported (Han et al., 2012; Nasir et al., 57 2012; Puttarak and Panichayupakaranant, 2012a). Asiatic acid has shown numerous therapeutic 58 activities and biotransformation of it by Penicillium lilacinum ACCC 31890, Fusarium equiseti 59 CGMCC 3.3658, and Streptomyces griseus CGMCC 4.18 strains was investigated and structure 60 were deduced for all new derivaties (Guo et al., 2012). The ELISA method was investigated as 61 an analytical tool for quality control and standardization of pharmaceutical products containing 62 asiaticoside and madecassoside (Juengwatanatrakul et al., 2011; Tassanawat et al., 2012). 63 Bioactive compounds isolated and characterized from C. asiatica are summarized in Table 2 64 with their physical properties. 65 Table 2: Structure and biological activities of bioactive compounds isolated from C. asiatica. Name of the Structure Biological activity compounds Referenc es Asiatic acid Aids in generation of neuroglia; promotes (Huang et (C30H48O5; wound healing, promotes cuticle al., 2011; mw = 488.71) cornification; stimulates granulation; induces Nasir et gene expression changes, enhancing learning al., 2011a, and memory properties, antinociceptive 2012; activity, anti-inflammation activity, Zhou et acetylcholinesterase inhibitory activity, anti al., 2011; apoptotic activity Song et al., 2012; Zhang et al., 2012) 4 Asiaticoside Anti-inflammatory; antioxidant induces gene (Tang et (C48H78O19; expression changes, wound healing, reduces al., 2011a; mw = 959.15) scar formation, neuroprotective activity, Zhou et improve collagen biosynthesis al., 2011; Lee et al., 2012; Nowwarot e et al., 2012; Paolino et al., 2012; Wan et al., 2012; Xu et al., 2012a) Madecassic acid Induces gene expression changes, (Zhou et (C30H48O6; al., 2011; mw = 504.71) Song et al., 2012) Madecassoside Induces gene expression changes, protection (Zhou et (C48H78O20; of endothelial cells from oxidative injury. al., 2011; mw = 975.14) Bian et al., 2012) Quercetin Anti-HIV-1, antiasthmatic, antibacterial, (Chong (C15H10O7; antihepatotoxin, antihypertensive, anti- NJ and mw = 302.24) inflammatory, antitussive, antiviral, coronary Aziz, vasodilator, antihypercholesterolemic, 5-HT 2011; inhibitor, smooth muscle relaxant, platelet Zhou et aggregation inhibitor, 3’,5’-cAMP- al., 2011) phosphodiesterase inhibitor, fatty acid synthetase inhibitor, aldose reductase inhibitor (eye lens), protein kinase C inhibitor; antihypertensive, reduces blood capillary brittleness, antioxidant 5 Kaempferol Anti-HIV-1, antibacterial; anti- (Chong (C15H10O6; inflammatory, antitussive to cure trachitis, NJ and mw = 286.24) antioxidant, ∆5 -lipoxygenase inhibitor; Aziz, iodinate thyronine deiodinase inhibitor; 2011; aldose reductase inhibitor Zhou et al., 2011) Apigenin Antibacterial, antiulcerative, antispasmodic (Bhandari (C15H10O5; mw = (smooth muscle), diuretic, aldose reductase et al., 270.24) inhibitor, antihypertensive, anti- 2007; inflammatory, antioxidant, nodulation signal Zhou et for metabiosis of pea and Rhizobium al., 2011) leguminosarum, Rutin (C27H30O16; Anti-inflammatory, antiviral, aldose (Bhandari mw = 610.53) reductase Inhibitor, insect antifeedant et al., (Heliothis zea), insect phagostimulant 2007; (Gastrophysa atrocynea), antioxidant, Zhou et inhibits cancer cell invasion, reduces blood al., 2011) capillary permeability and brittleness Luteolin (C15H10O6; Antiallergic, antibacterial, antifungal, (Bhandari mw = 286.24) cytotoxic, anti-inflammatory, antispasmodic, et al., antitussive, antiviral, enhances arterial 2007; tension and lowers intravenous tension, Zhou et enhances blood capillary permeability, al., 2011) immunoenhancer, increases coronary flow; dihydrocoenzyme I (NADH) oxidase inhibitor, iodine-induced thyronine deiodinase inhibitor, aldose reductase inhibitor, anti-inflammatory, anti-HIV activity Quercitrin Antibacterial, antineoplastic, (Bhandari (C21H20O11; antihepatotoxin, anti-inflammatory, et al., mw = 448.39) antimutagenic, antiviral, diuretic, 2007; Hemostatic, aldose reductase inhibitor, Zhou et antioxidant, insect antifeedant (Bombyx al., 2011) mor), insect phagostimulant (Gastrophysa atriocyaea), hepatoprotective 6 Naringin Antibacterial, anti-inflammatory, antiviral, (Zheng (C27H32O14; aldose reductase inhibitor, passive cutaneous and Qin, mw = 580.55) anaphylaxis inhibitor 2007; Zhou et al., 2011) Betulic acid Antineoplastic, cytotoxic, antitubercular, (Jamil et (C30H48O3; antibacterial al., 2007; Mw = 456.72) Zhou et al., 2011) α-Pinene (C10H16; Antifungal, antitussive, irritant. mw = 136.24; (Barnes et al., 2007; Zhou et al., 2011) β-Pinene (C10H16; Antifungal, anti-inflammatory, antitussive mw = 136.24; (Barnes et al., 2007; Zhou et al., 2011) Β-caryophyllene Flavorant (Barnes et (C15H24; al., 2007; mw= 204.36); Zhou et al., 2011) Linolenic acid Nutrient, inhibits cancer cell invasion, 5α- (Jamil et (C18H30O2; reductase inhibitor al., 2007; mw = 278.44) Zhou et al., 2011) Oleic acid Increases absorption through skin, (Jamil et (C18H34O2; dermatitis, inhibits cancer cell invasion al., 2007; mw = 282.47) Zhou et al., 2011) Stigmasterol Antihypercholesterolemic, antimutagenic, (Barnes et (C29H48O; cytotoxic inactive, antileishmanial, al., 2007; mw = 412.71) antimalarial, antitrypanosomal, platelet Zhou et aggregation inhibitor, antiviral al., 2011) Ascorbic acid Antioxidant, antibacterial, anti-infective, (Chong (C6H8O6; antidote, antihypercholesterolemic, inhibits NJ and mw = 176.13) production of Carcinogen, induces tissue to Aziz, produce collagen, hematopoietic activity 2011; 7 Zhou et al., 2011) Nicotinic acid Antihypercholesterolemic, vasodilator (Chong (C6H5NO2; (peripheral) NJ and mw = 123.11) Aziz, 2011; Zhou et al., 2011) β-Carotene (C40H56; EBV-EA activation inhibitor, anti-tumor (Chong mw = 536.89) promoter, ultraviolet screen, pigment, food NJ and additive Aziz, 2011; Zhou et al., 2011) Alanine (C3H7NO2; Food additive, reverses glucopenia and (Barnes et mw = 89.09) ketosis caused by starvation, glucagon al., 2007; secretion promotor Zhou et al., 2011) Chlorogenic acid Antioxidant, antineoplastic, cytotoxic, (Chong (C16H18O9; mw = antimutagenic, antiviral, choleretic, NJ and 354.32) hemostatic, leukopoietic, antimalarial, Aziz, 2011; Zhou et al., 2011) Irbic acid (C28H26O15; mw = Strong radical scavenging, collagenase (Antogno inhibitory activity ni et al., 2011) 602) 66 67 Pharmacological Activity 68 The primary constituents of C. asiatica is the triterpenic fractions which showed wide range of 69 defensive and therapeutic effects, most prominently influencing of collagen production and 70 deposition in wound healing. Titrated Extract of Centella asiatica (TECA) is used to treat several 71 microcirculatory problems, skin inflammation (eczema, atopic dermatitis, leprosy, varicose 8 72 ulcers, etc.) fever, intestinal problems and genitourinary conditions (Belcaro et al., 2011). C. 73 asiatica exerts diverse pharmacological activities such as antibacterial, antidepresent, antiemetic, 74 antineoplastic, antioxidant, antithrombotic, anxiolytic, gastroprotective, immunomodulatory, 75 antigenotoxic, nerve regenerative, reproductive, wound healing etc. due to the presence of 76 several saponin constituents, including asiaticoside, asiatic acid, madecassic acid and some other 77 bioactive compounds (Craker and Simon, 1986; Koh et al., 2009; Kim et al., 2011). 78 Anti-inflammatory activity: Asiatic acid and madecassic acid showed anti-inflammatory effect 79 by the inhibition of enzymes (iNOS, cyclooxygenase-2 (COX-2)), interleukins (IL-6, IL-1β), 80 cytokine tumor necrosis factor (TNF-α) expression through the down-regulation of NF-κB 81 activation in lipopolysaccharide (LPS) induced RAW 264.7 murine macrophage cells (Yun et al., 82 2008; Won et al., 2010). Madecassoside prevented collagen II (CII)-induced arthritis (CIA) in 83 mice (Liu et al., 2008). Ethanolic extract of C. aiatica at dose 100mg/kg of body weight showed 84 anti-inflammatory activity in rats similar to standard Ibuprofen (George et al., 2009). 3,5- 85 dicaffeoyl-4-malonylquinic acid, extract from C. asiatica demonstrated beneficial effect on 86 inflammatory bowel disease in rats (Di Paola et al., 2010). In experimental animal asiaticoside 87 dose inhibited LPS induced fever and inflammatory response, including serum TNF-α and IL-6 88 production, liver myeloperoxidase (MPO) activity, brain COX-2 protein expression and 89 prostaglandin E(2) (PGE(2) ) production (Wan et al., 2012). Asiaticoside G was also reported 90 having anti-inflammatory property in LPS-stimulated RAW 264.7 cells (Nhiem et al., 2011). 91 Anticancer activity: A large number of experimental reports proved that different solvent 92 extracts of C. asiatica has anti-cancerous activity. In vitro study on HeLa, HepG2, SW480 and 93 MCF-7 cell lines showed that methanolic extract had induced apoptosis in human breast 94 cancerous MCF-7 cells (Babykutty et al., 2009). Water extracts induced apoptosis in colonic 95 crypts and exerted chemopreventive effect on colon tumorigenesis in male F344 rats (Bunpo et 96 al., 2004). Asiatic acid induced apoptosis in human melanoma SK-MEL-2 cells (responsible for 97 skin cancer) and SW480 human colon cancer cells (Park et al., 2005; Tang et al., 2009). 98 Asiaticoside enhanced anti-tumor activity of vincristine in cancer cells (Huang et al., 2004). 99 Constituents in the methanol extract inhibited the proliferation of human gastric adenocarcinoma 100 (MK-1), human uterine carcinoma (HeLa), and murine melanoma (B16F10) cells (Yoshida et al., 101 2005). 9 102 Anticonvulsant activity: Oral administration of different extracts from C. asiatica for 1 week at a 103 dose of 200mg/kg of body weight of in pentylenetetrazol (induces seizure) induced rats increased 104 the level of acetylcholine (neurotransmitter) and decreased the activity of acetylcholinesterase, 105 causes perceptible changes in the cholinergic system which indicates the anticonvulsant activity 106 (Visweswari et al., 2010). 107 Antidepressant activity: Total triterpenes from C. asiatica showed reduced immobility time and 108 ameliorating the imbalance of amino acid levels in forced swimming mice indicate 109 antidepressant activity (Chen et al., 2003). Total triterpenes from C. asiatica also ameliorated the 110 function of hypothalamic-pituitary-adrenal axis (HPA axis), increased the contents of 111 monoamine neurotransmitters in rat brain and reduced the corticosterone level in serum (Chen et 112 al., 2005). 113 Antioxidant activity: C. asiatica possesses potent antioxidant activity, which can exerted 114 neuroprotective effect and effect against age related oxidative damage in rats brain (Subathra et 115 al., 2005). The anti-oxidant enzymes, like superoxide dismutase (SOD), catalase and glutathione 116 peroxidase (GSHPx) were significantly increased, and anti-oxidants like glutathione (GSH) and 117 ascorbic acid were decreased in lymphoma-bearing mice after oral treatment with 50mg/kg of 118 body weight per day of crude methanol extract of C. asiatica for 14 days (Jayashree et al., 2003). 119 Administration of aqueous extracts of C. asiatica showed to counteract lead-induced oxidative 120 stress male rats (Sainath et al., 2011). Flavonoid compounds were present in aqueous extract of 121 C. asiatica, showed highest antioxidant property (Pittella et al., 2009). The antioxidant properties 122 of essential oils and various extracts of this plant may be a great interest in food industry, since 123 their possible use as natural additives. To study the antioxidant properties and phenolic 124 compounds present in C. asiatica, the optimum brewing procedure was studied to use as herbal 125 teas (Ariffin et al., 2011). 126 Antiulcer activity: C. asiatica showed significant protection against ethanol, aspirin, cold 127 restraint stress and pyloric ligation induced gastric ulcers in rats when 200 and 600mg/kg of 128 body weight of fresh juice was given orally twice daily for five days (Sairam et al., 2001). Water 129 extract of C. asiatica containing asiaticoside were found to reduce the size of the acetic acid 130 induced gastric ulcers in rats (Guo et al., 2004). 10 131 Anxiolytic activity: 12g oral single dose of C. asiatica after 60 minutes significantly attenuated 132 the acoustic startle response (ASR) in human (Bradwejn et al., 2000). The elevated plus maze 133 (EPM) test for 5 minutes revealed that administration of standardized extract, methanol and ethyl 134 acetate extracts as well as pure asiaticoside had imparted anxiolytic activity in rats (Wijeweera et 135 al., 2006; Wanasuntronwong et al., 2012). Medication of 500 mg/capsule (concentrated 136 lyophilized of 70% hydro-ethanolic extract of C. asiatica), twice daily, after meal for 60 days in 137 33 patient (18 male and 15 female; average age 33 years) in Kolkata (India) demonstrated that C. 138 asiatica not only significantly had attenuated anxiety related disorders but it also significantly 139 had reduced stress phenomenon and its correlated depression (Jana et al., 2010). 140 Cardioprotective activity: Administration of alcoholic extract of C. asiatica at a dose of 141 1000mg/kg of body weight in Laboratory bred Sprague–Dawley rats significantly reduced the 142 necrosis of the myocardium (Pragada et al., 2004). C. asiatica extract demonstrated the 143 cardioprotective effect at a dose of 200 mg/kg of body weight in adult male albino rats of Wistar 144 strain on antioxidant tissue defense system during adriamycin induced cardiac damage 145 (Gnanapragasam et al., 2004). Madecassoside showed protective effect on myocardial ischemia- 146 reperfusion injury in rabbits and rats (Li et al., 2007; Bian et al., 2008). 147 Hepatoprotective activity: Total glucosides extract of C. asiatica showed significant anti-liver 148 fibrosis effect in dimethylnitrosamine induced liver fibrosis in rats (Ming et al., 2004). 149 Asiaticoside revealed hepatoprotective effect against acute liver injury induced by 150 lipopolysaccharide/D-galactosamine in mice (Zhang et al., 2010). 151 Effect on Skin: Asiaticoside stimulated skin aging inhibitor type 1 collagen synthesis in human 152 dermal fibroblast cells and potential use in the treatment and/or prevention of hypertrophic scars 153 and keloids was recommended (Lee et al., 2006; Tang et al., 2011b). Alcoholic extract of C. 154 asiatica showed useful effects in pruritis and other skin disease (Gohil et al., 2010). 155 Hydroalcoholic extract of C. asiatica was used to be made herbal creams along with four 156 medicinal plants (Curcuma caesia, Areca catechu, Cinnamon zeylanicum and Tamarindus 157 indica) which showed increased skin hydration, sebum levels, viscoelasticity, and decreased 158 melanin content (Saraf et al., 2012). Asiaticoside promotes skin cell behaviours involved in 159 wound healing by increasing migration rates of skin cells, enhancing the initial skin cell 11 160 adhesion, inducing an increase in the number of normal human dermal fibroblasts (Lee et al., 161 2012). Aqueous extract of C. asiatica was nano-encapsulated with gelatin and efficiently reduced 162 the expression of matrix metalloproteinase (MMP)-1 in UV-irradiated cells and inhibited 163 hyaluronidase expression in mouse skin (Kwon et al., 2012). 164 Immunomodulating activity: Triterpenoid saponins of C. asiatica showed immunomodulatory 165 effect (Plohmann et al., 1997). Methanolic extract of C. asiatica dramatically increased 166 phagocytic index and total WBC in Swiss Albino mice (Jayathirtha and Mishra, 2004). 167 Administration of water extract of C. asiatica significantly increased proliferation and the 168 production of IL-2 and TNF-α in human peripheral blood mononuclear cells (PBMCs) but 169 ethanol extract had inhibitory effect (Punturee et al., 2005). Asiatic acid and C. asiatica ethanol 170 and dichloromethane extracts showed inhibitory effect on three major cDNA, which expressed 171 human cytochrome P450 (CYP2C9, CYP2D6 and CYP3A4) isoforms (Pan et al., 2010). 172 Radioprotective activity: Aqueous extract C. asiatica showed more radioprotective effect than 173 standard drug “ondansetron” against conditioned taste aversion (behavioural perturbation) 174 induced by 60Co-γ irradiation at low dose 2Gy in male rats (Shobi and Goel, 2001). 175 Administration of 100mg/kg of body weight of aqueous extract of C. asiatica, just 1 hour before 176 irradiation with 8Gy 60Co- γ rays was found most radioprotective in Swiss Albino Mouse 177 (Sharma and Sharma, 2002) and further study revealed that 100mg/kg of body weight of dried 178 powdered extract of C. asiatica had found to be effective against modified 60Co-γ irradiation 179 induced damage in the mouse liver (Sharma and Sharma, 2005). 70% ethanolic extract of C. 180 asiatica significantly reduced radiation-induced damage to DNA (Joy and Nair, 2009). 181 microRNA (miRNA) expression profiling analysis was used to evaluate the protective effects of 182 C. asiatica against Ultraviolet B damage in human keratinocytes, disclosed that miRNAs with 183 altered expression were functionally related with cell proliferation and inhibition of apoptosis, 184 may prevent the skin damage (An et al., 2012). 185 Wound healing activity: A large number of reports have been found about the wound healing 186 activity of C. asiatica (Temrangsee et al., 2011). Aqueous extract of C. asiatica was used to 187 formulate ointment, cream and gel, which evaluate for wound healing in rats showed faster 188 epithelialisation and higher rate of wound contraction(Sunilkumar et al., 1998). Dexamethasone 12 189 suppressed wound in Wistar Albino rats could be healed by ethanolic leaf extracts as like as 190 normal model (Shetty et al., 2006). In a recent study in 200 diabetic patients revealed positive 191 result with C. asiatica extracted capsule without any adverse effect in the department of Surgery, 192 Thammasat University Hospital (Paocharoen, 2010). Wound healing activity of asiaticoside was 193 also reported in guinea pig model at dose 1 mg/kg of body weight and in the chick 194 chorioallantoic membrane model at concentration 40 µg/disk (Shukla et al., 1999). The effects of 195 asiaticoside in human periodontal ligament cells (HPDLs) proliferation, protein synthesis, and 196 osteogenic differentiation were investigated and showed enhanced periodontal tissue healing 197 (Nowwarote et al., 2012). At low concentrations aqueous extract of C. asiatica promote 198 epithelium wound healing in rabbit corneal epithelial (RCE) cells (Ruszymah et al., 2012). Ultra- 199 fine cellulose acetate fiber mats containing asiaticoside (in crude extract or pure substance) were 200 prepared and evaluated for wound dressings and loaded herbal substances were found stable up 201 to 4 months, promotes proliferation and upregulating the production of collagen of the seeded 202 (Suwantong et al., 2010). The clinical efficacy and side effects of the oral C. asiatica extract 203 capsule in the diabetic wound healing was investigated (Paocharoen, 2010). Madecassoside 204 showed enhance wound-healing and diminish keloid formation in primary keloid-derived 205 fibroblasts, originating from human earlobe keloids (Song et al., 2012). 206 Memory enhancing Activity: Since the ancient time, C. asiatica is used to enhance intelligence 207 and improve cognitive function. Oral administration with 200 mg/kg of body weight aqueous 208 extract during postnatal development stage increased brain function in juvenile and young adult 209 mice (Rao et al., 2005). Enhanced working memory and improved self-rated mood were 210 observed in 28 patients after higher dose administration of C. asiatiac extract preparations 211 (Wattanathorn et al., 2008). Asiatic acids isolated from C. asiatica showed enhancing learning 212 and memory properties in male Spraque–Dawley rats (Nasir et al., 2011b). 213 Burns: C. asiatica extract and its active constituents are very effective against burns caused by 214 boiling water, electric current or gas exploitation. Combination of C. asiatica extract with an 215 antibiotic was anti-infectious beside healing burns (Salas et al., 2005). Low dose 10−8 to 10−12% 216 (w/w) of asiaticoside application facilitated repairing in mice burned wound (Kimura et al., 217 2008). 13 218 Anti-psoriatic Activity: C. asiatica shows anti-psoriatic effect on SVK-14 keratinocyte due to the 219 presence of triterpenoid glycosides (Sampson et al., 2001). 220 Antimicrobial Activity: C. asiatica shows antibacterial activity on both Gram positive and Gram 221 negative bacteria. Growth inhibition of Gram positive Bacillus subtilis and Gram negative 222 Pseudomonas aeruginosa, P. cichorii and Escherichia coli was observed in the disc diffusion 223 test of hexane and ethyl acetate extracts of C. asiatica (Escop and Phytotherapy, 2003). 224 1000µg/disc of hot methanolic extract is moderately effective on Staphylococcus aureus and 225 Methicillin Resistant S. aureus (Wild Type) (Zaidan et al., 2005). Micobacterium tuberculosis 226 and M. leprae were reported to be more sensitive to liposomal asiatocoside than free asiatocoside 227 (Fugh-Berman, 2003). Higher antiviral activity was also reported with aqueous extract of C. 228 asiatica against type 2 Herpes simplex virus (Escop and Phytotherapy, 2003). 229 Lervicidal Activity: Haemaphysalis bispinosa (the adult cattle tick), Paramphistomum cervi 230 (sheep fluke), Anopheles subpictus and Culex tritaeniorhynchus showed sensitivity to hexane, 231 chloroform, ethyl acetate, acetone, methanol extract of C. asiatica but methanol extract was the 232 most effective on P. cervi and A. subpictus (Bagavan et al., 2009). 3-O-[a-L-arabinopyranosyl] 2 233 a, 3 ß, 6 ß, 23-a tetrahydroxyurs-12-ene-28-oic acid, a triterpenoid glycoside, exhibited 234 inhibitory activity against larvae of Spilarctia oblique (Shukla et al., 2000). 235 Anti-hyperglycemic effect: Oral administration of asiatic acid and glibenclamide to 236 streptozotocin induced diabetic rats for 45 days prevented the altered activities of key enzymes 237 (glucose-6-phosphatase and fructose-1,6-bisphosphatase) related with hyperglycemia 238 (Ramachandran and Saravanan, 2012). 239 Neuroprotective Activity: Aqueous extract showed neuroprotective effect by increasing the 240 antioxidant enzyme level in mice corpus striatum and hippocampus (Haleagrahara and 241 Ponnusamy, 2010). Fresh leaf extract of C. asiatica was investigated on dendritic morphology of 242 amygdaloid neurons on adult rats, one of the regions concerned with learning and memory, 243 showed a significant increase in the dendritic length and branching points (Rao et al., 2012). 244 Water extract of C. asiatica inhibit the activity of subtypes of phospholipase A2 (PLA2), which 245 is related with neurodegenerative disease (Defillipo et al., 2012). n-hexane, chloroform, ethyl 246 acetate, n-butanol extract of C. asiatica showed anticonvulsant and neuroprotective activity in 14 247 male albino rats (Visweswari et al., 2010). D-galactose induced oxidative and mitochondrial 248 dysfunction and cognitive impairment in mice, which could be significantly improved in six 249 weeks by administration of C. asiatica (150 and 300 mg/kg of body weight) (Kumar et al., 250 2011). Chronic aluminum exposure in rat induce cognitive dysfunction, apoptosis, oxidative 251 stress and mitochondrial enzyme alteration and administration of C. asiatica found significantly 252 decreased aluminum concentration, improved memory performance, oxidative defense, 253 acetylcholinestrease activity, caspase-3 and reversal of mitochondrial enzyme activity as 254 compared to control (Prakash and Kumar, 2012). The psychoactive and antioxidant role of 255 ethanolic extract of C. asiatica in middle cerebral artery occlusion (MCAO) in rats was 256 evaluated and revealed that administration of C. asiatica extract restored histological 257 morphology of brain, diminished infarction volume, greatly improved the neurobehavioral 258 activity (Tabassum et al., 2012). 259 Asiatic acid possess neuroprotective effects in vitro and in vivo (Xu et al., 2012b), nootropic 260 activity with therapeutic implications for patients with memory loss (Shinomol et al., 2011). 261 Increased dendritic length and branches was observed in rat after fresh leaves extract 262 administration (Mohandas Rao et al., 2006). Three derivatives of asiatic acid were significantly 263 effective in protecting excess glutamate exposed neurons on cultured cortical cells (Lee et al., 264 2000; Xu et al., 2012b). Non-polar fraction of ethanolic extract containing asiatic acid which 265 found to be increased in neurite outgrowth in human SH-SY5Y cells in the presence of nerve 266 growth factor and administration of ethanolic extract through drinking water demonstrated 267 axonal regeneration in Male Sprague-Dawley rats (Soumyanath et al., 2005). Asiatic acid was 268 reported for the treatment of cerebral ischemia in mice (Krishnamurthy et al., 2009). Asiatic acid 269 showed potential neuroprotective activity against C2-ceramides-induced cell death in primary 270 cultured rat cortical neuronal cells (Zhang et al., 2012) and asiaticoside significantly attenuated 271 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induce Parkinsonism in rat model (Xu et 272 al., 2012a). Asiaticoside was recommended for epilepsy, stroke, multiple sclerosis and other 273 neuropsychiatric disorders (Barbosa et al., 2008). 274 Venous insufficiency Activity: Patients suffering from venous hypertension were positively 275 effective to an oral preparation of total triterpenic fraction of C. asiatica (TTFCA) in the 276 improvement of microcirculation and edema (leg volume) in venous microangiopathy (Cesarone 15 277 et al., 2001). C. asiatica exract regulated mucopolysachharide metabolism in connective tissue in 278 patient with varicose veins (Arpaia et al., 1990). However, a large number of similar studies 279 were reported on venous insufficiency. 280 Others: Asiaticoside was revealed as protective against cecal ligation and puncture (CLP) 281 induced lung injury in mice (Zhang et al., 2010). This plant also increases vigority (Mato et al., 282 2011). C. asiatica extract in combination with Punica granatum significantly improved clinical 283 signs of chronic periodontitis in 15 patients (Sastravaha et al., 2005). Whole gene expression level 284 were analyzed using microarrays in human dermal fibroblasts (HDFs) to determine whether 285 H2O2 -induced senescence is affected by C. asiatica extracts to characterized the activity of 286 extract in stress-induced premature senescence (SIPS) and found that 39 mRNAs are expressed 287 differentially includes genes that regulate cell growth, apoptosis, DNA replication, transcription, 288 gene silencing, senescence and the spindle checkpoint (Kim et al., 2011). Oral administration of 289 water extract of C. asiatica protected the toxicity induced by exogenously added and 290 endogenously generated β-amyloid in the Tg2576 mouse, which is a murine model of 291 Alzheimer’s disease with high β-amyloid burden in SH-SY5Y cells and MC65 human 292 neuroblastoma cells from (Soumyanath et al., 2012). 293 Contradictions: Clinical study in patients suffering from jaundice showed that all patients had 294 improved with C. asiatica discontinuation and deteriorated after retaking due to having 295 hepatotoxic effect (Jorge and Jorge, 2005). This plant is not applicable for children, pregnant and 296 lactated women (Koh et al., 2009). 297 Traditional uses 298 Traditionally C. asiatica is used to treat differents aliments in different countries for over a long 299 time. Traditional uses of C. asiatica are summarized in table 3. 300 Table 3: Traditional uses of C. asiatica in different regions for different purposes Regions Traditional Uses References Brazil Elephantiasis, uterine cancer, leprosy (Leonard, 2006) China Bleeding, scabies and tinea / ringworm, skin ulcers, rash, and redness, abdominal (Leonard, pain, diarrhea, dysentery, vomiting, red eyes, swollen throat, tonsillitis, 2006; Koh 16 nosebleeds, jaundice, infectious hepatitis, boils, fistulas, furuncles and carbuncles et al., 2009) with toxic swelling, fever, trauma, falls, contusion, fractures, childhood tidal fevers, measles, asthma, bronchitis, respiratory problems, tuberculosis, pleurisy, urinary difficulty with stones or bleeding, arsenic poisoning, fear of cold, dizziness, leprosy, scrofula, improve of appetite, digestion Europe Varicose veins (Leonard, 2006) Fiji Skin ulcers, rash, and redness, pimples, stomachache, bleeding ulcer, constipation, (Leonard, hemorroids, eye problems, fractures, painful and swollen joints, rib pain, hildhood 2006) convulsions, post partum weakness, unwanted pregnancy Hawai'i India Indonesia Blotchy skin, cold extremities, white fingers, poor memory, impotence due to (Leonard, vascular disease, 2006) Eczema, skin ulcers, rash, and redness, abscesses, peptic ulcer, cataract, eye (Leonard, problems, fever, cholera, abdominal tumor, anxiety neurosis, insanity, poor 2006; Koh memory, general debility, blood disease et al., 2009) Wounds, colic (Koh et al., 2009) Malagasy Leprosy (Leonard, 2006) Malaya Dermatosis (Leonard, 2006) Mauritius Cancer (Leonard, 2006) Nepal Indigestion, rheumatism, poor memory, syphilis, general debility, leprosy (Leonard, 2006) Philippines Dysentery, headache, fever, wounds (Leonard, 2006) Samoa Tonga Turkey Eye problems, migraines, boils, fistulas, furuncles and carbuncles with toxic (Leonard, swelling, venereal disease, leprosy 2006) Juiced for eye ailments and nasally for migraines, convulsions, delayed closure of (Leonard, the fonatel, navel infection in babies 2006) Spasms, leprosy (Leonard, 2006) 301 302 In vitro propagation 17 303 Optimum shoots development of C. asiatica were achieved in Duchefa medium supplemented 304 with 2 mg/L 6 benzylaminopurine (BAP) and 0.1 mg/L 1-naphthaleneacetic acid (NAA) 305 (Moghaddam et al., 2011), Murashige and Skoog medium supplemented with 2.5 mg/l kinetin 306 (Prasad et al., 2012). Rooting can be done on full-strength MS medium containing 0.5 mg/L 307 indole-3-butyric acid (IBA) (Moghaddam et al., 2011). Varying level of asiaticoside content in 308 shoot could be achieved with the varying ratio of NH4+-N:NO3--N or Cu2+ concentration in the 309 medium (Prasad et al., 2012). 310 Conclusion 311 Since the time of immemorial C. asiatica is being used for the treatment of wide range of 312 maladies. So far, the reports on bioactivity and clinical trials in different models and human 313 concern the asiaticoside and its derivatives. Recent studies have confirmed the efficacy of this 314 plant and its constituents and extracts to injury, leprosy, tuberculosis, cancer, aging, 315 gastrointestinal disease, skin disease, neurological disorder, cardiovascular problems, ulcer, 316 radiation, respiratory problems and so on. 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