Euphorbia hirta (Feiyangcao): A review on its ethnopharmacology, phytochemistry and pharmacology

s. J. Biotechnol. 136:717-742. Singh GD, Kaiser P, Youssouf MS (2006). Inhibition of early and late phase allergic reactions by Euphorbia hirta L. Phytother. Res. 20(4):316-321. Sudhakar M, Ch V, Raob PM, Raoc DB, Rajua Y (2006). Venkateswarlu Antimicrobial activity of Caesalpinia pulcherrima, Euphorbia hirta and Asystasia gangeticum. Fitoterapia 77:378-380. Sunil KS, Ram P, Yadav ST, Ajay S (2005). Toxic effect of stem bark and leaf of Euphorbia hirta plant against freshwater vector snail Lymnaea acuminate. Chemosphere 59:263-270. Suresh K, Deepa P, Harisaranraj R, Vaira AV (2008). Antimicrobial and phytochemical investigation of the leaves of Carica papaya L., Cynodon dactylon (L.) Pers., Euphorbia hirta L., Melia azedarach L. and Psidium guajava L. Ethnobot. Leafl. 12:1184-1190. Tona L, Kambu K, Ngimbi N, Mesia K, Penge O, Lusakibanza M (2000). Antiamoebic and spasmolytic activities of extracts from some Antidiarrhoeal traditional preparations used in Kinshasa and Congo. Phytomedicine 7:31-38. The State Pharmacopoeia Commission of People’s Republic of China (2010). The Pharmacopoeia of the People’s Republic of China. Part I. Chemical Industry Press, Peking. Vijaya K, AnanthanS, Nalinib R (1995). Antibacterial effect of theaflavin, polyphenon 60 (Camelliasinensis) and Euphorbia hirta on Shigella spp. a cell culture study J. Ethnophannacol. 49:115-118. Huang et al. 5185 Widharna RM, Soemardji AA, Wirasutisna KR, KardonoL BS (2010). Anti Diabetes mellitus activity in vivo of ethanolic extract and ethyl acetate fraction of Euphorbia hirta L. herb international. J. Pharmacol. 6(3):231-240. Yadav RP, Singh A (2011). Efficacy of Euphorbia hirta latex as plant derived molluscicides against freshwater snails. J. Trop. Med. Inst. Sao Paulo. 53(2):101-106. Yan SJ, Ye DW, Wang Y (2011). Ent-Kaurane Diterpenoids from Euphorbia hirta. Rec. Nat. Prod. 5(4):247-251. Yin XH (2008). Yao yi chang yong zhi wu yao hua xue yu yao li yan jiu. Guangdong Tourism Publishing House. Youssouf MS, Kaiser P, Tahir M (2007). Anti-anaphylactic effect of Euphorbia hirta. Fitoterapia 78(7-8):535-539. Zhu CL, Zhao YH, Ma WG (2007). Dai yao xue. Chin. Publishing House Traditonal Chinese Medicine and Pharmacology. Zhong yao da ci dian (1986). Shanghai Sci-tech Press p.139. Zhong hua ben cao (1999), Shanghai Sci-tech Press 4:788.


INTRODUCTION
Euphorbia hirta, an important medicinal herb, belongs to genus Euphorbia, family Euphorbiaceae.As a widely used local and traditional Chinese medicine (TCM) in clinical practice, the whole plant is commonly applied to cure various diseases, especially gastrointestinal disorders (including intestinal parasites, diarrhea, peptic ulcers, heartburn, vomiting, and amoebic dysentery), afflictions of the skin and mucous membranes (including warts, scabies, tinea, thrush, aphthae, fungal afflictions, and measles), and respiratory system disorders (including asthma, bronchitis, hay fever, laryngeal spasms, emphysema, coughs, and colds) (Zhong yao da ci dian, 1986; Zhong hua ben cao, 1999).E. hirta is native to Central America.It was introduced into Southeast Asia a long time ago and has since spread throughout.It is a terpenoids, and phenols were isolated and identified as the main compositions of E. hirta.
In the current paper, an overview of the current knowledge and information about E. hirta is presented for the study of its ethnopharmacology, phytomchemistry, pharmacology, and toxicology.

BOTANY AND ETHNOPHARMACOLOGY
According to the description from Flora of China and Zhonghuabencao [Zhong hua ben cao, 1999;Flora of China, 1987], E. hirta is a small annual, branched herb prostrate to ascending with branches reaching 70 cm in height, reddish or purplish in color, with abundant latex and is covered with short hairs.Its leaves are opposite, distichous, and simple; its obvious stipules are linear.The leaf blades of E. hirta are lanceolate-oblong, long elliptic, or ovate-lanceolate; its base is very unequal; one side is cuneate, the other side is round; the apex is almost acute, and its margins are finely toothed, often with a purple blotch near the midvein.The inflorescence of E. hirta has a terminal or axillary cluster of flowers, called a 'cyathium', with several cyathia densely clustered into a cyme.The flowers of E. hirta are unisexual; the male flowers are sessile, the bracteoles are linear, fringed, the perianth is absent, and possesses one stamen, whereas the female flowers have short pedicel, the perianth is rimmed, the ovary is superior, covered with short hairs, three-celled, possesses three styles, minute, and the apex is two-fid.The fruit of E. hirta is exerted, acutely three-lobed, base truncate, covered in short hairs, and three-seeded.The seeds are oblong, four-sided prismatic, slightly wrinkled, pinkish brown, and caruncle absent.Flowering duration of individual plant is usually throughout the year.E. hirta often grows in cultivated areas in lowland, paddy fields, gardens, roadsides, and waste places.They prefer dry condition, from sea-level up to 2000 m altitude.
E. hirta has many synonyms in different countries.In China, it is called Feiyangcao, Dafeiyang, Jiejiehua, and Daruzhicao.The following are its other synonyms.Malaysia: Ambin jantan, kelusan; English: Asthma herb, hairy spurge; Indonesia: Daun biji kacang (Malay.Moluccas), nanangkaan (Sundanese); Papua New Guinea: Sip (Kurtatchi.Bougainville), kiki kana kuku (Gunantuna, New Britain); Philippines: Botobotonis (Tagalog), gatas-gatas (Bisaya,Tagalog); Laos: Mouk may, ungl yang; Thailand: Nam nomraatchasee (central Considering the effects of E. hirta on curing skin ulcer and swelling of body, it was first recorded in "Ling Nan Cai Yao Lu".More than ten folk medicinal books in China also have recorded this plant (Yin, 2008;Liang and Zhong, 2005;Zhu et al., 2007;He and Ma, 2006).The whole plant was officially recorded in a Chinese Pharmacopoeia (1977).However, E. hirta had been removed from the 1985 to 2005 edition, and have been re-listed as Feiyangcao in the Pharmacopoeia edition of 2010.The Pharmacopoeia stated the properties of E. hirta that cure fever, detoxify, promote diuresis, stop itching and induces prolactin.The clinical indications include pulmonary abscess, acute mastitis, diarrhea, eczema, furunculosis, pyogenic infections, and postpartum milk.The fresh whole plant or its crude powders were also traditionally used as veterinary medicine for treating esoenteritis, gastritis, diarrhea in pig, cattle, horse, sheep, and fish (The State Pharmacopoeia Commission of People's Republic of China, 2010).
E. hirta has also been widely used in medicine among minority groups, including Yao, Zhuang, Dai, Naxi, and Yi, who lived in the southern area of China.The Yao people use the entire plant for the treatment of bronchitis, external usage for scald and burned, decoction of dry plant, whereas as fresh crushed leaves are used to cure skin disease (Yin, 2008).For the Zhuang people, a decoction, infusion, or tincture of the plant is used to treat asthma, chronic bronchial disorders, and emphysema (Liang and Zhong, 2005).For Dai nationality, E. hirta, commonly known as Ya nan mo, is applied to stimulate milk secretion and to stopping cough (Zhu et al., 2007).Moreover, E. hirta is used to cure gonorrhea and hematuria in Naxi people [He and Ma, 2006].Therefore, E. hirta can be served clinically as potential hemostatic.
E. hirta is included in the African pharmacopoeia of the Organization of African Unity as a dysentery medication.In South Africa, E. hirta is commonly used for asthma treatment, which is one of the most common respiratory complaints [Ekpo and Pretorius, 2007].In West Africa, E. hirta is used as a livestock fodder.In the Gold Coast, E. hirta was ground, mixed with water, and used as an enema for constipation.In traditional Indian medicinal systems, the leaves are used in the treatment of coryza, cough, asthma, bronchial infections, bowel complaints, helminthic infestations, wounds, kidney stones, and abscesses.In addition, it is used for the treatment of syphilis.The latex is applied to the eyes to treat conjunctivitis and corneal ulcerations.The tender shoots are used as famine food, raw or steamed, but they may cause intestinal complaints.Moreover, E. hirta is used by nursing mothers with deficient milk supply.In the Philippines, leaves are mixed with datura metel leaves and flowers in the preparation of "asthma-cigarettes."The latex and fluid extract of the tincture are used in asthma, chronic bronchitis, emphysema, as well as in pulmonary cardiac disease and angina pectoris and ringworm.The decoction is used to allay the dyspnea of asthmatics.The decoction of the root is used to allay vomiting, chronic diarrheas, and fevers.Root decoction is also used for snake bites, sores, wounds, boils, and is beneficial for nursing mothers with deficient milk.The entire plant is prescribed as an antidote; it is considered hemostatic, sedative, and soporific.In Australia, the most common use of E. hirta is to treat hypertension, asthma, edema, and pectoral complaints.

PHYTOCHEMISTRY
E. hirta mainly contains flavonoids, terpenoids, phenols, essential oil, and other compounds.The major chemical structures of these compounds are shown in Figure 1.

PHARMACOLOGICAL PROPERTIES Antibacterial/antifungal activity
Since the 1980s, the antibacterial activity of E. hirta has been comprehensively investigated and proven.Vijaya et al. [1995] evaluated the antibacterial potential of the methanol extract of E. hirta in 1995.Results showed that the extract exhibited properties against dysentery causing Shigella spp.using the Vero cell line.Cytotoxicity studies of the extracts were performed using the cell line, and the non-cytotoxic concentration of the extract was tested for antibacterial activity against the cytopathic dose of the pathogen.The extracts were found to be non-cytotoxic and effective antibacterial agents.Jackson et al. (2009) evaluated the antimicrobial activity of nystatin and the methanol extract of the leaves of E. hirta against Candida albicans using the checkerboard method.The results showed that some combinations of the extract with nystatin could be synergistic in activity for some ratio combinations and similar for some others.
The antimicrobial activity of ethanol extracts of the aerial parts of E. hirta was then investigated.A remarkable antimicrobial effect has been revealed against Escherichia coli (enteropathogen), Proteus vulgaris, Pseudomonas aeruginosa, and Staphylococcus aureus.mm, respectively.The MIC values were 0.189, 0.2, 0.166, and 0.216 mg/ml [Sudhakar et al., 2006].The ethanol extract from the leaves of E. hirta was analyzed for antimicrobial activity against S. aureus, Bacillus cereus, Salmonella typhi, Klebsiella pneumonia, P. aeruginosa, and fungus species Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Rhizopus oryzae.Antimicrobial activity was attributed to tannins, flavonoids, alkaloids, glycosides, proteins, sterols, and saponins.Moreover, leaves collected from August to December showed more significant antimicrobial activities [Suresh et al., 2008].
Meanwhile, the crude ethanolic extract of E. hirta also showed marked antibacterial activity against the growth of E. coli, S. aureus, P. aeruginosa, and Bacillus subtil [Ogbulieet al., 2007].Nelofar et al. (2006) compared the antibacterial activity of the ethanol extract of E. hirta between Gram positive and Gram negative organisms, and results showed that the extract is more active against Gram positive organisms than Gram negative bacteria.An ethanolic extract of E. hirta showed an antifungal activity against the plant pathogens Colletotrichum capsici, Fusarium pallidoroseum, Botryodiplodia theobromae, Phomopsis caricae-papayae, and A. niger using the paper disc diffusion technique [Mohamed et al., 1996].Meanwhile, Akinrinmade and Oyeleye, (2010) investigated the efficacy and tissue reaction of the crude ethanolic extract of E. hirta in canine infected incised wounds.The results showed that the crude ethanolic extract of E. hirta neither promoted the growth of S. aureus, nor provoked tissue reaction in canine wounds, thus, it was recommended for use in surgical site preparation.Abubakar (2009) compared the antibacterial capability of the methanol, hexane, and water extract of E. hirta in E. coli, K. pneumoniae.Shigella dysentriae, S. typhi, and Proteus mirabilis, a group of Gram-negative bacteria that frequently cause enteric infections in humans.The results showed that the water extracts provided more antibacterial effectiveness than organic solvent extracts.Phytochemical screening of the crude extracts revealed the presence of tannins, saponins, phenolics, flavonoids, cardiac glycosides, anthroquinones, and alkaloids.These bioactive constituents have been linked to antimicrobial activity.
Finally, Mohammad Abu Basma Rajeh assessed the potential antimicrobial activity of E. hirta leaves, flower, stem, and root extracts using a broad arrange of microbial samples, including four Gram positive bacteria (S. aureus, Micrococcus sp., B. subtilis, and Bacillus thuringensis), four Gram negative bacteria (E.coli, K. pneumoniae, S. typhi, and P. mirabilis), and one yeast (C.albicans).Inhibition zones ranged between 16 and 29 mm.Leaf extract inhibited the growth of all tested microorganisms with large zones of inhibition, followed by that of the flowers, which also inhibited all the bacteria except C. albicans.The most susceptible microbes to all extracts were S. aureus and Micrococcus sp.Root extract displayed larger inhibition zones against Gram positive bacteria than Gram negative bacteria, and had larger inhibition zones compared with the stem extract.The lowest MIC values were obtained for E. coli and C. albicans (3.12 mg/ml), followed by S. aureus (12.50 mg/ml), and P. mirabilis (50.00 mg/ml).All other bacteria had MIC values of 100.00 mg/ml [Mohammad et al., 2010].The results support the use of E. hirta in traditional medicine.

Anti-allergic activity
The ethanolic extract of E. hirta was found to possess a prominent anti-anaphylactic activity.E. hirta inhibited passive cutaneous anaphylaxis (PCA) in rat and active paw anaphylaxis in mice.The suppressive effect of E. hirta was observed on the release of TNF-α and IL-6 from anti-DNP-HAS activated rat peritoneal mast cells.The findings of the current study prominently validate the traditional use of E. hirta as a herbal drug against Type I allergic disorders [Youssouf et al., 2007].The current study demonstrated that 90% of the ethanolic extract from the whole aerial parts of E. hirta possessed significant activity to prevent early and late phase allergic reactions caused by antihistaminic, antiinflammatory, and immunosuppressive properties.Moreover, the ethanolic extract of E. hirta can prevent and treat rat anaphylactic [Youssouf et al., 2007;Singh et al., 2006].

Antidiarrheal activity
The aqueous leaf extract of E. hirta significantly and dose-dependently decreased the gastrointestinal motility in normal rats and decreased the effect of castor oil-induced diarrhea in mice [Hore et al., 2006].The antidiarrheal effect of the E. hirta herb decoction was studied in mice.It demonstrated an activity in models of diarrhea induced by castor oil, arachidonic acid, and prostaglandin E 2. Quercitrin, a flavonoid isolated from this crude drug contributed to the antidiarrheal activity at a dose of 50 mg/kg, against castor oil and prostaglandin E2-induced diarrhea in mice [Galvez et al.., 1993[Galvez et al.., , 1993]].The water extract of E. hirta exhibited antidiarrheal, antibacterial, antiamoebic, and antitetanic properties.The polyphenolic extract of E. hirta inhibited the growth of Entamoeba histolytica with a minimum active concentration of less than 10 mg/ml [Tona et al., 2000].

Anti-inflammatory activity
In 1991, Lanhers et al. (1991) has proven that the aqueous extract of E. hirta had significant and dosedependent anti-inflammatory effects in carrageenaninduced edema test in rats (an acute inflammatory process) from a dose of 100 mg/kg].Martinez et al. (1999) evaluated the anti-inflammatory effect of the n-hexane extract of the aerial parts of E. hirta and its main triterpene constituents.The results showed that the extract and chemicals reduced the inflammatory hyperalgia in a dose-dependent manner and displayed significant antiinflammatory effects in the model of phorbol acetateinduced ear inflammation in mice.In 2007, Ekpo OE and Pretorius, evaluated the anti-inflammatory activity of the chemicals in E. hirta and concluded that the flavonoids quercitrin (converted to quercetin in the alimentary canal) and myricitrin, as well as the sterols 24-methylenecycloartenol and -sitosterol, exert noteworthy and dosedependent anti-inflammatory activity.Triterpene betaamyrin also seems to exert a similar anti-inflammatory activity [Ekpo and Pretorius, 2007].Shih et al 2010, elucidated the underlying pharmacological molecule mechanism of action in alleviating inflammation.The antiinflammatory activity of the extract of E. hirta and its active components were studied in lipopolysaccharide (LPS)activated macro-phage cells (RAW264.7) as an established inflammation model.After activation, nitric oxide (NO) production and expression of iNOS protein and iNOS mRNA were measured using colorimetric assay (Griess reagent), western blot analysis, and reverse transcription polymerase chain reaction (RT-PCR), respectively.The alteration in the content of PGE2, TNFa, and IL-6 was concurrently monitored using enzyme-linked immuno-sorbent assay (ELISA).The results showed that the ethanol extract of E. hirta and its component betaamyrin produced a remarkable anti-inflammatory effect, and are able to block most of the iNOS protein functions and NO induction, presenting a great potential as a new selective NO inhibitor for the treatment of arthritis inflammation [Shih et al., 2010].Johnson et al. (1999) has found that the ethanolic and aqueous leaf extracts of E. hirta could significantly induce diuresis in rats.It increased urine output and electrolytes.The diuretic effect of the ethanol extract was obvious at 6 h (for 100 mg/kg) and at 24 h (for 50 mg/kg) in a time-dependent manner.The water extract significantly increased the urine excretion of Na+, K+, and HCO 3 -, whereas the ethanol extract (100 mg/ml) caused a significant decrease in K+.The HCO 3 -urine output following the injection of both extracts was remarkably enhanced.Studies suggested that the active components in the water extract of E. hirta leaf had similar diuretic effect as that of acetazolamide.The results validate the traditional use of E. hirta as a diuretic agent by the Swahilis and Sukumas of East Africa [Johnsonet al., 1999].

Antioxidant activity
The methanol and water extracts of E. hirta showed Huang et al. 5181 antioxidant activities comparable to that of green and black teas.Sharma and Prasad, (2008) has evaluated the antioxidant effects of phenolic acids from aqueous leaf extracts of E. hirta in 2008.To ascertain the efficacy of phenolic acids (mainly hydroxyl cinnamic acid derivatives) to scavenge free radical and antioxidant potential, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and FRAP assays were performed.These techniques also investigated the protective potential of identified antioxidants against oxidative injury to BSA with the help of sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot techniques using anti-DNP primary antibody.These groups of phenolic acids possessed significant antioxidant activities.Phenolic acids demonstrated synergistic interaction with BSA, and their antioxidant activity was found to be enhanced after incubation with BSA to 20%.Different analytical methods, including DNPH, fluorescent quenching, SDS-PAGE, and immunoblot analysis supported and complemented the same research findings The results substantiated the significant contribution of phenolic acids with an effective value, EC50, of 150 g/ml in protection against oxidative injury to Phosphate Buffered Saline (PBS).The phenolic acid from E. hirta displayed enhanced free radical scavenging activity, and showed a promising role in the protection against oxidative damage to protein In addition, the aqueous extract of E. hirta demonstrated an antioxidant effect and a free radical scavenging effect in various in vitro models, such as total antioxidant and total ferric reducing power determination, free radical-scavenging activity assay using ABTS, DPPH, and hydroxyl radical scavenging assays.The extract showed maximum antioxidant and free radical scavenging activities, at the concentration of 0.25 mg/ml.The free radical scavenging effect on hydroxyl and DPPH was 73.36 ± 5.21 and 68.80 ± 5.21%, respectively (Sharma et al., 2007).The free radical scavenging effect of ethanolic extract and petroleum ether extracts of the flower of E. hirta was also evaluated through various in vitro antioxidant assays, including 1,1-diphenyl-2-picryl hydrazyl free radical scavenging activity, superoxide anion radical scavenging, NO scavenging, and reducing power assay.It was compared with standard antioxidant compounds, such as butylated hydroxyl anisole and ascorbic acid.All the extracts showed antioxidant activity (Kumar et al., 2010).
Finally, the antioxidant activity from different parts of E. hirta (leaves, stems, roots, and flowers) has been studied by Abu et al. (2011).Samples of leaves, stems, flowers, and roots from E. hirta were tested for total phenolic content, flavonoid content, and in vitro antioxidant activity using DPPH assay, and the reducing power was measured using the cyanoferrate method.DPPH assay and reducing power was measured using the cyanoferrate method.The results showed that the leaf extract exhibited a maximum DPPH scavenging activity of 72% followed by the flowers, roots, and stems with scavenging activity values of 52, 48, and 44%, respectively.The standard butylated hydroxytoluene (BHT) was 75%.The IC50 for leaves, flowers, roots, stems, and BHT were 0.803, 0.972, 0.989, 1.358, and 0.794 mg/ml, respectively.Leaf extracts had the highest total phenolic and total flavonoid content, followed by the flower, root, and stem extracts.The results suggested that E. hirta exhibited strong antioxidant activity and can serve as a new antioxidant agent using various in vitro anti-oxidant tests.

Anti-tumor activity
The antitumor activity of the aerial part of E. hirta was evaluated against EL-4 cell line (S.C.) in Swiss albino mice.A significant enhancement of mean survival time and reduction of solid tumor mass of EF-treated tumor-bearing mice was observed (Sandeep and Chandrakant, 2011).The methanol extract of the leaves of E. hirta on Hep-2 cells from human epithelioma of the larynx showed anti-proliferative activity (Brindha et al., 2010).Daphne et al. (2009) evaluated the mutagenic and antimutagenic activities of the aqueous and methanolic extracts and quercetin from E. hirta.The aqueous extract (100 g/ml) and methanolic extract (10 and 100 g/ml) demonstrated the mutagenicity of 2-aminoanthracene in S. typhimurium TA98 in the presence of S-9 metabolic activation.Quercetin was proven to be mutagenic and did not show any antimutagenic activity in the absence and presence of S-9 metabolic activation in S. typhimurium TA98.The findings indicate that the aqueous and methanolic extracts of E. hirta is a potential anti-carcinogenic agent.

Anti-diabetic activity
The antidiabetic activity of the ethanol and ethyl acetate extracts of E. hirta was assayed in vitro using the alpha glucosidase inhibitor method and confirmed through in vivo oral glucose tolerance test using various loading methods.Several mechanisms may be involved in the process, including the antioxidant activity, α-glucosidase inhibitory activity, and increasing the activity of insulin release form β cells of the Langerhans islets.The study of ethanolic extracts of leaf, flower, and stem of E. hirta on streptozotocin-induced diabetic mice showed significant reduction in blood glucose levels.Biochemical effects showed significant decreases in serum cholesterol with the elevation of HDL (Widharna et al., 2010).The ethanolic and petroleum ether extracts of the flower of E. hirta also demonstrated potential antidiabetic mellitus activities in alloxan diabetic mice.A significant reduction in serum cholesterol, triglycerides, creatinine, urea, and alkaline phosphatase levels were observed after the administration of the extract.However, high density lipoprotein levels and total proteins were found to increase (Kumar et al., 2010).

Anxiolytic and sedative activity
The hydroalcoholic extract of E. hirta was evaluated for anxiolytic property in chronically stressed rats subjected to two different stressors: Chronic immobilization stresses (CIS) and forced swim stress (FSS).The anxiety in the elevated plus maze (EPM) and the open field test (OFT) was assessed.To understand the mechanism underlying the anxiolytic action of this drug, antagonists of the GABAA receptor-benzodiazepine receptor-Cl_ channel complex with E. hirta were co-administered, and anxiety in the EPM was evaluated.The findings clearly demonstrate the anxiolytic potential of E. hirta, particularly in CIS induced anxiety.The actions of E. hirta could be mediated, at least in part, through the GABAA receptorbenzodiazepine receptor-Cl channel complex (Anuradha et al., 2008).Lanhers et al. (1990) also investigated the behavioral effects of the aqueous extract of E. hirta in mice.The results displayed sedative and anxiolytic properties, which validate the traditional use of E. hirta.E. hirta showed an activity profile different from that of benzodiazepines.The current study showed a central depressant and sedating effect with no hypnotic or neuroleptic effects, and validated the traditional use of E. hirta as a sedative with anxiolytic properties.

Antihypertensive / ACE inhibition
Angiotensin-converting enzyme inhibition and antidipsogenic activities of E. hirta extracts: The current study showed that the extract from leaves and stems of E. hirta inhibited the activity of angiotensin-converting enzyme (ACE).

Anthelmintic and larvicidal activity
The crude aqueous extract of E. hirta reduced the fecal egg count of the helminths in Nigerian dogs and exhibits a potential as an antihelmintic agent.At the same time, the aqueous stem bark and leaf extract of E. hirta significantly decreased the level of nucleic acids in various tissues of the vector sanil, and are potential inhibitors of DNA synthesis, resulting in the reduction of the RNA level.The current study indicated that the plant extract possess great value for the control of aquatic harmful vector snail organisms (Sunil et al., 2005).Preeti et al. (2009) highlighted the larvicidal property of the three forms of extracts of E. hirta against the third instar larvae of Anopheles stephensi, the urban malaria vector.Petroleum ether extract has the lowest LC50 values at 9,693.90 and 7,752.80ppm after a 24-and 48-h exposure period followed by carbon tetrachloride extraction (IC50 11,063.00and 10,922.00ppm after 24 and 48 h of exposure), and methanol extract ( the LC50 values are 19,280.00and 18,476.00ppm after 24 and 48 h of exposure).The current study reflects that the larvicidal potency of petroleum ether extracted fractions could be a promising insecticide of botanical source.
Moreover, the latex of E. hirta may be considered as a plant derived molluscicide agent against freshwater snails (Yadav and Singh, 2011).

Anti-malarial
In the study of the isolated flavonol glycosides afzelin, quercitin and myricitrin, the three compounds showed inhibition of the proliferation of Plasmodium falcifarum at different concentrations (Koli et al., 2002).

Immunomodulatory activity
In 2001, the whole plant of E. hirta has been reported to possess 45% immunomodulation activity through the inhibition of NO production (Jae-Ha et al., 2001).Ramesh and Vijaya, (2010) reported the in vitro and in vivo immunomodulatory properties of E. hirta, which has been proven through macrophage activity testing, carbon clearance test, and mast cell de-granulation assay.The aqueous extract of the leaves of E. hirta Linn could serve as an immunostimulant on the experiment of the pathogen-infected Cyprinus carpio Linn.(Cyprinidae).The higher concentration of the extract (50 g/kg diet) provided significant immune response (specific and nonspecific) on the fish.The 50 g/kg leaf extract of E. hirta enhanced the phagocytic ratio on the 10th and 15th day after infection.The findings will help the researchers for the discovery of significant aquaculture nutrients to improve its immunostimulant action on fish (Pratheepa and Sukumaran, 2011).

TOXICOLOGY
E. hirta has been used as a traditional herbal medicine for years worldwide.However, it contains some properties that may be slightly toxic.Unfortunately, the study of the relative systematic toxicity and safety evaluations of E. hirta have been lacking, and only few reports of targetorgan toxicity or side effects have been documented in literature.The aqueous crude extracts of E. hirta were administrated orally to a 38-week old mature male at the Huang et al. 5183 dose of 400 mg/kg to determine the effects of the extracts on the male reproductive organs.The results revealed that the extract caused varying degrees of testicular degeneration and reduction in the mean seminiferous tubular diameter (STD) in the treated rats.Thus, E. hirta have potentially deleterious effects on the tested and accessory organs of rats (Adedapo et al., 2003).
As previously described, the aqueous stem, bark, and leaf extracts of the E. hirta have potent molluscicidal activity.The sub-lethal doses of the extract (40 and 80% of LC50) also remarkably (p < 0.05) altered the levels of total protein, total free amino acid, and nucleic acids (DNA and RNA), and the activity of enzyme protease, acid, and alkaline phosphatase in various tissues of the vector snail Lymnaea acuminata in time and dose dependent manners (Sunil et al., 2005).Mohammad et al., (2010) evaluated the toxicity of E. hirta extract using brine shrimp lethality assay.The results showed that all the parts of E. hirta, except the flower extract, had LC50 values of almost l000 ug/ml.Therefore, great caution should be taken when consuming this plant as medicinal agents and a safety dosage must be considered as well.

CONCLUSION
E. hirta is a popular herb among practitioners of traditional herb medicine in China and other counties and areas, such as Africa, India, Phlippines, Australia, and Cambodia.It has long been used as a decoction or infusion for the treatment of various ailments, particularly intestinal disorders, diarrhea, amoebic dysentery, peptic ulcers, asthma, bronchitis, and skin diseases in China.However, in Australia, one of the most popular uses of E. hirta is for the treatment of hypertension.In Java and India, the tender shoots, raw or steamed, serve as famine food.In Philippine Medicinal Plants, people even use the entire plant of E. hirta for tea-making.Hence, there are versatile traditional usages among different regions.Since E. hirta is widely distributed in pan-tropic and partly subtropic areas, it may forms distinct ecotypes in different habitats and possesses distinct chemical profiles.Further detailed investigation is needed to clarify this phenomenon.
Currently, various compounds have been isolated and identified from E. hirta, among which, flavonoids, terpenoids, and phenols are the major constituents.These monomeric compounds and crude extracts from E. hirta have been screened for pharmacological activities in vivo and in vitro.Various experimental studies validated the traditional medicinal uses of E. hirta.However, the intrinsically active compounds and the chemical responsible have been determined yet, and some mechanisms of the action of E. hirta are still unknown.Thus, bioassay-guided isolation and identification of the bioactive components must be developed to reveal the structure-activity relationship of these active components.

Figure 1 .
Figure 1.The structure of main compounds from E. hirta.