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REVIEW Phytochemistry, Pharmacology and Medicinal Properties of Phyllanthus emblica Linn. Bhakta Prasad Gaire1, and Lalita Subedi2 ABSTRACT Phyllanthus emblica L. (syn. Emblica officinalis ) is commonly known as Indian gooseberry. In Ayurveda, P. emblica has been extensively used, both as edible (tonic) plants and for its therapeutic potentials. P. emblica is highly nutritious and is reported as an important dietary source of vitamin C, minerals and amino acids. All parts of the plant are used for medicinal purposes, especially the fruit, which has been used in Ayurveda as a potent Rasayana (rejuvenator). P. emblica contains phytochemicals including fixed oils, phosphatides, essential oils, tannins, minerals, vitamins, amino acids, fatty acids, glycosides, etc. Various pharmaceutical potential of P. emblica has been reported previously including antimicrobial, antioxidant, anti-inflammatory, analgesic and antipyretic, adaptogenic, hepatoprotective, antitumor and antiulcerogenic activities either in combined formulation or P. emblica alone. The various other Ayurvedic potentials of P. emblica are yet to be proven scientifically in order to explore its broad spectrum of therapeutic effects. On this regards we, in this review, tried to explore the complete information of P. emblica including its pharmacognosy, phytochemistry and pharmacology. KEYWORDS Phyllanthus emblica , pharmacological properties, ethnomedicinal uses, phytochemistry, pharmacological effects, Ayurvedic medicine
Phyllanthus emblica Linn., belonging to the family euphorbiaceae, are widely distributed throughout most tropical and subtropical countries. Phyllanthus is a very large genus of approximately 550 to 750 species which is subdivided into 10 to 11 subgenera.(1,2) It is native to tropical south eastern Asia and found in mixed forest of tropical and sub-tropical regions at altitude of 150–1400 m. The fruit of P. emblica is one of the important and most widely used herbal drugs in Ayurvedic and Unani system of medicine.(3) P. emblica is a medium sized deciduous tree growing up to the height of 10–18 m. It is used both as a medicine and as a tonic to build up lost vitality and vigor.(1,4) According to the two main classic texts on Ayurveda, Charaka Samhita and Sushruta Samhita, P. emblica is regarded as "the best among rejuvenator", and "the best among the sour fruits".(5) It is a major ingredient in important medicinal preparations including Triphala and Chyawanprash, a general tonic for people of all ages that improves mental and physical well-being. Among the myths, it was reported that Chyawanprash was allegedly developed to rejuvenate an aging ancient sage by Chyavana Maharishi, a great meditator in Hindu religion, upon his marriage to a young wife.(6) P. emblica contains vitamin C, minerals, amino acids, tannins, phyllembelic acid, phyllemblin, rutin, curcuminoids, emblicol and some phenolic compounds. (7,8) Previous studies reported that P. emblica has antimicrobial,(9) antioxidant,(10,11)
anti-inflammatory,(12) analgesic and antipyretic,(13,14) adaptogenic, (15) hepatoprotective, (16) antitumor (17) and antiulcerogenic (18) activities. However, the pharmacological effects of P. emblica is often discussed with the Triphala, an Ayurvedic preparation consisting of equal amounts of three medicinal plants fruits namely: P. emblica , Terminellia chebula and T. belerica .(15,19,20) Though P. emblica is the most important medicinal plant in Ayurvedic medicine, little is known about the botany, phytochemistry, pharmacology, toxicology and ethnomedicinal uses. On this regards we, in this review, tried to explore the complete information including pharmacognosy, phytochemistry and pharmacology of P. emblica .
Botany Synonyms and Classification The local name of P. emblica L. in Nepal is Amala, and it is called as Vayasyaa, Adiphala, Amrita,
©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2014 1. Department of Pharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, 406-799, Republic of Korea; 2. Department of Pharmaceutical Sciences, School of Health and Allied Sciences, Pokhara University, PO Box. 427, Kaski, Nepal Correspondence to: Lalita Subedi, Tel: 977-61-561046, E-mail: [email protected] DOI: 10.1007/s11655-014-1984-2
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Dhatriphala, Kayastha, Shriphala, Vayastha in Sanskrit. The other common names of this plant include, Ganlanshu, Youganzi (Chinese); Emblic myrobalan, Indian Goose berry (English); Kemloko (Japanese); Chu me, Kam lam (Vietnames). Cicca emblica , Emblica officinalis , Mirobalanus embilica , P. mairei , P. laxifolius , Dichelastina nodicaulis are the synonyms of P. emblica . It can be classified as kingdom: plantae; division: flowering plant; class: magnoliopsida; order: malpighiales; family: euforbiaceae/phyllanthaceae; tribe: phyllantheae; subtribe: flueggeinae; genus: Phyllanthus ; species: P. emblica .
A
B
C
D
1.25–2 cm long, distichously disposed on branchlets, give a misleading impression of finely pinnate foliage. The feathery leaves are linear-oblong, with a rounded base and obtuse or acute apex. It has axillary cymes, densely fascicled along the leaf bearing branchlets, often on the naked portion below the leaves. Style arms are dichotomously bifid, flat and re-curved, greenish, and sparsely puberulus. The arms from the tip of the ovary measure about 5–7 mm long. The fruit diameter ranges between 1.8 and 2.5 cm. Groove markings along the septa are very shallow. The tender fruits are green, fleshy, globose and shining, and change to light yellow or brick-red when mature.(24-27)
Propagation P. emblica is generally propagated by seeds. However, in commercial purpose the grafting methods have also been discussed. Propagation studies revealed that, season of grafting had profound influence on graft success. Maximum success 87.50% was recorded in November grafting followed by 66.69% in case of December.(28)
Ethnomedicinal Uses P. emblica is an important herbal drug used in E
Figure 1.
F
Plants of P. Emblica
Notes: A: leaf; B: stem; C: flower; D, E: fruit; F: seed
Distribution P. emblica is widely distributed in most tropical and subtropical countries including China, Indonesia, and on the Malay Peninsula. P. emblica is native to tropical southeastern Asia, particularly in central and southern India, Nepal, Pakistan, Bangladesh, Bhutan, Sri-lanka, Malaya, Myanmar and the Mascarene Islands. It is abundant in deciduous forests of Madhya Pradesh. Originally, it was cultivated in Madascar.(21-23)
Botanical Description P. emblica L. is a tree of small or moderate size with a greenish-grey bark and greenish-yellow flowers, formed in axillary clusters. Branchlets are alternate superposed and they all face in one plane. Length of the branchlets is up to 40 cm and more than 100 leaves are in arranged in the branchlets. Barks are brown in color and peels into small irregular flake. The miniature, oblong leaves, only 3 mm wide and
Unani and Ayurvedic systems of medicine. Fruits of P. emblica have been used for thousands of years in the traditional Indian medicine for the treatment of several diseases. All parts of the plant are used for medicinal purposes, especially the fruit. In traditional medicine, it is used for the treatment of diarrhea, jaundice, and inflammation. The fruits are sour, astringent, bitter, acrid, sweet, cooling, anodyne, ophthalmic, carminative, digestive, stomachic, laxative, aphrodisiac, rejuvenative, diuretic, antipyretic and tonic. They are useful in diabetes, cough, asthma, bronchitis, cephalalgia, ophthalmopathy, dyspepsia, diuretic, anemia, biliousness, colic, flatulence, hyperacidity, peptic ulcer, erysipelas, skin diseases, leprosy, haematogenesis, inflammations, anemia, emaciation, hepatopathy, jaundice, strangury, dysentery, hemorrhages, leucorrhoea, menorrhagia, cardiac disorders, intermittent fevers and greyness of hair. In addition, the pulp of the fruit is smeared on the head to alleviate headache and dizziness, snakebite and scorpion-sting. The fruits are known to be a rich source of vitamin C and are frequently used in making pickles, preserves and jellies. The leaves are used in aphrodisiac, antipyretic, useful in biliousness, asthma, bronchitis, and vomiting. The roots, bark and the ripe
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fruit are astringent whereas flowers are refrigerant and aperient. The unripe fruit is cooling, diuretic and laxative. The exudation from the incisions on the fruit is used as an external application in inflammation of eye. Juice of the fresh bark with honey and turmeric is given in gonorrhea. Decoction of the roots has given in myalgia following upon some febrile condition.(27,29-34)
OH O O
Pharmacological Activity Antimicrobial Effect Aqueous infusion extract of P. emblica exhibited potent antimicrobial activity against Enterobacter cloacae followed by Escherichia coli and Klebsiella pneumoniae .(39) Aqueous infusion and decoction of E. officinalis exhibited strong antibacterial activity against E. coli , K. pneumoniae , K. ozaenae , Proteus mirabilis , Pseudomonas aeruginosa , Salmonella typhi , S. paratyphi A, S. paratyphi B and Serratia marcescens .(40) 1,2,4,6-tetra-O-galloyl-β-D-glucose, from P. emblica was reported for anti-viral activity against anti-herpes simplex virus in vitro .(41) P. emblica leaf extract was reported to possess antimalarial potency with the 50% inhibitory concentration (IC50) 7.25 μg/mL for
H
H
O
O
O
O
O
N
CH2OH
O
H
O
O OH
HO
Sesamine
Phyllantidine
Ascorbic acid
Beta carotene
O OH
CH3 HO
H
Phytochemistry Ascorbic acid (vitamin C) is the most abundant constituents of P. emblica fruit. Beside this, other phytochemicals isolated from this plant include fixed oils, phosphatides, essential oils, tannins, minerals, vitamins, aminoacids, fatty acids, glycosides etc. Fatty acids reported from from P. emblica include, linolenic, linoleic, oleic, stearic, palmitic and myristic acids. D-glucose, D-fructose, D-myo-inositol, D-galacturonic acid, D-arabinosyI, D-rhamnosyl, D-xylosyI, D-glucosyI, D-mannosyl and D-galactosyI residues are the sugars. Emblicanin A and Emblicanin B, pedunculagin and punigluconin are the major tannins reported from this plant. Other compounds isolated from this plants are gallic acids, amlaic acid, arginine, aspartic acid, astragallin, β-carotene, β-sitosterol, chebulagic acid, chebulic acid, chebulaginic acid, chebulinic acid, corilagic acid, corilagin, cysteine, ellagic acid, emblicol, gibberellins, glutamic acid, glycine, histidine, isoleucine, kaempferol, leucodelphinidin, methionine, phenylalanine, phyllantidine, phyllemblic acid, quercetin, riboflavin, rutin, thiamin, threonine, tryptophan, tyrosine, valine, zeatin, etc.(34-38) Structures of some of the major phytochemicals from P. emblica are presented in Figure 2.
H
O
H
H
O
OH
HO
OH
O
Estradiol
H3C H
CH3 H3C
H O H 3C
Lupeol
H 3C H CH3 H3C
CH3 H
CH3
H
CH3 CH3
CH3 H3C
CH3
H CH3
H
CH3
O
Ellagic acid
CH3
CH2
CH3
OH
HO
OH O
HO
Astragallin
H 3C
H
HO
OH O
O
OH
O
HO
HO
CH3
H 3C
Leucodelphinidin
CH3 CH3
Beta amvirin
OH
O
HO OH
HO
O
OH
Rutin
OH
O
OH
H3C O
HO HO
O
O CH3
HO HO OH
OH
HO
CH3
CH3
O
O
Kaempferol
H 3C
OH
O O O
HO
OH OH
Lupenone
O HO
O
OH
O-rutinose OH
OH
OH HO
OH
CH3 H
H
H
H
Pedunculagin
Beta sitosterol
N
H3C
N
N
O
HO
OH OH
H3CO
O
H
OH OH
Riboflavin
H
CH2OCH3
OH
OH HO
H3CO
OH
NH
N
Zeatin
O H 3C
H N
N
OH HO
OH HO
NH N
OCH3
O
Quercetin
CH2OCH3
Phylianthin
OCH3
Figure 2. Chemical Structures of Selected Compounds from P. emblica
ethyl acetate extract and 3.125 μg/mL for methanol extract against Plasmodium falciparum parasite .(42) The chloroform soluble fraction of the P. emblica methanolic extract exhibited significant antimicrobial activity against some gram positive and gram negative pathogenic bacteria and strong cytotoxicity having a IC50 of 10.257±0.770 μg/mL.(43)
Antioxidant Effect Previously many researches have been studied about the antioxidant and free radical scavenging activity of P. emblica and the main reason behind it is the ascorbic acid, tannins and polyphenolic constituents of P. emblica . Different extract of P. emblica and phytoconstituents are reported to have
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antioxidant efficacies against several free radicals such as 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH) free radicals, superoxide, nitric oxide, iron (Ⅲ) reduction, 5,5-dimethyl-1-pyrroline-N-oxide, etc. Phytochemicals from P. emblica are also reported as good metal ion chelator as it can prevent the oxidative cascades.(44-47)
Laxative Effect The fresh ripe fruits are used extensively in India as a laxative, and one or two fruits being sufficient for a single dose. They have been exported to Europe, preserved in sugar, and are valued as a pleasant laxative for children and made into a confection consisting of the pulp of the de-seeded fruit. It also possesses prokinetic and laxative activities in mice along with spasmodic effect in the isolated tissues of guinea pig and rabbit, and this action is mediated partially through activation of muscarinic receptors, suggesting a rationale for the medicinal use of P. emblica fruits in indigestion and constipation.(48)
Antidiabetic Effect The hydro-methanolic extract of E. officinalis leaves effectively normalize the impaired antioxidant status in streptozotocin-induced diabetes at dosedependent manner than the glibenclamide. The extract exerted rapid protective effects against lipid peroxidation by scavenging the free radicals and reducing the risk of diabetic complications. (49) A previous report suggests that E. officinalis and an enriched fraction of Emblica tannoids are effective in delaying development of diabetic cataract in rats.(50)
Antidiarrheal Effect In Ayurvedic medicine, fruit decoction of P. emblica is mixed with sour milk and given in cases of dysentery. Infusion of the leaves with fenugreek seed is given for chronic diarrhea. Recent report suggest that the P. emblica fruit extract possesses antidiarrheal and spasmolytic activities, mediated possibly through dual blockade of muscarinic receptors and Ca2+ channels, thus explaining its medicinal use in diarrhea.(51)
Analgesic and Antipyretic Effect Decoction of P. emblica leaves is used to treat fever and the fresh fruit is refrigerant. The seeds are given internally as a cooling remedy in bilious affections and nausea, and in fevers. A modified indigenous Siddha formulation Kalpaamruthaa, containing Semecarpus anacardium nut milk extract,
dried powder of Emblica officinalis fruit and honey is reported to have potent antinociceptive and antipyretic activities. (13) In another study, the ethanol and aqueous extracts of E. officinalis fruits at a single dose of 500 mg/kg caused a significant lowering in rectal temperature of hyperthermic rats, comparable to that of aspirin and also caused an inhibition on writhing produced by acetic acid when administered intraperitoneally in mice.(18)
Anti-inflammatory Effect A poly herbal formulation, Aller-7, containing P. emblica , possess the powerful anti-inflammatory activity against compound 48/80-induced paw edema in both Balb/c mice and Swiss Albino mice and against carrageenan-induced paw edema in Wistar albino rats. Aller-7 also exhibited a dose-dependent antiinflammatory effect against Freund's adjuvant-induced arthritis in Wistar Albino rats and an approximately 63% inhibitory effects and good trypsin inhibitory activity. (52) The water fraction of P. emblica fruits butanol extract has the potential anti-inflammatory efficacy against indomethacin-induced gastric ulcer.(53)
Hypo-cholesterolemic Effect P. emblica fruit treatment for 28 days in hypercholesterolemic patients showed decreases in total serum cholesterol levels(54) P. emblica extract was shown to inhibit cholesteremia at a higher level than the anti-cholesterol drug Probucol. In another study, rats fed extract along with a high cholesterol diet for 20 days showed significantly reduced the levels of total, free and low-density lipoprotein (LDL) cholesterol compared to that of diet fed group. An oxidized LDL (ox-LDL) level in the animal blood serum was also reduced. Serum thiobarbituric acid-reactive substance levels were decreased after oral administration of extract, suggesting that P. emblica may be effective for hypercholesterolemia and prevention of atherosclerosis.(55) Two soluble tannins of the herb P. emblica , corigalin and its analogue were found to be effective in inhibiting the progress of atherosclerosis by alleviating oxidation injury and by inhibiting ox-LDL-induced rat vascular smooth muscular cells proliferation.(56)
Hypo-lipidemic Effect The lipid-lowering and anti-atherosclerotic actions of P. emblica fruits were evaluated in rabbits fed a high cholesterol diet. The fresh juice of fruits at a dose of 5 mL/(kg • day) for 60 days lowered
Chin J Integr Med
serum cholesterol, triglycerides, phospholipids and LDL levels. Analysis of the animal urine showed increased amounts of cholesterol and phospholipids, suggesting that P. emblica may have affected the mode of absorption as well. Another study revealed that P. emblica also reduces serum, aortic and hepatic cholesterol in rabbits.(30,57)
Hepatoprotective Effect P. emblica and its flavonoid quercetin were found to be hepatoprotective against acetaminophen-induced liver damage in Albino rats and mice. The research results indicated that the possible mechanism of P. emblica for hepatoprotective activity is in decreasing glutathione depletion and preventing stimulation of cytochrome P450. Since quercetin alone was more effective than the P. emblica extract, it is thought to be the active principle. Toxic effects induced by lead nitrate and aluminum sulphate were also counteracted by the administration of P. emblica extract and ascorbic acid in albino rats. It is also reported that P. emblica has strong hepatoprotective effect against carbon tetrachloride-induced hepatic damage.(16,58)
Immunomodulatory Effect Laboratory experiment in mice showed that an aqueous P. emblica extract natural killer cell activity and antibody-dependent cellular cytotoxicity in mice. Ethanol extract of P. emblica showed biphasic activity in ulcerated mice with dose-dependent healing effect. It efficiently reduced pro-inflammatory cytokine, tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) levels and appreciably up-regulate the antiinflammatory cytokine (IL-10) concentration.(59)
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and lipid peroxidation (LPO) activities. This study supports the claim that anti-oxidants of E. officinalis may act as cardioprotective agents.(60)
Antiproliferative Effect The antiproliferative activity of phenolic compounds obtained from P. emblica was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MMT) assay, using three tumor cell lines, MK-1, HeLa, and B16F10 cells. All the phenolic compounds showed strong inhibition against B16F10 cell growth at a concentration of less than 68 mg/mL compared to HeLa and MK-1 cell growth. Norsesquiterpenoid glycosides, phyllemblicins B and C, exhibited significant inhibitory effects on the three tumor cell lines in the order of B16F10 >HeLa >MK-1. Compounds with a galloyl or pyrogalloyl moiety showed higher activity than the flavonoid. The results suggest that such compounds are worthy of consideration as a potential cancer chemopreventive agent.(38)
Anticancer Effect P. emblica aqueous extract showed the anticancer effect against mouse skin tumerogenesis by reducing the tumor number and volume and it was found to be very effective against breast cancer as well. (61) Aqueous extract of fresh E. officinalis fruits at a concentration of 16.5 mg/mL was found to significantly inhibit the growth of cytotoxic L929 cells in culture. The E. officinalis extract was also found to significantly reduce solid tumors induced by Dalton lymphoma ascites (DLA) cells while having only a moderate effect on ascites tumor.(62)
Antitussive Effect Cardioprotective Effect A study to investigate the anti-oxidant effect of bioactive tannoid principles of E. officinalis was carried out on cardiac ischemic-reperfusion-induced oxidative stress in rat heart. In this study, an emblicanin A and emblicanin B enriched fraction of fresh juice of E. officinalis fruits was extracted with aqueous methanol fraction and used for testing. The extract of E. officinalis and vitamin E (as standard oxidizing agent) were administered orally twice daily for 14 consecutive days prior to the perfusion experiments. The results demonstrated that E. officinalis significantly reversed the effects of ischemia-reperfusion on major antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX)
The antitussive activity of E. officinalis was tested in conscious cats by mechanical stimulation of the laryngopharyngeal and tracheobronchial mucous areas of airways. The ethanol extract of the fruits of E. officinalis seems to have a good ability to inhibit mechanically-provoked cough, but only at higher doses (200 mg/kg body weight) suggesting the presence of antitussive activity of E. officinalis in conscious cats, which is dose-dependent but higher than the antitussive activity of the commonly used non-narcotic antitussive drug, dropropizine. It is supposed that the antitussive activity of the dry extract of E. officinalis is due not only to antiphlogistic, antispasmolytic and antioxidant efficacy effects, but also due to its effect on mucus secretion in the airways.(63)
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Neuroprotective Effect Pretreatment with hydroalcoholic extract of E. officinalis fruit (500 and 700 mg/kg) significantly (P
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REVIEW Phytochemistry, Pharmacology and Medicinal Properties of Phyllanthus emblica Linn. Bhakta Prasad Gaire1, and Lalita Subedi2 ABSTRACT Phyllanthus emblica L. (syn. Emblica officinalis ) is commonly known as Indian gooseberry. In Ayurveda, P. emblica has been extensively used, both as edible (tonic) plants and for its therapeutic potentials. P. emblica is highly nutritious and is reported as an important dietary source of vitamin C, minerals and amino acids. All parts of the plant are used for medicinal purposes, especially the fruit, which has been used in Ayurveda as a potent Rasayana (rejuvenator). P. emblica contains phytochemicals including fixed oils, phosphatides, essential oils, tannins, minerals, vitamins, amino acids, fatty acids, glycosides, etc. Various pharmaceutical potential of P. emblica has been reported previously including antimicrobial, antioxidant, anti-inflammatory, analgesic and antipyretic, adaptogenic, hepatoprotective, antitumor and antiulcerogenic activities either in combined formulation or P. emblica alone. The various other Ayurvedic potentials of P. emblica are yet to be proven scientifically in order to explore its broad spectrum of therapeutic effects. On this regards we, in this review, tried to explore the complete information of P. emblica including its pharmacognosy, phytochemistry and pharmacology. KEYWORDS Phyllanthus emblica , pharmacological properties, ethnomedicinal uses, phytochemistry, pharmacological effects, Ayurvedic medicine
Phyllanthus emblica Linn., belonging to the family euphorbiaceae, are widely distributed throughout most tropical and subtropical countries. Phyllanthus is a very large genus of approximately 550 to 750 species which is subdivided into 10 to 11 subgenera.(1,2) It is native to tropical south eastern Asia and found in mixed forest of tropical and sub-tropical regions at altitude of 150–1400 m. The fruit of P. emblica is one of the important and most widely used herbal drugs in Ayurvedic and Unani system of medicine.(3) P. emblica is a medium sized deciduous tree growing up to the height of 10–18 m. It is used both as a medicine and as a tonic to build up lost vitality and vigor.(1,4) According to the two main classic texts on Ayurveda, Charaka Samhita and Sushruta Samhita, P. emblica is regarded as "the best among rejuvenator", and "the best among the sour fruits".(5) It is a major ingredient in important medicinal preparations including Triphala and Chyawanprash, a general tonic for people of all ages that improves mental and physical well-being. Among the myths, it was reported that Chyawanprash was allegedly developed to rejuvenate an aging ancient sage by Chyavana Maharishi, a great meditator in Hindu religion, upon his marriage to a young wife.(6) P. emblica contains vitamin C, minerals, amino acids, tannins, phyllembelic acid, phyllemblin, rutin, curcuminoids, emblicol and some phenolic compounds. (7,8) Previous studies reported that P. emblica has antimicrobial,(9) antioxidant,(10,11)
anti-inflammatory,(12) analgesic and antipyretic,(13,14) adaptogenic, (15) hepatoprotective, (16) antitumor (17) and antiulcerogenic (18) activities. However, the pharmacological effects of P. emblica is often discussed with the Triphala, an Ayurvedic preparation consisting of equal amounts of three medicinal plants fruits namely: P. emblica , Terminellia chebula and T. belerica .(15,19,20) Though P. emblica is the most important medicinal plant in Ayurvedic medicine, little is known about the botany, phytochemistry, pharmacology, toxicology and ethnomedicinal uses. On this regards we, in this review, tried to explore the complete information including pharmacognosy, phytochemistry and pharmacology of P. emblica .
Botany Synonyms and Classification The local name of P. emblica L. in Nepal is Amala, and it is called as Vayasyaa, Adiphala, Amrita,
©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2014 1. Department of Pharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, 406-799, Republic of Korea; 2. Department of Pharmaceutical Sciences, School of Health and Allied Sciences, Pokhara University, PO Box. 427, Kaski, Nepal Correspondence to: Lalita Subedi, Tel: 977-61-561046, E-mail: [email protected] DOI: 10.1007/s11655-014-1984-2
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Dhatriphala, Kayastha, Shriphala, Vayastha in Sanskrit. The other common names of this plant include, Ganlanshu, Youganzi (Chinese); Emblic myrobalan, Indian Goose berry (English); Kemloko (Japanese); Chu me, Kam lam (Vietnames). Cicca emblica , Emblica officinalis , Mirobalanus embilica , P. mairei , P. laxifolius , Dichelastina nodicaulis are the synonyms of P. emblica . It can be classified as kingdom: plantae; division: flowering plant; class: magnoliopsida; order: malpighiales; family: euforbiaceae/phyllanthaceae; tribe: phyllantheae; subtribe: flueggeinae; genus: Phyllanthus ; species: P. emblica .
A
B
C
D
1.25–2 cm long, distichously disposed on branchlets, give a misleading impression of finely pinnate foliage. The feathery leaves are linear-oblong, with a rounded base and obtuse or acute apex. It has axillary cymes, densely fascicled along the leaf bearing branchlets, often on the naked portion below the leaves. Style arms are dichotomously bifid, flat and re-curved, greenish, and sparsely puberulus. The arms from the tip of the ovary measure about 5–7 mm long. The fruit diameter ranges between 1.8 and 2.5 cm. Groove markings along the septa are very shallow. The tender fruits are green, fleshy, globose and shining, and change to light yellow or brick-red when mature.(24-27)
Propagation P. emblica is generally propagated by seeds. However, in commercial purpose the grafting methods have also been discussed. Propagation studies revealed that, season of grafting had profound influence on graft success. Maximum success 87.50% was recorded in November grafting followed by 66.69% in case of December.(28)
Ethnomedicinal Uses P. emblica is an important herbal drug used in E
Figure 1.
F
Plants of P. Emblica
Notes: A: leaf; B: stem; C: flower; D, E: fruit; F: seed
Distribution P. emblica is widely distributed in most tropical and subtropical countries including China, Indonesia, and on the Malay Peninsula. P. emblica is native to tropical southeastern Asia, particularly in central and southern India, Nepal, Pakistan, Bangladesh, Bhutan, Sri-lanka, Malaya, Myanmar and the Mascarene Islands. It is abundant in deciduous forests of Madhya Pradesh. Originally, it was cultivated in Madascar.(21-23)
Botanical Description P. emblica L. is a tree of small or moderate size with a greenish-grey bark and greenish-yellow flowers, formed in axillary clusters. Branchlets are alternate superposed and they all face in one plane. Length of the branchlets is up to 40 cm and more than 100 leaves are in arranged in the branchlets. Barks are brown in color and peels into small irregular flake. The miniature, oblong leaves, only 3 mm wide and
Unani and Ayurvedic systems of medicine. Fruits of P. emblica have been used for thousands of years in the traditional Indian medicine for the treatment of several diseases. All parts of the plant are used for medicinal purposes, especially the fruit. In traditional medicine, it is used for the treatment of diarrhea, jaundice, and inflammation. The fruits are sour, astringent, bitter, acrid, sweet, cooling, anodyne, ophthalmic, carminative, digestive, stomachic, laxative, aphrodisiac, rejuvenative, diuretic, antipyretic and tonic. They are useful in diabetes, cough, asthma, bronchitis, cephalalgia, ophthalmopathy, dyspepsia, diuretic, anemia, biliousness, colic, flatulence, hyperacidity, peptic ulcer, erysipelas, skin diseases, leprosy, haematogenesis, inflammations, anemia, emaciation, hepatopathy, jaundice, strangury, dysentery, hemorrhages, leucorrhoea, menorrhagia, cardiac disorders, intermittent fevers and greyness of hair. In addition, the pulp of the fruit is smeared on the head to alleviate headache and dizziness, snakebite and scorpion-sting. The fruits are known to be a rich source of vitamin C and are frequently used in making pickles, preserves and jellies. The leaves are used in aphrodisiac, antipyretic, useful in biliousness, asthma, bronchitis, and vomiting. The roots, bark and the ripe
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fruit are astringent whereas flowers are refrigerant and aperient. The unripe fruit is cooling, diuretic and laxative. The exudation from the incisions on the fruit is used as an external application in inflammation of eye. Juice of the fresh bark with honey and turmeric is given in gonorrhea. Decoction of the roots has given in myalgia following upon some febrile condition.(27,29-34)
OH O O
Pharmacological Activity Antimicrobial Effect Aqueous infusion extract of P. emblica exhibited potent antimicrobial activity against Enterobacter cloacae followed by Escherichia coli and Klebsiella pneumoniae .(39) Aqueous infusion and decoction of E. officinalis exhibited strong antibacterial activity against E. coli , K. pneumoniae , K. ozaenae , Proteus mirabilis , Pseudomonas aeruginosa , Salmonella typhi , S. paratyphi A, S. paratyphi B and Serratia marcescens .(40) 1,2,4,6-tetra-O-galloyl-β-D-glucose, from P. emblica was reported for anti-viral activity against anti-herpes simplex virus in vitro .(41) P. emblica leaf extract was reported to possess antimalarial potency with the 50% inhibitory concentration (IC50) 7.25 μg/mL for
H
H
O
O
O
O
O
N
CH2OH
O
H
O
O OH
HO
Sesamine
Phyllantidine
Ascorbic acid
Beta carotene
O OH
CH3 HO
H
Phytochemistry Ascorbic acid (vitamin C) is the most abundant constituents of P. emblica fruit. Beside this, other phytochemicals isolated from this plant include fixed oils, phosphatides, essential oils, tannins, minerals, vitamins, aminoacids, fatty acids, glycosides etc. Fatty acids reported from from P. emblica include, linolenic, linoleic, oleic, stearic, palmitic and myristic acids. D-glucose, D-fructose, D-myo-inositol, D-galacturonic acid, D-arabinosyI, D-rhamnosyl, D-xylosyI, D-glucosyI, D-mannosyl and D-galactosyI residues are the sugars. Emblicanin A and Emblicanin B, pedunculagin and punigluconin are the major tannins reported from this plant. Other compounds isolated from this plants are gallic acids, amlaic acid, arginine, aspartic acid, astragallin, β-carotene, β-sitosterol, chebulagic acid, chebulic acid, chebulaginic acid, chebulinic acid, corilagic acid, corilagin, cysteine, ellagic acid, emblicol, gibberellins, glutamic acid, glycine, histidine, isoleucine, kaempferol, leucodelphinidin, methionine, phenylalanine, phyllantidine, phyllemblic acid, quercetin, riboflavin, rutin, thiamin, threonine, tryptophan, tyrosine, valine, zeatin, etc.(34-38) Structures of some of the major phytochemicals from P. emblica are presented in Figure 2.
H
O
H
H
O
OH
HO
OH
O
Estradiol
H3C H
CH3 H3C
H O H 3C
Lupeol
H 3C H CH3 H3C
CH3 H
CH3
H
CH3 CH3
CH3 H3C
CH3
H CH3
H
CH3
O
Ellagic acid
CH3
CH2
CH3
OH
HO
OH O
HO
Astragallin
H 3C
H
HO
OH O
O
OH
O
HO
HO
CH3
H 3C
Leucodelphinidin
CH3 CH3
Beta amvirin
OH
O
HO OH
HO
O
OH
Rutin
OH
O
OH
H3C O
HO HO
O
O CH3
HO HO OH
OH
HO
CH3
CH3
O
O
Kaempferol
H 3C
OH
O O O
HO
OH OH
Lupenone
O HO
O
OH
O-rutinose OH
OH
OH HO
OH
CH3 H
H
H
H
Pedunculagin
Beta sitosterol
N
H3C
N
N
O
HO
OH OH
H3CO
O
H
OH OH
Riboflavin
H
CH2OCH3
OH
OH HO
H3CO
OH
NH
N
Zeatin
O H 3C
H N
N
OH HO
OH HO
NH N
OCH3
O
Quercetin
CH2OCH3
Phylianthin
OCH3
Figure 2. Chemical Structures of Selected Compounds from P. emblica
ethyl acetate extract and 3.125 μg/mL for methanol extract against Plasmodium falciparum parasite .(42) The chloroform soluble fraction of the P. emblica methanolic extract exhibited significant antimicrobial activity against some gram positive and gram negative pathogenic bacteria and strong cytotoxicity having a IC50 of 10.257±0.770 μg/mL.(43)
Antioxidant Effect Previously many researches have been studied about the antioxidant and free radical scavenging activity of P. emblica and the main reason behind it is the ascorbic acid, tannins and polyphenolic constituents of P. emblica . Different extract of P. emblica and phytoconstituents are reported to have
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antioxidant efficacies against several free radicals such as 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH) free radicals, superoxide, nitric oxide, iron (Ⅲ) reduction, 5,5-dimethyl-1-pyrroline-N-oxide, etc. Phytochemicals from P. emblica are also reported as good metal ion chelator as it can prevent the oxidative cascades.(44-47)
Laxative Effect The fresh ripe fruits are used extensively in India as a laxative, and one or two fruits being sufficient for a single dose. They have been exported to Europe, preserved in sugar, and are valued as a pleasant laxative for children and made into a confection consisting of the pulp of the de-seeded fruit. It also possesses prokinetic and laxative activities in mice along with spasmodic effect in the isolated tissues of guinea pig and rabbit, and this action is mediated partially through activation of muscarinic receptors, suggesting a rationale for the medicinal use of P. emblica fruits in indigestion and constipation.(48)
Antidiabetic Effect The hydro-methanolic extract of E. officinalis leaves effectively normalize the impaired antioxidant status in streptozotocin-induced diabetes at dosedependent manner than the glibenclamide. The extract exerted rapid protective effects against lipid peroxidation by scavenging the free radicals and reducing the risk of diabetic complications. (49) A previous report suggests that E. officinalis and an enriched fraction of Emblica tannoids are effective in delaying development of diabetic cataract in rats.(50)
Antidiarrheal Effect In Ayurvedic medicine, fruit decoction of P. emblica is mixed with sour milk and given in cases of dysentery. Infusion of the leaves with fenugreek seed is given for chronic diarrhea. Recent report suggest that the P. emblica fruit extract possesses antidiarrheal and spasmolytic activities, mediated possibly through dual blockade of muscarinic receptors and Ca2+ channels, thus explaining its medicinal use in diarrhea.(51)
Analgesic and Antipyretic Effect Decoction of P. emblica leaves is used to treat fever and the fresh fruit is refrigerant. The seeds are given internally as a cooling remedy in bilious affections and nausea, and in fevers. A modified indigenous Siddha formulation Kalpaamruthaa, containing Semecarpus anacardium nut milk extract,
dried powder of Emblica officinalis fruit and honey is reported to have potent antinociceptive and antipyretic activities. (13) In another study, the ethanol and aqueous extracts of E. officinalis fruits at a single dose of 500 mg/kg caused a significant lowering in rectal temperature of hyperthermic rats, comparable to that of aspirin and also caused an inhibition on writhing produced by acetic acid when administered intraperitoneally in mice.(18)
Anti-inflammatory Effect A poly herbal formulation, Aller-7, containing P. emblica , possess the powerful anti-inflammatory activity against compound 48/80-induced paw edema in both Balb/c mice and Swiss Albino mice and against carrageenan-induced paw edema in Wistar albino rats. Aller-7 also exhibited a dose-dependent antiinflammatory effect against Freund's adjuvant-induced arthritis in Wistar Albino rats and an approximately 63% inhibitory effects and good trypsin inhibitory activity. (52) The water fraction of P. emblica fruits butanol extract has the potential anti-inflammatory efficacy against indomethacin-induced gastric ulcer.(53)
Hypo-cholesterolemic Effect P. emblica fruit treatment for 28 days in hypercholesterolemic patients showed decreases in total serum cholesterol levels(54) P. emblica extract was shown to inhibit cholesteremia at a higher level than the anti-cholesterol drug Probucol. In another study, rats fed extract along with a high cholesterol diet for 20 days showed significantly reduced the levels of total, free and low-density lipoprotein (LDL) cholesterol compared to that of diet fed group. An oxidized LDL (ox-LDL) level in the animal blood serum was also reduced. Serum thiobarbituric acid-reactive substance levels were decreased after oral administration of extract, suggesting that P. emblica may be effective for hypercholesterolemia and prevention of atherosclerosis.(55) Two soluble tannins of the herb P. emblica , corigalin and its analogue were found to be effective in inhibiting the progress of atherosclerosis by alleviating oxidation injury and by inhibiting ox-LDL-induced rat vascular smooth muscular cells proliferation.(56)
Hypo-lipidemic Effect The lipid-lowering and anti-atherosclerotic actions of P. emblica fruits were evaluated in rabbits fed a high cholesterol diet. The fresh juice of fruits at a dose of 5 mL/(kg • day) for 60 days lowered
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serum cholesterol, triglycerides, phospholipids and LDL levels. Analysis of the animal urine showed increased amounts of cholesterol and phospholipids, suggesting that P. emblica may have affected the mode of absorption as well. Another study revealed that P. emblica also reduces serum, aortic and hepatic cholesterol in rabbits.(30,57)
Hepatoprotective Effect P. emblica and its flavonoid quercetin were found to be hepatoprotective against acetaminophen-induced liver damage in Albino rats and mice. The research results indicated that the possible mechanism of P. emblica for hepatoprotective activity is in decreasing glutathione depletion and preventing stimulation of cytochrome P450. Since quercetin alone was more effective than the P. emblica extract, it is thought to be the active principle. Toxic effects induced by lead nitrate and aluminum sulphate were also counteracted by the administration of P. emblica extract and ascorbic acid in albino rats. It is also reported that P. emblica has strong hepatoprotective effect against carbon tetrachloride-induced hepatic damage.(16,58)
Immunomodulatory Effect Laboratory experiment in mice showed that an aqueous P. emblica extract natural killer cell activity and antibody-dependent cellular cytotoxicity in mice. Ethanol extract of P. emblica showed biphasic activity in ulcerated mice with dose-dependent healing effect. It efficiently reduced pro-inflammatory cytokine, tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) levels and appreciably up-regulate the antiinflammatory cytokine (IL-10) concentration.(59)
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and lipid peroxidation (LPO) activities. This study supports the claim that anti-oxidants of E. officinalis may act as cardioprotective agents.(60)
Antiproliferative Effect The antiproliferative activity of phenolic compounds obtained from P. emblica was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MMT) assay, using three tumor cell lines, MK-1, HeLa, and B16F10 cells. All the phenolic compounds showed strong inhibition against B16F10 cell growth at a concentration of less than 68 mg/mL compared to HeLa and MK-1 cell growth. Norsesquiterpenoid glycosides, phyllemblicins B and C, exhibited significant inhibitory effects on the three tumor cell lines in the order of B16F10 >HeLa >MK-1. Compounds with a galloyl or pyrogalloyl moiety showed higher activity than the flavonoid. The results suggest that such compounds are worthy of consideration as a potential cancer chemopreventive agent.(38)
Anticancer Effect P. emblica aqueous extract showed the anticancer effect against mouse skin tumerogenesis by reducing the tumor number and volume and it was found to be very effective against breast cancer as well. (61) Aqueous extract of fresh E. officinalis fruits at a concentration of 16.5 mg/mL was found to significantly inhibit the growth of cytotoxic L929 cells in culture. The E. officinalis extract was also found to significantly reduce solid tumors induced by Dalton lymphoma ascites (DLA) cells while having only a moderate effect on ascites tumor.(62)
Antitussive Effect Cardioprotective Effect A study to investigate the anti-oxidant effect of bioactive tannoid principles of E. officinalis was carried out on cardiac ischemic-reperfusion-induced oxidative stress in rat heart. In this study, an emblicanin A and emblicanin B enriched fraction of fresh juice of E. officinalis fruits was extracted with aqueous methanol fraction and used for testing. The extract of E. officinalis and vitamin E (as standard oxidizing agent) were administered orally twice daily for 14 consecutive days prior to the perfusion experiments. The results demonstrated that E. officinalis significantly reversed the effects of ischemia-reperfusion on major antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX)
The antitussive activity of E. officinalis was tested in conscious cats by mechanical stimulation of the laryngopharyngeal and tracheobronchial mucous areas of airways. The ethanol extract of the fruits of E. officinalis seems to have a good ability to inhibit mechanically-provoked cough, but only at higher doses (200 mg/kg body weight) suggesting the presence of antitussive activity of E. officinalis in conscious cats, which is dose-dependent but higher than the antitussive activity of the commonly used non-narcotic antitussive drug, dropropizine. It is supposed that the antitussive activity of the dry extract of E. officinalis is due not only to antiphlogistic, antispasmolytic and antioxidant efficacy effects, but also due to its effect on mucus secretion in the airways.(63)
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Neuroprotective Effect Pretreatment with hydroalcoholic extract of E. officinalis fruit (500 and 700 mg/kg) significantly (P
