356-372 Published Online 2014 February 15

American-Eurasian Journal of Sustainable Agriculture

JOURNAL home page: http://www.aensiweb.com/aejsa.html 2013 December; 7(5): pages 356-372 Published Online 2014 February 15. Research Article

A Review on a Mangrove Species from the Sunderbans, Bangladesh: Barringtonia racemosa (L.) Roxb.

Md. Zahirul Kabir, Sk. Mizanur Rahman, Md. Rashedul Islam, Prashanta Kumer Paul, Shahnaz Rahman, Rownak Jahan, Mohammed Rahmatullah

Faculty of Life Sciences, University of Development Alternative, Dhanmondi, Dhaka-1209, Bangladesh

Received: November 03, 2013; Revised: January 13, 2014; Accepted: January 17, 2014

ABSTRACT

Barringtonia racemosa is considered a mangrove associated species and found in various regions of Southeast and East Asia, as well as Micronesian and Polynesian islands and northern Australia. Important chemicals that have been found in the plant include betulinic acid, ellagic acid, gallic acid, germanicol, germanicone, lupeol, stigmasterol and taraxerol. Antibacterial, antifungal and antinociceptive activities have been reported for extracts from the plant. Traditional medicine practices include the whole plant as a remedy for itch; the roots are considered to be antimalarial, the bark and/or leaves are used in case of boils, snake bites, rat poisonings, gastric ulcer, high blood pressure, chicken pox and as a depurative, the fruits are used as remedy for cough, asthma and diarrhea, while the seeds are used for cancer like diseases and for eye inflammation.

Key words: Barringtonia racemosa, Sunderbans, medicinal, Bangladesh

INTRODUCTION Barringtonia racemosa (L.) Blume Eugenia racemosa L. Barringtonia racemosa is considered a Butonica apiculata Miers mangrove associated species and found in various Barringtonia insignis Miq. regions of Southeast and East Asia, as well as Barringtonia pallida (Miers) Koord. & Valeton Micronesian and Polynesian islands and northern Barringtonia salomonensis Rech. Australia. Kingdom: Plantae Other names: Phylum: Tracheophyta Fish-killer tree, fish-poison tree, fish-poison Class: Magnoliopsida wood, freshwater mangrove, small-leaved Family: Lecythidaceae barringtonia, powder-puff tree, wild guava, brack- Genus: Barringtonia water mangrove, common putat, hippo apple Species: racemosa (L.) Spreng. (English), Godamidella (Sri Lanka / Sinhala), Other species belonging to this genus are Arattam (Tamil), Kye-bin, kyi (Burmese), Putat Barringtonia asiatica, Barrington acutangula, ayam, putat ayer, putat aying, putat kampong Barringtonia edilus, Barringtonia lanceolata, (Malay), Chik ban, chik suan (Thai), Apalang Barringtonia macrostachya, and Barringtonia (Filipino), Butan darat, butun darat, penggung, putat spicata. sungai (Indonesian), Samudraphala (Sanskrit), Ingar (Hindi), Mtomondo (Swahili). Scientific synonyms: Barringtonia racemosa (L.) Spreng

Corresponding Author: Professor Dr. Mohammed Rahmatullah, Pro-Vice Chancellor, University of Development Alternative, House No. 78, Road No. 11A (new), Dhanmondi R/A, Dhaka-1209, Bangladesh. Phone: 88-01715032621 Fax: 88-02-8157339 E-mail: [email protected] 357 Dr. M. Rahmatullah et al, 2013 / American-Eurasian Journal of Sustainable Agriculture 7(5), December, Pages: 356-372

Distribution: Botanical features: B. racemosa, which is considered a mangrove Barringtonia racemosa is a small tree of associate, can also be found in tropical rainforest mangrove associate type, capable of reaching 20 m areas, open lowlands and thickets. It occurs always or more with leaves tufted at the ends of stout twigs. near water: along riverbanks and in freshwater The leaves can be up to 40 cm long and 15 cm wide, swamps, and occasionally in the less saline areas of are pointed at the tip, have slightly toothed edges and mangrove swamps, where it may develop very pronounced veins. Flowers are arranged in long pneumatophores. The species cannot tolerate even spikes coming out of the centre of leaf groups, and light frost. It favours the wet tropical, moist topical have four white petals surrounded by a profusion of and wet subtropical climatic zones. It is distributed white filaments. The fruit is egg shaped and about 9 from eastern Africa and Madagascar to Bangladesh cm long. The bark is generally grey and smooth. (Sundarbans), Sri Lanka, India, Myanmar, southern China, Taiwan, the Ryukyu Islands (Japan), Chemical constituents and their reported Thailand, the Andaman and Nicobar Islands (India), pharmacological activities: throughout the Malaysian region towards Two new triterpenoids, olean-18-en-3beta-O-E- Micronesia, Polynesia (east to Fiji and Samoa) and coumaroyl ester and olean-18-en-3beta-O-Z- northern Australia. coumaroyl ester, were isolated from the stem bark along with 5 known compounds, germanicol, germanicone, betulinic acid, lupeol, and taraxerol [143].

O E S H H R Me O R R Me Me Me Me S R Me R H Me R

Olean-18-en-3beta-O-E-coumaroyl ester

O Z S H H R Me O R R OH Me Me Me Me S R Me R H Me R

Olean-18-en-3beta-O-Z-coumaroyl ester

Me Me

H Me

S R Me Me R R R R H Me S R HO H Me Me

Germanicol (Morol)

358 Dr. M. Rahmatullah et al, 2013 / American-Eurasian Journal of Sustainable Agriculture 7(5), December, Pages: 356-372

Me Me

H Me

S R Me Me R R R R H Me R O H Me Me

Germanicone

Ethyl acetate extract of the stem bark of the dihydromyticetin, gallic acid, bartogenic acid, and plant yielded 3,3’-dimethoxy ellagic acid, stigmasterol [127].

Gallic acid

An ethanolic extract of the roots afforded two Saponin namely barringtonin and sapogenins novel neo-clerodane-type diterpenoids, methyl-15,16- such as R1-barrigenol, barringtogenol and epoxy-12-oxo-3,13(16),14-neo-clerodatrien-18,19- barringtogenic acid have been isolated from the fruit olide-17-carboxylate (nasimalun A) and dimethyl- [73,4]. 15,16-epoxy-3,13(16),14-neo-clerodatrien-17,18- Similar saponins and sapogenins were also dicarboxylate (17-carboxy methylhardwickiic acid found in the seeds [60]. Me ester, nasimalun B) [40].

O O

S MeO R R R Me H O O

Nasimalun A

359 Dr. M. Rahmatullah et al, 2013 / American-Eurasian Journal of Sustainable Agriculture 7(5), December, Pages: 356-372

O H Me R R R OMe R

MeO O

Nasimalun B

Me Me

S S

Me Me H CO 2H HO R S R R R H Me R R HO S Me H CO 2H

Barringtogenic acid

Me Me

S S OH Me Me H HO R S R R R H Me R R HO R Me H

Barringtogenol

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Betulinic acid

Germanicol: sciadophylloides (higher fatty acid esters of Germanicol may have anti-inflammatory [96] taraxerol, Yasue et al, [145]); leaves of and anti-bacterial potentials [89]. Germanicol and Acanthopanax trifoliatus (along with nevadensin, derivatives are also present in the following plants as kaur-16-en-19-oic acid, and taraxerol acetate; Du and described below. Germanicol acetate has been Gao, [31]); from the chloroform leaf extract of isolated from the roots of Euphorbia nematocypha Alchornea latifolia [along with taraxerone, friedelin, (along with nematocyphol, nepehinol acetate, euphol, epifriedelinol, seco-3,4-friedelin (dihydroputranjivic tanaxastanol, 24-methylenecloartanol, and nepehinol; acid), and seco-3,4-taraxerone; Setzer et al, [120]; Cao et al, [15]). The compound has also been taraxerol acetate from dichloromethane extracts of isolated from methanol insoluble extract of Araujia the roots of Ambrosia artemisiifolia (Billodeaux et sericifera [78]; methanolic extract of the twigs of al, [12]); 3alpha- and 3beta-taraxerol (along with Celtis sinensis (along with epifriedelanol, trans-N- 3alpha-E-feruloyltaraxerol, 3alpha-Z- caffeoyltyramine, cis-N-coumaroyltyramine, feruloyltaraxerol, 3beta-E-feruloyltaraxerol, 3beta-Z- pinoresinol glycoside, pinoresinol rutinoside, and feruloyltaraxerol, 3alpha-E-coumaroyltaraxerol, and steroids; Kim et al, [59]); Festuca argentina (along 3alpha-Z-coumaroyltaraxerol from the fruits of with pentacyclic triterpenols such as beta-amyrin, Bruguiera cylindrica (Laphookhieo et al, [66]); from isobaurenol, lupeol, hopenol-a, hopeol, and low the twigs and buds of Calophyllum cordato- amounts of sterols like cholesterol, campesterol, oblongum - methyl ether of cordatolide B, cordato- stigmasterol, sitosterol, and dihydrositosterol; oblongic acid, friedelin, canophyllol, and sitosterol Casabuono and Pomilio, [16]); aerial parts of (Dharmaratne et al, [30]); Careya arborea (Mahato Koelpinia linearis [along with koelpinin A (28-nor- et al, [85]); Clerodendrum bungei (along with beta- lup-12,17-dien-3beta,16alpha-diol), koelpinin B sitosterol, glochidone, glochidonol, and glochidiol; (3beta-acetoxy-28-nor-lup-12,17-dien-16alpha-ol, Gao et al, [34]); Clitoria ternatea [6]; Codonopsis koelpinin C (28-nor-lup-12,17-dien-3beta-ol-16- pilosula (along with friedelin, alpha-spinasterol, one), 30-nor-lup-3beta-ol-20-one, and taraxeryl alpha-spinasterol-beta-D-glucopyranoside, n-butyl- acetate; Koul et al, [62]; hexane extract of alpha-D-fructofuranoside, and n-butyl-beta-D- Marsypianthes chamaedrys, a common herb found in fructopyranoside; Chen et al, [19]); Crossostephium the north and northeast regions of Brazil (along with chinense [118]; taraxerol-3-beta-O-tridecyl ether alpha-amyrin, beta-amyrin, lupeol, chamaedrydiol, from the aerial part of Derris trifoliata [142]; ethyl castanopsol, 2alpha-hydroxylupeol, and acetate extract of Embelia schimperi leaves [along epigermanidiol; de Sousa Menezes et al, [29]); with 3beta,16alpha-di-O-acetyl-13beta,28- alpha-germanicol from aerial parts of the medicinal epoxyoleanane, 3beta-acetyl-16-oxo-13beta,28- plant, Phoradendron reichenbachianum (along with epoxyoleanane, 3beta-acetyl-16alpha-hydroxy- moronic acid, 3,4-seco-olean-18-ene-3,28-dioic acid, 13beta,28-epoxyoleanane, 3beta-acetyl-16alpha- squalene, glycerol trilinoleate, morolic acid, hydroxyoleanane-13beta,28-olide, 3beta-acetyl-28- betulonaldehyde, betulinaldehyde, lupeol, beta- hydroxy-16-oxo-12-oleanene, 3beta,28-di-O-acetyl- sitosterol, and beta-sitosteril glucopyranoside; Rios 16alpha-hydroxy-12-oleanene, 3beta-acetyl- et al, [113]); and hexane extract from leaves of 11alpha,28-dihydroxy-16-oxo-12-oleanene, Vernonia brasiliana (along with lupeol and beta- 3beta,11alpha,16alpha,28-tetrahydroxy-12-oleanene, amyrin; Alves et al, [3]). 3beta-acetyl-16alpha,28alpha-dihydroxy-13beta,28- oxydooleanane, 3beta,28alpha-dihydroxy-16-oxo- Taraxerol: 13beta,28-oxydooleanane, 3beta,16alpha-dihydroxy- Besides Barringtonia racemosa, taraxerol has 13beta,28-epoxyoleanane (protoprimulagenin A), also been isolated from the plants Acanthopanax 3beta-hydroxy-16-oxo-13beta,28-epoxyoxyoleanane

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(aegicerin), 3,16-dioxo-13beta,28-epoxyoleanane catenarin, skyrin, (+)-aromadendrin, ventiloquinone (embilionone), 3beta,28-dihydroxy-16-oxo-12- K, ventiloquinone I, and stigmasterol; Lin et al, oleanene (schimperinone), taraxerone, and [72]); and wood of Vepris punctata (along with stigmasterol; Manguro et al, [86]; leaves of glechomanolide, isogermafurenolide, (E,E)- Macaranga triloba (along with 4,5-dihydro-5’alpha- germacra-1(10),4,7(11)-triene, alpha-amyrin, lupeol, hydroxy-4’alpha-methoxy-6a,12a-dehydro-alpha- lupeyl acetate, and 3-epi-taraxerol; Chaturvedula et toxicarol, (+)-clovan-2beta,9alpha-diol, ferulic acid, al, [18]). 3,7,3’,4’-tertramethylquercetin, 3,7,3’- Taraxerol has been reported to exhibit trimethylquercetin, 3,7-dimethylquercetin, abscisic significant inhibitory effects on Epstein-Barr virus acid, 1beta,6alpha-dihydroxy-4(15)-eudesmene, early antigen (EBV-EA) induced by the tumor 3beta-hydroxy-24-ethylcholest-5-en-7-one, loliolide, promoter, 12-O-tetrade-canoylphorbol-13-acetate scopoletin, and 3-epi-taraxerol; Jang et al, [47]); (TPA) in Raji cells. Furthermore, taraxerol exhibited leaves of Mangifera persiciformis (along with potent antitumor-promoting activity in the two-stage friedelin, beta-sitosterol, mangiferin, and quercetin; carcinogenesis tests of mouse skin using 7,12- Si et al, [123]); ethyl acetate and butanol-soluble dimethylbenz[a]anthracene (DMBA) as an initiator portions of the ethanol extract from the bark of and TPA as a promoter [130]. Mitragyna rotundifolia (along with dauricine, 3,4- Taraxerol has been reported to significantly dihydroxybenzoic acid, beta-sitosterol, scopleton, reduce carrageenan-induced paw edema and exhibit 3,4,5-trimethoxyphenol-1-glucopyranoside, 4- low anti-microbial activity [125]. Taraxer-14-en- hydroxy-3-methyloxybenzoic acid, 3-hydroxy-4- 3beta-ol, its acetate and ketone also demonstrated methyloxybenzoic acid, caffeic acid, gambirine, anti-inflammatory activity against TPA-induced gambireine, and 1,1-dimethyl-2-acetyl-diethyl ether; mouse ear edema [94]. Kang et al, [53]); root bark of Myrica cerifera [104]; Taraxerol exhibited significant inhibition of stems of Opuntia dillenii (along with opuntisterol, acetylcholinesterase (AchE) activity with an IC50 opuntisteroside, β-sitosterol, friedelin, methyl value of 79 microM [69]. linoleate, 7-oxositosterol, 6β-hydroxystigmast-4-ene- 3-one, daucosterol, methyl eucomate, and eucomic Bartogenic acid: acid; Jiang et al, [49]); Pachysandra terminalis [58]; Bartogenic acid isolated from fruits of Rhizophora mangle [139]; root of Rhododendron Barringtonia racemosa has been shown to have anti- molle (along with rhodojaponin-III and beta- arthritic activity [102]. The acid, isolated from seeds sitosterol; Xiang et al, [141]); Rhodendron ovatum of the plant reportedly showed alpha-glucosidase and (along with 3,5,7-trihydroxylchromone 3-O-beta-D- amylase inhibitory activities [37]. The latter two xylopyranoside, beta-sitosterol, betulinic acid, activities can be important for treatment of diabetes. quercetin, quercetin-3-O-alpha-L-rhamnopyranoside, A number of acids like chlorogenic acid, betulinic and D-glucose; Feng et al, [32]); Sageretia theezans acid, syringic acid, vanillic acid, bartogenic acid, (along with friedelin, syringic acid, beta-sitosterol, oleanolic acid, dehydrotrametenolic acid, corosolic daucosterol, and gluco-syringic acid; Xu et al, acid, ellagic acid, ursolic acid, and gallic acid have [142]); leaves of Sebastiania adenophora (along with been identified as alpha-glucosidase inhibitors and so 3-epi-beta-amyrin, beta-amyrinone, 3-epi-lupeol, can prove useful in treatment of diabetes [9]. lupenone, and taraxerone; Macias-Rubalcava et al, [82]); taraxer-14-en-3beta-ol from the leaves of Gallic acid: Sterculia foetida (Naik et al, 2004); 95% ethanol Gallic acid (3,4,5-trihydroxy benzoic acid) along extract, benzene fraction of Strobilanthes callosus with other phenolic compounds like methyl gallate, (Singh et al, [125]); ethyl acetate soluble fraction of ethyl gallate, m-digallic acid and other gallic acid stem bark of Styrax japonica (along with derivatives are potent antioxidants. Their medicinal styraxlignolide B, styraxlignolides C-F, syringin, and properties have been extensively studied and cover a (-)-pinoresinol glucoside; Min et al, [91]); roots of wide range from anti-microbial to cytotoxic and Taraxacum japonicum (along with taraxasterol and other properties. other triterpenoids; Takasaki et al, [130]); The anti-diabetic effects of gallic acid have been Tetrastigma hemsleyanum (along with taraxerone, reported. Gallic acid reportedly protected RINm5F beta-sitosterol, and ergosterol; Liu and Yang, [74]); beta-cells from glucolipotoxicity by its antiapoptotic hexane and ethyl acetate extracts of Uvaria hookeri and insulin-secretagogue actions [116]. The and Uvaria narum (along with glutinol, glutinone, antihyperglycemic, antilipid peroxidative, and beta-sitosterol, uvariamicins I-III, antioxidant effects of the compound have been isodesacetyluvaricin, squamocin-28-one, narumicins- demonstrated in streptozotocin-induced diabetic I and II stereoisomeric mixture, squamocin, and Wistar rats [105]. Insulin-secretagogue and panalicin; Padmaja et al, [97]); methanolic extract of antihyperlipidemic effects of gallic acid isolated twigs of Vaccinium oldhami (along with scopoletin; from Terminalia bellerica Roxb. have been Lee et al, [69]); Ventilago leiocarpa (along with demonstrated in streptozotocin-induced diabetic rats lupeol, chrysophanol, islandicin, parietin, emodin, [67]. Unripe Carissa carandas L. fruit extract has

362 Dr. M. Rahmatullah et al, 2013 / American-Eurasian Journal of Sustainable Agriculture 7(5), December, Pages: 356-372 been shown to exhibit antidiabetic potential, which metabolism in stroke-prone spontaneously has been attributed to some extent to gallic acid hypertensive rats [5]. Lupeol has been shown to present in the extract [45]. The protective action of protect against acetaminophen-induced oxidative gallic acid has been shown on hepatic lipid peroxide stress and cell death in rat primary hepatocytes [63]. metabolism in streptozotocin-induced type II diabetic The protection has been attributed to altering the Wistar rats [106]. gallic acid also shoed Bax/Bcl-2 ratio and altering oxidative stress- cardioprotective effects in diabetes-induced mediated mitochondrial signaling cascade [64]. myocardial dysfunction in rats [10]. In vivo and in Extract of Rhinacanthus nasutus (L.) Kurz has vitro antidiabetic effect of Cistus laurifolius L. has been shown to prevent glutamate and amyloid-beta been shown; a major phenolic compound present in neurotoxicity in HT-22 mouse hippocampal cells; the extract was gallic acid [95]. The bark of this protection has been attributed to presence of Terminalia paniculata Roth has also been shown to lupeol in the extract along with stigmasterol and reduce blood glucose levels in in vivo and in vitro beta-sitosterol [14], these compounds being also diabetic model; one of the responsible phytochemical present in Barringtonia racemosa. for the antidiabetic action has been postulated to be gallic acid [111]. Gallic acid reportedly also Betulinic acid: demonstrated protective effect in oxidative stress- Betulinic acid has been shown to protect against linked streptozotocin-induced pancreatic dysfunction cerebral ischemia-reperfusion injury in mice by in diabetic rats [52]. reducing oxidative and nitrosative stress [79]. Anti- depressant activity has been described for betulinic Lupeol: acid, isolated from Rosmarinus officinalis L. [81]. The anticancer, cancer chemo-preventive, The compound has been reported to regulate cardioprotective, hepatoprotective, antimicrobial, generation of neuroinflammatory mediators antiprotozoal, anti-inflammatory, antiurolithiatic, responsible for tissue destruction in multiple antidiabetic, anti-snake venom, gastroprotective, and sclerosis in vitro [13]. Hepatoprotective activity of anticonvulsant activities of lupeol, and to some betulinic acid has been demonstrated through its extent betulinic acid has been reviewed [33]. Since prevention of d-galactosamine/lipopolysaccharide- then, the results of some further studies on lupeol and induced liver toxicity, which has been shown to be betulinic acid are described (below). triggered by activation of Bcl-2 and antioxidant It has been shown that lupeol specifically targets mechanisms [146]. The hepatoprotective potential of Wnt/beta-catenin signaling in human melanoma cells Tecomella undulata (Roxb.) Seeman stem bark has and so inhibit cell proliferation [131]. A similar been partially attributed to the presence of betulinic observation has been made with colorectal cancer acid in the stem bark [46]. The anti-inflammatory cells [132]. In human hepatocellular carcinoma cells, effect of betulinic acid has been reported [134]. In lupeol has been shown to inhibit growth and induce other experiments, betulinic acid inhibited apoptosis [41]. Lupeol has been postulated to be superoxide anion-mediated impairment of useful for treatment of prostate cancer because of its endothelium-dependent relaxation in rat aortas [107]. inhibitory ability of the androgen receptor [124]. Betulinic acid has further been shown to have Lupeol has been found to prevent tumor formation beneficial effect in chemically induced during 7, 12-demethybenz(a)anthracene-induced oral hypothyroidism [1]. carcinogenesis [100]. The enhanced effect of lupeol The anti-obesity effect of betulinic acid has been on the destruction of gastric cancer cells by NK cells reported. It has been shown that combined treatment has been described [140]. with betulinic acid and extract of Orthosiphon The anti-inflammatory effect of lupeol, isolated stamineus Benth. can lead to decreased body weight from Himatanthus drasticus (Mart.) Plumel has been in high fat-fed mice [22]. Betulinic acid has further described [80]. Lupeol, isolated from Calotropis been reported to alleviate non-alcoholic fatty liver by gigantea (L.) Ait. latex, has been shown to inhibiting sterol regulatoryelement-binding protein 1 ameliorate primary and secondary complications of (SREBP1) via the AMPK-mTOR-SREBP signaling Fruend’s Complete Adjuvant induced adjuvant pathway [108]. SREBPs are transcription factors that disease in experimental rats [117]. Lupeol also have bind to the sterol regulatory element DNA sequence antinociceptive properties, which may be due to TCACNCCAC. Notably, the adenosine inhibition of cytokines [27]. Balanophora spicata monophosphate-activated protein kinase (AMPK)- Hayata and one of its phytochemical constituents, SREBP1 pathway has been implicated in orotic acid lupeol acetate, has been shown to possess induced development of fatty liver [51]. It has also antinociceptive and anti-inflammatory activities in been reported that betulinic acid ameliorates acute vivo and in vitro [20]. ethanol-induced fatty liver via Toll-like receptor 4 The antioxidant and antidiabetic property of (TLR4) and signal transducer and activator of lupeol has been demonstrated in experimental transcription 3 (STAT3) in vivo and in vitro [137]. hyperglycemia [39]. Lupeol supplementation has The anticancer effects of betulinic acid against also been shown to improve blood pressure and lipid different cancer cell lines have been well established.

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Betulinic acid reportedly inhibited proliferation, endothelial growth factor (VEGF), Cox2 and migration, and cell cycle and stimulated apoptosis of survivin expression in ovarian epithelial cancer cells pancreatic cancer cells [50]. A combination of [65]. Thus betulinic acid may have possibly betulinic acid and mithramycin A has been shown to beneficial effects in cases of ovarian epithelial effectively suppress pancreatic cancer by inhibiting carcinoma. Notably, betulinic acid has also been proliferation, invasion, and angiogenesis [35]. Lamin shown to target YY1 (a ubiquitously distributed proteins are thought to be involved in nuclear transcription factor belonging to the GLI-Kruppel stability, chromatin structure and gene expression. It class of zinc finger proteins) and ErbB2 [a member has recently been shown that Lamin b1 is a of the epidermal growth factor receptor therapeutic target of betulinic acid in pancreatic (EGFR/ErbB) family; amplification or over- cancer [71]. expression of this gene has been shown to play an In in vitro experiments, betulinic acid inhibited important role in the development and progression of growth of cultured vascular smooth muscle cells by certain aggressive types of breast cancer] through inducing G1 arrest and apoptosis [135]. The anti- cannabinoid receptor-dependent disruption of angiogenic activity of betulinic acid has been microRNA-27a:ZBTB10 in breast cancer [75]. reported in hypoxic PC-3 prostate cancer cells, and Microencapsulated betulinic acid, obtained from sour has been shown to be mediated through suppression jujube fruits, has been shown to induce apoptosis of of STAT3 and HIF-1 alpha [122]. In prostate cancer human breast cancer cells through the mitochondria cells, betulinic acid selectively increased protein transduction pathway [128]. Anticancer activity has degradation and enhanced prostate cancer-specific been reported for betulinic acid against MCF-7 apoptosis, possibly through inhibition of (human breast cancer cell line) tumors in nude mice deubiquitinase activity [112]. Polyubiquitin [24]. conjugation of key pro- and anti-apoptotic molecules In human multiple myeloma cells, in vitro, can play a role in regulating apoptosis [68]. In other betulinic acid has been shown to inhibit autophagic human cancer cells, co-treatment with ginsenoside flux and induce apoptosis [144]. Betulinic acid has Rh2 and betulinic acid reportedly induced apoptosis been shown to suppress neutrophil gelatinase along with enhanced caspase-8 activation, bax associated lipocalin (NGAL)-induced epithelial to translocation, and cytochrome c release [70]. In HCT mesenchymal transition in melanoma [36]. NGAL is 116 colorectal carcinoma cells, alpha-mangostin has also known as oncogene 24p3, uterocalin, siderocalin been shown to enhance betulinic acid cytotoxicity or lipocalin 2 and plays multiple roles in [2]. Betulinic acid has been shown to exert an anti- inflammation and cancer [17]. In 7,12- tumor effect on cervical carcinoma (U14) tumor- dimethybenz(a)anthracene-treated Sprague Dawley bearing mice [138]. rats, administration of betulinic acid has been shown In colon cancer cells, betulinic acid inhibited to play a role in modulating the activities of cancer cell and tumor growth and induced xenobiotic and antioxidative enzymes that have proteasome-dependent and independent putative roles in cancer initiation and proliferation downregulation of specificity proteins (Sp) [55]. transcription factors [21]. Notably, Sp1 transcription A possible influence of betulinic acid in the factor is a zinc finger transcription factor that binds clearance of human papilloma virus has been to GC-rich motifs of many promoters, and is reported [119]. The virus can cause serious health involved in many cellular processes including cell problems, including genital warts and certain growth and apoptosis. Inhibition of lung cancer cancers. Induction of Bax/Bak-independent growth by betulinic acid has been attributed to cytochrome c release has been noted with betulinic decreases in Sp1 levels via increasing the acid in human nasopharyngeal carcinoma cells; such sumoylation of Sp1 [43]. SUMO proteins are a induction would inhibit cell growth through family of small proteins that are covalently attached promoting apoptosis [76]. Taken together, betulinic to and detached from other proteins in cells to acid has important therapeutic effects against various modify their function, and sumoylation is a post- cancers, including pancreatic cancer, against which translational modification involved in various cancer there being no effective allopathic treatments. cellular processes like nuclear-cytosolic transport, transcriptional regulation, apoptosis, protein stability, Ethnomedicinal uses: response to stress, and progression through the cell Roots are claimed to be as good as cinchona in cycle. terms of medicinal value. Fruits are effective in Betulinic acid has been shown to decrease ER cough, asthma and diarrhea. The seeds are aromatic (endocrine receptor)-negative breast cancer cell and useful in colics and ophthalmia [57]. growth in vivo and in vitro; a role of Sp transcription In Bagerhat district of Bangladesh, the plant is factors and microRNA-27a:ZBTB10 has been used as an insect repellent and for alleviation of pain reported [88]. The microRNA-27a: ZBTB10- (including headache, toothache, and muscle pain) specificity protein pathway is also involved in [92]. The root of the plant is used to treat diarrhea by follicle stimulating hormone-induced vascular folk medicinal practitioners of Bangladesh [25].

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In Sri Lanka, the plant is widely used in reportedly inhibited Staphylococcus aureus in vitro traditional medical practices in the form of [84]. Antifungal activity has been observed with decoction. The bark and leaves are used to treat different extracts of leaves, sticks, and barks of the snake-bites, rat poisoning and in boils; the seeds plant, which activity has been attributed to several along with some other ingredients are used in the isolated compounds from the plant, namely, gallic preparation to treat itch, piles and typhoid fever; the acid, ferrulic acid, naringin, rutin, luteolin, and bark is claimed to have specific uses in gastric ulcers kaempferol [44]. The methanol extract of the bark [28,48]. exhibited significant activity against plant pathogenic In some villages of Kerala (India), the seeds are fungi Curvlaria sp., Colletotrichum gloeosporiodes, used to treat cancer like diseases [133]. The plant is Cylindrocladium quinqueseptatum and Rigiodiporus used against jaundice in Kannur district, Kerala, lignosus [99]. India [126]. The plant is used against dog bite Seed kernel extract showed toxicity against the wounds by different communities of Uttara Kannada golden apple snail, Pomacea canalliculata [93]. district, Karnataka, India [11]. The aqueous bark extract was found to have Root, bark and juice are used medicinally in the significant antinociceptive activity when screened in East; the Zulu tribe of South Africa uses the fruit as a rat model when evaluated with the hot plate and remedy for malaria. The fruit is used to treat cough, formalin test and such activity was supposed to be asthma and diarrhea; pulverized fruit is used as snuff. mediated via opioid mechanism [28]. Ethanol extract Seeds are used to treat eye inflammation and by of bark showed significant antioxidant, analgesic and midwives for parturition. In Malaysia, the leaves antidiarrheal activity [114]. Ethanolic extract of fruits traditionally are used to treat high blood pressure and also demonstrated anti-inflammatory and analgesic as a depurative. Pounded leaves are said to treat activities Shikha et al, [121]. Extract of leaves of the chicken pox [http://www.worldagroforestry plant has been shown to have antioxidant and anti- centre.org/sea/Products/AFDbases/af/asp/SpeciesInfo inflammatory properties [8]. The antioxidant activity .asp?SpID=307]. of various solvent extracts of aerial parts of the plant The plant has multiple uses in Micronesian has been reported [87,61]. islands (Palau, Yap, Chuuk, Pohnpei, Kosraeand the The protein fraction isolated from the stem bark Marshall islands), which include to treat soumwahu has been shown to have high mitogenic activity in en kau (sickness caused by sorcery, to treat mouse lymphocytes [129] whilst the ethanol extract soumwahu en nansapw (sickness from the cultivated of leaves was found to be cytotoxic against HeLa fields, to reduce the need to go to the bathroom when (human cervila carcinoma) cell line with a CD50 a person will be attending a big funeral part and there value of 10 microg/ml [83]. Intraperitoneal will be too many people around, to stop diarrhea, to administration of 50% methanol extract of seeds to treat back pain, to treat headache, to treat poisoning mice challenged with 1 million Dalton’s Lymphoma caused by eating food and drink that may have been Ascite (DLA) cells resulted in remarkable dose- hexed by sorcerers, to treat soumwahu en ohl, to dependent anti-DLA activity and this study validated reduce a high fever, to treat or clean the uterus, to the ethnomedical use of the same to treat some forms treat salengamat (ear infection) in babies (symptoms of tumor [133]. Quercetin 3-O-rutinoside, isolated include a bad smell from the painful ear from the plant has shown promising results against accompanied by copious amounts of white sticky acute lymphoblastic leukemia [115]. fluid coming from the ear), to treat babies with Hydroalcoholic extract of fruits showed cracked skin where the ears join the head (there is no immunomodulatory activity in albino Wistar rats local name for this illness), to treat rash similar to when evaluated in delayed type hypersensitivity chicken pox, to treat a rash on a child, to treat a bad reaction and humoral antibody response assays [103]. rash given by a sorcerer due to jealousy, to treat skin rash, to treat itchiness, to treat soumeahu en ohl Some reported phytochemicals, biological activities, (men’s sickness), and to treat a fungal infection and ethnomedicinal uses of other Barringtonia [People and Plants of Micronesia, quoted from the species: website: http://manoa.hawaii.edu/botany/plants_of_ Some reported phytochemical constituents and micronesia/index.php/scientific-names/288- biological activities of other Barringtonia species are barringtonia-racemosa-0]. discussed below. An aqueous extract of the bark of In some parts of Australasia, the plant is used to Barrington acutangula yielded nine triterpene treat itchiness [http://www. saponins, acutangulosides A-F and acutanguloside aseanbiodiversity.org/medicinal_plants/page2.htm]. D-F methyl esters and a single triterpene aglycone [90]. Crude extracts and VLC fractions from the stem Reported biological activities of Barringtonia bark of B. acutangula (particularly the petroleum racemosa: ether extract) showed good activity against two The ethanol extract of root, its chloroform Gram-positive bacterria, two Gram-negative bacteria soluble fraction and isolated triterpenoids exhibited and two fungi. The VLC fraction PE16 was found to in vitro antibacterial activity [57]. The plant be very effective against Bacillus subtilis (MIC = 25

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microg/ml) and Aspergillus niger (MIC = 12.5 district, Orissa, India [25]. The plant is also microg/ml). The major compound from PE16 was reportedly used by other tribes in Mayurbhanj district identified as 12,20(29)-lupadien-3-ol [109]. Extracts to treat diarrhea and dysentery [54]. The stem bark of from the leaf of the plant demonstrated inhibitory the plant is used to treat boils and wounds in activity against all strains of Helicobacter pylori Kutchum district, Yasothon Province, Thailand [23]. tested with an MIC value of 25 microg/ml [10]. From Barringtonia asiatica has medicinal and poisonous the dried seeds of B. acutangula, three properties; the fresh leaves are applied externally to monodesmosidic glucuronide saponins of relieve rheumatism and when heated used to remedy barringtogenol C, named barringtosides A, B and C stomach pain; the seeds are used in regulated doses have been isolated as their methyl esters. The against intestinal parasites; in Indonesia the plant is structures of these saponins have been elucidated as used as a remedy against scabies. barringtoside A [3-O-beta-D-xylopyranosyl (1––›3)- Barringtonia macrostachya is used to counter [beta-D-galactopyranosyl (1––›2)]-beta-D- ringworm. Barringtonia spicata is used against glucuronopyranosyl barringtogenol C], barringtoside itchiness B [3-)-beta-D-xylopyranosyl (1––›3)-]beta-D- [http://www.aseanbiodiversity.org/medicinal_plants/ galactopyranosyl (1––›2)]-beta-D- page2.htm]. Barringtonia acutangula is used for its glucuronopyranosyl-21-O-tigloyl-28-O-isobutyryl analgesic properties by the aborigines from Western barringtogenol C], and barringtoside C [3-O-alpha-L- Australia arabinopyranosyl (1––›3)-[beta-D-galactopyranosyl [http://www.gu.edu.au/research/stories/health/content (1––›2)]-beta-D-gluuronopyranosyl barringtogenol _pain_relief_mangroves.html]. The fruits of C] [98]. Triterpenoid sapogenins have also been Barringtonia edilus (local name, kinu) are eaten by isolated from the fruits of this plant [7]. the people of Savo island (an island in the Solomon The crude methanolic extract of leaves, fruits, Islands archipelago). seeds, stem and root barks of Barringtonia asiatica and subsequent petrol, dichloromethane, ethyl acetate Other uses of Barringtonia racemosa: and butanol fractions exhibited broad spectrum Young leaves are eaten as a vegetable; seeds are antibacterial and antifungal activity [56]. Antifungal pounded to extract the starchy content, which is activity of the plant has also been reported by others made into cakes. It provides suitable firewood. It has [77]. The methanol extract of the seeds yielded two been applied in various kinds of wood-based panels major saponins. Their structures have been such as hardboard, particleboard and blockboard, and elucidated as 3-O-[[beta-D-galactopyranosyl (1––›3)- has been used for the production of pulp. In Kenya, beta-D-glucopyranosyl (1––›2)]-beta-D- the bark is utilized as cordage. Barringtonia glucuronopyranosyloxy]-22-O-(2- racemosa yields a medium-weight hardwood with a methylbutyroyloxy)-15,16,28-trihydroxy- density of 480-815 kg/m³ at 15% mc. The wood is (3beta,15alpha,16alpha,22alpha-olean-12-ene and 3- light and soft and is used for light work that does not O-[[beta-D-galactopyranosyl (1––›3)-beta-D- require great strength. The wood is utilized for glucopyranosyl (1––›2)]-beta-D-glucuronopyrano- temporary construction, local house building (posts syloxy]-22-O-[2-(E)-methyl-2-butenyloyloxy]- and beams), general planking, flooring, boat 15,16,28-trihydroxy building, mouldings, interior finish, handles of non- (3beta,15alpha,16alpha,22alpha)-olean-12-ene. Both striking tools, household utensils, agricultural saponins showed antifeedant properties against the implements, boxes and crates and wooden pallets. It larvae of Epilachna [42]. The plant has a history of is suitable for veneer and plywood manufacturing. In use in Polynesian traditional medicine. India, it is used additionally for carts, rice pounders Barringtonia lanceolata is used as a medicinal and cabinetwork. In the Philippines, it has been plant in Riau province, Sumatra, Indonesia. Three to reported that when treated with preservatives, the four young leaves are eaten as a remedy for insomnia timber can be used to make good ties and paving [38]. blocks. In the Pacific region, the wood has Several Barringtonia species have additionally been used for carving and turnery. The ethnobotanical uses throughout the world. That of bark yields tannin. Seeds of the species contain Barringtonia racemosa has been discussed earlier in saponins, which are used as a fish poison; the whole the main text. In Bagerhat district, Bangladesh, the fruit, bark, wood and root can be used. Extracts of fruit pulp of Barringtonia acutangula is used as pain the plant have proved effective against Citrus aphis; reliever, and the seeds used when children develop in Bengal the seed is used as an insecticide, and to cough but fail to expel mucus from the chest [136]. poison people; coconut is said to be the antidote The bark of the plant is used against gingivitis, [http://www.worldagroforestrycentre.org/sea/Product toothache, and foul odor of mouth in Shitol Para s/ AFDbases/af/asp/SpeciesInfo.asp?SpID=307]. village, Jhalokati district, Bangladesh [110]. 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