Hydnocarpus: An ethnopharmacological, phytochemical and pharmacological review

Hydnocarpus: An ethnopharmacological, phytochemical and pharmacological review

Journal of Ethnopharmacology 154 (2014) 17–25 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier...

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Journal of Ethnopharmacology 154 (2014) 17–25

Contents lists available at ScienceDirect

Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep

Review

Hydnocarpus: An ethnopharmacological, phytochemical and pharmacological review Manas Ranjan Sahoo a, S.P. Dhanabal b,n, Atul N. Jadhav a, Vishali Reddy b, Ganesh Muguli a, U.V. Babu a, Paramesh Rangesh a a b

The Himalaya Drug Company, Makali, Tumkur Road, Bangalore 562 123, India Dept. of PhytoPharmacy and Phytomedicine, JSS College of Pharmacy, Post Box No. 20, Rocklands, Ootacamund, Dist. Nilgiri, Tamil Nadu 643001, India

art ic l e i nf o

a b s t r a c t

Article history: Received 26 July 2013 Received in revised form 13 March 2014 Accepted 13 March 2014 Available online 13 April 2014

Ethnopharmacological relevance: The genus Hydnocarpus (Flacourtiaceae) includes forty species that are spread across the globe. In the Indian System of Medicine, Hydnocarpus pentandrus (Buch.-Ham.) Oken. is primarily used for treating leprosy and other skin disorders. It is known as “Chaulmoogra” and is also used to treat other indications including constipation, inflammation, blood disorders, and worm infestations. Various species of Hydnocarpus are also used in traditional medicine in China, Thailand, Malaysia, and Myanmar for several skin disorders. To assess the therapeutic potential of species from the Hydnocarpus genus and to determine future avenues for research. Methods: All relevant scientific literature published up to the end of December 2013 was retrieved via a library and electronic search (SciFinder, PubMed, ScienceDirect, and Google Scholar). Manual searches of traditional books like to ancient classics, including Vaidya Yoga Ratnavali, Siddha Materia Medica, and contemporary references including The Ayurvedic Pharmacopoeia of India and The Ayurveda Formulary, were also performed. Results: Seed oil from species of the Hydnocarpus genus is used for medicinal purposes, predominantly for various skin disorders. This oil is reported to contain a characteristic class of compounds known as cyclopentenyl fatty acids. Furthermore, seeds of this genus are reported to contain triglycerides of fatty acids, sterols, flavonoids, and flavonolignans. Hydnocarpin, a flavonolignan, is reported to potentiate antimicrobial and anticancer activity. The extracts and compounds isolated from this plant show a wide spectrum of pharmacological properties, including antibacterial, antileprotic, antitubercular, antipsoriatic, antirheumatic, hypolipidemic, antidiabetic, anticancer, anti-inflammatory, and antioxidant activities. The antileprotic activity is postulated to be due to the cyclopentenyl fatty acids present in the seed oil. Conclusion: Flavonolignans have an interesting chemical motif, and hydnocarpin and its congeners should be investigated for their activities and the mechanism underlying these activities. Multi-drug-resistant microbes are on the increase, and the possible inhibitory effect of these compounds when used with current antimicrobials should also be evaluated. Furthermore, unique cyclopentenyl fatty acids should also be investigated to understand the exact mechanism of action underlying antileprotic activity. Additional in depth phytochemical investigations of seed oil and extracts are required to tap the true potential of species from the Hydnocarpus genus. & 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Hydnocarpus Leprosy Cyclopentene fatty acids Traditional uses

Contents 1. 2. 3.

n

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Traditional uses of the genus Hydnocarpus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytochemistry and pharmacological activities of genus Hydnocarpus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Hydnocarpus alcalae C. DC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Hydnocarpus anthelminthicus Pierre ex Laness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Hydnocarpus dawnensis C. E. Parkinson & C.E.C. Fisch (status unresolved) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Hydnocarpus hutchinsonii Merr. (status unresolved) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: þ 91 423 2443393; fax: þ 91 423 2442937. E-mail address: [email protected] (S.P. Dhanabal).

http://dx.doi.org/10.1016/j.jep.2014.03.029 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.

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3.5. Hydnocarpus ilicifolia King (status unresolved) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Hydnocarpus laurifolius Sleumer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Hydnocarpus wightianus Blume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Hydnocarpus kurzii (King) Warb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Hydnocarpus alpinus Wight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Hydnocarpus annamensis (Gagnep.) Lescot & Sleumer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. Hydnocarpus hainanensis Merr. (Sleumer) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12. Hydnocarpus octandra Thaw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.13. Hydnocarpus venenata Gaertn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14. Hydnocarpus pentadrus (Buch.-Ham.) Oken . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Mechanism of action in leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Globally, the genus Hydnocarpus (Flacourtiaceae) includes approximately forty species of shrubs and trees. It is commonly used in the Indian System of Medicine including Ayurveda and Siddha, and four species are found in India (Mudaliar, 1936; Sharma and Hall, 1991). Hydnocarpus species are used widely for both traditional and modern means primarily in Southeast Asia. Local and traditional uses of some of the Hydnocarpus species reviewed are listed in Table 1. Pharmacological screening has confirmed the claimed effect of Hydnocarpus species on leprosy. Cyclopentenyl fatty acids isolated from the seed oil have been shown to underlie this effect. Another interesting class of compounds, the flavonolignans, has shown several pharmacological activities. Extracts from different species have been screened and show various pharmacological activities in-vivo and in-vitro. Hence, herein, we review phytochemical and pharmacological studies of this genus to support its ethnopharmacological use and to instigate researchers globally to explore their full potential.

In this report, phytochemical and pharmacological publications on various Hydnocarpus species are reviewed. Manual searches of books of traditional medicines, including The Ayurvedic Pharmacopoeia of India, The Ayurvedic Formulary of India, and Siddha Material Medica were performed to retrieve information on traditional usage. We also used electronic databases, including SciFinders, PubMeds, ScienceDirects, and Google Scholar™. These searches were carried out using combination of flowing keywords: Ayurveda, phytochemical, Hydnocarpus, skin disease, and leprosy.

2. Traditional uses of the genus Hydnocarpus The Ayurvedic Pharmacopoeia of India lists the seeds of Tuvaraka as Hydnocarpus pentandrus (Buch.-Ham.) Oken. In Ayurvedic practice, it is commonly known as Tuvaraka (Syn. katukapittha) but has different regional names including Jangali Badami or Garudaphala in Kannada, Maravattai in Tamil, and Adavibadamu in Telugu (Lucas, 2008a).

Table 1 Traditional uses of Hydnocarpus species. Species

Parts used

Traditional use

Country

References

H. anthelminthicus Pierre ex Laness (H. anthelminthica)

Seed

Leprosy, dermatosis, elephantiasis, syphilis

China, India

Cole and Cardoso. (1939a,b)

H. alpinus Wight

Leaf Bark decocotion –

Cancer, dermatological disorder. Skin disease and internal disorder

India, Thailand, Burma, Malaysia

Chopra et al. (1996), Lee et al. (2010) Dr. Duke’s Phytochemical and Ethnobotanical Databases Duraipandiyan and Ignacimuthu. (2011), Chellappandian et al. (2012)

Leprosy Curing wounds

Luzon, Philippine

Seed

Skin infection and leprosy

India

– Seed, leaf & stem

Dermatosis – Blood circulation enhancer, Thailand Leprosy, psoriasis, opthalmia, rheumatism, sciatica, febrifuge, sedative eczema, dermatitis Bruise, emetic, Piscicide, antihelminthic – Purgative, rheumatism, sciatica, wound. Sprain, antiinflammation

H. alcalae C.DC

H. castaneus Hook. f. & Thomson H. heterophyllus Blume H. kurzii (King) Warb. (Taractogenos kurzii King.)

Bactericide, incontinence

H. laurifolia Sleumer (H. laurifolius Sleumer)



H. pentandrus (Buch.-Ham.) Oken H. wightianus Blume. (H. wightiana Blume) H. venenata Gaertn.

Seed Seed Seed

Scabies, leprosy, obesity, skin disorders, wound healing Leprosy, syphilis, rheumatism, tuberculosis, antibacterial, opthalmia Fish poison, leprosy, cutaneous disease

20 20 22 22 22 22 22 23 23 23 23 23 23 23

Dr. Duke’s Phytochemical and Ethnobotanical Databases Cole. (1933) Chopra et al. (1996) -doPanyaphu et al. (2011) Khare (2007a)

India

Dr. Duke’s Pillai and Desai (1975) Phytochemical and Ethnobotanical Databases Khare (2007b) Shyam et al. (2013)

India

Reddy et al. (2005), Bhattacharya. (2011)

India

Chopra et al. (1996), Kirtikar and Basu (1984)

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Table 2 Classical Ayurvedic formulations containing Hydnocarpus species. Preparation name

Other ingredients

Traditional and clinical uses

References

Nimbadi Taila

Azadirachta indica A. Juss. Camphor

Anonymous (1994)

Tuvaraka Lepa Tuvarakaha Taila

Cocos nucifera L. Acacia catechu (L.f.) Wild.

Antiseptic and healing, tissue regeneration, lepromatous ulcers. Eczema, leukoderma, lepromatous affection Major and minor skin diseases, excessive flow of urine

It is recommended for use in cases with abdominal distension with constipation (Anaha), hemorrhoids (Arsa), sciatica (Grdhrasi), cervical lymphadenitis (Gandamala), abdominal lump (Gulma), fever (Jvara), itching (Kandu), disorders due to Kapha and Vata dosha (Kaphavataja roga), worm infestation (Krumi), diseases of skin (Kustha), inflammation (Sotha), cases with metabolic disorder (Prameha), disorders of the blood (Raktavikara), skin disease (Tvakroga), various minor skin diseases (Ksudra Kustha), various major skin diseases (Maha Kustha), diseases of the abdomen (Udara), partial intestinal obstruction (Udavarta), and ulcers (Vrana). Tuvaraka is also recommended for treating diabetes (pramehaghna) in the Indian System of Medicine. To cure leprosy, it is traditionally administered orally with honey, ghee or as a tea. The dose administered is 3–5 g of seeds, as a powder (bija churna), or 5–10 drops of seed oil (Lucas, 2008a,b). Ayurveda recognizes three biological systems (Tridhatus)—‘Vata’ (air, the energy that moves), ‘Pitta’ (fire, the energy that digests) and ‘Kapha’ (mucus, the energy that lubricates the tissues and joints) (Jadhav and Bhutani, 2005). Some of the classical formulations of Hydnocarpus species (Table 2) include a formulation called Tuvarakaha taila, which is used externally (Anonymous, 2008; Anonymous, 2000). A preparation called “Tuvaraka kalpa”, mentioned in Sushrutha Samhitha (1000 B.C.), is used in the management of skin diseases where the patient is made to drink the oil of the Chaulmoogra seed. It is also suggested to have Rasayana properties (Vaidya, 1968). Rasayana drugs are said to prevent ageing and increase the strength of the body (Lucas, 2008b). In the Siddha system Hydnocarpus kurzii (King) Warb. is known as Niradi-muttu and is used in the treatment of thyroid goiters, leprosy, arthritis, dermatitis, urticaria, eczema, herpes, erythema and scabies (Mudaliar, 1936). On the western coast of India, the seeds have used for some resistant skin diseases, opthalmia and in wound dressings. In the treatment of scabious eruptions, seed oil is used with equal amounts of oil of Jatropha curcas L. with sulfur, camphor, and lime juice. Another formulation made from an equal proportion of oil and lime water is used as a liniment for a scalded head, burnt skin, leprosy, and joint pain. The paste of the seeds is useful in treating eczema, white patches, itching, and infection. Seed oil from Hydnocarpus wightiana Blume is reputed to be a remedy in the Konkan region of India for the treatment of ulcers occurring during rains (local-Barsati) in horses (Kirtikar and Basu, 1984; Zahid et al., 2013). The crushed leaf extract of Hydnocarpus pentadrus (Buch.-Ham.) Oken. is applied to the scalp to induce hair growth and for its cooling effects (Rajith and Ramachandran, 2010). In Southeast Asia, cold-expressed seed oil of Hydnocarpus kurzii (King) Warb. was a standard remedy for Hansen’s disease (leprosy) even before the advent of chemotherapeutics, such as dapsone and rifampicin (Norton, 1994). Its use for skin diseases in Traditional Chinese Medicine, primarily leprosy, dates back approximately 2000 years. Seeds of Hydnocarpus anthelminthicus Pierre ex Laness. are known as ‘lukrabo’ in Thailand and as ‘ta-fung-tsze’ in China (Power and Barrowcliff, 1905a). In Thailand, Cambodia, and China, the oil expressed from the seeds of Hydnocarpus anthelminthicus Pierre ex Laness. is used extensively for the treatment of leprosy

Anonymous (1994) Anonymous (2000)

(Cole and Cardoso, 1939a; Sharma and Hall, 1991; Norton, 1994). Of the other species of Hydnocarpus, Hydnocarpus annamensis (Gagnep.) Lescot & Sleumer, which is primarily distributed in the Guangxi province of China, is used in folk medicine for the treatment of rheumatoid arthritis and syphilis (Shi et al., 2006). In Japan, chaulmoogra seeds were used as early as 1716 to treat leprosy (Cole, 1933). The stem and leaf of Hydnocarpus kurzii (King) Warb., known as Dia Chan Mao in Thailand, has been used traditionally to improve blood circulation (Panyaphu et al., 2011). The Hydnocarpus species most widely used to make antileprosy oil are Hydnocarpus kurzii (Kalaw-Burma), Hydnocarpus pentandrus (Buch.-Ham.) Oken. (Tuvaraka-India), Hydnocarpus anthelminthicus Pierre ex Laness. (Da feng zi-China), Hydnocarpus venenata Gaertn. (Makulu-Sri Lanka), Hydnocarpus alcalae C.D.C. (Dudo’s-Philippines), Hyperolius castaneus Hook. f. & Thomson, Hydnocarpus macrocarpus Warb. and other species from the flacourtiaceae, including Caloncoba echinata (Oliv.) Gilg, Carpotroche brasiliensis (Raddi) A. Gray, and Gynocardia odorata Roxb. In the late 19th century, western physicians began using Hydnocarpus oil in oral, topical, and parenteral forms to treat lepromatous diseases (Cottle, 1879). A typical regimen for a patient included subcutaneous injections of 15 ml of oil beneath the lesions twice weekly for 10 weeks. This protocol resulted in pain and caused fevers, abscesses, and phlebitis. In addition, an oral administration was also unfavorable due to the severe emesis induced. Hence, formulations with reduced side effects, such as Alepol (sodium hydnocarpate) and Moogrol (creosoted ester of Hydnocarpus oil) manufactured by Burroughs-Welcome and Antileprol (iodized ethyl esters of chaulmoogra oil-Dean’s derivative) manufactured by Bayer were developed (Bhandari, 1932; Semon, 1935; Norton, 1994; Rae, 2005). There is little available toxicological data on these plants, except for one study reporting on ocular side effects of Chaulmoogra (Hydnocarpus species), which caused visual disturbances (Fraunfelder, 2004).

3. Phytochemistry and pharmacological activities of genus Hydnocarpus Hydnocarpus species are popular for the oils expressed from their seeds. Cyclopentenyl fatty acids are the major constituents of this oil (Table 3). Cyclopentenyl fatty acids constitute up to 85% of the total fatty acids of the seeds (Spener and Mangold, 1975). These cyclopentenyl fatty acids, e.g. hydnocarpic, chaulmoogric, and gorlic acid have also been reported in other species of flacourtiaceae, such as Carpotroche brasiliensis (Raddi) A. Gray (Lima et al., 2005). 3.1. Hydnocarpus alcalae C. DC. This species is from the province of Albay on the Phillipine Islands, where indigenous people call it dudoa or dudu–dudu. The seeds yield a dark brown oil (38%), of which approximately 90% is chaulmoogric acid with little or no hydnocarpic acid. The remaining 10% is primarily palmitic acid with only traces of oleic acid (Santos and West, 1929; Cole, 1933).

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Table 3 Cyclopentenyl fatty acids. No.

Trivial name

Chemical name

1

Chaulmoogric acid

(1S)-2-Cyclopentene-1-tridecanoic acid

2

Hydnocarpic acid

(1R)-2-Cyclopentene-1-undecanoic acid

3

Gorlic acid

(E)-13-cyclopent-2-en-1-yltridec-6-enoic acid

3.2. Hydnocarpus anthelminthicus Pierre ex Laness Phytochemical investigations report presence of two cyclopentenoid cyanohydrin glucosides, taraktophyllin and epivolkenin (Jaroszewski et al., 1987). It also contains the cyclopentenoid fatty acids anthelminthicins A–C and the flavonolignans anthelminthicol-A, isohydnocarpin, hydnocarpin-D, hydnocarpin, and sinaiticin (Wang et al., 2011). Moreover, several other compounds have been isolated from its seeds including p-hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 5-hydroxyindole-3-ald ehyde, ω-hydro-xypropioguaiacone, evofolin-B, erythro-1,2-bis-(4hydroxy-3-methoxyphenyl)-propane-1,3-diol, threo-1,2-bis-(4-hy droxy-3-methoxyphenyl)-propane-1,3-diol, erythro-1-(4-hydroxy3-methoxyphenyl)-2-{4-[2-formyl-(E)-vinyl]-2-methoxyphenoxy}propane-1,3-diol, threo-1-(4-hydroxy-3-methoxyphenyl)-2-{4-[2formyl-(E)-vinyl]-2-methoxyphenoxy}-propane-1,3-diol, daucosterol, oleanolic acid, chrysoeriol, 5,40 -dihydroxy-7-methoxyflavone and luteolin (Junfeng et al., 2011). Chaulmoogric acid (8%), ethyl chaulmograte and hydnocarpic acid (67%) are reported to be the principal constituents of the oil together with homologs of hydnocarpic acids including alepric acid, alprestic acid, alprylic acid, aleprolic acid, oncobic acid, and manoaic acid. It also contains more general fatty acids, such as myristic, palmitic, stearic, palmitoleic, oleic, linoleic, and linolenic acids. Steroidal compounds, such as 24-methylenecycloartenol, campesterol, stigmasterol, and β-sitosterol, have also been reported (Power and Barrowcliff, 1905a, 1905b; Cole and Cardoso, 1939b; Zhang et al., 1989; Garcia et al., 2012). In addition to its seeds, the leaves of Hydnocarpus anthelminthicus are reported to contain minor amounts of cyclopentenyl fatty acids (0.5–1.5%) together with major fatty acids, such as palmitic, linoleic, and α-linolenic. Other major lipids reported include monogalactosyl diglycerides, digalactosyl diglycerides, and phosphatidyl cholines. The straight-chain monounsaturated fatty acids comprise primarily Δ9 isomers, whereas the polyunsaturated fatty acids are the Δ9 series exclusively (Spener and Mangold, 1975). Hydro-methanolic extract (50%) is reported to inhibit enzymes involved in carbohydrate metabolism, for example rat intestinal sucrase and maltase by 5% and 25%, respectively, which is suggestive of antidiabetic activity (Anurakkun et al., 2007). Anthelminthicin-C is reported to be an inhibitor of p-aminobenzoic acid (PABA; MIC 11.3 μM) because it inhibited the formation of PABA from chorismate. Anthelminthicins inhibited Mycobacterium tuberculosis (MTB) (Table 4) but were not active against Candida albicans SC5314 at concentrations of up to 100 μM (Wang et al., 2010). Flavonolignans showed antiinflammatory activity by inhibiting nitric oxide production in the LPS-stimulated macrophage cell line RAW 264.7 (Table 4) when compared with the positive control (MG132) carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (Wang et al., 2011). In addition, cytotoxic compounds from the endophytic fungus Phomopsis sp. of Hydnocarpus anthelminthicus include mycoepoxydiene, deacetylmycoepoxydiene and 2,3-dihydromycoepoxydiene (Prachya et al., 2007).

Structure

Different extractions using n-hexane, ethyl acetate or n-butanol of seeds of Hydnocarpus anthelminthicus Pierre ex Laness. (commonly known as Hydnocarpi semen-HS in Latin) have been evaluated for wound healing activity using an in-vitro acute inflammation model and an in-vivo diabetic ulcer model. Of these extracts, the butanol extract showed the most potent activity at a dose of 2 mg/kg in diabetic mice with ulcers. Moreover, the authors elucidated the possible mechanisms and indicated that healing was mediated via the activation of macrophages, an increase in production of TNF-α and nitric oxide (NO) and the secretion of VEGF, TGF-β and MMP-9, which induce angiogenesis and fibroblast proliferation. These results suggest that the extract may be a novel therapeutic candidate for the treatment of diabetic ulcers (Lee et al., 2010, 2012a). The ethyl acetate fraction induces inflammation in-vitro, and it is proposed that the constituents chaulmoogric, hydnocarpic, and gorlic acids may not underlie this activity (Lee et al., 2012b). 3.3. Hydnocarpus dawnensis C. E. Parkinson & C.E.C. Fisch (status unresolved) This species is reported to grow in Myanmar, and the seed oil contains hydnocarpic acid and chaulmoogric acid (Cole, 1933). 3.4. Hydnocarpus hutchinsonii Merr. (status unresolved) This species is reported to grow on the Phillipine Islands, and the seed oil contains both hydnocarpic and chaulmoogric acids (Cole, 1933). 3.5. Hydnocarpus ilicifolia King (status unresolved) It is reported to be found in abundance in Thailand, and its seed oil is also reported to contain chaulmoogric and hydnocarpic acids (Cole, 1933). 3.6. Hydnocarpus laurifolius Sleumer The taxonomy of this species is not yet fully unresolved in The Plant List and in the International Plant Names Index. The seed oil has been found to contain chaulmoogric, hydnocarpic, gorlic, lignoceric, palmitic, oleic, and stearic acids. Of these fatty acids, chaulmoogric and hydnocarpic are present in the highest amounts (Sini et al., 2005). Flavonolignans, including hydnocarpin, hydnowightin, neohydnocarpin have also been reported in seeds from this species. The stem bark and leaves are reported to contain triterpenes, acelylbetulinic, betulinic, ursolic, and acetylursolic acids (Khare, 2007a,b). A metabolism study of petroleum ether extract of the seeds in Sprague-Dawley rats revealed that the oil is metabolized and excreted from the body within 72 h of administration. No genotoxic effects were observed in bone marrow

Table 4 Pharmacological activity of extracts and pure compounds. Active compound/extract

Screen

MIC/(IC50)/dose/inhibition

Reference std. (dose and activity)

Pharmacological effect

References

H. anthelminthicus Pierre ex Laness.

Chaulmoogric acid Ethyl chaulmograte Athelminthicins A Athelminthicins B Athelminthicins C Anthelminthicol A

MTB MTB MTB MTB MTB Murine monocytic RAW 264.7 macrophages -do-do-do-doSTZ-induced diabetic male ICR mice

9.82 16.8 5.54 16.7 4.38 425 μM

– – – – – MG-132 IC50—0.085 μM

Anti microbial Anti microbial Anti microbial Anti microbial Anti microbial Anti-inflammation

Wang et al. (2010) -do-do-do-doWang et al. (2011)

Wound healing

-do-do-do-doLee et al. (2010)

Induce inflammation

Lee et al. (2012a)

2 mg/kg 400 mg/kg/day (120 mg/dl)

Anti- inflammation Anti-diabetic

ABTS DPPH DPPH DPPH DPPH

7.5 μM 50 μM/64.3% 50 μM/69.4% 50 μM/68.8% 50 μM/60.9%

-doTrolox 50 μM/96.6% -do-do-do-

Anti-oxidant Anti oxidant and anti diabetic -doAnti oxidant -do-do-do-

Lee et al. (2012b) Sharma and Hall (1991) Reddy et al. (2005 -do-doShi et al. (2006) -do-do -do-

COX-2

10 μM/61.7%

Celecoxib 1 μM/92.4%

Anti-inflammatory

-do-

-do-do -do

10 μM/60.3% 10 μM/63.4% 10 μM/63.4%

-do-do-do-

-do-do-do-

-do-do-do-

Isohydnocarpin Hydnocarpin-D Hydnocarpin Sinaiticin 80% (v/v) aqueous methanol Ethyl acetate fraction

H. wightianus Blume

BuOH fraction Ethanol extract Acetone Luteolin

H. annamensis (Gagnep.) Lescot & Sleumer

Hydnocarpin 5-Hydroxy-3-methoxybenzyl alcohol Syringaresinol-4-O-β-D-glucoside Threo-10 ,20 -guaicyl glycerol Thero-syrigoylglycerol 7-O-β-Dglucoppyranoside 2-(3-Benzoyl-β-D-glucopyranosyl)-5hydroxybenzyl alcohol 2,6-Dimethoxy-p-benzoquinone Poliothyroside Cremanthodioside

Mouse macrophage cell line, RAW 264.7 Mice STZ induced diabetic Sprague Dawley (male) rat DPPH, ABTS and AGI DPPH, ABTS and AGI

425 μM 7.81 μM 9.38 μM 10.55 μM 50 mg/kg oral and 10 mg/kg – dermal 40 μg/ml – – Acarbose180 μg/kg/day ) (115 mg/dl) 32.54, 2.21 and 10.55 μg/ml Probucol & trolox 17.47, 1.32, 23.52 μM -do-

M.R. Sahoo et al. / Journal of Ethnopharmacology 154 (2014) 17–25

Name of the plant

21

22

M.R. Sahoo et al. / Journal of Ethnopharmacology 154 (2014) 17–25

erythrocytes of Swiss mice when compared with methyl methane sulfonate (Sini et al., 2005). 3.7. Hydnocarpus wightianus Blume The taxonomy of this species is not yet fully resolved. The seed oil of Hydnocarpus wightiana contains cyclopentenyl fatty acids including hydnocarpic acid (50%), gorlic acid (10%) chaulmoogric acid, and some lower homologs of the same acids (32%) together with other straight chain fatty acids (Power and Barrowcliff, 1905b; Cole and Cardoso, 1939a; Blaise et al., 1997; Sengupta et al., 1973). Seeds of this species are reported to contain flavonolignans, including hydnowightin, hydnocarpin, neohydnocarpin, isohydnocarpin, and methoxyhydnocarpin, flavonoid-luteolin, apigenin, chrysoeriol, steroids- β-sitos terol glucoside, β-sitosterol, lupeol, β-amyrin, and betulinic acid (Ranganathan and Seshadri, 1974a,1974b; Parthasarathy et al., 1979; Sharma et al., 1979; Sharma and Hall, 1991; Sharma 2006). From the fruits, leucopelargonidin, a leucoanthocyanin is reported (Nair and Ramaiah, 1971). Triterpenes, including acetylbetulinic acid, acetylursolic acid, betulinic acid, and ursolic acid, have been reported from the stem bark and leaves of the plant (Nair and Rao, 1993). A number of saturated and unsaturated fatty acids, e.g., palmitic, behemic, lignoceric, and cerotic acids, which together constitute more than 60% of the total fatty acids, have been identified in surface lipids of Hydnocarpus wightiana leaves. In contrast to the seed lipids, the surface lipids of Hydnocarpus wightiana leaves do not contain cyclopentenyl carboxylic acids (Shukla and Paulose, 1979). Single flavonolignans isolated from the species have been tested for their hypolipidemic potential. Hydnocarpin, neohydnocarpin, and hydnowightin showed hypolipidemic activity in mice following intraperitoneal (i.p.) administration at 8 mg/kg/day. Both serum cholesterol and triglyceride levels decreased by 32–41% on the 16th day, compared with clofibrate administered at 150 mg/kg/day (24–27%). Of the tested compounds, hydnowightin and hydnocarpin were found to be more effective than neohydnocarpin because they lowered serum cholesterol levels by 38–41%. Hydnocarpin, at 8 mg/kg, demonstrated antiinflammatory activity because it reduced (42%) carrageenaninduced inflammation in CF1 mice compared with hydnowightin and neohydnocarpin, whereas the positive control, phenylbutazone, administered at 50 mg/kg, reduced inflammation by 47% (Sharma and Hall, 1991). The flavonolignans hydnowightin, hydnocarpin, and neohydnocarpin were evaluated for cytotoxicity in murine and human cell lines including the murine lymphoid leukemia line L-1210 (1), the human-KB nasopharynx line (2), a colon adrenocarcinoma line (3), HeLa-S3 uterine sarcoma cells (4), bone osteosarcoma cells (5), lung carcinoma cells (6), Tmolt3 cells (7), and a glioma cell line (8). All of these compounds are reported to inhibit the growth of the above cell lines (1, 2, 3, 4, and 5) with ED50s of 3.07, 1.96, 2.38, 3.01, 2.50 μg/ml, respectively. Of the three compounds, hydnocarpin and neohydnocarpin have shown activity against 7 with an ED50 of 2.94 and 3.05 μg/ml, respectively, and only hydnocarpin was active against 8, with an ED50 of 2.59 μg/ml. However, none of the above three compounds showed activity against cell line number 6. The results were compared using the positive standards 5-fluorouracil, cytosine arabinoside, and hydroxyurea (Sharma and Hall, 1991). Ethanol and acetone extracts are reported to show antidiabetic and antioxidant activity, respectively (Table 4) (Reddy et al., 2013). Bioassay-guided fractionation of the acetone extract led to the isolation of luteolin as the active constituent. The standards used in these studies for antioxidant assay were probucol and trolox, which showed inhibition against DPPH and ABTS at 21.7, 4.61 and 32, 7.26 μM, respectively (Reddy et al., 2005). The flavonolignan 50 -methoxyhydnocarpin (50 -MHC), isolated from Hydnocarpus wightiana Blume, is reported to show synergistic antimicrobial effects (at 10 μg/ml) with the alkaloid berberine

because it reduced the MIC from 256 to 16 μg/ml. Stermitz et al. attributed this effect to the inhibition of efflux of berberine from Staphylococcus aureus. It also potentiate the activity of other antimicrobials, e.g. norfloxacin (from 1 down to 0.25 μg/ml), tetraphenylphosphonium (from 16 down to 4 μg/ml), pentamidine (from 64 down to 4 μg/ml), benzalkonium chloride (from 1 down to 0.125 μg/ ml), and palmatine (from 256 down to 64 μg/ml) when used on wild and mutant strains of Staphylococcus aureus (Stermitz et al., 2000). It has also been observed that 10 μM hydnocarpin (42% growth inhibition) combined with vincristine at 1.5 and 0.75 μM (66% and 39% growth inhibition) increased the potency of vincristine to 83% and 61% respectively, in the acute lymphoblastic leukemia 697 cell line (Bueno Perez et al., 2013). 3.8. Hydnocarpus kurzii (King) Warb The seeds of Hydnocarpus kurzii contain 30% oil, of which the three principal fatty acids are hydnocarpic, chaulmoogric, and gorlic acids. The oil also contains lower amounts of homologs, including myristic, palmitic, stearic, palmitoleic, oleic, linoleic and linolenic acids (Levy, 1973). 3.9. Hydnocarpus alpinus Wight This plant (name unresolved thus far) is commonly known as neervetti in the Tamilnadu region, and its seeds are reported to contain cyclopentenyl fatty acids (Chopra et al., 1996; Duraipandiyan and Ignacimuthu, 2011). The pesticidal effect of hexane, chloroform, and ethyl acetate extracts of Hydnocarpus alpinus leaves against Spodoptera litura at different concentrations revealed ethyl acetate as the most potent extract. It is reported to show antifeedant (72.2%) and insecticidal (66.6%) activity at a concentration of 5%. Moreover, a formulation blend of neem oil and one of the column fractions of the ethyl acetate extract showed 78.6% antifeedant and 82.4% insecticidal activity at concentrations of 100 ppm, a greater effect when compared with the individual components. A preliminary phytochemical investigations revealed the presence of phenols, flavonoids and triterpenoids in the bioactive ethyl acetate fraction (Ezhil et al., 2010). 3.10. Hydnocarpus annamensis (Gagnep.) Lescot & Sleumer From the ethanol extract of the bark chemical constituent, including phenolic glycosides, e.g. 2-(3-benzoyl-β-D-glucopyranos yl)-5-hydroxybenzyl alcohol and 2-(4-benzoyl-β-D-glucopyranosyl)-5-hydroxybenzyl alcohol, and β-sitosterol, 40 -hydroxypropiophenone, 2,6-dimethoxy-p-benzoquinone, coniferaldehyde, 5-hy droxy;-3-methoxybenzyl alcohol, benzoic acid, (2S)-3-(4-hydroxy3-methoxyphenyl)-propane-1-one), daucosterol, syringaresinol-4O-β-D-glucoside, threo-10 ,20 -guaicyl glycerol, 2-phenylpropane-1,3-diol, poliothyroside, junipetrioloside-A, cremanthodioside, salirepin, 2,4,6,trimethoxyphenol 1-O-β-D-apifuranosyl-(1-6)-β-D-glucopyranoside, thero-syrigoylglycerol 7-O-β-D-glucoppyranoside have also been reported. Some of these compounds (Table 4) showed antioxidant activity and COX-2 inhibition (Shi et al., 2006). Shi et al. (2007) also subsequently reported the separation of two isomeric neolignans by capillary electrophoresis to yield 1-(4-hydroxy-3-methoxy)-phenyl-2-[4-(1,2,3-tri-hydroxy-propyl)-2-methoxy]-phenoxy-1,3-propandiol from bark. 3.11. Hydnocarpus hainanensis Merr. (Sleumer) The ethanol extract of the stem is reported to contain coniferaldehyde, mulberroside, mulberrofuran G, mulberrofuran, morusin, and daucosterol. From these compounds, coniferaldehyde have shown inhibitory activities on the growth of the human hepatoma cell line (SMMC-7721), the human gastric carcinoma (SGC-7901) and

M.R. Sahoo et al. / Journal of Ethnopharmacology 154 (2014) 17–25

mulberrofuran G and morusin was active in SGC-7901 (Mei et al., 2011). The leaves of this plant are reported to contain glutinol, fernenol, lupeol, α-armyrin, 2,9-dimethyldeca-2,8-diene, phytenal, phytol, 3,7,11,15-tetramethylhexadecane-1,2-diol and 3,5-dimethoxy4-hydroxybenzaldehyde (Li et al., 2012). From the stem compounds including wogonin, liquiritigenin, sapinofuranone B, (þ)-yangabin, phydroxybenzoic acid, and β-sitosterol have been isolated (Hui et al., 2011). A significant inhibitory activity on the growth of the human glioma cell line U251 has been reported for the ethanol extract of Hydnocarpus hainanensis, and is suggested for use as an antitumor drug (Jiangnan et al., 2013).

23

acids were highly lipophilic, they dissolved the mycolic acid coat of the mycobacterim, resulting in cell death (Oommen et al., 1999). This oil has also been patented for its harmonizing effects on skin pigmentation following sun exposure. This activity is due to its enhancing effect on dendricity, which enables the transfer of melanin to adjacent keratinocytes cells (Leclere, 1996).

5. Conclusion

The novel cyclopentenoid cyanohydrin glycosides (1S,4R)and (1R,4S)-1-[6-O-(α- L-rhamnopyranosyl)-β- D-glucopyranosyloxy]-4-hydroxy-2-cyclopentene-1-carbonitrile are reported from the seeds. The seeds are known to contain epivolkenin and taraktophyllin (Jaroszewski et al., 1988).

Compounds from the species within the genus Hydnocarpus are used globally in traditional medicine and have not been studied in depth to determine the validity of their traditional use. However, the pharmacological studies reviewed support its traditional use in leprotic disease. Several mechanisms, including host lipase activation, chemotaxis, inhibition of microbial biotin, antioxidant effects of the cyclopentenyl fatty acids and the lipophilicity of the long chain carboxylic acids, have been proposed to underlie their activity. Cyclopentenyl fatty acids have been suggested to be the bioactive compounds in oils generated from these species but substantial mechanistic studies that prove their bioactivity are lacking. Effects on inflammatory markers only partially support its broad-spectrum use in skin diseases, which necessitates more in depth studies to evaluate their broad spectrum traditional use in skin disorders. Traditional usage promotes their use in infectious diseases, such as elephantiasis, syphilis, and tuberculosis; however, again, this usage has not been substantiated with objective data. Unique cyclopentenyl fatty acids have been reported to be the bioactive constituents from the seed oil of this genus. To date, only three of these acids have been reported upon. Many of the reports are prior to the availability of hyphenated instrumental techniques; hence prompts the need for further phytochemical investigations on the seed oil. The flavonolignan hydnocarpin is a bioactive compound that exhibits promising activity in various cancer cell lines. Hydnocarpin has also been reported to potentiate the anticancer activity of vincristine and 50 -methoxy and the antimicrobial activity of norfloxacin. This compound or its analogues should be studied with other anticancer and antimicrobial agents and also in diverse screens. This potentiation may be driven by the inhibition of the cellular transport pump. Using a through mechanistic study of these potentiation effects may lead to the identification of novel drug targets, as is the case with some natural products. In addition a detailed toxicological and pharmacokinetic study is required to ascertain safety for use in clinical practice.

4. Mechanism of action in leprosy

Acknowledgements

3.12. Hydnocarpus octandra Thaw This species (name unresolved thus far) is native to Sri Lanka. Triterpenoids, e.g., octandrolal, octandrolol, octandrolic acid, octandronal, octandronol, octandronic acid, trichadenic acid B, and mangostin, have been reported to be contained in bark of Hydnocarpus octandra. β-Sitosterol and friedelin have been isolated from the fruit pericarp (Gunasekera et al., 1973; Gunasekera and Sultanbawa, 1973, 1977; Tanaka et al., 1988). Its leaves are reported to contain ursolic acid (Nair and Rao, 1993). The major cyclopentenyl acid contained in its seed oil is chaulmoogric acid, with a small amount of hydnocarpic acid are also found (Cole, 1933). 3.13. Hydnocarpus venenata Gaertn The oil from Hydnocarpus venenata Gaertn, (name unresolved thus far) is known as “Kavetel” in Malabar and also as false chaulmoogra oil. Chemical constituents of its oil are reported to be similar to those of other Hydnocarpus oils, for example, Hydnocarpus kurzii (Brill, 1916). Gunasekera et al. studied the presence of triterpenes in this species together with other plants from the flacourtiaceae family and reported the presence of β-amyrin, betulinic acid, friedelin, and ursolic acid (Gunasekera et al., 1977). 3.14. Hydnocarpus pentadrus (Buch.-Ham.) Oken

Hydnocarpus oil is used in the treatment of leprosy and has shown beneficial effects. The antileprotic action of chaulmoogra oil may occur via the activation of host lipases to destroy all foreign lipids including both the chaulmoogra oil and the cell wall of Mycobacterium leprae. It is also postulated that once the cell wall is penetrated, normal immunologic processes destroy the bacterium. Another postulated mechanism includes chemotaxis, whereby chaulmoogra causes the accumulation of phagocytes in the proximity of the bacterium (Norton, 1994). It has also been reported that cyclopentenyl fatty acids may act by blocking the co-enzyme activity of biotin or that it may inhibit microbial biotin synthesis. Furthermore, it has been suggested that saturation of the double bonds reduces antimicrobial activity, indicating that the double bond in the cyclopentene ring is essential for activity (Jacobsen and Levy, 1973). Oommen et al. (1999) hypothesized that the double bond in cyclopentenyl fatty acids underlies its antioxidant effects and causes the pro-healing activity of chaulmoogra oil. The authors also postulated that because the long chain carboxylic

Authors are grateful to Dr. Kannan for his assistance with Siddha references and Dr. Ashok for suggestions during the preparation of this manuscript. References Anonymous, 1994. Vaidya Yoga Ratnavali (Formulary of Ayurvedic Medicines), fourth ed. The Indian Medical Practitioner’s Pharmacy & Stores (IMCOPS), Madras, pp. 261–468. Anonymous, 2000. Ayurvedic Formulary of India, second ed. Ministry of Health and Family Welfare p. 136 (Government of India. Part-I). Anonymous, 2008. first ed.Ayurvedic Pharmacopoeia of India, vol. VI. Ministry of Health and Family Welfare, pp. 285–287 (Government of India. Part-I). Anurakkun, N.J., Bhandari, M.R., Kawabata, J., 2007. α-Glucosidase inhibitors from Devil tree (Alstonia scholaris). Food Chemistry 103, 1319–1323. Bhattacharya, S., 2011. Seeds as herbal drugs. In: Preedy, R.V., Watson, R.R., Patel, V.B. (Eds.), Nuts and Seeds in Health and Disease Prevention. Elsevier Inc., USA, pp. 15–24. Bhandari, A.D., 1932. Alepol in the treatment of leprosy. Indian Medical Gazette 67, 244–246.

24

M.R. Sahoo et al. / Journal of Ethnopharmacology 154 (2014) 17–25

Blaise, P., Farines, M., Soulier, J., 1997. Identification of cyclopentenyl fatty acids by 1 H and 13C nuclear magnetic resonance. Journal of American Oil Chemical Society 74, 727–730. Brill, H.C., 1916. Hydnocarpus venenata Gaertner: false chaulmoogra. Philippine Journal of Science, Section A: Chemical Sciences 11, 75–80. Bueno Perez, L., Pan, L., Sass, E., Gupta, S.V., Lehman, A., Kinghorn, A.D., Lucas, D.M., 2013. Potentiating effect of the flavonolignan (-)-hydnocarpin in combination with vincristine in a sensitive and P-gp-expressing acute lymphoblastic leukemia cell line. Phytotherapy Research 27, 1735–1738. Chellappandian, M., Mutheeswaran, S., Pandikumar, P., Duraipandiyan, V., Ignacimuthu, S., 2012. Quantitative ethnobotany of traditional Siddha medical practitioners from Radhapuram taluk of Tirunelveli District, Tamil Nadu, India. Journal of Ethnopharmacology 143, 540–547. Chopra, R.N., Nayar, S.L., Chopra, I.C., 1996. Glossary of Indian Medicinal Plants, fourth ed. National Institute of Science Communication, New Delhi, India, pp. 136–137. Cole, H.I., 1933. Chemistry of leprosy drugs. International Journal of Leprosy 1, 159–194. Cole, H.I., Cardoso, H.T., 1939a. Analysis of chaulmoogra oils. IV. Hydnocarpus anthelmintica oil. V. Tarktogenous Kurzii (chaulmoogra) oil. Journal of American Chemical Society 61, 3442–3445. Cole, H.I., Cardoso, H.T., 1939b. Alepric, aleprylic, alprestic, and aleprolic acid, new, new homologs of chaulmoogric acid. Journal of American Chemical Society 61, 2349–2351. Cottle, W., 1879. Chaulmoogra oil in leprosy. The British Medical Journal June 28, 968–969. Duraipandiyan, V., Ignacimuthu, S., 2011. Antifungal activity of traditional medicinal plants from Tamil Nadu, India. Asian Pacific Journal of Tropical Biomedicine 1, S204–S215. Ezhil, V.S., Lingathurai, S., Gabriel, P.M., Ignacimuthu, S., 2010. Bioefficacy of neem oil formulation with Hydnocarpus alpina leaf extract against Spodoptera litura. International Journal of Current Research 3, 78–82. Fraunfelder, F.W., 2004. Ocular side effects from herbal medicines and nutritional supplements. American Journal of Ophthalmology 138, 639–647. Garcia, A., Bocanegra-Garcia, V., Palma-Nicolas, J.P., Rivera, G., 2012. Recent advances in antitubercular natural products. European Journal of Medicinal Chemistry 49, 1–23. Gunasekera, S.P., Sultanbawa, M.U.S., 1973. Six new triterpenoids from the bark of Hydnocarpus octandra (Flacourtiaceae). Chemistry & Industry 16, 790–791. Gunasekera, S.P., Sultanbawa, M.U.S., Balasubramaniam, S., 1973. Mangostin from the barks of Hydnocarpus species. Phytochemistry 12, 232–233. Gunasekera, S.P., Sultanbawa, M.U.S., 1977. Chemical investigation of Ceylonese plants. Part 23. Extractives of Hydnocarpus octandra Thaw. (Flacourtiaceae); isolation and characterization of six new triterpenoids. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry 4, 418–423. Gunasekera, S.P., Sultanbawa, M.U.S., Balasubramaniam, S., 1977. Chemical investigations of Ceylonese plants. Part 26. Triterpenes of some species of Flacourtiaceae. Phytochemistry 16, 788–789. Hui, L., Wenjian, Z., Wenli, M., Huimin, Z., Haofu, D., 2011. Chemical constituents from stem of Hydnocarpus hainanensis. Zhongguo Yaowu Huaxue Zazhi 21, 144–146. Jacobsen, P.L., Levy, L., 1973. Mechanism by which hydnocarpic acid inhibits Mycobacterial multiplication. Antimicrobial Agents and Chemotherapy 3, 373–379. Jadhav, A.N., Bhutani, K.K., 2005. Ayurveda and gynecological disorders. Journal of Ethnopharmacology 97, 151–159. Jaroszewski, J.W., Andersen, J.V., Billeskov, I., 1987. Plants as a source of chiral cyclopentenes: taraktophyllin and epivolkenin, new cyclopentenoid cyanohydrin glucosides from flacourtiaceae. Tetrahedron 43, 2349–2354. Jaroszewski, J.W., Bruun, D., Clausen, V., Cornett, C., 1988. Novel cyclopentenoid cyanohydrin rhamnoglucosides from flacourtiaceae. Planta Medica 54, 333–337. Jiangnan, Y., Yingshu, F., Ximing, X., Shanshan, T., Hongfei, L., Yan, Y., 2013. Extract, preparation method and application of antitumor effective component from Hydnocarpus hainanensis. Faming Zhuanli Shenqing, 20130410 (CN 103027931A). Junfeng, W., Yang, Y., Huimin, Z., Huimin, H., Yongxian, C., 2011. Chemical constituents from seeds of Hydnocarpus anthelminthica. Zhongcaoyao 42, 2394–2397. Khare, C.P., 2007a. Indian Medicinal Plants, an illustrated dictionary. Springer, New Delhi, p. 316. Khare, C.P., 2007b. Indian Medicinal Plants, an illustrated dictionary. Springer, New Delhi, p. 317. Kirtikar, K.R., Basu, B.D., 1984. Indian Medicinal Plants, second ed. Bishen Singh Mahendra Pal Singh. Dehradun, India. (vol. 1) pp. 224–227. Leclere, J., 1996. Use of Oil of Chaulmoogra in the Cosmetic and Pharmaceutical Domain, Particularly in Dermatology, for Harmonizing the Pigmentation of the Skin. US 5514712A. Lee, G.S., Choi, J.Y., Choi, Y.J., Yim, D.S., Kang, T.J., Cheong, J.H., 2010. The wound healing effect of Hydnocarpi semen extract on ulcer in diabetic mice. Biomolecules & Therapeutics 18, 329–335. Lee, G.S., Yim, D., Cheong, J.H., Kang, T.J., 2012a. The n-hexane, ethyl acetate, and butanol fractions from Hydnocarpi semen enhanced wound healing in a mice ulcer model. Immunopharmacology and Immunotoxicology 34, 968–974. Lee, G.S., Shim, H., Lee, K., Kim, S.H., Yim, D., Cheong, J.H., Kang, T.J., 2012b. The role of the ethylacetate fraction from Hydnocarpi Semen in acute inflammation in vitro model. Immune Network 12, 291–295.

Levy, L., 1973. The activity of chaulmoogra acids against Mycobacterium leprae. American Review of Respiratory Disease 111, 703–705. Li, X.J., Xie, Z., Wang, Y.H., Yan, Y.M., Pei, G., Zhou, X.J., 2012. Study on the chemical constituents from the leaf of Hydnocarpus hainanensis. Zhong Yao Cai 35, 1782–1784. Lima, J.A., Oliveira, A.S., de Miranda, A.L.P., Rezende, C.M., Pinto, A.C., 2005. Antiinflammatory and antinociceptive activities of an acid fraction of the seeds of Carpotroche brasiliensis (Raddi) (Flacourtiaceae). Brazilian Journal of Medical and Biological Research 38, 1095–1103. Lucas, D.S., 2008a. Study of Dravya-Materia Medica, Dravyaguna-Vijnana, first ed. Chaukhamba Visvabharati, Oriental, India, pp. 35–37. Lucas, D.S., 2008b. Study of Dravya-Materia Medica, Dravyaguna-Vijnana, first ed. Chaukhamba Visvabharati, Oriental, India p. 272. Mei, W., Li, H., Zhong, H., Zuo, W., Dai, H., 2011. Bioactive Constituents from Hydnocarpus hainanensis (Merr.) Sleum. Journal of Tropical and Subtropical Botany 4, 351–354. Mudaliar, K.S.M., 1936. Gunapadam-Siddha Materia Medica, medicinal plants division. Department of Indian Medicine and Homoeopathy vol. I, 583–584. Nair, K.A., Ramaiah, N., 1971. Leucopelargonidin from Hydnocarpus wightiana. Current Science 40, 187. Nair, S.P., Rao, M.J., 1993. Triterpenes from Hydnocarpus wightiana. Fitoterapia 64, 282–283. Norton, S.A., 1994. Useful plants of dermatology. I. Hydnocarpus and Chaulmoogra. Journal of the American Academy of Dermatology 31, 683–686. Oommen, S.T., Rao, M., Raju, C.V.N., 1999. Effect of oil of Hydnocarpus on wound healing. International Journal of Leprosy 67, 154–158. Panyaphu, K., On, T.V., Sirisa-ard, P., Srisa-nga, P., ChansaKaow, S., Nathakarnkitkul, S., 2011. Medicinal plants of the Mien (Yao) in Northern Thailand and their potential value in the primary healthcare of postpartum women. Journal of Ethnopharmacology 135, 226–237. Parthasarathy, M.R., Ranganathanan, K.R., Sharma, D.K., 1979. Carbon-13 NMR of flavonolignans from Hydnocarpus wightiana. Phytochemistry 18, 506–508. Pillai, S.N., Desai, M.V., 1975. Antihelminthic property of “Marotti” cake (Hydnocarpus laurifolia). Pesticides 9, 37–39. Power, F.B., Barrowcliff, M., 1905a. The Source and Constituent of Chaulmoogra Oil and Hydnocarpus Oil and. The Lancet, 982. Power, F.B., Barrowcliff, M., 1905b. XCI.-The constituents of the seeds of Hydnocarpus wightiana and of Hydnocarpus anthelmintica. Isolation of a homologue of chaulmoogric acid. Journal of the Chemical Society 87, 884–896. Prachya, S., Wiyakrutta, S., Sriubolmas, N., Ngamrojanavanich, N., Mahidol, C., Ruchirawat, S., Kittakoop, P., 2007. Cytotoxic mycoepoxydiene derivatives from an endophytic fungus Phomopsis sp. isolated from Hydnocarpus anthelminthicus. Planta Medica 73, 1418–1420. Rae, I.D., 2005. Granville perkins and leprosy chemotherapy in the Philippines. Bulletin for the History of Chemistry 30, 10–18. Rajith, N.P., Ramachandran, V.S., 2010. Ethnomedicines of Kurichyas, Kannur district, Western Ghats, Kerala. Indian Journal of Natural Products and Resources 1, 249–253. Ranganathan, K.R., Seshadri, T.R., 1974a. Constitution of isohydnocarpin isolated from the seed hulls of Hydnocarpus wightiana. Indian journal of chemistry 12, 888–889. Ranganathan, K.R., Seshadri, T.R., 1974b. Constitution of isohydnocarpin isolated from the seed hulls of Hydnocarpus wightiana. Indian Journal of Chemistry 12, 993. Reddy, J.K., Rao, B.S., Reddy, T.S., Priyanka, B., 2013. Antidiabetic activity of ethanolic extract of Hydnocarpus wightiana Blume using stz. induced diabetes in SD rats. IOSR Journal of Pharmacy 3, 29–40. Reddy, S.V., Tiwari, A.K., Kumar, U.S., Rao, R.J., Rao, J.M., 2005. Free radical scavenging, enzyme inhibitory constituents from antidiabetic Ayurvedic medicinal plant Hydnocarpus wightiana Blume. Phytotherapy Research 19, 277–281. Santos, I.D., West, A.P., 1929. Resins in the seed coats of Philippine chaulmoogra seeds (Hydnocarpus alcalae). Philippine Journal of Science 40, 485–492. Semon, H., 1935. Lupus erythematosus treated by Antileprol injections. Proceedings of the Royal Society of Medicine 29, 90–91. Sengupta, A., Gupta, J.K., Dutta, J., Ghosh, A., 1973. The component fatty acids of Chaulmoogra oil. Journal of the Science of Food and Agriculture 24, 669–674. Sharma, D.K., Hall, I.H., 1991. Hypolipidemic, anti-inflammatory and antineoplastic activity and cytotoxicity of flavonolignans isolated from Hydnocarpus wightiana seeds. Journal of Natural Products 54, 1298–1302. Sharma, D.K., Ranganathan, K.R., Parthasarathy, M.R., Bhushan, B., Seshadri, T.R., 1979. Flavonolignans from Hydnocarpus wightiana. Planta Medica 37, 79–83. Sharma, D.K., 2006. Pharmacological properties of flavonoids including flavonolignanas-Integration of petrocrops with drug development from plants. Journal of Scientific & Industrial Research 65, 477–484. Shi, H.M., Wen, J., Jia, C.Q., Jin, W., Zhang, X.F., Yao, Z.R., Tu, P.F., 2006. Two new phenolic glycosides from the barks of Hydnocarpus annamensis and their antiInflammatory and anti-Oxidation activities. Planta Medica 72, 948–950. Shi, H.M., Liu, Y., Jiang, Y., Sun, Z., Tu, P.F., Ling, X.M., 2007. Two neolignans isolated from Hydnocarpus annamensis studied by NMR spectroscopy. Acta Metallurgica Sinica 24, 77–83. Shukla, V.K.S., Paulose, M.M., 1979. The surface lipids of Hydnocarpus wightiana leaves. Chemistry and Physics of Lipids 25, 1–6. Shyam, K.M., Dhanalakshmi, P., Yamini, S.G., Sudhalakshmi, G., Gopalakrishnan, S., Manimaran, A., Sindhu, S., Sagadevan, E., Arumugam, P., 2013. Evaluation of phytochemical constituents and antioxidant activity of Indian medicinal plant

M.R. Sahoo et al. / Journal of Ethnopharmacology 154 (2014) 17–25

Hydnocarpus pentandra. International Journal of Pharmacy and Pharmaceutical Sciences 5, 453–458. Sini, H., Mohanan, P.V., Devi, K.S., 2005. Studies on the insecticidal activity, cytogenecity and metabolism of fatty acid rich fraction of Hydnocarpus laurifolia. Toxicological &. Environmental Chemistry 87, 91–98. Spener, F., Mangold, H.K., 1975. Straight-chain unsaturated fatty acids and cyclopentenyl fatty acids in leaf lipids of Caloncoba echinata and Hydnocarpus anthelminthica. Phytochemistry 14, 1369–1373. Stermitz, F.R., Lorenz, P., Tawara, J.N., Zenewicz, L.A., Lewis, K., 2000. Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 50 -methoxyhydnocarpin, a multidrug pump inhibitor. Proceedings National Academy of Science 97, 1433–1437. Tanaka, R., Matsunaga, S., Ishida, T., 1988. Revised structure of trichadenic acid B, a stem bark constituent of Phyllanthus flexuosus. Tetrahedron Letters 29, 4751–4754. Vaidya, B.G., 1968. Nigantu Adarsha, first ed. Chowkhambha Bharathi Academy, Varanasi, p. 107.

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Wang, J.F., Dai, H.Q., Wei, Y.L., Zhu, H.J., Yan, Y.M., Wang, Y.H., Long, C.L., Zhong, H.M., Zhang, L.X., Cheng, Y.X., 2010. Antituberculosis agents and an inhibitor of the para-aminobenzoic acid biosynthetic pathway from Hydnocarpus anthelminthica seeds. Chemistry & Biodiversity 7, 2046–2053. Wang, J.F., Yin, G.F., Zhou, X.Z., Suj, J., Li, Y., Zhong, H.M., Duan, G., Cheng, Y.X., 2011. Anti-inflammatory flavonolignans from Hydnocarpus anthelminthica seeds. Journal of Asian Natural Products Research 13, 80–83. Zahid, I.H., Bawazir, A.S., Naser, R., 2013. Plant based native therapy for skin problems in Aurngabad District (M.S.). Journal of Pharmacognosy and Phytochemistry 2, 241–244. Zhang, J.Y., Wang, H.Y., Yu, Q.T., Liu, B.U., Huang, Z.H., 1989. The structure of cyclopentenyl fatty acids in the seed oil of Flacourtiaceae species by GC–MS of their 4,4,-dimethyloxazoline derivatives. Journal of Oil Chemist Society 66, 242–246.