Psoralea Corylifolia L. (Buguchi) — Folklore to Modern Evidence: Review

Fitoterapia 90 (2013) 44–56

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Review Psoralea corylifolia L. (Buguchi) — Folklore to modern evidence: Review

Bhawna Chopra a,⁎, Ashwani Kumar Dhingra a, Kanaya Lal Dhar b a Guru Gobind Singh College of Pharmacy, Yamuna Nagar 135001, Haryana, India b Department of Pharmaceutical Sciences, Shoolini University, Solan 173212, Himachal Pradesh, India article info abstract

Article history: Psoralea corylifolia is an important medicinal plant which is used in several traditional Received 25 May 2012 medicines to cure various diseases. The plant extracts have been reported to possess Accepted in revised form 24 June 2013 antibacterial, antitumor, antioxidant, anti-inflammatory, antifungal and immunomodulatory Available online 4 July 2013 activity. A wide range of chemical compounds including psoralen, isopsoralen, bakuchiol, psoralidin, bakuchalcone, bavachinin, flavones, volatile oils, lipids etc. are found in different Keywords: parts of the plant. The present review is therefore, an effort to give a detailed survey of Psoralea corylifolia the literature on its botany, phytochemistry and ethnopharmacology along with special Buguchi emphasis given on pharmacological activities of plant P. corylifolia. Bakuchiol © 2013 Elsevier B.V. All rights reserved. Furanocoumarins Leuckoderma

Contents

1. Introduction ...... 45 2. Occurrence,botanicaldescriptionandethnopharmacology...... 45 3. Phytochemistry ...... 46 3.1. Whole plant ...... 46 3.2. Seeds ...... 46 3.3. Fruits ...... 47 3.4. Roots ...... 47 3.5. Other phytoconstituents ...... 47 4. Bioactivity ...... 47 4.1. Antimicrobial activity ...... 49 4.2. Estrogenic activity ...... 51 4.3. Antitumour activity ...... 51 4.4. Antioxidant ...... 51 4.5. Anticarcinogenic activity ...... 52 4.6. Immunomodulatory activity ...... 52 4.7. Anti-inﬂammatory activity ...... 52 4.8. Antimycobacterial activity ...... 52 4.9. Antiﬁlarial activity ...... 52 4.10. Antidepressant activity ...... 52 4.11. Protective effect ...... 52 4.12. Antidiabetic activity ...... 53 4.13. Hepatoprotective activity ...... 53

⁎ Corresponding author. Tel.: +91 9896151755. E-mail address: [email protected] (B. Chopra).

4.14. Antifungal and antidermaophytic activity ...... 53 4.15. Osteoblastic activity ...... 53 4.16. Antiashtmatic ...... 53 4.17. Antihypercholesterolemic ...... 53 4.18. Cytotoxity ...... 53 4.19. Antiulcer activity ...... 53 4.20. Hepatotoxicity ...... 54 4.21. Pesticidal activity ...... 54 4.22. Antiplatelet activity ...... 54 5. Clinical studies ...... 54 6. Conclusion ...... 54 Conﬂict of interest ...... 54 References ...... 54

1. Introduction India in Himalayas, Dehra Dun, Oudh, Bundelkhand, Bengal, Bombay, some valley in Bihar, Deccan, Karnataka and in various Among the largest families of flowering plants – Leguminosae, plains of India, especially semi-arid regions of Rajasthan and contains about 500 genera and more than 12,000 species, some of Eastern districts of Punjab, adjoining the Uttar Pradesh [6,24]. the genera contains biologically active compounds for example- This plant is also widely distributed in tropical and subtropical Species of Psoralea, Pongamia, Alhegi and Indigofera which are regions of the world, especially China and Southern Africa reported for the treatment of variety of ailments. A species of [9,10,20]. It grows up to 30–180 cm in height, requires warm Psoralea, indigenous to United States, commonly found in location and does not grow in shade. The plant prefers sandy, Southern States and west of the Alleghenies had attracted great loamy, clay soils and can also thrive in acid, neutral and alkaline attention as a medicine. The name of the genus is derived from the soils. The plant seeds are sown in March–April in lines, 30 cm Greek psoraleos,whichmeans“affected with the itch or with apart, at the rate of seven kilograms per hectare. Seeds get leprosy”. mature in November, and under proper care the plant may grow for 5–7years. Psoralea fruit is perennial, but cannot 2. Occurrence, botanical description and ethnopharmacology withstand frost and has small sized flowers which look like red clover. The plant fruit is odorless, but on chewing bears a bitter, Psoralea corylifolia (Leguminosae), is an erect annual herb unpleasant and acrid taste, and emits a pungent odor [25].The widely used in Ayurvedic medicine as well as in Traditional leaves are arranged in racemes, simple, incisodentate, broadly Chinese medicine almost throughout India [1]. The name of the elliptic and the five main nerves spring from the base of the genus is derived from the Greek word psoraleos,whichmeans leaf. The leaves are also clothed with white hairs on both “affected with the itch or with leprosy” [2]. In India, it is known the surfaces. The plant flowers during rains are bluish purple by its vernacular names, the most commonly used ones are or yellow in color, dense axillary with long-penduncled Bemchi, Bawchi, Babachi (Hindi), Aindavi, Avalguja, Bakuchi, heads in 10–30 flowered racemes. The plant pods are small Chanderlekha, Chanderprabha, Kushthahantri, Sitavari, Somaraji, (3.5–4.5 mm × 2.0–3.0 mm), flat closely pitted, ovoid-oblong, Vejani, Vakuchi, Sugandha kantak, Krishnaphala, Chandraraji, dark chocolate to almost black in color and mucronate in Asitatvacha, Kalameshi, Somavalli, Bakuci, Sasankarekha nature. Psoralea is a one seeded plant which is elongated and (Sanskrit), Babchi, Bavacha, Bawachi (Urdu), Babechi, Babchi, smooth in nature. The glabrous closely pitted seeds are Bavacha, Babichi, Bawchi (Gujarati), Bavachya, Bavachi Babachi, compressed, dark brown in color, non endospermic, oily and Bavanchi (Marathi), Bavanchalu, Bavanchi-vittulu, Bogi-vittulu, free of starch. The word seed has been used though botanically Karu-bogi, Kala-ginja (Telegu), Karpokarishi, Karpuva-arishi, these are indehiscent pods of the plant, the pericarp closely Karpuvanshi, Kaarboka-arisi, Karpogalarisi (Tamil), Somaraji, adhering to the seed [25]. Psoralea plant is warm by nature and Bavanchigida, Karbekhiga (Kanad), Karkokil, Karkokilari, therefore manifests various therapeutic actions on kidney and Kaurkoalari (Malyalam), Habucha (Assam), Bakuchi (Oriya), spleen meridians [26]. The germination percentage can be Barachi, Bavachi, Hakuch, Latakasturi, Kakuch, Bakuchi (Bengal), considerably increased by sowing the seeds during March– Babchi seeds, Psoralea seeds, Malay tea, Scurf-pea, Fountain April and leaving them in the heat of the soil. Seed coverings bush, and West Indian Satinwood (English). In the other when mechanically punctured or treatment of seeds with parts of world, Ku Tzu, Pu Ku Chih (China), Ravoli (Srilanka), concentrated sulfuric acid for 1 h before sowing had been Bakuchi (Nepalese), Loelab el abid, Mahalep (Arabic), Bawchan found effective in breaking the dormancy of the seeds and (German), Buckidana (Bangladesh), Bavanchi (Kanarese), increasing the germination percentage considerably. The Waghchi, Vabkuchi, Ba bakhi (Persian), and Bodi (Sinhalese) crop takes 7–8 months to reach the stage of maturity. As seeds [3–22]. P. corylifolia has also known by other biological names; continue to mature continuously, 4–5 pickings usually can be Cullen corylifolium, Cullen corylifolia, Lotodes corylifolia, Psoralea taken between the month of December and March. Clonal patersoniae and Trifolium unifolium [23]. propagation of P. corylifolia through shoot tip and auxiliary bud AspeciesofPsoralea, indigenous to United States, commonly culture is done. Survival rate on transfer to field was 95% [6]. found in Southern States and west of the Alleghenies had The plant has been widely used in Ayurvedic and Chinese attracted great attention as a medicine [2]. It is found as a medicine system as a cardiac tonic, vasodilator, pigmentor, common weed of winter season distributed throughout antitumor, antibacterial, cytotoxic and antihelmenthic [27–29]. 46 B. Chopra et al. / Fitoterapia 90 (2013) 44–56

The seeds of the plant possess greater medicinal value and are cough [41]. Powder of Bakuchi seeds when administered with used in indigenous system of medicine as laxative, aphrodisiac, the decoction of Bibhitaka (Terminalia bellirica bark) and anthelminitic, diuretic and diaphoretic in febrile conditions. Kaakodumbara (Ficus hispida) was good to treat vitiligo. For Oral administration and local external application of seeds in ringworm infections, one part of Tila (sesame seeds), mixed form of ointment or paste have been valued in Ayurveda and with Bakuchi was prescribed [15]. An external application of thus recommended in the treatment for leucoderma, leprosy, bakuchi with Haratala bhasma gives relief against leukoderma psoriasis, hair loss and inflammatory diseases of the skin such [43]. Various chemical and pharmacologic investigations had as eczema [1,25,30]. For instance, In leucoderma, the seed been carried out which [44–47] led to the isolation of the powder is mixed with haratala bhasma (yellow arsenic) in 4:1 bioactive components; proportion and mashed with the cow's urine to form the paste which is applied on the lesions of leucoderma where as in case (i) Psoralen: which stimulates the formation of melanin of scabies and ringworm infections, the bakuchi seed powder is and is used therapeutically for the treatment of mixed with buttermilk and applied externally. The seed oil is leucoderma [48]. – highly beneficial externally in numerous skin ailments and (ii) A monoterpene phenol, bakuchiol [49 51] and other recommended orally with beatlenut leaf in leprosy. The various related compounds [52]: possess potent antibacterial valuable adjuvants like Amalaki and khadira, can also be used [44], DNA polymerase inhibitory activity [53] and are with bakuchi to treat dermatoses. A mixture of bakuchi and useful in treatment of psoriasis [54]. karanja oil is commonly employed with Vaseline in chronic skin diseases [31]. Seeds are helpful in production of perfumes 3. Phytochemistry and are effective in bilious disorders; scorpion-sting and snake bite [4,5,8]. Roots of the plant are useful in dental caries; fruits The plant includes volatile oil, coumarins, flavones, mono- are laxative and aphrodisiac in nature. Leaves are good for the terpenoids phenols, chalcones, lipids, resins and stigmasteroids. treatment of diarrhea [25,29]. Apart from this, it is also used in Phytochemical study of P. corylifolia reveals that the nature and alopecia areata [42]. The ethanolic extract has been used in amount of phytochemical vary according to climatic condi- Japan as a food additive for the preservation of some processed tions. Researchers found that the seeds contain more active foods or pickles [32]. The seed cake left after removal of fixed constituent than any other parts of plant. The phytochemistry oil was rich in nitrogen (6.7%) and minerals (7.8%) and used as of different parts of plant is described below. feed or manure [9]. Essential oil of fruits shows irritant effects on the skin and mucous membrane and also distinct stimu- 3.1. Whole plant latory action on voluntary muscles in high concentrations [30,33,34]. The anthelmintic activity of P. corylifolia seeds is Psoralen, isopsoralen, corylifolin, corylin and psoralidin clinically proved on flatworms and roundworms [25].Another have been isolated from the petroleum ether and chloroform study evaluates a microemulsion gel-based system of babchi oil extract of the whole plant of P. corylifolia [55]. In 1996, Peng for the treatment of psoriasis which results in effective and et al. isolated a new compound Neo-psoralen from P. corylifolia. improved permeation of the drug through the skin along with The structures have been established on the basis of chemical increased patient compliance. Thus, microemulsion gels are evidence and spectroscopic methods [56]. proved to be potential vehicles for topical delivery of babchi oil as well as for psoralen [35]. Recently, Bakuchiol, ameroterpene 3.2. Seeds phenol of plant origin promising a new agent as a complement, enhances the effectiveness of currently marketed available anti Sen, Chatterjee and Datta carried out a thorough exam- - acne formulations. In addition, it also possesses excellent ination of seeds and conclude that it contains unsaponifiable safety profile and proves to be non-irritant, none sensitized and oil having the chemical formula C17H24O (boiling point 180– therefore, can be used throughout the day [36].Babuetal.,in 190 °C) whereas the alcoholic extract possesses a yellow acid

2011, conclude that P. corylifolia extracts have been used as an type substance with a chemical formula C40H45O10. More- ingredient for herbal compositions in combination with other over, a methyl glucoside containing four OH groups (melting medicinal herb extracts and use the same in the treatment of point of 105–127 °C) was also identified. In 1927, Chopra and psoriasis and various skin disorders [37]. In view of numerous Chaterjee state that the chief active principle of the seeds is activities possessed by the plant various Ayurvedic marketed an essential oil (0.05%), a fixed oil, a dark brown resin (8.6%) formulations are available such as Safuf Bars, Roughan Bars — and traces of alkaloidal content. Dymock stated that the seeds jaded, Zimad Kibrit, Bakuci bija curna and taila, Svitrakara contain 13.2% of extractive matter, albumin, sugar, 7.4% of vati, Khadirarista, Mahamanjisthadi kvatha, Algushadi yoga, ash, and traces of manganese [3,4]. From the straw colored Sarvangasundari gutika, Bhallatakawaleha, Dhatrayawaleha, essential oil the following constants were determined at 25 °C; Shashanglekhadileha, Maheshwara ghrita, Ayorajodi lepa, specific gravity 0.9072; refractive index 1.5025; solubility in Sashishekara vati, Brihatsomaraji taila, Mahatrinaka taila, water about 0.0197%; and the oil was also found to be optically Kandarpasara taila, Somaraji ghrita, and Bawchi teil, Bawchi active [8]. A monoterpene phenol, bakuchiol [55,58] and the churna [38–40]. Other suggested combinations are helpful two novel dimeric monoterpenoids, bisbakuchiols A and B, [59] to cure various ailments; Manjistha, Neem, and Kutki for have been isolated from the seeds of P. corylifolia. The isolated skin conditions; Nutmeg and Haritaki for chronic diarrhea bakuchiol has one asymmetric center and shown to possess with cold symptoms and loose, watery stool; Haritaki and (S)-chirality [60]. Banerjee and Gajanan (1983) report the Gokshura for urinary frequency; Ashwagandha and Bala biosynthesis of bakuchiol and examined it by using phenylal- for reproductive imbalances; and Pippali and Ashwagandha for anine and mevalonic acid as substrates. It has been B. Chopra et al. / Fitoterapia 90 (2013) 44–56 47 demonstrated that bakuchiol is derived from one phenylpropane seeds contains isobavachalcone, neobavaisoflavone and bavachin (with the loss of one carbon atom) and two isoprenoid (C5) units [83]. [61]. He also carried out biosynthesis of bakuchiol by utilizing cinnamic and p-coumaric acids and observes that the specific 3.3. Fruits 14 14 incorporation of L-[U- C] phenylalanine, [U- C] cinnamic acid and P-[2-14C] coumaric acid into bakuchiol and concludes that The fruits of P. corylifolia consist of a sticky oily pericarp the aromatic moiety along with two carbon atoms of the side (12% of the seed), a hard seed coat and kernel [9]. A new chain is biosynthetically derived via phenylpropane pathway isoflavone, corylinin, [84] (7,4′-dihydroxy-3′-[(E)-3,7-dimethyl- and not by alternate pathway [62]. 2,6-octadienyl] isoflavone) along with six known compounds, Bisbakuchiols A and B contain an unprecedented dimeric isopsoralen, psoralen, sophoracoumestan A, neobavaisoflavone, monoterpenoid skeleton in which two monoterpenes are daidzein and uracil, have been reported from the dried fruits of linked through a dioxane bridge. The ethereal seed extract P. corylifolia. The presence of three isoflavonoids—daidzein, showed the presence of Corylinal [63] as well as C-formylated genistein, and biochanin A in the fruit of P. corylifolia was chalcone and Isoneobavachalcone [64]. Psoralenol, [65] anew optimized by a high-performance liquid chromatographic isoflavone has been isolated from seeds of P. corylifolia. method [85]. (+)-Bakuchiol, a phenolic monoterpene was Psoralen and isopsoralen were separated from P. corylifolia isolated from hexane extract of fruits of plants [86].Yaoetal. by high-speed counter-current chromatography [66].Five determine the bakuchiol content in the fruits of P. corylifolia novel compounds, psoracorylifols A–E [67] as well as chalcone collected from the different areas. Determination of bakuchiol and Bavachromanol [68] have been reported from seed samples. was carried out by using gas chromatography employing The structure of psoracorylifols A–E including their absolute with FID detector having the stationary phase SE-30 with an configurations was confirmed on the basis of spectral methods injection temperature of 250 °C, and column temperature of and by a single crystal X-ray diffraction. Psoracorylifols D and E 200 °C. The linear range was 0.24–2.4 μg, average recovery represent an unprecedented carbon skeleton [67]. Three new was 98.82% and RSD 1.58%. The overall content range of phenylflavonoids, namely Corylifols A–C [69] and bavachalcone eleven samples of fruit was 1.2–7.1%; eight of them were [70] were isolated from the seeds of P. corylifolia. Bakuchicin below 3%, two of them reach 2–3% and only one reached [71] was isolated from the seeds of P. corylifolia.The 7.1% [88]. supercritical extract (9.1%) showed the presence of psoralen and isopsoralen with combined yield of 2.5 mg/g of dry 3.4. Roots seeds, purified by high-speed counter-current chromatography [72]. Four flavonoids bavachinin, bavachin, isobavachin and Chintalwar et al. in 1992 reported the insect antifeedants isobavachalcone were isolated from the seeds of P. corylifolia from the roots of P. corylifolia. Petroleum ether extract of (Figs. 1, 2 and 3) [73]. Psoralenoside and Isopsoralenoside roots of P. corylifolia caused feeding inhibition to the 48th [74], two new benzofuran glycosides were also isolated. instar Spodoptera litura larvae. The furanocoumarins psoralen Bavachinin—a flavanone isolated from seeds of P. corylifolia and isopsoralen were characterized as active principle [89]. has been reported [75]. The insoluble portion of the ethanol extract of P. corylifolia yields neobavachalcone, bavachromene 3.5. Other phytoconstituents and 7-methyl bavachin [76]. A new compound, cyclobakuchiol C [77] was isolated from the non-polar fraction of the seeds of Corylidin, 8-methoxy psoralen, psoralidin-2′,3′-oxide, P. corylifolia. A new flavonol glycoside; 3,5,3′,4′-tetrahydroxy- corylin, glucose, corylifolinin, neobavaisoflavone, stigmasterol, 7-methoxyflavone-3′-O-alpha-L-xylopyranosyl(1–N3)-O-alpha- daucosterol, triacontane, β-sitosterol-D-glucoside and saponins L-arabinopyranosyl(1–N4)-O-beta-D-galacto pyranoside has were isolated from the P. corylifolia [91]. In 1989, Zaka et al. been isolated from the methanol soluble fraction of the reported the presence of lipid and fatty acid composition of defatted seeds of P. corylifolia [78]. Coumestans-3,5′-dihydroxy- P. corylifolia. The lipid classes identified were triacylglycerols, 6′,6′-dimethyldihydropyrano(2′,3′:8,9)coumestan, 3-hydroxy- free fatty acids, diacylglycerols, monoacylglycerols, free fatty 5′-(1-hydroxy-1-methylethyl) 4′,5′-dihydrofuro(2′,3′:8,9) acids, hydrocarbons, wax esters and polar lipids. The purified coumestan, sophoracoumestan A have been isolated and crude lipids of P. corylifolia seed were analyzed by thin layer identified from the seeds of P. corylifolia [79]. Two new and gas chromatography. With the exception of polar lipids, metabolites psoralester and psorachromene have been isolated C18:1 was the major component. The di- and mono-acyl and characterized by detailed spectroscopic studies. On the glycerol fractions contained large amounts of C14:0 and C18:0 basis of study, it was characterized that psoralester is a long and the hydrocarbons — wax ester fractions were rich in C22:0. chain ester possessing a ten membered lactone moiety and The polar lipids contained high levels of C18:3 and low levels psorachromene was found to be trans isomer of bavachromene of C18:1 compared to other fractions. Unidentified long chain [80]. Another study by N.A. Khatune et al. isolated a new fatty acids were present in significant amount in all fractions coumestan derivative 6-(-3-methylbut-2-enyl)-6N-7-dihydroxy- [92]. Volatile oil includes limonene, terpin-4-ol, linalool, coumestan from the chloroform extract of the seeds of P. corylifolia β-caryophyllene and geranyl acetate [93]. [81]. Lin and Kuo isolates two new benzofuran derivatives, corylifonol and isocorylifonol along with astragalin, p-hydroxy 4. Bioactivity benzoic acid and four other known constituents from the seed extract of P. corylifolia. The structures of new isolated derivatives P. corylifolia has been found to possess significant anti- were confirmed by spectral evidence and chemical transformation bacterial, antifungal, antioxidant, antitumour, estrogenic and [82]. The bioassay directed fractionation of methanol extract of immunomodulatory properties. 48 B. Chopra et al. / Fitoterapia 90 (2013) 44–56

Fig. 1. Flavonoids from the P. corylifolia plant. B. Chopra et al. / Fitoterapia 90 (2013) 44–56 49

Fig. 2. Chalcones form P. corylifolia plant.

4.1. Antimicrobial activity 0.009–0.073 mM [69]. In another study, P. corylifolia seed extract obtained in ether showed antimicrobial activity against Ethanolic seed extract of P. corylifolia showed remarkable various strains of bacteria in vitro. The antimicrobial activity growth inhibitory activity against Staphylococcus aureus ATCC was due to the presence of monoterpene phenol, bakuchiol 25923 and S. epidermidis ATCC 12228 in vitro testing due to the responsible for the inhibition of cell growth of Streptococcus presence of bakuchiol previously reported as an antibacterial mutans in a concentration dependent manner, and the growth agent [58]. The extract was also active against different of S. mutans was completely prevented by 20 μg/ml of microbes even after the removal of bakuchiol and some fatty bakuchiol. Bakuchiol also showed temperature dependent acids inferring that some other components were responsible bactericidal effect on S. mutans against all bacteria with MICs for the activity. In view of that, ethanolic extract was par- of 1–4 μg/ml and the sterilizing concentration for 15 min titioned with petroleum ether and ethyl acetate and was ranging from 5 to 20 μg/ml. Furthermore, bakuchiol was also evaluated for antibacterial activity. Both the fractions showed effective against adherent cells of S. mutans in water-insoluble significant activity due to the presence of bakuchiol in glucan in the presence of sucrose and inhibited the reduc- petroleum ether extract and phenylflavonoid compounds — tion of pH in the broth. Thus, bakuchiol would be a useful Corylifols A–C in ethyl acetate extract at the level of MIC's compound for the development of antibacterial agents against 50 B. Chopra et al. / Fitoterapia 90 (2013) 44–56

Fig. 3. Other phytoconstituents of P. corylifolia plant. B. Chopra et al. / Fitoterapia 90 (2013) 44–56 51 oral pathogens and has great potential for use in food additives ascitic tumor growth and stimulates natural killer cell activity, and mouthwash for preventing and treating dental caries [94]. antibody-dependent cellular cytotoxicity, antibody-forming Seeds of P. corylifolia contain psoralidin, bakuchicin, psoralen cells and the antibody complement-mediated cytotoxicity and angelicin which show significant antibacterial activities during tumor development [99]. The coumarins, psoralen against Gram positive and negative bacteria using Kanamycin and isopsoralen were found to be present in the chloroform as a standard drug. Psoralidin showed stronger activity against extract of P. corylifolia L. with the yields of 0.048% and 0.11% Gram (−) Shigella sonnei and S. flexneri while psoralen and and were found to exhibit antitumor activity against the angelicin exhibited the highest activity against Gram (+) proliferation of BGC-823 cancer cell in vitro. These com- S. aureus [71]. pounds showed IC50 value — 5.82 μg/ml and 148.8 μg/ml In another study, methanolic extracts of Solanum trilobatum, for psoralen and isopsoralen respectively [100].Ethanolic Andrographis paniculata and P. corylifoliai herbs were bio- extracts of P. corylifolia showed their pharmacological potential encapsulated in Artemia and fed to Penaeus monodon post larvae as antineoplastic agents against the HEp-2 cell line and A549 PL 1–25, medium inoculated with Pseudomonas aeruginosa, cell lines with an IC50 value of 22 μg/ml against HEp-2 cell lines S. aureus, Salmonella typhi and Vibrio species helped to increase and 68 μg/ml against A549 cells. The 3.1-fold difference in IC survival and specific growth rate and reduced bacterial load in values may be due to cell-turnover rates; HEp-2 cells double the P. monodon culture system. Among the three herbal extracts, every 3.5 days compared with one day for A549 cells. Sung et P. corylifolia enriched Artemia fed post larvae showed higher al. studied and conclude that P. corylifolia contains constituents survival (N50%), growth rate (11.5 averaged) and low bacterial which were DNA polymerase and topoisomerase II inhibitors, load (1.12 × 105 cfu/g) [95]. which inhibit DNA replication enzymes. Studies carried out by Wang in 1991 conclude that Isobavachalcone from P. corylifolia 4.2. Estrogenic activity is antineoplastic against bone-muscle, lung and intestinal tumor at a dosage of 15–25 g/day in China [101]. The estrogenic potential of P. corylifolia supports to be used The methanolic seed extract of P. corylifolia had potential to for the treatment of menopausal symptoms ras well as for inhibit hypoxia-inducible factor-1 (HIF-1) activation induced hormone replacement therapy. The estrogenic activity was by hypoxia in a HIF-1-mediated reporter gene assay in AGS evaluated and has been assessed by using a recombinant yeast human gastric cancer cells. (S)-bakuchiol was responsible in system with both a human estrogen receptor expression inhibiting the hypoxic activation of HIF-1 with an IC50 value of plasmid and a reporter plasmid. On examination, it was 6.1 μM [59]. Research investigated that seed extract obtained concluded that the ethanolic fruit extracts of P. corylifolia from P. corylifolia has been used for the treatment of various showed relative potency with EC50 at 120.6 μg/ml comparable inflammatory diseases of the skin. Along with this, it also with 17β-estradiol, used as the positive control, 0.205 ± decreases the mitochondrial complex I and proteasome 0.025 ng/ml (RP = 100) [96]. activities and oxidative stress [102]. Ryu et al. reported the antitumour activity of P. corylifolia. The activity oriented 4.3. Antitumour activity fractionation of P. corylifolia led to an isolation of a (+)-bakuchiol as an active principle of its antitumour property in vitro The P. corylifolia plant extract has a significant antitumour [103]. A study was carried out to investigate the cancer activity. The methanol extract and the isolated bioactive chemopreventive effect of seed soluble fractions P. corylifolia. compounds of P. corylifolia have been evaluated for antican- The study concludes that ethyl acetate soluble fraction of cer activity by the cytotoxicity on KB, KBv200, K562, and methanolic extract and isolated psoralidin was found to be K562/ADM cancer cells with MTT assay. On the fractionation inducing the quinone reductase against mouse Hepa 1c1c7 of the extract, Fraction IV significantly inhibits the growth of cells. This quinone reductase is a protective Phase II enzyme cancer cells in a dose-dependent manner with IC50 values which blocks the generation of mutagenic quinone metabolites 21.6, 24.4, 10.0 and 26.9 respectively. In the same study, and carcinogens [90]. In 2011, psoralen isolated from seeds isolated compounds, psoralen and isopsoralen from fraction of P. corylifolia was found to have potential capability of IV also exhibit a dose-dependent anticancer activity with the inhibiting the initiation and/or promotion of carcinogenesis

IC50 values of 88.1, 86.6, 24.4 and 62.6 for psoralen and 61.9, by inducing quinine reductase activity, inhibiting 12-O- 49.4, 49.6 and 72.0, for isopsoralen respectively. The study tetradecanoylphorbol 13-acetate (TPA) induced orthinine concluded that the apoptosis of tumor cell significantly decarboxylase activity and tumor promotion in mouse epider- increased after the treatment with psoralen and isopsoralen mal JB 6 cells [57]. and the induction of apoptotic activity was confirmed by flow cytometry after staining with Annexin V/PI [97]. Ketaki 4.4. Antioxidant Bapat et. al. studied that radiolabeled bakuchiol with 125I exhibits enhanced cytotoxicity in in-vitro uptake using LS-A There is considerable interest in the more potent antioxi- (lymphosarcoma) and barcl-95 (radiation-induced thymic dant compounds to treat diseases involving oxidative stress. lymphoma) ascitic and solid tumor cells of murine origin. P. corylifolia L. fruit extract showed higher antioxidant activity In both LS-A and barcl-95, 125I-bakuchiol showed signif- in the 2,2V-azinobis[3-ethylbenzothiazoline-6-sulfonate] (ABTS) icant uptake and the viability studies showed that the assay [104]. The powder, chloroform and ether extracts of radioiodinatedcompoundshowedgreatercytotoxiceffect P. corylifolia L. are found to possess strong antioxidant effects in than bakuchiol [98]. lard at 100 °C by using the oxidative stability instrument (OSI). In another study, interperatonial administration of ethanolic The compounds bakuchiol, psoralen, isopsoralen, corylifolin, seed extract (100 and 200 mg/kg) of P. corylifolia inhibits EAC corylin and psoralidin have been detected in the extracts and 52 B. Chopra et al. / Fitoterapia 90 (2013) 44–56 also have been investigated individually for their antioxidant 4.9. Antiﬁlarial activity activities in comparison with butylated hydroxytoluene (BHT) and a-tocopherol by the OSI at 100 °C. Bakuchiol, corylifolin, The aqueous and alcohol extracts of the leaves and seeds corylin and psoralidin showed strong antioxidant activities, of P. corylifolia showed significant antifilarial activity against and especially psoralidin showed stronger antioxidant proper- Setaria cervi. The extracts cause the inhibition of spontane- ty than BHT, whereas psoralen and isopsoralen do not possess ous movements of the whole worm and the nerve muscle antioxidant activities at 0.02% and 0.04% levels [55]. preparation of S. cervi which was characterized by initial, The chloroform fraction of the ethanol extract of P. corylifolia short lasting small increase in tone of contractions followed seeds was found to possess broad antioxidative activities in rat by paralysis. Moreover, alcohol extracts of both leaves (LC50 liver microsomes and mitochondria by inhibiting NADPH-, and LC90 being 15 and 25 ng/ml) and seeds (LC50 and LC90 ascorbate-, t-BuOOH- and CCl4-induced lipid peroxidation in being 12 and 18 ng/ml) caused death of microfilariae in vitro microsomes and also prevents NADH-dependent and ascorbate- respectively [111]. induced mitochondrial lipid peroxidation [73].Inanotherstudy, it was concluded that phenolic compounds in P. corylifolia have 4.10. Antidepressant activity potent antioxidant activity against microsomes and protective against oxidative haemolysis in human red blood cells, and in Chronic mild stress [112] and Forced swimming model various biological membranes and mitochondrial functions [113] of depression in mice have been utilized to determine the [73,105]. antidepressant potential of P. corylifolia seeds. The activity was due to the presence of furocoumarins in both the models but it was found quite interesting that the results were opposite 4.5. Anticarcinogenic activity in each case. In chronic mild stress [112] furocoumarins result in reversal of biochemical changes produced by mice whereas Seeds of the P. corylifolia possess significant anti- in case of forced swimming test [113], it reduces the immobility carcinogenic activity. Topical application of active fraction time significantly at the doses from 7.5 to 100 mg/kg in (100 mg: kg of body weight) inhibited the growth and delayed comparison with amitriptyline (10 and 20 mg/kg)and fluoxe- the onset of papilloma formation in mice, initiated with 7, tine (13 mg/kg) respectively. Total furocoumarins showed 12-dimethyl benz(a) anthracene and promoted using croton maximum effects at 30 mg/kg, when the efficacy appeared to oil. Moreover, its oral administration significantly inhibits the be more than that of amitriptyline and fluoxetine. Thus, by growth of subcutaneously injected 20-methylcholanthrene mechanism, furocoumarins significantly inhibit monoamine (MCA)-induced soft tissue fibrosarcomas. However, gas chro- oxi-dase A and B activity in the brain and liver as well as liver matography analysis showed the presence of mixture of superoxide dismutase activity and malondialdehyde level glycerides of fatty acids [106]. with dose-dependent relationship. Thus, it was concluded that furocoumarins possess potent and rapid antidepressant properties mediated via monoamino oxidase, the hypothalamic– 4.6. Immunomodulatory activity pituitary–adrenal axis and by oxidative systems in a dose- dependent manner, it proves to be a potentially valuable drug Seed extract of P. corylifolia obtained in alcohol had found for the treatment of depression in the elderly [112,113]. to stimulate the immune system in mice by increasing cell- Psoralidin isolated from P. corylifolia seeds was found to mediated and humoral immune responses [99]. have antidepressant effect in ICR strain of male mice investi- In another study, the active principle of P. corylifolia seed gated in the forced swimming test. This study reveals that there extract elicits the immunological function [107,108]. is marked reduction in immobility time after oral administration for 1 h or 3 consecutive days without affecting the locomotor activity. In addition, psoralidin significantly 4.7. Anti-inﬂammatory activity increased 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels in various brain regions, as well as, changed The aqueous extract of P. corylifolia seeds contains dopamine levels in striatum in mice exposed to forced Bakuchiol which may be used for the development of swimming test. Psoralidin also ameliorated the elevations in anti-inflammatory diseases related to iNOS over-expression serum corticotropin-releasing factor, adrenal corticotropin- as bakuchiol inhibits NO production in RAW 264.7 macro- releasing hormone and corticosterone concentrations induced phages activated with interferon-G and lipopolysaccharide by swimming stress in mice. The potent antidepressant activity through the inactivation of nuclear transcription factor-kB of psoralidin was mediated via monoamine neurotransmitter [109]. and the hypothalamic–pituitary–adrenal axis systems [114].

4.11. Protective effect 4.8. Antimycobacterial activity (S)-bakuchiol from the seeds of P. corylifolia showed In vitro screening of crude methanolic seed extract of protective effect on rat liver injury in vitro and in vivo, P. corylifolia showed significant antimycobacterial activity induced either by Carbon tetrachloride or D-galactosamine. against two model species of mycobacteria, Mycobacterium Treatment with bakuchiol inhibits lipid peroxidation and aurum and Mycobacterium smegmatis at MIC of 62.5 μg/ml intracellular glutathione depletion significantly in hepatocytes [110]. induced by tert-butyl hydroperoxide, carbon tetrachloride or B. Chopra et al. / Fitoterapia 90 (2013) 44–56 53

D-galactosamine. In addition, it also reduced the levels of asthmatics in the convalescent stage to prevent emphysema aspartate transaminase and alanine transaminase in serum at [122]. 25 or 50 mg/kg, p.o. [115]. 4.17. Antihypercholesterolemic 4.12. Antidiabetic activity Acyl-coenzyme A: cholesterol acyltransferase (ACAT) is Ethylacetate seed extract of P. corylifolia afforded two responsible for intracellular esterification of free cholesterol compounds, psoralidin and bakuchiol which were found to with fatty acids and plays an important role in cholesterol inhibit the protein tyrosine phosphatase1B level with IC50 and hepatic production of lipoprotein. Ethanol extract of − μ − μ values of 9.4 +/ 0.5 M and 20.8 +/ 1.9 M, respectively P. corylifolia showed a significant inhibition of acyl-coenzyme in a dose dependent manner [116]. A: cholesterol acyltransferase (ACAT). The bioactive activity guided fraction of extract contains two prenylated flavonoids; 4.13. Hepatoprotective activity bavachin and isobavachalcone. The IC50 values were 86.0 μM (bavachin) and 48.0 μM (isobavachalcone) in ACAT assay using One hepatoprotective compound, bakuchiol, along with rat liver microsome [87]. two moderately active compounds, bakuchicin and psoralen, were isolated from Bioassay-guided fractionation of the water extract of the seeds of P. corylifolia. The isolated compounds 4.18. Cytotoxity proved to be hepatoprotective with EC50 values 1.0, 47.0, and 50.0 μg/ml, respectively on tacrine-induced cytotoxicity in Seeds of the P. corylifolia possess cytotoxic activity against human liver-derived Hep G2 cells using silymarin as a positive SNU-1 and SNU-16 stomach carcinoma cell lines having IC50 values of 53 and 203 μg/ml due to the presence of a cytotoxic control with EC50 value of 5.0 μg/ml [117]. coumestan derivative, psoralidin [123]. In another study, 4.14. Antifungal and antidermaophytic activity psoralidin was found to be a cytotoxic against the HT-29 (colon) and MCF-7 (breast) human cancer cell lines with the μ P. corylifolia furnished an antifungal protein, Psc-AFP of IC50 values of 0.3 and 0.4 g/ml. On the other hand, in the molecular mass-18 kDa having partial N-terminal sequence same study, angelicin was found to be marginally cytotoxic where as psoralen was found to be inactive against the A541 of NH2-EWEPVQNGGSSYYMVPRIWA determined by Edman degradation which displayed homology with plant trypsin (lung) and HepG2 (liver hepatoma) cancer cell lines [124]. inhibitors. It is interesting to suggest that Psc-AFP had The ethanolic extract of P. corylifolia was found to be defensive role against Alternari brassicae, Aspergillus niger, cytotoxic against L929-cells in cell culture. The isolated Fusarium oxysporum and Rhizoctonia cerealis by inhibiting compound bakuchiol was responsible for the activity. The the mycelial growth [118]. Methanolic seed extract (250 μg/ml) structure of the bakuchiol was confirmed by means of of P. corylifolia showed to be antifungal as antidermatophytic spectral evidence. The cytotoxic activity was observed in against Trichophyton, Epidermophyton and Microsporum species. short time and was irreversible in nature. Thus, overall study The activity was due to the presence of flavonoid compound, concludes that the bakuchiol was being cytotoxic in nature 4-methoxy flavone. MIC of the active compound along with [33]. (+)-Bakuchiol isolated from the hexane extract of fruit standard miconazole as a standard drug was carried out using exhibits mild cytotoxicity against five kinds of human cell tube dilution technique [119]. lines. The activity is due to cell injury or hemolytic activity of bakuchiol [86]. The synthesized 2,3-epoxide derivative of 4.15. Osteoblastic activity bakuchiol showed similar activity as bakuchiol, whereas the oxidation derivatives including acetyl derivative showed P. corylifolia L. fruit extracts exhibited osteoblastic prolifera- decreased activity [103]. tion stimulating activity in UMR106 cell line cultured in vitro. An Further, Iwamura et al. synthesized new analogs of – analysis of extract indicates the presence of two flavonoids, bakuchiol. In this study, the chemical structure cytotoxic corylin and bavachin which were found to be active against activity relationship of bakuchiol and its analogs was investi- osteoporosis [120]. Another research effort shows that gated and it was proved that an alkyl group was necessary for non-polar crude fractions (Ho-0 and Ho-1) of acetone cytotoxic activity whereas double bonds in the unsaturated extract was used as a remedy for bone fracture, osteoma- hydro-carbon group exert little influence on the activity. lacia, osteoporosis, and related conditions. Research also In comparison, it was concluded that the bakuchiol was the investigated that administration of Ho-1 results in signifi- strongest cytotoxic agent among its analogs examined [34]. cant elevation of the serum inorganic phosphorus level as well as promotes bone calcification. In addition, administra- 4.19. Antiulcer activity tion of 30 mg/kg of Ho-1 also reduces osteoid volume in rachitic rats and improves the condition of hyperosteoidosis Psoracorylifols A–E, isolated from seeds of P. corylifolia whereas Ho-0 promotes bone calcification only [121]. show significant antiulcer activity against two strains of Helicobacter pylori (SS1 and ATCC 43504) in vitro. Moreover, 4.16. Antiashtmatic psoracorylifols A–E were found to be 5–10 times stronger (MIC of 12.5–25 mg/mL) than metronidazole (MIC of 128 mg/mL), An analysis of Chinese herbal decoction of six herbs along which can be used as critical ingredients for combination with 15 g of P. corylifolia indicates prompt treatment for therapies of H. pylori (ATCC 43504) infection [67]. 54 B. Chopra et al. / Fitoterapia 90 (2013) 44–56

4.20. Hepatotoxicity from various parts have medicinal applications from time immemorial, modern drugs can be developed after extensive The potential hepatotoxicity of herbal remedies is usually investigation of its bioactivity, mechanism of action, phar- ignored in daily life but it was claimed that the use of macotherapeutics, toxicity and after proper standardization P. corylifolia seeds in amounts over 10 times the usual dose in and clinical trials. Psoralea, is the good source of various a postmenopausal woman results in an acute cholestatic types of compounds having diverse chemical structure. hepatitis [125]. In fact, time has come to make good use of century-old knowledge on buguchi and its bioactive constituents through 4.21. Pesticidal activity modern approaches of drug development. For the last few years, there has been an increasing trend and awareness in The chloroform extract of the seeds of P. corylifolia contains the research of Psoralea. Quite a significant amount of research a new coumestan derivative 6-(-3-methylbut-2-enyl)-6N- has already been carried out during the past few decades 7-dihydroxycoumestan which was found to have good pesti- in exploring the chemistry and medicinal importance of cidal effect against both adults and different instars of Tribolium seed part of buguchi. Several therapeutically and industri- casteneum Hebrst [81]. ally useful preparations and compounds have also been marketed (Maheshwara ghrita, Ayorajodi lepa, Sashishekara 4.22. Antiplatelet activity vati, Brihatsomaraji taila), which generates enough encourage- ment among the scientists in exploring more information Chen et al. (1996) reported that the methanolic extract of about this medicinal plant. An extensive research and devel- seeds of P. corylifolia was found to inhibit the aggregation of opment work should be undertaken on other parts of Psoralea rabbit platelets induced by arachdonic acid, collagen and platelet and its products for their better economic and therapeutic activating factor. On fractionation, three flavonoids were utilization. isolated; out of which isobavachalcone and neobavaisoflavone inhibit platelet aggregation [83]. Conﬂict of interest

5. Clinical studies None.

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