Dioscorea Plants: a Genus Rich in Vital Nutra- Pharmaceuticals-A Review

Iranian Journal of Pharmaceutical Research (2019), 18 (Special Issue): 68-89 DOI: 10.22037/ijpr.2019.112501.13795 Received: September 2019 Accepted: December 2019 Review Paper Dioscorea Plants: A Genus Rich in Vital Nutra- pharmaceuticals-A Review

Bahare Salehia, Bilge Senerb, Mehtap Kilicb, Javad Sharifi-Radc*, Rabia Nazd, Zubaida Yousafe, Fhatuwani Nixwell Mudauf, Patrick Valere Tsouh Fokoug, Shahira M. Ezzath, i*, Mahitab H. El Bishbishyh, Yasaman Taherij, k*, Giuseppe Lucariellol, Alessandra Durazzom, Massimo Lucarinim, Hafiz Ansar Rasul Sulerian and Antonello Santinil*

aStudent Research Committee, School of Medicine, Bam University of Medical Sciences, Bam, Iran. bDepartment of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey. cZabol Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol, Iran. dDepartment of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan. eDepartment of Botany, Lahore College for Women University, Jail Road Lahore, Pakistan. fDepartment of Agriculture and Animal Health, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X6, Florida, 1710, South Africa. gDepartment of Biochemistry, Faculty of Science, University of Yaounde 1, Yaounde Po.Box 812, Cameroon. hDepartment of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo 11562, Egypt. iDepartment of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 12611 Cairo, Egypt. jPhytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. kDepartment of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. lDepartment of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy. mCREA-Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Rome, Italy. nDepartment of Agriculture and Food Systems, The University of Melbourne, Melbourne 3010, Australia.

Abstract

Dioscorea species, known as “Yams,” belong to family Dioscoreaceae. This genus consists of more than 600 species distributed from Africa, Asia, the Caribbean’s South America, and the South Pacific islands. Their organoleptic properties make them the most widely used carbohydrate food and dietary supplements. The underground and/or aerial tubers represent valuable sources of proteins, fats, and vitamins for millions of people in West Africa. This review gives a shot of secondary metabolites of Dioscorea plants, including steroids, clerodane diterpenes, quinones, cyanidins, phenolics, diarylheptanoids, and nitrogen-containing compounds. This review collected the evidence on biological properties of description Dioscorea, including in-vitro and in-vivo studies. Dioscorea species contain promising bioactive molecules i.e. diosgenin that support their different biological properties, including antioxidant, hypoglycaemic, hypolipidemic, anti- antimicrobial, inflammatory, antiproliferative, androgenic, estrogenic, and contraceptive drugs. Indeed, besides its nutrient values, Dioscorea is a potential source of bioactive substances of interest in the prevention/ treatment of several diseases, and thus represents a great challenge in developing countries. However, ethnomedicinal potential should be validated and further researches on pharmacological properties and phytochemical composition should be carried out. Particularly, doing some studies to convert the preclinical results to clinical efficacy should be guaranteed.

Keywords: Dioscorea; Food plant; Traditional use; Phytochemistry; Pharmacological activities.

* Corresponding author: E-mail: [email protected]; [email protected]; [email protected]; [email protected] Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89

Introduction tubers of Dioscorea species and possible medicinal usage. The most common Dioscorea belongs to the family secondary metabolites are saponins, and more Dioscoreaceae, sub-family Dioscoreoideae, than 100 steroidal saponins (based on aglycon consisting of 600 species. Dioscorea species part as stigmastanol, furostanol, spirostanol, are native to the old-world including high cholestanol, ergostanol, and pregnanol temperatures tropics and subtropic regions glycosides (Figure 1)) were isolated from of the world. The major part of species occur various Dioscorea species. Besides these in West Africa, Southern Asia, and Tropical steroids, clerodane diterpenes, phenolics, America: they are herbaceous climbers with cyanidins, quinones, diarylheptanoids, and rhizome or tubers Dioscorea species and, being nitrogen-containing compounds in the tubers usedin the formulation of pharmaceutical of Dioscorea species were quantified (4). products, have a high medicinal, industrial Steroidal saponins mainly consist of furostane, and commercial importance (1). Indeed, a pentacyclic ring system with a sixth open Dioscorea species account for the most ring; spirostane, a hexacyclic ring system; important dietary supplements ingredients and pregnane, a tetracyclic ring system. The used in cosmetics and pharmaceutical sugar part is mainly composed of glucose industries. It has also been commonly used by and rhamnose in various proportions and local people, mostly those who are engaged linkages. Steroidal saponins are glycosides in the trade of medical plants worldwide. consisting of an aglycone (diosgenin) and Indeed, tubers of different Dioscorea species several glycosyl moieties. The most common are used as a cure for different diseases and sugars encountered in saponins are pentoses ailments (cough, cold, stomach ache, leprosy, (arabinose, xylose, etc.), hexoses (glucose, burns, fungal infections, dysentery, skin galactose, etc.) and 6-deoxyhexose (rhamnose, diseases, rheumatism, arthritis, etc.) in several etc.). The saponins of this plant species are formulations, and even for birth control (1). both water-soluble and water-insoluble steroid It is well known the potential of this plant saponins. Dioscorea species are well known is related due to the different phytochemical for containing steroidal saponins, which were compounds found in Dioscorea. Tubers and used as marker compounds for quality control roots contain steroidal sapogenins, mostly of the botanical products. As reported by diosgenin as well as volatile compounds Jesus et al., 2016, diosgenin (3-β-hydroxy-5- (2, 3). Chemical substances like diosgenin spirostene) is the primary furostanol saponin found in Dioscorea are commercially used found in several plants, including Dioscorea in the pharmaceutical industry. The high species, and is described as a promising demand for the medicinal use of this plant in bioactive compound with several medicinal different parts of the world suggests a strong properties, i.e. hypolipidemic, antioxidant, need for conservation strategies. However, anti-inflammatory, hypoglycaemic, and the conservation might not be easy or simple antiproliferative activities (5). Diosgenin as it must involve plant protection and well- obtained by hydrolysis of yam saponin controlled access to its resources. There still a were the main raw material for the huge need for more research and information industrial production of steroid drug i.e. on the food, nutraceutical, and medicinal value anti-inflammatory, androgenic, estrogenic, worldwide of this plant species. Therefore, this and contraceptive drugs, by underlying its review tends to fill this gap by summarizing potential in the prevention/treatment of data on the current medicinal importance of several diseases. Dioscorea villosa L. roots Dioscorea species. and rhizomes, also are known as “wild yam”, is a rich source of diosgenin. Today, dietary supplements containing wild yam extracts are Dioscorea plants phytochemical composition popular among women for the alleviation of menopausal symptoms and are widely used as Researches have been brought new alternatives to hormone replacement therapy knowledge about chemical compounds in (5).

69 Dioscorea Plans: Nutra-pharmaceuticals

Figure 1. Chemical structures of selected compounds isolated from Dioscorea species. Figure 1. Chemical structures of selected compounds isolated from Dioscorea species.

Dioscorea alata L. Rakatobe et al., 2010 reported Two clerodane Dioscorea alata L. is one of the most diterpenoids, antadiosbulbins A and B and popular varieties of yams. Dioscorea alata two furanoid 19-norclerodane diterpenes, (D. alata) were implicated in the promotion 8-epidiosbulbins E and G along with the of the health of postmenopausal women. known diterpenoid diosbulbin E as well as nine Wild Mexican yam was marketed for the known phenolics including five phenanthrenes treatment of irritability, hot flashes, insomnia, and four flavonoids in the ethyl acetate soluble and depression. Cheng et al., 2007, reported part of the methanolic extract of the tubers (7). the isolation and identification of two

new compounds, hydro-Q9 chromene, and Dioscorea bulbifera L. γ-tocopherol-9; together with four known Dioscorea bulbifera L. (D. bulbifera L.), compounds (RRR-α-tocopherol, coenzyme commonly known as air potato, is originated

Q9, cycloartane, and 1-feruloylglycerol): these from Africa and Southern Asia. The rhizome compounds had phenolic hydroxyl group in of D. bulbifera L. is called as “Huang Yao Zi” common with the known phytoestrogens and in traditional Chinese medicine and used for have also antioxidant activity. Moreover, their the treatment of thyroid diseases and cancers. estrogenic activity was evaluated based on In the northern districts of Bangladesh, this the ligand-dependent transcription activation herb is used for the treatment of cancers and assay (6). leprosy. This plant has two types of storage organs, namely bulbils in the leaf axils of the Dioscorea antaly Jum. and H. Perrier stem and tubers. Bulbils have been used as a Dioscorea antaly Jum. and H. Perrier is folk remedy to treat diarrhea, conjunctivitis, originated from Madagascar, diffused in the and the extracts of the plant exhibit anti-tumor West and North-West regions. The study of activity. The mannose-binding lectin from

70 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89 bulbils of D. bulbifera was studied for its cayenensis tubers contained 66.79 g moisture, clinical potential in HIV and cancer research 2.62 g crude protein, 0.27 g lipid, 0.17 g fiber, (8). Phytochemical studies reported as main 0.63 g ash, 29.69 g carbohydrates, 262.30 mg bioactive compounds of this plant: flavonoids, potassium, 61.53 mg magnesium, 0.79 mg clerodane diterpenoids, and steroidal saponins iron, 0.39 mg zinc, and yielded 108.26 kcal and phenolic compounds. As instance, energy with insignificant vitamin content/100 Liu et al. 2011 reported the isolation and g edible portion (14). identification of two new compounds, bibenzyl type-2,5,2′,5′-tetrahydroxy-3′- Dioscorea esculenta (Lour.) Burk. methoxybibenzyl and diarylheptanone Dioscorea esculenta also called as a containing a dihydrophenanthrene moiety “lesser yam” of Dioscorea species, is widely named as diobulbinone A along with sixteen distributed Southern Asia and the Pacific. The known compounds (9). Nine norclerodane tubers of D. esculenta were used traditionally diterpenoids were isolated from the tubers of in the treatment of various diseases. Moreover, D. bulbifera L. including two new compounds fiteen steroidal saponins were isolated from its (diosbulbin N and diosbulbin P), and a tuber powder, and from the leaf of Dioscorea naturally occurring compound (diosbulbin esculenta (D. esculenta); four of them O) along with six known diosbulbins A-D, belonged to furostanol-type saponin,eleven as F, and G (10). Another study also showed the spirostane-type saponins (15). molecular changes of liver dysfunction and reveal overall metabolic and physiological Dioscorea japonica Thunb. mechanisms of the subchronic toxic effect of The rhizome of Dioscorea japonica Dioscorea bulbifera rhizome (11). Thunb., known as “San Yak” in Korea, is used as food and medicine. The plant was Dioscorea cayenensis Lam.-Holl used in traditional Chinese medicine to Dioscorea cayenensis Lam.-Holl known as control/eliminate diarrhea, dilute sputum, “yellow yam” is native to tropical West Africa improve anorexia, and moisturize skin (16). and its rhizomes are used as food and as a remedy Phytochemical studies on Dioscorea japonica for treating burns and fevers. A new furostanol (D. japonica) showed the presence of active glycoside namely 26-O-β -D-glucopyranosyl- hypoglycemic compounds (dioscorans A–F), 3β,26-dihydroxy-20,22- seco-25(R)-furost-5- sesquiterpene, and acetophenone along with en-20,22-dione-3-O-α-L-rhamnopyranosyl- the steroidal constituents, including spirostane, (1→4)-α-L-rhamnopyranosyl-(1→4)- furostane, and cholestane types (16). [α-L-rhamnopyranosyl-(1→2)]-β-D- glucopyranoside was isolated from the Dioscorea membranacea Pierre methanolic extract of the rhizome of The rhizomes of Dioscorea membrancea Dioscorea cayenensis growing in Cameroon, (D. membranacea) Pierre have been used together with the known spirostanol saponins in Thai traditional medicine. As instance, described as methyl protodioscin, asperoside Thongdeeying et al. 2016 isolated from and prosapogenin A of dioscin (12). the cytotoxic chloroform fraction of the Prosapogenin A of dioscin having a spirostan rhizomes a new steroid (epi-panthogenin skeleton showed antifungal activity against B), a known steroid (panthogenin B), Candida species with MIC values between two napthofuranoxepins dioscorealide A 6.25 and 25 mg/mL (12). Two new fatty acid- and dioscorealide B, phenanthraquinone spirostan steroid glycoside esters, progenin (dioscoreanone) and three phenanthrene; III palmitate, and progenin III linoleate, the same authors reported that also, three were isolated from the methanol extract of steroids (β-sitosterol, stigmasterol, and β-D- the rhizomes of Dioscorea cayenensis (13). sitosterolglucoside) and two steroidal saponins It is worth mentioning the recent studies on [(diosgenin-3-O-α-L-rhamnopyranosyl the nutrient and antinutrient composition (1→2)-β-D-glucopyranoside and diosgenin- of yellow yam (Dioscorea cayenensis) and 3-O - β -D-glucopyranosyl(1-3)-β -D- their products; as instance raw Dioscorea glucopyranoside)] were obtained from D.

71 Dioscorea Plans: Nutra-pharmaceuticals membranacea (17). were also confirmed as furastan-type steroids (21). It is worth mentioning the study of Li Dioscorea nipponica Makino et al. 2017 that explore the chemical basis of Dioscorea nipponica (D. nipponica) the rhizomes and aerial parts of Dioscorea Makino is bitter-sweet in taste and warm in nipponica Makino by a combination of nature according to the traditional Chinese cheminformatics and bioinformatics, medicine. The rhizomes of D. nipponica particularly their potential therapeutic and were traditionally used in China as herbal toxicity targets were screened through the medicine and food supplement for more than DrugBank’s or T3DB’s ChemQuery structure four thousand years; particularly, these plant search: the compounds in the rhizomes species mainly act on the liver, kidney, and possessed 391 potential therapeutic targets lungs, displaying anti-rheumatic, analgesic, and 216 potential toxicity targets (22). blood circulation-stimulating, lung channel- dredging, digestive, anti-diuretic, anti-tussive, Dioscorea opposita Thunb. panting-calming, and phlegm-dispelling Dioscorea opposita Thunb. has been activities. Medicinally, it is commonly used for cultivated in China, Japan, and Korea the treatment of rheumatoid arthritis, pain in as a food, and widely used as traditional the legs and lumbar area, Kashin-Beck disease, medicine, for a very long time. There are bruises, sprains, chronic bronchitis, cough and about 80 yam cultivars that are originated asthma and communication, and adherence to in China, including the so-called “trueborn” therapy is one of the main concerns (4, 18 and Chinese yam. The important ingredient of 19). Recently, it has been used as an important the yam is sugar, which provides energy and industrial raw material for the synthesis of sweetness and adds to the general flavor of steroidal drugs. Concerning the phytochemical foods. Also, the Chinese yam assists in food profile, twelve cyclic diarylheptanoids were digestion and is beneficial in cases of stomach isolated from the rhizomes of Dioscorea disorders (23). Phytochemical investigations nipponica (20), among which two new cyclic of Dioscorea opposite (D. opposita) have diarylheptanoids, diosniponol A and B; revealed many chemical components such as moreover, as reported by the same authors, purine derivatives, phenanthrenes, stilbenes, these compounds were evaluated for their sapogenins, and saponins. Phytochemical effects on nitric oxide production without cell studies of the chloroform soluble fraction of D. toxicity in lipopolysaccharide-activated BV-2 opposita Thunb. have resulted in the isolation cells. Therefore, diarylheptanoid derivatives of four new compounds, two dihydrostilbenes: from D. nipponica may be potential candidates 3,5-dihydroxy-4- methoxybibenzyl, 3,3′,5- for the treatment of various neurodegenerative trihydroxy-2′-methoxybibenzyl; and dibenz- diseases associated with neuroinflammation oxepins 10,11-dihydro-dibenz[b,f]oxepin-2,4- (20). Another study described the water- diol and 10,11-dihydro-4-methoxy-dibenz[b,f] soluble non-saponin components [benzyl oxepin-2-ol, together with an additional 1-O-β-D-glucopyranoside, leonuriside fifteen known compounds. All the nineteen A, icariside D2, pyrocatechol-1-O-β-D- isolated compounds were tested in the DPPH, glucopyranoside, (+) syringaresinol-4-O- superoxide anion radical scavenging assays β-D-glucopyranoside, cyclo-(leu-tyr), and and cyclooxygenases (COXs) inhibition adenosine], and phenolic acid (piscidic acid) assay. Among them, 3,3′,5-trihydroxy-2′- from the rhizomes of D. nipponica (21). On the methoxybibenzyl showed the most potent other hand, 7-oxodioscin a new spirostan-type COX-2 inhibitory activity (23). Bioassay- steroid along with known dioseptemloside guided fractionation of D. opposita extracts G, (25R)-dracaenoside G, orbiculatoside led to the isolation and identification of 23 B, dioscin, progenin III, gracillin were phenolic compounds. Of them, 15 compounds determined. The presence of (3β,22α,25R)-26- reduced porcine pancreatic lipase activity

(β-Dglucopyranosyloxy)-22-methoxyfurost- at IC50 values of less than 50 mM and from 5-en-3-yl-O-[α-L -rhamnopyranosyl-(1→4)]- them 3,3′,5-trihydroxy-2′-methoxybibenzyl β-D-glucopyranoside and methylprotodioscin and (4E,6E)-1,7-bis(4-hydroxyphenyl)-

72 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89

4,6-heptadien-3-one showed the highest Dioscorea preussii Pax inhibition with an IC50 value of 8.8 mM and D. preussii Pax collected in Bambui, dose-dependently in the concentration range Cameroon, was reported to have in-vitro 5-100 mM (24). These findings provide that cytotoxic, antileishmanial and antifungal phenolic compounds with stilbenoids are activities. Three new steroidal saponins, considered to play important roles in the named as diospreussinosides A, B, C, lipase inhibition of the D. opposita extract. along with two known compounds were Especially, the stilbenoids possessing determined as (25R)-17α-hydroxyspirost-5- 3,5-dihydroxybibenzyl moiety showed en-3β-yl O-α-L-rhamnopyranosyl-(1→4)- higher inhibitory potencies than the others. O-α-L-rhamnopyranosyl-(1 →4)-β-D- The lipase inhibitory activities of stilbenoids glucopyranoside and (25R)-17α-hydroxyspirost- depend on the presence of the hydroxyl 5-en-3β-yl O-α-L-rhamnopyranosyl-(1 →2) group in the C-3 position. The structural -O-[O-α-L-rhamnopyranosyl-(1→4)- difference also influences the inhibitory α -L-rhamnopyranosyl-(1→4)]-β-D- effect of diarylheptanoids on pancreatic glucopyranoside were isolated from rhizomes lipase. Dihydrostilbene phenanthrene and of D. preussii (27). diarylheptanoid structures were deemed to be responsible for lipase inhibition activity of Dioscorea pyrifolia Kunth this species (24). D. opposita Thunb. is also D. pyrifolia Kunth is called also as “Akar rich in starch, water-soluble polysaccharides, Kemeyan Paya” in Malaysia. These plants and mucilage defined as a polysaccharide with grow wild and are diffused particularly in unique viscosity characteristics are widely Peninsular Malaysia. Sharlina et al. 2017 used in the pharmaceutical and food industries reported that the starch extracted from D. as a thickening agent and emulsion stabilizer. pyrifolia was characterized by the high These agents are important in the food industry amylose content (44.47 ± 1.86%); the same as they improve the sensory quality, flavor, authors marked how D. pyrifolia Kunth texture, palatability, mouthfeel, and general represents a very important source of starch appearance of the final products. Therefore, for food and non-food applications, such as the mucilage of this plant species is a potential crispy food, coating materials, hydrogels, candidate for food emulsifier resource of a films, bio-membranes, and adhesives (28). natural emulsifier, especially under alkaline conditions obtained from industrial processing Dioscorea septemloba Thunb. waste such as Gum Arabic, Yellow mustard, Cholestane glycosides, dioseptemlosides and Chia (Salvia hispanica L.) (25). A and B, together with six spirostane glyco- sides, dioseptemlosides C-H, were isolated Dioscorea polygonoides Humb. et Bonpl. from the rhizomes of D. septemloba. Among D. polygonoides Humb. et Bonpl. these, spirostane aglycones containing hy- is distributed from Mexico to Brazil, droxyl group at C-7 were reported in the fam- including Colombia. The phytochemical ily Dioscoreaceae. Spirostane-type glycosides investigation of the tubers of D. showed strong activity on nitric oxide produc- polygonoides has resulted in the isolation tion (29). On the other hand, three new diaryl- of three new polyhydroxylated spirostanol heptanoids, dioscorol A, dioscorosides E1, E2; saponins determined as (23S,24R,25S)- two new stilbenes, dioscorosides F1 and F2 were 23,24-dihydroxyspirost-5-en-3β-yl-O-α-L- isolated from the rhizomes of Dioscorea sep- rhamnopyranosyl-(1→2)-β-D-glucopyranosid, temloba. Besides, 1,7-bis(4-hydroxyphenyl)- (23S,25R)-12α,17α,23-trihydroxyspirost-5- hepta-4E,6E-dien-3-one, 1,7-bis(4-hydroxy- en-3β-yl-O-α-L-rhamnopyranosyl-(1→2)-β phenyl)-1,4,6-heptatrien-3-one, 3,5-dihy- -D-glucopyranoside, and (23S,25R)-14α,17α droxy-1,7-bis(4-hydroxyphenyl)heptane, ,23-trihydroxyspirost-5-en-3β-yl-O-α-L- (3R,5R)-3,5-dihydroxy-1,7-bis(4-hydroxy- rhamnopyranosyl-(1→2)-β-D-glucopyrano- phenyl)heptane 3-O-β-D-glucopyranoside, side (26). (3R,5R)-3,5-dihydroxy-1,7-bis(4-hydroxy-

73 Dioscorea Plans: Nutra-pharmaceuticals

3-methoxyphenyl)-heptane 3-O-β-D-gluco- van-3-ol glycosides were also isolated from pyranoside, and 3-O-[α-L-arabinopyrano- D. villosa and fifteen steroidal compounds, syl(1→6)-β-D-glucopyranosyl]oct-1-ene-3-ol including two new metabolites, were isolated were also obtained as known compounds. from the tubers of D. villosa; these compounds They have also shown a significant increase in were characterized as cholestane type steroi- the glucose consumption in differentiated L6 dal glycosides named as dioscoreavillosides A myotubes and displayed triglyceride inhibito- and B (33). Dong et al., 2012 described how ry effects in HepG2 cells (Zhang et al., 2017). the rhizomes were also afforded 14 diarylhep- Eight new compounds namely, dioscorosides tanoids, five of which were new compounds G, H1, H2, dioscorol B, dioscorosides I, J, containing a tetrahydropyran ring in the hep- K1, and K2, together with twelve known ones tane portion of the molecule (34). In another were isolated from the rhizomes of Dioscorea study, three furostanol saponins, parvifloside, septemloba. Moreover, the authors showed methyl protodeltonin, and trigofoenoside that some of these compounds were found to A-1 were isolated from the n-butanol sol- display significant inhibition of nitrite pro- uble extract of D. villosa by using HSCCC; duction evaluated in-vitro anti-inflammatory moreover the authors reported that subsquent potential using LPS-stimulated RAW 264.7 normal-phase HSCCC separation also led to murine macrophages (30). Currently, He et al. the identification of four spirostanol saponins 2019 have identified and elucidated the struc- identified as zingiberensis saponin I, deltonin, ture of a new phenanthropyran, dioscorone B, dioscin, and prosapogenin A of dioscin (35). and a new phenanthrene, together with seven On the other hand, two series of lipidated ste- known compounds, is from the 75% ethanol roid saponins were isolated from D. villosa extract of Dioscorea septemloba rhizomes. (36). The series A was identified as a mixture Moreover, the authors reported that new iso- of five lipidated steroid saponins: 5-en-spi- lated phenanthropyran, tested for antioxidant rostanol-2′-Orha-3-O-glucoside-6′-O-hexade- activity, showed excellent activities with IC50 canoate, 5-en-spirostanol-2′-O-rha-3-O-glu- values of 0.07 ± 0.10 μM and 0.13 ± 0.09 μM, coside-6′-O-octadecanoate, 5-en-spirosta- respectively (31). nol-2′-O-rha-3-O-glucoside-6′-O-9Z-octade- cenoate, 5-enspirostanol- 2′-O-rha-3-O-glu- Dioscorea tokoro Makino coside-6′-O-9Z,12Z-octadecadienoate, and D. tokoro is one of those wild yams, and 5-en-spirostanol-2′-O-rha-3-O-glucoside- its rhizome was generally used for daily food.; 6′-O-9Z,12Z,15Z-octadecatrienoate. The se- in particular in the northern part of Japan, the ries B was characterized as a mixture of the rhizome was used as health-promoting food. following five compounds: 5-en-clionaster- D. tokoro was characterized by steroidal ol-3-O-glucoside-6′-O-hexadecanoate,5-en- saponins, such as dioscin and gracillin, but no clionasterol-3-O-glucoside-6′-O-octa- data were found about its health-promoting decanoate,5-en clionasterol-3-O-gluco- effect. The acetonitrile extract of D. tokoro side-6′-O-9Z-octadecenoate, 5-en-clionas- rhizome fractionation led to protodioscin terol-3-O-glucoside-6′-O-9Z,12Z-octadeca- as an antiproliferative compound to HL-60 dienoate, and 5-enclionasterol-3-O-gluco- leukemic cells (32). side-6′-O-9Z,12Z,15Z-octadecatrienoate (36). These findings revealed two classes as new Dioscorea villosa L. biomarkers: the diarylheptanoids and the lip- The most well-known species of this genus idated steroid saponins. is Dioscorea villosa, also called “wild yam.” Two furanostane type saponins, namely meth- Dioscorea zingiberensis C. H. Wright yl parvifloside, and protodeltonin, were isolat- The rhizome of Dioscorea zingiberensis ed from D. villosa as well as two spirostane C.H. Wright is known as ‘‘Huang Jiang” and types deltonin and glucosidodeltonin (zingib- represents an important source of diosgenin. erensis I), whereas minor saponins were meth- D. zingiberensis were used for the treatment of ylprotodioscin, disoscin, and prosapogenin lung heat, pyretic stranguria, anthracia, coro- (33). The same authors reported that two fla- nary heart disease, and swelling; in particular,

74 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89 the rhizome of Dioscorea zingiberensis is ex- (2,5-dihydroxy-4,6-dimethoxy-9,10-dihy- tensively used for the extraction of diosgenin drophenanthrene.), together with two known sapogenin and its glycoside dioscin, used for bibenzyls (3,5-dihydroxy-4-methoxybibenzyl the synthesis of sex hormones and corticoste- 3,5′,-dihydroxy-3′,4-dimethoxybibenzyl and roids. It is worth mentioning the current study four known diarylheptanoids ((3R,5R)-3,5-di- of Zhang et al., 2018 that give comprehensive hydroxy-1,7-bis(4-hydroxyphenyl)hep- overview of the traditional usage and phyto- tane, (3R,5R)-3,5-dihydroxy-1-(3,4-dihy- chemistry of the Dioscorea zingiberensis C.H. droxyphenyl)-7-(4-hydroxyphenyl)heptane, Wright: -more than 70 compounds have been (3R,5R)-3,5-dihydroxy-1-(4-hydroxy-3-me- identified; -several of these have been tested thoxyphenyl)-7-(4-hydroxyphenyl)-heptane in preclinical assays and clinical trials; -a wide and (3R,5R)-3,5-dihydroxy-1,7-bis(4-hy- spectrum of biological effects including car- droxy-3-methoxyphenyl)-heptane were isolat- diovascular, anti-thrombosis, hyperlipidemia, ed from the dichloromethane soluble fraction neuroprotection, anti-inflammatory, and an- of the rhizomes of D. zingiberensis (39). All thelmintic effect has been verified (37). Wang these phenolic compounds were evaluated for et al. 2010 reported how spirostanol based their anti-pancreatitic activities on sodium aglycon containing steroidal saponins are the taurocholate-induced pancreatic acinar necro- representative steroidal saponins, and their sis as inhibition of necrotic cell death pathway quantity is higher than that of furostanol ste- activation. Among them, (3R,5R)-3,5-dihy- roidal saponins in D. zingiberensis (38). Apart droxy-1-(3,4-dihydroxyphenyl)-7-(4-hy- from the steroidal saponins, other kinds of droxyphenyl) heptane which bears a trihy- constituents were also identified from D. zin- droxy-diarylheptane skeleton was shown to giberensis. Until now, four steroids have been protect against pancreatic acinar cell injury isolated from this plant including β-sitoster- through mediating novel potential therapy for ol, sterol, zingiberenin F, and (25R)-3β-hy- pancreatic necrosis (39). droxyspirost-Δ5,20(21)-dien-3-O-β-D-glu- copyranosyl-(1→4)-[α-L-rhamnopyrano- Biological activities Dioscorea plants syl-(1→2)]-β-D- glucopyranoside. In addition to the common steroidal saponins, other con- The tubers of different Dioscorea stituents classified as alkaloid, phenyl-glyco- species present a wide variation of side, and benzoic acid derivatives have also bioactive compounds, responsible for their been determined. 4-aminomethyl-phenol, pharmacological activities. Generally, the 2-O-β-D-glucopyranosyl-4-hydroxyben- evaluation of bioactive components and the zoic acid and another nonsteroidal saponin assessments of their interactions could be called 2-O-β-D-glucopyranosyl-4-methoxy- viewed as the first step for the determination benzoic acid, were isolated and identified of potential of a plant (40-46). Also, their from the n-buthanol extracts of fresh rhi- ethnopharmacological importance promotes zomes. Following the regular phytochem- further investigations of Dioscorea metabolites ical research procedure, five compounds as a source of potential therapeutic agents to were obtained from D. zingiberensis (38). ameliorate different diseases (Table 1). They consisted of two new phenanthrene derivatives, namely 2,5,7-trimethoxy-1,4-di- In-vitro biological activities of Dioscorea one-9,10-dihydrophenanthrene and 2,5,6-tri- species hydroxy-3,4-dimethoxy-9,10-dihydrophenan- Cytotoxic activity threne; a new anthracenedione, i.e., 2,5,7-tri- D. bulbifera ethanolic crude extract and methoxy-1,4-dione-anthracene; and two different fractions (hexane, ethyl acetate, and known 9,10-dihydrophenanthrenes, called water) at concentrations of 50, 100, and 200 5,6-dihydroxy-2,4-dimethoxy-9,10-dihy- μg/mL were found to possess a potent cytotoxic drophenanthrene and 2,5-dihydroxy-3,4,6-tri- activity against human colorectal carcinoma methoxy-9,10-dihydrophenanthrene. One (HCT116), human colorectal adenocarcinoma new bibenzyl (3,5-dihydroxy-4,40-dime- (HT-29), human lung carcinoma (A549), thoxybibenzyl.) and one new phenanthrene human breast carcinoma (MCF-7), human

75 Dioscorea Plans: Nutra-pharmaceuticals

Table 1.Table Pharmacological 1. Pharmacological activities activities of Dioscorea of Dioscorea species. species.

Botanical name Plant parts Pharmacological activities In-vitro In-vivo Dioscorea alata L. Tuber Immune-modulating activity (47) Gastroprotective activity (50) Anti-inflammatory properties (48) Cardioprotective properties Antibacterial activity (49) (51) Anti-inflammatory activity (52)

Dioscorea antaly Jum. Tuber Toxicity on embryo-larval development Not known and H. Perrier (53)

Dioscorea belophylla Tuber Not known Not known (Prain) Haines

Dioscorea batatas Tuber Immune-modulating activity (54). Enhance murine splenocyte Decne Anti-inflammatory activity (55) proliferation ex-vivo and Anti-severe acute respiratory syndrome improve regeneration of bone associated coronavirus (56). marrow cells (58) Gastroprotective activity (57) Immunomodulatory activity (59) Anti-inflammatory activity (55). Dioscorea bulbifera L. Tuber, Rhizome Anticancer/antitumor (60). Antinociceptive activity (62). Bacterial and fungal infections, Inflammation and pain, Inflammation and pain, Diabetes and Diabetes and digestive digestive problems, Oxidative stress and problems, Tumor and cancer degenerative diseases (61). (61)

Dioscorea cayenensis Tuber Antifungal activity (12) Not known Lam.-Holl

Dioscorea collettii var. Rhizome Anticancer activity (63, 64) Not known hypoglauca

Dioscorea deltoidea Rhizome Antibacterial activity (65) Anti-inflammatory activity Wall. (66)

Dioscorea esculenta Tuber Antioxidant activity (67) Anti-inflammatory activity (Lour.) Brukill (68)

Dioscorea hamiltonii Tuber Antimicrobial activity (69) Not known Hook.f.

Dioscorea hemsleyi Rhizome Antidiabetic activity and Antioxidant Not known activity (70) Dioscorea hispida Tuber, tendrils No toxicity on small intestine cells (71) Not known Dennst. Antioxidant activity (72) Dioscorea japonica Rhizome Neuroprotective activity (16) Anti-inflammatory activity Thunb. (DJ) Antioxidant activity (73) (73) Anti-inflammatory activity (73)

Dioscorea Rhizome Anti-inflammatory activity (74) Anti-inflammatory activity membranacea Immunomodulatory activity (75) (74) Anticancer activity (17, 75).

Dioscorea nipponica Tuber, rhizome Neuroprotective activity (16, 76) Anti-hyperlipidemic (80) and Makino Anti-neuroinflammatory activities (76) antioxidative activity (81) Antiallergic activity (77) Antifungal activity (Rajendra et al., 2014) Uricosuric effect (78, 79)

Dioscorea oppositifolia Tuber Neuroprotective activity (82) Neuroprotective activity (82) L. syn: Dioscorea Rhizome Antioxidant activity (83) Antidiabetic activity (85) opposita Thunb Mediated Synthesis of Gold and Silver Nanoparticles with Catalytic Activity (84)

76 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89

Continued Table 1. Pharmacological activities of Dioscorea species.

Botanical name Plant parts Pharmacological activities In-vitro In-vivo Dioscorea panthaica Rhizome Antioxidant activity (86) Antihyperlipidemic and Prain et Burkill (DP) Antitumor activity (81) antioxidative activity (81) Anti-hypercholesterolemic effect (87) Anti-platelet aggregation activity (87) Antifungal activity (88)

Dioscorea pentaphylla Tuber Antioxidant activity and antibacterial Not known L. activity (86) Dioscorea Tuber Not known Anti-hypercholesterolemia polygonoides Humb. et activity (89) Bonpl. Antidiabetes activity (90)

Dioscorea preussii Pax Tuber Antileishmanial activity (27) Not known Antifungal activity (27)

Dioscorea pubera Tuber Not known Not known Blume Dioscorea septemloba Rhizome Anti-inflammatory activity (74) (91) Anti-hyperuricemia activity Triglyceride inhibitory effects (31) (52)

Dioscorea tokoro Rhizome Antiproliferative activity (32) Anti-hyperuricemic activity Makino (92) Dioscorea trinervia Tuber Not known Not known Roxb.

Dioscorea trifida L.f. Tuber Antioxidant activity (93) Anti-inflammatory activity (94) Dioscorea villosa Tuber, root Antibacterial activity (95) Antinociceptive activity (97) Willd. Hepatoprotective activity (96) Anti-inflammatory activity (97) No acute or subchronic toxicity (97)

Dioscorea Rhizome Anti-pancreatitis activity (39) Anti-arthritic effect, zingiberensis C. H. Anti-arthritic activity (98) antioxidant and anti- Wright Anthelmintic activity and low toxicity inflammatory activities in rats (38) (Wang et al., 2010) (98) Antihyperlipidemic and antioxidative activity (81)

cervix epidermoid carcinoma (Ca Ski), and cell shrinkage, and DNA fragmentation as human colon normal (CCD-18Co) (60). The shown by flow cytometry. The authors also D. bulbifera ethyl acetate fraction (DBEAF), revealed that DBEAF induces apoptosis effects significantly inhibited the survivability of on HCT116 cells through externalization of HCT116, HT-29, and A549 cells; particularly phosphatidylserine and by promoting the loss DBEAF had the best potency against HCT116 of mitochondrial membrane potential (MMP), cells and reduced its cell viability in a time- dysregulation of the Bcl-2 family proteins dependent manner, having IC50 values of 163.59, and the downregulation of the expression 88.49, and 37.91 μg/mL at 24, 48, and 72 h, of procaspase -8, -9, -10 and -3 and PARP respectively and did not exhibit any cytotoxic protein expression. Furthermore, their results effect towards the normal colon cells (CCD- suggested that the inhibitory effect of DBEAF 18Co). DBEAF acts by increasing significantly on ERK1/2 and the activation of JNK were the induction of early and late apoptosis, closely associated with the apoptotic cell death characterized by chromatin condensation, induction in human colorectal carcinoma (60).

77 Dioscorea Plans: Nutra-pharmaceuticals

D. collettii var. hypoglauca and its active C3H/HeJ mice. Dioscorin also stimulated metabolite protoneodioscin, a furostanol multiple signaling molecules (NF-jB, ERK, saponin, was also evaluated for its cytotoxic JNK, and p38) and induced the expression of activity against 60 cell lines including cytokines (TNF-a, IL-1b, and IL-6) in murine human leukemia, melanoma, and cancers of RAW 264.7 macrophages (47). lung, colon, brain, ovary, renal, breast, and prostate. Protoneodioscin exhibited significant Neuroprotective activity cytotoxicity with 50% growth inhibition (GI50) Different Dioscorea species were used ranging from 0.5 to 9 mM against all cell lines traditionally for the treatment of memory- from leukemia and most solid tumors (64). related disorders and dementia, i.e. Alzheimer In the following year, the same research team disease and other neurodegenerative diseases evaluated two other compounds, namely; (82). The chloroform extract from D. opposite methyl protoneogracillin and gracillin. The rhizomes significantly reduced the glutamate- results revealed that methyl protoneogracillin induced toxicity in a dose-dependent manner exhibited significant cytotoxicity with 50 (GI ) with a maximum neuroprotective effect at ≤ 2 mM. Leukemia, CNS cancer, and prostate 10 µg/mL (82). Kim et al., 2011 reported cancer were the most sensitive subpanels, the agonistic action of a 1:3 mixture of D. while ovarian cancer was the least sensitive japonica Thunb. (DJ) and D. nipponica subpanels. On the other hand, gracillin lacked Makino (DN) rhizomes which contribute to selectivity against human cancer diseases (29). their neuroprotective effect against diabetic A different approach was undertaken by Ashri peripheral neuropathy (16). Moreover, the and co-workers (2018) (71), who evaluated compounds isolated from D. nipponica the cytotoxicity of modified D. hispida starch- rhizomes exhibited anti-neuroinflammatory based hydrogels on small intestine cell line and neuroprotective activities, the most (FHS-74 Int) to ensure the safety of their active of which was 3,7-dihydroxy-2,4,6- use. Their results revealed that the prepared trimethoxy-phenanthrene. The later was hydrogels did not show any cytotoxicity and the most potent nerve growth factor (NGF) could be employed for future pharmaceutical inducer, with 162.36% stimulation, and use. strongly reduced nitric oxide (NO) levels with

an IC50 value of 19.56 μM in LPS-activated Immunostimulant activity BV2 microglial cells. Also, it significantly A mucopolysaccharide of yam (D. batatas increased neurite outgrowth in mouse Decne) (YMB) was found to increase the neuro2a (N2a) cells and therefore possessed a cytotoxic activity of mouse splenocyte against significant neuroprotective activity (76). leukemia cell at 10 µg/mL concentration. However, it did not affect the viability of Antidiabetic activity splenocytes. The production of IFN-γ was Different extraction procedures as significantly increased in the YMP treated ultrasonic-assisted extraction, cold water splenocytes. At 50 µg/mL concentration, extraction, warm water extraction and hot it increases the up taking capacity and water extraction significantly influenced lysosomal phosphatase activity of peritoneal the antidiabetic potential of the rhizomes of macrophages. In addition, YMP (10–100 D. hemsleyi as determined via both alpha- µg/mL) significantly increased the viability glucosidase and alpha-amylase inhibition of peritoneal macrophages (54). Dioscorin, assays, where the IC50 values of alpha- the glycoprotein isolated from D. alata was glucosidase inhibition assay varied from 27.41 reported to activate Toll-like receptor 4 to 274.36 µg/mL while those of alpha-amylase (TLR4) and induce macrophage activation inhibition assay varied from 3.66 to 47.57 mg/ via typical TLR4-signaling pathways at mL (70). 100 µg/mL concentration. It induces TLR4- downstream cytokine expression in bone Antioxidant activity marrow cells isolated from TLR4-functional The antioxidant activity of the extracts of C3H/HeN mice but not from TLR4-defective Dioscorea species received much scientific

78 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89 attention (67, 72, 73 and 83). Different extracts ERK1/2 (55). A current study of Hwang et al. of rhizomes of D. hemsleyi, D. hispida Dennst, 2019 reported the anti-inflammatory effect of D. opposite Thunb., D. nipponica Makino, D. aerial bulblets of Dioscorea japonica Thunb esculenta (Lour). Burkill, D. japonica Thunb. extract through inhibition of NF-κB and var. pseudojaponica and D. pentaphylla L. MAPK signaling pathway in RAW 264.7. were all studied for their antioxidant properties by different in-vitro assays namely; reducing Antiallergic activity power assay, ferric reducing antioxidant power D. membranacea ethanolic extract and assay (FRAP), DPPH radical scavenging assay, compounds showed antiallergic activities by hydroxyl radical scavenging assay, superoxide inhibiting beta-hexosaminidase release as a radical assay, self-oxidation of 1,2,3-phentriol marker of degranulation in RBL-2H3 cells, assay and antioxidant activity by radical cation with an IC50 value of 37.5 µg/mL. From this (ABTS) assay. Generally, the studied extracts extract, dioscorealide B showed the highest from different Dioscorea species showed a activity with an IC50 value of 5.7 µg/mL (77). significant antioxidant potential which may account for their involvement in the treatment Anti-pancreatitis and anti-arthritic of various disorders via radical scavenging activities mechanisms. Du et al. 2017 reported how several compounds were isolated from the rhizomes of Anti-inflammatory activity D. zingiberensis i.e. (3R,5R)-3,5-dihydroxy-1- Lipopolysaccharide-stimulated RAW 264.7 (3,4-dihydroxyphenyl) -7-(4-hydroxyphenyl) cells were employed to determine the anti- heptane at a concentration of 0.5 mM inflammatory properties of the ethanolic showed anti-pancreatitis activities on sodium extract of tubers of D. japonica Thunb. taurocholate -induced pancreatic acinar var. pseudojaponica and individual steroid necrosis with an inhibitory effect of 19.0%. glycosides isolated from D. septemloba Moreover, the same authors marked that this rhizomes (29, 73). D. japonica extract at compound’s protective effects were mainly doses of 500 and 1000 µg/mL significantly dependent on ATP inhibition and excessive inhibited LPS-induced iNOS and COX-2 ROS production and thus saving the cells from protein expressions, also, the nitrite relative mitochondrial dysfunction (39). Another study concentration percentage ranged between reported that the steroidal saponins obtained 11.3% to 107.5% for the steroid glycosides from the rhizomes of D. zingiberensis showed isolated from D. septemloba rhizomes. Similar anti-arthritic activities on the LPS stimulated to the total ethanol extract of D. membranacea 264.7 macrophage cells through induction of presented a potent inhibitory activity, with both p65 and IκBα protein expressions (98). an IC50 value of 23.6 µg/mL. Its most potent metabolite included diosgenin-3-O-alpha-L- Antibacterial activity rhamnosyl (1-->2)-beta-D-glucopyranoside The methanolic extract of tubers of D. that showed a powerful inhibitory activity with pentaphylla L. showed antibacterial activity

IC50 value as low as 3.5 µg/mL (74). The study against S. pyogenes, S. mutans, V. cholera, S. of the mechanism of anti-inflammatory activity typhi, and S. flexneri. The best activity was: of the ethanolic extract from the bark of D. 19.00 mm and 16.00 mm inhibition zone batatas DECNE showed that it inhibited both diameter observed (at 50 μg/disc and 200 μg/

NO and PGE2 production with an IC50 of 87– disc) against S. pyogenes using disc diffusion, 71 µg/mL respectively. It was also suggested agar well diffusion assays, respectively. The that the extract act suppressing DNA-binding MIC values were 100 μg/mL for the extract activity and reporter gene activity as well as against V. cholera, S. typhi and S. flexneri translocation of the NF-jB p65 subunit. It while it was 50 μg/mL against S. pyogenes and also down-regulated IjB kinase (IKK), thus S. mutans. Similarly, Rajendra et al. reported inhibiting LPS-induced both phosphorylation the antibacterial activities of 5% and 10% and the degradation of IjBa. In addition, it methanolic extract of D. deltoidea Wall ex also inhibited the LPS-induced activation of Griseb rhizomes against S. aureus and E. coli,

79 Dioscorea Plans: Nutra-pharmaceuticals but this concentration does not show activity pH by increasing acetic acid and butyric against S. typhi and P. aeruginosa. It could be acid concentration in the feces. The study concluded that, in general, Dioscorea species done on mice with high-fat diet showed that do not exhibit a potent antibacterial activity both native and modified starch from Yam (86). had anti-hyperlipidemic activity through a significant decrease of both cholesterol and Antifungal activity triglycerides and the liver index. The reduction The study of Cho et al. 2013 studied dioscin, of superoxide dismutase (SOD) and increase isolated from wild yam D. nipponica root malondialdehyde (MDA) was observed in bark, for its potential as an antifungal agent hyperlipidemic mice while they were both via the propidium iodide assay and calcein- improved in all starches-treated mice proving leakage measurement, in addition to, its ability their antioxidant effect (Table 1) (100). to disrupt the plasma membrane potential, using 3,3′-dipropylthiadicarbocyanine iodide Gastroprotective activity and bis-(1,3-dibarbituric acid)-trimethine Four types of resistant starch (RS) including oxanol. As reported by Cho et al. 2013 native (RS2), retrograded (RS3), cross- the results showed that dioscin exerts a linked with sodium trimetaphosphate/sodium considerable antifungal activity, where, the tripolyphosphate (RS4) and complexed dye-stained cells showed a significant increase with palmitic acid (RS5) resistant starches in fluorescent intensity after treatment with from winged yam (D. alata L.) showed the dioscin, demonstrating that dioscin possess an gastroprotective activity of in ethanol-induced effect on the membrane potential. The auhors gastric ulcer in mice. The increase in gastric concluded that dioscin could act by disrupting emptying rate may help in reducing the the fungal membrane structure resulting in cell contact time of ethanol and gastric mucosa death (99). and helps to prevent the gastric tissue damage. Therefore, an increase in gastric emptying In-vivo studies on genus Dioscorea induced by RS is a possible mechanism of Globally a large number of Dioscorea anti-gastric ulcer. Moreover, RS3 and RS5 plants have investigated in-vivo. Data on groups generated more short chain fatty acids Dioscorea species potency on the animal which are produced through fermentation model are summarized in Table 1. of the starch by the colon microflora. The fatty acids have many physiological and Animal models studies biological functions, such as increasing The anti-constipation activity the immunity of the stomach. EtOH-ulcer Dioscorea opposita Thunb. yam tuber is can result from the imbalance between the rich in starch, which has always been ignored generated reactive oxygen species (ROS) and and discarded during the isolation of bioactive the natural antioxidant power. Thus, the free compounds. Huang et al., 2016 studied the radical scavenging is one of the mechanisms anti-constipation effect of native yam starch for inhibition of gastric ulcer (101). Mao et al. (NS), dual enzyme-treated starch (DES), and 2018 reported the decrease of SOD activity in cross-linked carboxymethyl starch (CCS) in ethanol-treated rats with an increase in MDA constipation model induced by loperamide levels in gastric mucosa indicating severe in KM mice. The modified starches (DES oxidation reaction in ethanol-induced gastric and CCS) could benefit the bowel function ulcer mice. RS3 (6.4 g/kg) and RS4 (6.4 g/kg) by increasing stool frequency and defecation exhibited the best antioxidant effect. Therefore, moisture as they have the good water-binding the inhibition of oxidative stress by the four capacity and swelling ability, the modified types of RS is a possible mechanism that starches could increase the water-holding may assist in decreasing the gastric mucosal capacity of stools to remain soft. DES and damage. Generally, the high dose groups CCS groups had improved small intestinal of RS3 and RS5 (6.4 g/kg) showed the best propulsion through the production of more activity (50). A current study also reported the short chain fatty acids (SCFAs) and decrease protective effects of Dioscorea batatas flesh

80 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89 and peel extracts against an ethanol-induced peroxidation. EEDJ was able to reduce nitric gastric ulcer in mice (57). oxide which was excessively released after administration of carrageenan and also could Anti-thrombotic activity reduce the levels of MDA through increasing Li et al. 2010 reported the significant anti- the enzymatic antioxidant defense systems thrombotic and anticoagulation effect of the such as catalase (CAT), superoxide dismutase total steroidal saponin extract (TSSE) from (SOD) and glutathione peroxidase (GPx) in the the rhizomes of D. zingiberensis C.H. Wright paw oedema which are the natural protectors on inferior vena cava ligation thrombosis against lipid peroxidation (73). rat model and pulmonary thrombosis mice The anti-arthritic effect of the total saponin model. Oral administration of the extract extract from the rhizomes of D. zingiberensis significantly inhibited adenosine diphosphate- C.H. Wright (TSRDZ) in Freund’s complete induced platelet aggregation (PAG) in-vivo, adjuvant (FCA) induced arthritis in rats (98). which was more effective than Xue-sai-tong, In this study, a significant increase in arthritis a commercial product of triterpenoid saponins scores and ankle perimeter were observed from Panax ginseng having antithrombosis after 4 days from intraplantar administration activity in China. In addition, TSSE inhibited of FCA, which reaches its maximum on the thrombosis in a dose-dependent manner day 16. Administration of TSRDZ at 100 (more than 50% inhibition rate) which was and 200 mg/kg produced substantial dose more powerful than the standard Xue-sai- suppressive significant effect in the treated tong at 64.7, and 129.4 mg/kg doses of TSS, groups. TSRDZ at 100 and 200 mg/kg also and markedly reduced thrombus weight. caused a marked reduction of FCA-induced TSSE also exhibited in a dose-dependent elevated indexes of the thymus and spleen. manner prolongation of thromboplastin time The high dose of TSRDZ caused only mild (APTT) (which is an intrinsic clotting index), synovial infiltration with few inflammatory prothrombin time (PT) (that evaluates the cells and no obvious damage in cartilage bone extrinsic clotting pathway), and thrombin time erosion, which appeared in histopathological (TT) (which is a test of fibrin formation, the study. The efficient regulation of TSRDZ addition of thrombin directly induces that). on the inflammatory cytokines at 200 mg/ The more pronounced effect of TSSE on PT kg, was almost equivalent to that caused by and TT than APTT indicates that it inhibits the the standard methotrexate. Moreover, the extrinsic pathway of coagulation and fibrin mitigation of TSRDZ on the prostaglandins formation, and cut down the thrombotic risk (PGE2), at 200 mg/kg, was almost equivalent (102). to that of standard methotrexate. Furthermore, administration of TSRDZ at 200 mg/kg Anti-inflammatory activity resulted in attenuating the production of MDA The ethanolic extract of the tubers of D. and NO, while elevating the SOD activity japonica Thunb. var. pseudojaponica (EEDJ) compared with the control group (98). showed in-vivo anti-inflammatory activity The total 80% ethanol extract of the by significantly inhibiting the development tubercles of D. trifida L.f. as well as its three of Carrageenan-induced paw edema in mice subfractions, dichloromethane, butanol, and after the 4th and 5th hour of the treatment at aqueous fractions showed anti-inflammatory 1.0 g/kg. It also decreased the levels of TNF-α, activity in food allergy induced by ovalbumin which is a mediator of Carrageenan-induced in BALB/c mice (94). Ova-sensitized BALB/c inflammatory response and induced the release mice received the Ova solution to develop of kinins and leukotrienes. Carrageenan- local signs of inflammation characterized by induced paw edema causes oxidative stress eosinophil infiltration, edema, an increase with the release of peroxidation products, in a number of mast cells in the intestinal including malondialdehyde (MDA) and nitric submucosa, mucus secretion, an increase in oxide. MDA increased levels of oxygen free serum anti-OVA IgG1 and IgE, and weight radicals, which attack polyunsaturated fatty loss because of hyper-catabolism caused by acids in cell membranes and causing lipid the production of inflammatory cytokines. The

81 Dioscorea Plans: Nutra-pharmaceuticals crude extract of D. trifida tested at the doses of have demonstrated that oral administration of 100 and 300 mg/kg/day corresponding to 36.6 allantoin attenuates the production of IgE, IL- and 109.8 mg/kg/day of allantoin, and 3.0 and 4, and IL-5, has an anti-inflammatory effect 9.0 mg of diosgenin correlated substances/kg/ and promotes healing (68). day, respectively did not affect the body weight, The methanol extract of the rhizomes but they inhibited IgE production compared of D. deltoidea Wall.ex Griseb. at 200 mg/ to untreated groups. The inhibition tended to kg inhibited the rat hind paw carrageenan- be more significant in aqueous fraction and induced edema. The maximum percentage butanol fraction, which contains allantoin, than of inhibition was achieved at 3 h after the dichloromethane, which contains diosgenin. intraperitoneal administration of the extract The ethanolic extract and its fractions exerted (106). a reduction in several mastocytes and edema, which was also probably due to the presence Neuroprotective activity of diosgenin and allantoin (94). Diosgenin In a study made by Yang et al., the was also reported to reduce the production of chloroform soluble extract of the rhizomes anti-OVA IgE and the inflammatory infiltrate of D. opposita (CSDO) showed cognitive in allergic BALB/c mice intestines, resulting enhancing effects on spatial memory and in a reduction in edema (103). BALB/c mice learning function of mice against scopolamine- having food allergy showed an increase in induced amnesic deficits via Morris water mucus production by the caliciform cells in maze and passive avoidance tests. In Morris the small intestine (104). An important allergic water maze test, both acute treatment by CSDO response that is induced by interleukins IL-4 (200 mg/kg body weight, p.o.) and prolonged- and IL-3 is hypersecretion of mucus. Mucus treatment (10 days’ daily administration has a protective effect on the intestinal cells by of 50 mg/kg body weight, p.o.) exhibited limiting the antigen absorption. The presence significant shorter escape latencies in daily of eosinophil peroxidase (EPO) indirectly first trial than the scopolamine-administered reflects the infiltration of eosinophils into group during a 4-consecutive-day training intestinal mucosa, which was reduced by period, which suggested that CSDO improves administration of the ethanolic extract of D. the impaired reference memory (long-term trifida. Mollica et al. also showed that D. memory) induced by scopolamine. Especially, trifida extract and fractions reduced all of the acute treatment group showed a marked the inflammatory parameters associated with decrease in escape latencies in each daily trial food allergies in Ova-sensitised animals and compared with the prolonged treatment group. this activity is correlated with the presence of In this study, CSDO also showed significant allantoin and diosgenin correlated substances enhancing effects on spatial memory retention (94). The animals treated with ethanolic extract in the probe trial. Similar results were showed a reduction in mucus production, obtained in the passive avoidance test. CSDO and this result was also observed for the treatment significantly increased step-through other fractions. Previous studies showed latencies of scopolamine-induced amnesic that diosgenin and allantoin activities reduce mice compared to control untreated group. mucus production in animals allergic to OVA The results of the two animal behavioral (103). tests demonstrated that CSDO improves The crude extracts of D. membranaceae and spatial learning and memory function against D. birmania, which contain high amounts of scopolamine-induced amnesia (82). The sapogenins, inhibited the production of nitric study of Jeon et al., 2014 investigated the oxide (NO) most probably through inhibiting neuroprotective effect of herbal mixture from the nitric oxide synthetase (iNOS) and TNF-α, Euphoria longana, Houttuynia cordata, and with consequent reduction of intestinal edema Dioscorea japonica, by testing the hypothesis (74, 77). A study by Olayemi and Ajaiyeoba that administration of herbs reverses memory also associated the antiedematogenic activity deficits and promotes the protein expression of crude extract from D. esculenta to the of brain-derived neurotrophic factor (BDNF) presence of sapogenins (105). In-vivo studies in the mouse brain: these herbs demonstrated

82 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89 an inductive effect on BDNF, cyclic-AMP superoxide dismutase (SOD) level in blood. response element-binding protein (CREB) and Thus, the combination of trillin and lovastatin phospho-CREB (pCREB) (107). in treating hyperlipidemia could represent a more effective therapy (Wang et al. 2012). Antinociceptive activity The authors of this research marked how these The study of the antinociceptive effect findings greatly support the significant role of of the methanol extract of the bulbs of D. nipponica in protecting the cardiovascular Dioscorea bulbifera L. var sativa (MEDB) system in-vivo against hyperlipidemia (80). was performed by Nguelefack et al. (2010) Tang et al. 2015 studied the mechanism by The effects of MEDB persisted for 5 days which the total saponins of the rhizomes of D. after two administrations in CFA-induced nipponica Makino (DN), D. panthaica Prain et hypernociception at 250 and 500 mg/ Burkill (DP), and D. zingiberensis C.H. Wright kg. MEDB significantly inhibited acute (DZ), attenuated myocardial ischemia (MI) lipopolysaccharides (LPS)-induced pain induced by injection of isoprenaline (ISO) at 500 mg/kg but did not affect thermal in rats, and compared the therapeutic effect hypernociception and capsaicin-induced of total saponins from the three species on spontaneous nociception. The antinociceptive myocardial antioxidant levels and myocardial effects of MEDB in prostaglandin-E2 histology (87); the authors reported how high (PGE2) model was antagonized by either serum levels of lactate dehydrogenase (LDH), nitro-L-arginine methyl ester (l-NAME) or aspartate aminotransferase (AST) and creatine glibenclamide. This indicated that the plant kinase (CK) indicated cell membrane damage exerted its antinociceptive effect through and were thus elevated in the ISO model group. partial activation of the NO–cGMP–ATP- Intra-gastric injection of total saponins of the sensitive potassium channels pathway (62). three species could restore the activities of myocardial injury marker enzymes to the same Antihyperlipidemic and antioxidative activity extent. Oxidative stress plays an essential role The intraperitoneal administration in the pathogenesis of MI injury. SOD, catalase of n-butanol extract of the D. nipponica (CAT), GPx, and total antioxidant capacity rhizomes at 50 mg/kg regulates the blood (T-AOC) levels were reduced significantly cholesterol, triglyceride, HDL and LDL than in the ISO model group with the increase in the chloroform (50 mg/kg) and water extracts MDA. The activities of these enzymes were (50 mg/kg) (80). Wang et al. 2012 reported the normalized by intragastric injection of the potential activity of trillin, a steroidal saponin total saponins of the three species. The study isolated from D. nipponica rhizomes, as anti- revealed that the anti-MI mechanism of hyperlipidemic and anti-oxidative agent in- Dioscorea saponins is related not only to the vivo. The intraperitoneal administration of enzymatic antioxidant, such as GPx and CAT trillin (0.5 mg/kg dissolved in 0.5% DMSO) but also to nonenzymatic antioxidants and enhanced the blood circulation and could its effect on myocardial histology (87). The increase the bleeding time for more than current studies reported the beneficial effects 50% and coagulation in the rats fed on a of purple yam (Dioscorea alata L.) resistant high-fat diet in which the blood viscosity starch on hyperlipidemia in high-fat-fed would be changed resulting in shorter blood hamsters (108, 109). coagulation time. The improvement effect of trillin in restoring the blood coagulation Uricosuric effect abnormality in high-fat diet fed rat was due The total saponins from Rhizoma to its ability to reduce the levels of blood Dioscoreae Nipponicae could effectively cholesterol, triglyceride and two critical reverse potassium oxonate-induced alterations lipoproteins (HDL and LDL). The level of in renal mouse urate transporter 1, glucose lipid oxidation was increased in high-fat diet transporter 9, organic anion transporter 1, rats, causing oxidative stress. Trillin exerted and organic anion transporter 3mRNA and an anti-oxidative effect through lowering protein levels, resulting in enhancement of lipid peroxidation, via the enhancement of renal urate excretion in mice (79). Moreover,

83 Dioscorea Plans: Nutra-pharmaceuticals the authors concluded that the total saponins are warranted to address the poor conversion from Rhizoma Dioscoreae Nipponicae had of the preclinical results to clinical efficacity. a uricosuric effect on the regulation of renal Therefore, an attempt should be made to organic ion transporters in hyperuricemic understand their mechanism of action, animals. In a further paper, the same authors pharmacokinetics/pharmacodynamics, here was the potent uricosuric effect of TDN and bioavailability and to conduct clinical on hyperuricemic rats by decreasing the trials. Overall, these findings suggested that expressions of renal rURAT1 while increasing Dioscorea should not be ignored and should the expressions of renal rOAT1 and rOAT3 rather be considered as a good alternative (78). source of active molecules that can prevent or alleviate both functional and infectious disease Clinical trials burden, representing a current big challenge A double-blind, placebo-controlled, cross- in developing countries. The knowledge gaps over study was conducted to evaluate the in this review such as insufficient data on a effects of a wild yam cream in 23 healthy clinical trial to support preclinical results will women suffering from troublesome symptoms help the further initiative to turn Dioscorea of the menopause. Every female was treated into drug and stimulate activity to promote with the active cream and a placebo for 3 their production and utilization as not only months randomly. After 3 months treatment valuable components of a well-balanced diet with topical wild yam extract in women but also for disease prevention. suffering from menopausal symptoms it was found that the cream is free from side-effects, References and has little effect on menopausal symptoms (110). (1) Kumar S, Das G, Shin HS and Patra JK. Dioscorea spp. (a wild edible tuber): a study on its Conclusion ethnopharmacological potential and traditional use by the local people of Similipal Biosphere Reserve, Dioscorea species make a significant India. Front. Pharmacol. (2017) 8: 52. contribution both as root crops and vegetables (2) Romano R, Giordano A, Le Grottaglie L, to the diets around the world. Despite their Manzo N, Paduano A, Sacchi R and Santini A. importance as a food source, Dioscorea Volatile compounds in intermittent frying by gas plant parts are quite useful in the treatment chromatography and nuclear magnetic resonance. of various ailments and disorders due to the Eur. J. Lipid Sci. Tech. (2013) 115: 764-73. presence of several bioactive compounds (3) Miyazawa M, Shimamura H and Kameoka H. such as diosgenin. However, several Volatile Components of the Rhizomes of Dioscorea reported ethnomedicinal potential need to japonica. Nat. Prod. Lett. (1997) 9: 245-8. (4) Ou-yang SH, Jiang T, Zhu L and Yi T. Dioscorea be validated and detailed investigations on nipponica Makino: a systematic review on its Dioscorea pharmacological properties and ethnobotany, phytochemical and pharmacological phytochemical composition should be carried profiles. Chem. Cent. J. (2018) 12: 57. out to standardize the formulations used. (5) Jesus M, Martins AP, Gallardo E and Silvestre S. Indeed, some pharmacological properties Diosgenin: recent highlights on pharmacology and such as hypolipidemic, hypoglycaemic, analytical methodology. J. Anal. Methods Chem. antioxidant, anti-inflammatory, antimicrobial, (2016) 2016: 4156293. antiproliferative, androgenic, estrogenic, and (6) Cheng WY, Kuo YH and Huang CJ. Isolation and contraceptive have been reported. However, identification of novel estrogenic compounds in most of the active constituents have not been yam tuber (Dioscorea alata Cv. Tainung No. 2). J. characterized. Thus, authentication of all the Agr. Food. Chem. (2007) 55: 7350-8. secondary metabolites (alkaloids, saponin, (7) Rakotobe L, Mambu L, Deville A, Dubost L, flavonoids, tannins, and phenols) from Jeannoda V, Rakoto D and Bodo B. Clerodane Dioscorea should be performed thoughtfully and 19-norclerodane diterpenoids from the tubers to standardize and validate its quality and of Dioscorea antaly. Phytochemistry (2010) 71: biological potentials. Moreover, investigations 1007-13.

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(8) Sharma M, Hotpet V, Sindhura B, Kamalanathan (19) Scala D, Menditto E, Armellino MF, Manguso F, A, Swamy BM and Inamdar SR. Purification, Monetti VM, Orlando V, Antonino A, Makoul G characterization and biological significance of and De Palma M. Italian translation and cultural mannose binding lectin from Dioscorea bulbifera adaptation of the communication assessment tool bulbils. Int. J. Biol. Macromol. (2017) 102: 1146- in an outpatient surgical clinic. BMC Health Serv. 55. Res. (2016) 16: 163. (9) Liu H, Tsim KW, Chou GX, Wang JM, Ji LL and (20) Woo KW, Moon E, Kwon OW, Lee SO, Kim Wang ZT. Phenolic compounds from the rhizomes SY, Choi SZ, Son MW and Lee KR. Anti- of Dioscorea bulbifera. Chem. Biodivers. (2011) 8: neuroinflammatory diarylheptanoids from the 2110-6. rhizomes of Dioscorea nipponica. Bioorg. Med. (10) Tang Y, Xue YB, Zhou L, Zhang JW, Yao GM, Chem. Lett. (2013) 23: 3806-9. Luo ZW, Du G and Zhang YH. New norclerodane (21) Ali Z, Smillie TJ and Khan IA. 7-Oxodioscin, a diterpenoids from the tubers of Dioscorea new spirostan steroid glycoside from the rhizomes bulbifera. Chem. Pharm. Bull. (2014) 62: 719-24. of Dioscorea nipponica. Nat. Prod. Commun. (11) Zhao DS, Wu ZT, Li ZQ, Wang LL, Jiang LL, Shi (2013) 8: 1-3. W, Li P and Li HJ. Liver-specific metabolomics (22) Li XZ, Zhang SN and Yang XY. Combination of characterizes the hepatotoxicity of Dioscorea cheminformatics and bioinformatics to explore bulbifera rhizome in rats by integration of GC-MS the chemical basis of the rhizomes and aerial and 1H-NMR. J. Ethnopharmacol. (2018) 226: parts of Dioscorea nipponica Makino. J. Pharm. 111-9. Pharmacol. (2017) 69: 1846-57. (12) Sautour M, Mitaine-Offer AC, Miyamoto T, (23) Yang MH, Yoon KD, Chin YW, Park JH and Kim J. Dongmo A and Lacaille-Dubois MA. Antifungal Phenolic compounds with radical scavenging and steroid saponins from Dioscorea cayenensis. cyclooxygenase-2 (COX-2) inhibitory activities Planta Med. (2004) 70: 90-2. from Dioscorea opposita. Bioorg. Med. Chem. (13) Ali Z, Smillie TJ and Khan IA. Two spirostan (2009) 17: 2689-94. steroid glycoside fatty esters from Dioscorea (24) Yang MH, Chin YW, Yoon KD and Kim J. Phenolic cayenensis. Nat. Prod. Commun. (2013) 8: 323-6. compounds with pancreatic lipase inhibitory (14) Adepoju OT, Boyejo O and Adeniji PO. Effects of activity from Korean yam (Dioscorea opposita). J. processing methods on nutrient and antinutrient Enzyme Inhib. Med. Chem. (2014) 29: 1-6. composition of yellow yam (Dioscorea cayenensis) (25) Ma F, Zhang Y, Yao Y, Wen Y, Hu W, Zhang J, Liu products. Food Chem. (2018) 238: 160-5. X, Bell AE and Tikkanen-Kaukanen C. Chemical (15) Lee HJ, Watanabe B, Nakayasu M, Onjo M, components and emulsification properties of Sugimoto Y and Mizutani M. Novel steroidal mucilage from Dioscorea opposita Thunb. Food saponins from Dioscorea esculenta (Togedokoro). Chem. (2017) 228: 315-22. ‎Biosci. Biotechnol. Biochem. (2017) 81: 2253-60. (26) Osorio JN, Mosquera Martinez OM, Correa (16) Kim N, Kim SH, Kim YJ, Kim JK, Nam MK, Navarro YM, Watanabe K, Sakagami H and Rhim H, Yoon SK, Choi SZ, Son M and Kim SY. Mimaki Y. Polyhydroxylated spirostanol saponins Neurotrophic activity of DA-9801, a mixture extract from the tubers of Dioscorea p olygonoides. J. Nat. of Dioscorea japonica Thunb. and Dioscorea Prod. (2005) 68: 1116-20. nipponica Makino, in-vitro. J. Ethnopharmacol. (27) Tabopda TK, Mitaine-Offer AC, Tanaka C, (2011) 137: 312-9. Miyamoto T, Mirjolet JF, Duchamp O, Ngadjui BT (17) Thongdeeying P, Itharat A, Umehara K and and Lacaille-Dubois MA. Steroidal saponins from Ruangnoo S. A novel steroid and cytotoxic Dioscorea preussii. Fitoterapia (2014) 97: 198-203. constituents from Dioscorea membranacea (28) Sharlina ME, Yaacob W, Lazim AM, Fazry S, Pierre against hepatocellular carcinoma and Lim SJ, Abdullah S, Noordin A and Kumaran cholangiocarcinoma cells. J. Ethnopharmacol. M. Physicochemical properties of starch from (2016) 194: 91-7. Dioscorea pyrifolia tubers. Food Chem. (2017) (18) Menditto E, Cahir C, Aza-Pascual-Salcedo M, 220: 225-32. Bruzzese D, Poblador-Plou B, Malo S, Costa E, (29) Zhang Y, Yu HY, Chao LP, Qu L, Ruan JY, Liu YX, González-Rubio F, Gimeno-Miguel A and Orlando Dong YZ, Han LF and Wang T. Anti-inflammatory V. Adherence to chronic medication in older steroids from the rhizomes of Dioscorea populations: application of a common protocol septemloba Thunb. Steroids (2016) 112: 95-102. among three European cohorts. Patient Prefer. (30) Zhang Y, Chao L, Ruan J, Zheng C, Yu H, Qu L, Adherence (2018) 12: 1975-87. Han L and Wang T. Bioactive constituents from

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the rhizomes of Dioscorea septemloba Thunb. Eur. J. Pharm. Sci. (2017) 96: 53-61. Fitoterapia (2016) 115: 165-72. (42) Santini A and Novellino E. Nutraceuticals - shedding (31) He T, Liu Y, Xiong RF, Li XY, Wang SF and light on the grey area between pharmaceuticals and Cheng CR. A new phenanthropyran and a new food. Expert Rev. Clin. Pharmacol. (2018) 11: 545- biphenanthrene from the rhizomes of Dioscorea 7. septemloba and their antioxidant activities. Nat. (43) Santini A, Cammarata SM, Capone G, Ianaro A, Prod. Res. (2019) 19: 1-6. Tenore GC, Pani L and Novellino E. Nutraceuticals: (32) Oyama M, Tokiwano T, Kawaii S, Yoshida Y, Opening the debate for a regulatory framework. Mizuno K, Oh K and Yoshizawa Y. Protodioscin, Br. J. Clin. Pharmacol. (2018) 84: 659-72. isolated from the rhizome of Dioscorea (44) Daliu P, Santini A and Novellino E. From tokoro collected in northern japan is the major pharmaceuticals to nutraceuticals: Bridging antiproliferative compound to HL-60 leukemic disease prevention and management. Expert Rev. cells. Curr. Bioact. Compd. (2017) 13: 170-4. Clin. Pharmacol. (2019) 12: 1-7. (33) Ali Z, Smillie TJ and Khan IA. Cholestane steroid (45) Durazzo A, D’Addezio L, Camilli E, Piccinelli glycosides from the rhizomes of Dioscorea villosa R, Turrini A, Marletta L, Marconi S, Lucarini M, (wild yam). Carbohyd. Res. (2013) 370: 86-91. Lisciani S and Gabrielli P. From plant compounds (34) Dong SH, Nikolić D, Simmler C, Qiu F, van to botanicals and back: A current snapshot. Breemen RB, Soejarto DD, Pauli GF and Chen Molecules (Basel, Switzerland) (2018) 23: 1844. SN. Diarylheptanoids from Dioscorea villosa (wild (46) Durazzo A and Lucarini M. Current shot and re- yam). J. Nat. Prod. (2012) 75: 2168-77. thinking of antioxidant research strategy. Braz. J. (35) Yoon KD, Chin YW, Yang MH, Choi J and Kim Anal. Chem. (2018) 5: 9-11. J. Application of high‐speed countercurrent (47) Fu SL, Hsu YH, Lee PY, Hou WC, Hung LC, Lin chromatography–evaporative light scattering CH, Chen CM and Huang YJ. Dioscorin isolated detection for the separation of seven steroidal from Dioscorea alata activates TLR4-signaling saponins from Dioscorea villosa. Phytochem. pathways and induces cytokine expression in Analysis (2012) 23: 462-8. macrophages. Biochem. Biophys. Res. Commun. (36) Dong SH, Cai G, Napolitano JG, Nikolić D, Lankin (2006) 339: 137-44. DC, McAlpine JB, van Breemen RB, Soejarto DD, (48) Dey P, Roy Chowdhuri S, Sarkar MP and Pauli GF and Chen SN. Lipidated steroid saponins Chaudhuri TK. Evaluation of anti-inflammatory from Dioscorea villosa (wild yam). Fitoterapia activity and standardisation of hydro-methanol (2013) 91: 113-24. extract of underground tuber of Dioscorea alata. (37) Zhang X, Jin M, Tadesse N, Dang J, Zhou T, Pharm. Biol. (2016) 54: 1474-82. Zhang H, Wang S, Guo Z and Ito Y. Dioscorea (49) Pugazhendhi S, Sathya P, Palanisamy P and zingiberensis CH Wright: An overview on its Gopalakrishnan R. Synthesis of silver nanoparticles traditional use, phytochemistry, pharmacology, through green approach using Dioscorea alata and clinical applications, quality control, and toxicity. their characterization on antibacterial activities and J. Ethnopharmacol. (2018) 220: 283-93. optical limiting behavior. J. Photochem. Photobiol. (38) Wang GX, Jiang DX, Li J, Han J, Liu YT and Liu B (2016) 159: 155-60. XL. Anthelmintic activity of steroidal saponins (50) Mao X, Lu J, Huang H, Gao X, Zheng H, Chen from Dioscorea zingiberensis CH Wright against Y, Li X and Gao W. Four types of winged yam Dactylogyrus intermedius (Monogenea) in goldfish (Dioscorea alata L.) resistant starches and their (Carassius auratus). Parasitol. Res. (2010) 107: effects on ethanol-induced gastric injury in-vivo. 1365-71. Food Hydrocoll. (2018) 85: 21-9. (39) Du D, Jin T, Zhang R, Hu L, Xing Z, Shi N, Shen (51) Chen CT, Wang ZH, Hsu CC, Lin HH and Chen Y and Gong M. Phenolic compounds isolated JH. Taiwanese and Japanese yam (Dioscorea from Dioscorea zingiberensis protect against spp.) extracts attenuate doxorubicin-induced pancreatic acinar cells necrosis induced by sodium cardiotoxicity in mice. J. Food Drug Anal. (2017) taurocholate. Bioorg. Med. Chem. Lett. (2017) 27: 25: 872-80. 1467-70. (52) Chen T, Hu S, Zhang H, Guan Q, Yang Y and Wang (40) Andrew R and Izzo AA. Principles of X. Anti-inflammatory effects ofDioscorea alata L. pharmacological research of nutraceuticals. Br. J. anthocyanins in a TNBS-induced colitis model. Pharmacol. (2017) 174: 1177-94. Food Funct. (2017) 8: 659-69. (41) Santini A, Tenore GC and Novellino E. (53) Rakotobe L, Berkal M, Huet H, Djediat C, Jeannoda Nutraceuticals: A paradigm of proactive medicine. V, Bodo B, Mambu L, Crespeau F and Edery M.

86 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89

Effects of Madagascar yam extracts, Dioscorea 128: 567-74. antaly, on embryo-larval development of medaka (63) Hu K and Yao X. The cytotoxicity of fish, Oryzias latipes. Toxicon. (2010) 55: 87-91. protoneodioscin (NSC-698789), a furostanol (54) Choi EM, Koo SJ and Hwang JK. Immune cell saponin from the rhizomes of Dioscorea collettii stimulating activity of mucopolysaccharide isolated var. hypoglauca, against human cancer cells in- from yam (Dioscorea batatas). J. Ethnopharmacol. vitro. Phytomedicine (2002) 9: 560-5. (2004) 91: 1-6. (64) Hu K and Yao X. The cytotoxicity of methyl (55) Jin M, Suh SJ, Yang JH, Lu Y, Kim SJ, Kwon protoneogracillin (NSC‐698793) and gracillin S, Jo TH, Kim JW, Park YI and Ahn GW. Anti- (NSC‐698787), two steroidal saponins from the inflammatory activity of bark ofDioscorea batatas rhizomes of Dioscorea collettii var. hypoglauca, DECNE through the inhibition of iNOS and COX- against human cancer cells in-vitro. Phytother. Res. 2 expressions in RAW264. 7 cells via NF-κB and (2003) 17: 620-6. ERK1/2 inactivation. Food Chem. Toxicol. (2010) (65) Kunwar RM, Burlakoti C, Chowdhary CL and 48: 3073-9. Bussmann RW. Medicinal plants in farwest Nepal: (56) Wen CC, Shyur LF, Jan JT, Liang PH, Kuo CJ, Indigenous uses and pharmacological validity. Arulselvan P, Wu JB, Kuo SC and Yang NS. Med. Aromat. Plant Sci. Biotechnol. (2010) 4: 28- Traditional Chinese medicine herbal extracts of 42. Cibotium barometz, Gentiana scabra, Dioscorea (66) Upreti RP and Gyawali R. Antimicrobial activity batatas, Cassia tora and Taxillus chinensis inhibit and phytochemical screening of some traditionally SARS-CoV replication. J. Tradit. Complement. used Nepalese medicinal plants. Int. J. Pharm. Med. (2011) 1: 41-50. Biol. Arch. (2015) 6: 20-5. (57) Byeon S, Oh J, Lim J, Lee J and Kim JS. Protective (67) Murugan M and Mohan VR. In-vitro antioxidant effects of Dioscorea batatas flesh and peel extracts studies of Dioscorea esculenta (Lour). Burkill. against ethanol-induced gastric ulcer in mice. Asian Pac. J. Trop. Biomed. (2012) 2: S1620-S4. Nutrients (2018) 10: E1680. (68) Lee MY, Lee NH, Jung D, Lee JA, Seo CS, Lee (58) Su PF, Li CJ, Hsu CC, Benson S, Wang SY, H, Kim JH and Shin HK. Protective effects of Aravindaram K, Chan SI, Wu SH, Yang FL and allantoin against ovalbumin (OVA)-induced lung Huang WC. Dioscorea phytocompounds enhance inflammation in a murine model of .asthma Int. murine splenocyte proliferation ex-vivo and Immunopharmacol. (2010) 10: 474-80. improve regeneration of bone marrow cells in-vivo. (69) Kaladhar D, Rao VN, Barla S and Harasreeramulu Evid. Based Complement. Alternat. Med. (2011) S. Comparative antimicrobial studies of Dioscorea 2011: 731308. Hamiltonii hook. f. tubers with Azadirachta indica (59) Su PF, Staniforth V, Li CJ, Wang CY, Chiao Stem. J. Pharm. Sci. Technol. (2010) 2: 284-7. MT, Wang SY, Shyur LF and Yang NS. (70) Zhao C, Li X, Miao J, Jing S, Li X, Huang L and Immunomodulatory effects of phytocompounds Gao W. The effect of different extraction techniques characterized by in-vivo transgenic human GM- on property and bioactivity of polysaccharides CSF promoter activity in skin tissues. J. Biomed. from Dioscorea hemsleyi. Int. J. Biol. Macromol. Sci. (2008) 15: 813-22. (2017) 102: 847-56. (60) Hidayat AFA, Chan CK, Mohamad J and Kadir HA. (71) Ashri A, Amalina N, Kamil A, Fazry S, Sairi MF, Dioscorea bulbifera induced apoptosis through Nazar MF and Lazim AM. Modified Dioscorea inhibition of ERK 1/2 and activation of JNK hispida starch-based hydrogels and their in-vitro signaling pathways in HCT116 human colorectal cytotoxicity study on small intestine cell line carcinoma cells. Biomed. Pharmacother. (FHS-74 Int). Int. J. Biol. Macromol. (2018) 107: (2018) 104: 806-16. 2412-21. (61) Ghosh S, Parihar V, More P, Dhavale D and (72) Theerasin S and Baker A. Analysis and Chopade B. Phytochemistry and therapeutic identification of phenolic compounds inDioscorea potential of medicinal plant: Dioscorea bulbifera. hispida Dennst. Asian J. Food Agro-Industry. Med. chem. (2015) 5: 154-9. (2009) 2: 547-60. (62) Nguelefack TB, Dutra RC, Paszcuk AF, Andrade (73) Chiu CS, Deng JS, Chang HY, Chen YC, Lee EL, Tapondjou LA and Calixto JB. Antinociceptive MM, Hou WC, Lee CY, Huang SS and Huang activities of the methanol extract of the bulbs GJ. Antioxidant and anti-inflammatory properties of Dioscorea bulbifera L. var sativa in mice is of Taiwanese yam (Dioscorea japonica Thunb. dependent of NO–cGMP–ATP-sensitive-K+ var. pseudojaponica (Hayata) Yamam.) and its channel activation. J. Ethnopharmacol. (2010) reference compounds. Food Chem. (2013) 141:

87 Dioscorea Plans: Nutra-pharmaceuticals

1087-96. (2016) 7: 1-7. (74) Tewtrakul S and Itharat A. Nitric oxide inhibitory (85) Li Q, Li W, Gao Q and Zou Y. Hypoglycemic effect substances from the rhizomes of Dioscorea of Chinese yam (Dioscorea opposita rhizoma) membranacea. J. Ethnopharmacol. (2007) 109: polysaccharide in different structure and molecular 412-6. weight. J. Food Sci. (2017) 82: 2487-94. (75) Panthong S, Ruangnoo S, Thongdeeying P, (86) Kumar S, Mahanti P, Singh NR, Rath SK, Jena PK Sriwanthana B and Itharat A. Immunomodulatory and Patra JK. Antioxidant activity, antibacterial activity of Dioscorea membranacea Pierre potential and characterization of active fraction of rhizomes and of its main active constituent Dioscorea pentaphylla L. tuber extract collected Dioscorealide B. BMC Complement. Altern. Med. from Similipal Biosphere Reserve, Odisha, India. (2014) 14: 403. Braz. J. Pharm. Sci. (2017) 53: 1-10. (76) Woo KW, Kwon OW, Kim SY, Choi SZ, Son MW, (87) Tang YN, He XC, Ye M, Huang H, Chen HL, Peng Kim KH and Lee KR. Phenolic derivatives from WL, Zhao ZZ, Yi T and Chen HB. Cardioprotective the rhizomes of Dioscorea nipponica and their anti- effect of total saponins from three medicinal neuroinflammatory and neuroprotective activities. species of Dioscorea against isoprenaline-induced J. Ethnopharmacol. (2014) 155: 1164-70. myocardial ischemia. J. Ethnopharmacol. (2015) (77) Tewtrakul S and Itharat A. Anti-allergic substances 175: 451-5. from the rhizomes of Dioscorea membranacea. (88) Yang L, Liu X, Zhuang X, Feng X, Zhong L and Bioorg. Med. Chem. (2006) 14: 8707-11. Ma T. Antifungal effects of Saponin extract from (78) Zhou Q, Yu DH, Liu SM and Liu Y. Total saponins Rhizomes of Dioscorea panthaica Prain et Burk from Discorea nipponica makino ameliorate urate against Candida albicans. Evid. Based Complement. excretion in hyperuricemic rats. Pharmacogn. Alternat. Med. (2018) 2018: 6095307. Mag. (2015) 11: 567-73. (89) McKoy ML, Thomas PG, Asemota H, Omoruyi (79) Zhou Q, Yu DH, Zhang C, Liu SM and Lu F. Total F and Simon O. Effects of Jamaican bitter yam saponins from Discorea nipponica ameliorate urate (Dioscorea polygonoides) and diosgenin on blood excretion in hyperuricemic mice. Planta Med. and fecal cholesterol in rats. J. Med. Food (2014) (2014) 80: 1259-68. 17: 1183-8. (80) Wang T, Choi RC, Li J, Bi CW, Ran W, Chen (90) McAnuff M, Omoruyi F, Morrison ESA and X, Dong TT, Bi K and Tsim KW. Trillin, a Asemota H. Changes in some liver enzymes in steroidal saponin isolated from the rhizomes of streptozotocin-induced diabetic rats fed sapogenin Dioscorea nipponica, exerts protective effects extract from bitter yam (Dioscorea polygonoides) against hyperlipidemia and oxidative stress. J. or commercial diosgenin. West Indian Med. J. Ethnopharmacol. (2012) 139: 214-20. (2005) 54: 97-101. (81) Tang Y. Comparative study on the morphology, (91) Chen Y, Chen XL, Xiang T, Sun BG, Luo HX, chemistry, metabolism and anti-myocardial Liu MT, Chen ZX, Zhang SJ and Wang CJ. Total ischemia activity of three medicinal species of saponins from Dioscorea septemloba thunb reduce Dioscorea [dissertation]. HKBU Institutional serum uric acid levels in rats with hyperuricemia Repository, Hong Kong (2015) 1-176. through OATP1A1 up-regulation. J. Huazhong (82) Yang MH, Yoon KD, Chin YW, Park JH, Kim Univ. Sci. Technol. Med. Sci. (2016) 36: 237-42. SH, Kim YC and Kim J. Neuroprotective effects (92) Fei Y, Ye D, Fan X and Dong F. Effect of Dioscorea of Dioscorea opposita on scopolamine-induced tokoro Makino extract on hyperuricemia in mice. memory impairment in in-vivo behavioral tests and Trop. J. Pharm. Res. (2016) 15: 1883-7. in vitro assays. J. Ethnopharmacol. (2009) 121: (93) Teixeira A, Oliveira I, Lima E and Matsuura T. The 130-4. use of purple yam (Dioscorea trifida) as a health- (83) Liu Y, Li H, Fan Y, Man S, Liu Z, Gao W and promoting ingredient in bread making. J. Res. Biol. Wang T. Antioxidant and antitumor activities (2013) 3: 747-58. of the extracts from Chinese yam (Dioscorea (94) Mollica JQ, Cara DC, D’Auriol M, Oliveira VB, opposite Thunb.) flesh and peel and the effective Cesar IC and Brandão MG. Anti-inflammatory compounds. J. Food Sci. (2016) 81: H1553-64. activity of American yam Dioscorea trifida Lf (84) Ghosh S, Gurav S, Harke A, Chacko M, Joshi in food allergy induced by ovalbumin in mice. J. K, Dhepe A, Charolkar C, Shinde V, Kitture R Funct. Foods (2013) 5: 1975-84. and Parihar V. Dioscorea oppositifolia mediated (95) Roy A, Geetha R and Lakshmi T. Valuation of synthesis of gold and silver nanoparticles with the antibacterial activity of ethanolic extract of catalytic activity. J. Nanomed. Nanotechnol. Dioscorea villosa tubers-an in-vitro study. Int. J.

88 Salehi B et al. / IJPR (2019), 18 (Special Issue): 68-89

Pharm. Pharm. Sci. (2012) 4: 314-6. characterization of steroidal saponins from (96) Siddiqui MA, Ali Z, Chittiboyina AG and Khan Dioscorea zingiberensis CH Wright. Fitoterapia IA. Hepatoprotective effect of steroidal glycosides (2010) 81: 1147-56. from Dioscorea villosa on hydrogen peroxide- (103) Huang CH, Ku CY and Jan TR. Diosgenin induced hepatotoxicity in HepG2 cells. Front. attenuates allergen-induced intestinal inflammation Pharmacol. (2018) 9: 797. and IgE production in a murine model of food (97) Lima CM, Lima AK, Melo MGD, Serafini MR, allergy. Planta Med. (2009) 75: 1300-5. Oliveira DL, de Almeida EB, Barreto RSS, de (104) Saldanha J, Gargiulo D, Silva S, Carmo-Pinto F, Lima Nogueira PC, de Souza Moraes VR and Andrade M, Alvarez-Leite J, Teixeira M and Cara Oliveira ÉRA. Bioassay-guided evaluation of D. A model of chronic IgE-mediated food allergy Dioscorea villosa–an acute and subchronic toxicity, in ovalbumin-sensitized mice. Braz. J. Med. Biol. antinociceptive and anti-inflammatory approach. Res. (2004) 37: 809-16. BMC Complement. Altern. Med. (2013) 13: 195. (105) Olayemi J and Ajaiyeoba E. Anti-inflammatory (98) Zhang XX, Ito Y, Liang JR, Liu JL, He J and Sun WJ. studies of yam (Dioscorea esculenta) extract on Therapeutic effects of total steroid saponin extracts wistar rats. Afr. J. Biotechnol. (2007) 6: 1913-5. from the rhizome of Dioscorea zingiberensis CH (106) Gyawali R, Dhakal A, Bohara DB and Adhikari N. Wright in Freund’s complete adjuvant induced Anti-inflammatory and antimicrobial property of arthritis in rats. Int. Immunopharmacol. (2014) 23: Dioscorea deltoidea L from Nepal. (2010) 5: 72-5. (107) Jeon S, Lee CH, Liu QF, Kim GW, Koo BS and 407-16. Pak SC. Alteration in brain-derived neurotrophic (99) Cho J, Choi H, Lee J, Kim MS, Sohn HY and factor (BDNF) after treatment of mice with herbal Lee DG. The antifungal activity and membrane- mixture containing Euphoria longana, Houttuynia disruptive action of dioscin extracted from cordata and Dioscorea japonica. DARU (2014) Dioscorea nipponica. Biochim. Biophys. Acta 22: 77. (2013) 1828: 1153-8. (108) Li T, Teng H, An F, Huang Q, Chen L and Song H. (100) Huang H, Jiang Q, Chen Y, Li X, Mao X, Chen The beneficial effects of purple yam (Dioscorea X, Huang L and Gao W. Preparation, physico– alata L.) resistant starch on hyperlipidemia in chemical characterization and biological activities high-fat-fed hamsters. Food Funct. (2019) 10: of two modified starches from yam (Dioscorea 2642-50. Opposita Thunb.). Food Hydrocoll. (2016) 55: (109) Teng H, An F, Huang Q, Chen L and Song H. The 244-53. beneficial effects of purple yam (Dioscorea alata (101) Mei X, Xu D, Xu S, Zheng Y and Xu S. Novel L.) resistant starch on hyperlipidemia in high-fat- role of Zn (II)–curcumin in enhancing cell fed hamsters. (2019) 10: 2642-50. proliferation and adjusting proinflammatory (110) Komesaroff PA, Black CVS, Cable V and Sudhir cytokine-mediated oxidative damage of ethanol- K. Effects of wild yam extract on menopausal induced acute gastric ulcers. Chem. Biol. Interact. symptoms, lipids and sex hormones in healthy (2012) 197: 31-9. menopausal women. Climacteric (2001) 4: 144-50. (102) Li H, Huang W, Wen Y, Gong G, Zhao Q and This article is available online at http://www.ijpr.ir Yu G. Anti-thrombotic activity and chemical

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Minerva Access is the Institutional Repository of The University of Melbourne

Author/s: Salehi, B; Sener, B; Kilic, M; Sharifi-Rad, J; Naz, R; Yousaf, Z; Mudau, FN; Fokou, PVT; Ezzat, SM; El Bishbishy, MH; Taheri, Y; Lucariello, G; Durazzo, A; Lucarini, M; Suleria, HAR; Santini, A

Title: Dioscorea Plants: A Genus Rich in Vital Nutra-pharmaceuticals-A Review

Date: 2019-09-01

Citation: Salehi, B., Sener, B., Kilic, M., Sharifi-Rad, J., Naz, R., Yousaf, Z., Mudau, F. N., Fokou, P. V. T., Ezzat, S. M., El Bishbishy, M. H., Taheri, Y., Lucariello, G., Durazzo, A., Lucarini, M., Suleria, H. A. R. & Santini, A. (2019). Dioscorea Plants: A Genus Rich in Vital Nutra- pharmaceuticals-A Review. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH, 18 (Suppl1), pp.68-89. https://doi.org/10.22037/ijpr.2019.112501.13795.

Persistent Link: http://hdl.handle.net/11343/245947

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