Phytochemical, Phytotherapeutical and Pharmacological Study of Momordica dioica

Momordica dioica is a perennial, dioecious, cucurbitaceous climbing creeper (commonly known as kakrol, spiny gourd or teasle gourd). It is native to Asia with extensive distribution in India and Bangladesh. It is used not only as preventive and curative agent for various diseases but also as vegetable with a significant nutritional value over thousands of years. This review aims to take an attempt to evaluate the phytochemical, ethnobotanical, phytotherapeutical and pharmacological properties of kakrol according to the view of traditional medicinal plant based treatment including ayurveda along with recent scientific observations. Kakrol is considered as an underutilized vegetable, although having significant presence of certain compounds containing higher nutritional value than many frequently consumed vegetables. Moreover, as a traditional medicinal plant, it is still potential for its phytochemical components that increase the demand of further extensive evaluation to justify its other therapeutical roles. Therefore, this effort will be helpful to researchers who interested to disclose the unjustified phytotherapeutical role of Momordica dioica.


Introduction
Momordica dioica Roxb. is a perennial, dioecious (2 = 28) climber included in Cucurbitaceae family ( Figure 1). Momordica genus contains about 80 species [1,2]. According to the latest revision of Indian Momordica, there are six well identified species of which four are dioecious and two are monoecious [3]. Although this genus is originated from Indo-Malayan region, it is now found to grow in India, Bangladesh, Srilanka, Myanmar, China, Japan, South East Asia, Polynesia, Tropical Africa, and South America [4,5]. Its cultivation up to an altitude of 1500 meters in Assam and Garo hills of Meghalaya is reported [6]. It is commonly known as spine gourd, teasel gourd or small bitter gourd worldwide whereas in Bangladesh it is known as kakrol and in India as kankro, kartoli, kantoli, kantola, kantroli, ban karola, or janglee karela [7][8][9][10]. Kakrol is about 5-7 meters in length, a popular summer vegetable of which its fruit, young twigs and leaves are used as vegetable [11][12][13].

Ethnobotanical and Phytotherapeutical Study
According to Ayurveda (Table 2), not only its fruits have diuretic, laxative, hepatoprotective, antivenomous, antihypertensive, anti-inflammatory, antiasthmatic, antipyretic, antileprosy, antidiabetic, and antidepressant properties but also its leaves have antihelminthic, aphrodisiac, antihemorroidal, hepatoprotective, antibronchitic, antipyretic, antiasthmatic, and analgesic properties [33,34]. Fresh fruit juice and cooked fruit in small amount of oil are prescribed for hypertension and diabetes, respectively. Oral administration of 50 mL of root juice is advised once a day with empty stomach to beat diabetes. The juice of root is a domestic remedy for the inflammation caused by contact with the urine of the house lizard. The juice of the leaves are mixed with coconut, pepper, red sandalwood, and so forth in order to form an ointment and applied to the head to relieve pain. Dried fruit powder applied into the nostrils produces a powerful errhine effect and provokes a copious discharge from the schneiderian mucous membrane [35]. Root juice has stimulant, astringent, antiseptic, antidiabetic, anti-inflammatory, and antiulcerant effect. The mucilaginous tubers act as antihelminthic, spermicidal, and antifertility abortifacient agent [36]. The root of the male plant is used in snake bites and scorpion sting [37]. The superficial use of root paste over the whole body is believed to act as a sedative in high fever with delirium [38,39]. Beside the superficial and oral administration of leaf paste for skin disease, tender fruits are rubbed on skin for pimples and acne and roasted seeds are used for eczema and other skin problems [40]. Root powder is also applied for softening skin and reducing perspiration. The protective role of the leaves against chronic skin diseases is also reported. A preparation called "Panchatikta ghrita" is made by boiling 800 g each of neem bark, leaves of Momordica dioica, Solanum surattense, Tinospora cordifolia, and bark of Adhatoda vasica, in 5-6 liters of water up to its reduction to quarter and then adding of 3.5 liters of butter and about 3 kg myrobalans and is recommended as one tablespoonful with little hot milk internally twice daily in chronic skin diseases [41]. Mucilaginous tuber of female plant and toasted root are used in bleeding piles and bowel infections. The traditional use of Momrdica dioica against bleeding piles (hemorrhoids) is also reported [42,43].

Antioxidant Activity.
Compounds derived from natural sources are capable of providing protection against free radicals [44]. The alcoholic extract inhibited the formation of oxygen derived free radicals (ODFR) in vitro with 4000 g/mL ascorbic system [45]. In another work, the free radical scavenging potential of the tuberous roots was studied by different in vitro methods, namely, DPPH radical scavenging, ABTS radical scavenging, iron chelating activity, total antioxidant capacity, and haemoglobin glycosylation assay. Total antioxidant capacity of ethanolic extract was found to be 26 g/mL which is equivalent to ascorbic acid. Protein -Q u a n t i t a t i v e a n a l y s i s s h o w e d 3 . 1 / 1 0 0 g [15] -Q u a n t i t a t i v e a n a l y s i s s h o w e d 1 9 . 3 8 % [16] Crude lipid -Quantitative analysis showed 3.25% [14] Fat -Q u a n t i t a t i v e a n a l y s i s s h o w e d 3 . 1 / 1 0 0 g [15] -Q u a n t i t a t i v e a n a l y s i s s h o w e d 4 . 7 % [16] Crude fiber -Quantitative analysis showed 22.9% [14] Carbohydrate -Q u a n t i t a t i v e a n a l y s i s s h o w e d 5 9 . 3 1 % [14] -Q u a n t i t a t i v e a n a l y s i s s h o w e d 7 . 7 / 1 0 0 g [15] Niacin -Not specified [15] Thiamin -Not specified [15] Carotene -Not specified [15] -Quantitative analysis showed 162 mg/100 g of edible portion [18,19] Ascorbic acid -Not specified [24] Potassium -Quantitative analysis showed 4.63 mg/100 g dry weight [14] -Quantitative analysis showed 8.3 mg/g [16] Sodium -Quantitative analysis showed 1.62 mg/100 g dry weight [14] -Q u a n t i t a t i v e a n a l y s i s s h o w e d 1 . 5 m g / g [16] Calcium -Quantitative analysis showed 7.37 mg/100 g dry weight [14] -Quantitative analysis showed 0.5 mg/g [16] Iron -Quantitative analysis showed 5.04 mg/100 g dry weight [14] -Quantitative analysis showed 0.14 mg/g [16] Zinc -Quantitative analysis showed 3.83 mg/100 g dry weight [14] -Q u a n t i t a t i v e a n a l y s i s s h o w e d 1 . 3 4 m g / g [16] -Not specified [21] -Quantitative analysis showed 4.91 mg/kg (peeled), 11.0 mg/g (unpeeled) [22] Manganese -Not specified [20] Iodine -Not specified [23] Chromium -Quantitative analysis showed 0.27 mg/kg (peeled), 0.26 mg/kg (unpeeled) [22] -Not specified [21] Phytic acid -Quantitative analysis showed 2.8 mg/g [16] Total phenolic compound -Quantitative analysis showed 3.7 mg/g [16] Alkaloids -Identified in ethyl acetate, methanol extract [25] Flavonoid -Identified in methanol, hexane extract [25] Steroids -Identified in ethyl acetate, methanol, aqueous extract [25] Saponins -Identified in methanol, aqueous extract [25] Triterpenoids -Identified in ethyl acetate, methanol, aqueous extract [25] Seed Alkaloid Momordicin Identified in seed oil [26] Lectin Anti-H-Lectin Not specified [30] 4 Evidence-Based Complementary and Alternative Medicine Stearic acid -Identified in methanol extract [31] Steroid -spinasterol octadecanoate Identified in methanol extract Identified in methanol extract [31] Triterpenoid Oleanolic acid Identified in methanol extract [32] Gypsogenin Identified in methanol extract [32] Hederagenin Identified in methanol extract [32] 3 -O-benzoyl-6-oxo-ursolic acid Identified in methanol extract Identified in methanol extract [32] 3-O--D-glucopyranosyl hederagenin Identified in methanol extract [31] 3-O--D-glucopyranosyl gypsogenin Identified in methanol extract [31] 3-O--D-glucuronopyranosyl gypsogenin Identified in methanol extract [31] Moreover, its ethanol extract showed percentage inhibition of haemoglobin glycosylation as 66.63 and 74.14 at conc. of 500 and 1000 g/mL, respectively, while that of standard DL -tocopherol was 61.53% and 86.68% inhibition at same concentration [46]. The antioxidant activities of methanol and aqueous extract of fruits were analyzed and the presence of phenolic compounds, flavonoids, sterol, alkaloids, amino acids, and so forth, were found [47]. Among those compounds, due to the presence of flavonoids, its fruit was reported as a potent antioxidant [48].

Analgesic Activity. Ilango et al. and Vaidya and
Shreedhara reported that both hexane extract and soluble portion of methanolic extract of Momordica dioica fruit pulp exhibited analgesic activity when compared to standard drug [49,50]. Petroleum ether, ethyl acetate, and methanol extracts exhibited significant analgesic activity in acetic acid induced writhing syndrome when compared to the vehicle treated control group. But among them petroleum ether and methanol extract gave more significant analgesic activity than ethyl acetate extract [51].

Nephroprotective Activity.
The ethanol extract of seeds was screened and marked nephroprotective as well as curative activities was found without any toxicity caused by nephrotoxin-like gentamicin [52]. The nephroprotective and curative activities of its fruit extract ware also observed [53]. Gupta et al. evaluated the renal protective effect of Momordica dioica extract in streptozotocin-diabetic rats [54].

Neuroprotective
Activity. The effect of methanol and aqueous extract of fruit pulp was observed on the central nervous system by using neuropharmacological experimental models in mice. These extracts were used for a dosedependent reduction of the onset and duration of a reduction in locomotor activity. It was suggested that methanol and aqueous extract of fruit pulp (100 mg/kg and 200 mg/kg) had neuroprotective activities [55].

Antiallergic Activities.
The antiallergic activity of its extract in mice was observed [56]. The alcoholic extract was evaluated and its efficacy to inhibit passive cutaneous anaphylaxis was found in mouse and rat [57].
4.6. Antiulcer Activity. Vijayakumar screened Momordica dioica extract mediated antiulcerogenic effect on ethanolinduced ulcer model of rat. A significant decrease occurred in the level of H + -K + ATPase, volume of gastric juice, and acid output. Gastric wall mucus, p H , and catalase enzyme were increased significantly but antioxidant enzyme levels of superoxide dismutase were decreased [58]. Its gastroprotective and ulcer healing activities were also observed by Vijayakumar et al. [59].

Diabetes
Cooked fruit in small amount of oil [35] Pimple and acne protectant Tender fruits are rubbed on skin for pimples and acne [40] Diuretic Not specified [33,34] Laxative Not specified [33,34] Hepatoprotective agent Not specified [33,34] Antihypertensive Not specified [33,34] Anti-inflammatory agent Not specified [33,34] Antipyretic Not specified [33,34] Antivenomous agent Not specified [33,34] Antiasthmatic agent Not specified [33,34] Antidepressant Not specified [33,34] Antileprosy agent Not specified [33,34] Root Diabetes Oral administration of 50 mL of root juice is advised once a day with empty stomach. [35,36] Anti-inflammatory agent The juice of the root is a domestic remedy for the inflammation caused by contact with the urine of the house lizard. [35,36] Stimulant Root juice [36] Antiseptic Root juice [36] Antiulcerant Root juice [36] Antitoxic agent The root of the male plant uses in snake bites and scorpion sting [37] Antipyretic The root paste smearing over the whole body act as a sedative fever with delirium [38,39] Skin softening agent Root powder is applied for softening skin [41] Antiperspirant Root powder is applied for reducing perspiration. [41] Antihemorroidal agent Toasted roots are used in bleeding piles [42,43] Bowel infection reducer Toasted roots are used in bowel infections [42] Mucilaginous tuber Antihelminthic agent Not specified [36] Spermicidal agent Not specified [36] Antifertility agent Not specified [36] Antihemorroidal agent Mucilaginous tuber of female plant are used in bleeding piles [42,43] Bowel infection reducer Mucilaginous tuber of female plant are used in bowel infections [42] Seed Eczema protectant Roasted seeds are used for eczema and other skin problems [40] Leaf Analgesic Leaf juice is mixed with coconut, pepper, red sandalwood, and so forth in order to form an ointment to relieve pain. [35] Antihelminthic Not specified [33,34] Antihemorroidal Not specified [33,34] Antibronchitic Not specified [33,34] Skin disease reducer A preparation called "Panchatikta ghrita" is made by boiling 800 g each of neem bark, leaves of Momordica dioica, Solanum surattense, Tinospora cordifolia, and bark of Adhatoda vasica, in 5-6 liters of water up to its reduction to quarter and then the addition of 3.5 liters of butter and 3 kg myrobalans, is recommended as one tablespoonful with little hot milk internally twice daily in chronic skin diseases [40,41] [56]. The saponin fraction of Momordica dioica (27.5 and 55 mg/kg) administered to the CCl 4 treated rats to protect the liver cells from liver damages on hepatocytes and silymarin (100 mg/kg), a well-known natural antihepatotoxic drug was used as standard [71]. The hexane extract and ethyl acetate soluble fraction of the methanolic extract of the fruit pulp at a dose of 400 mg/kg administered for 7 days in rat exhibited a significant therapeutic effect [72]. Sato et al.
observed significant lowering of liver cholesterol and triacylglycerol levels in rats. Fecal lipid excretion was increased and lymphatic transport of triacylglycerol and phospholipids were decreased in rats which were fed the kakrol after permanent lymph cannulation. Moreover, -butanol extract caused a significant reduction in the pancreatic lipase activity in vitro and liver lipids by inhibiting lipid absorption [73].  [78,79]. Allelopathy refers to the chemical inhibition of one species by another by releasing chemicals into the environment where it affects the development and growth of neighboring plants. Ahire and Deokule observed the leaf extract of M. dioica mediated allelopathic activity on seedling growth as well as seed germination of P. aconitifolius and found major toxicity at a dose of 2.0% and 2.5% w/v of phytoextracts [80]. These above information are summarized in Table 3.

Conclusion
The traditional use of medicinal plants has a long history. Ancient people as well as our ancestors were mainly dependent on plants for their recovery against diseases. But, the recent tendency to avoid natural sources rather than artificial Evidence-Based Complementary and Alternative Medicine 7 Inhibited the formation of oxygen derived free radicals (ODFR) in vitro with 4000 g/mL ascorbic system. [45] Root Ethanol extract DPPH radical scavenging, ABTS radical scavenging, iron chelating activity, total antioxidant capacity and haemoglobin glycosylation assay were studied. Total antioxidant capacity was 26 g/mL equivalents to ascorbic acid. [46] Fruit Methanol, aqueous extract Found the presence of phenolic compound, flavonoids, sterol, alkaloids and amino acids. [47] Leaf Ethanol, aqueous extracts The presence of flavonoids was reported as a potent antioxidant [48] Analgesic activity Fruit Hexane, methanol extract Exhibited analgesic activity when compared to standard drug [49] Fruit Petroleum ether, methanol, ethyl acetate extract Petroleum ether and methanol extract gave more significant analgesic activity than ethyl acetate extract. [51] Nephroprotective activity Seed Ethanol extract Found marked nephroprotective and curative activities without any toxicity caused by nephrotoxin-like gentamicin. [52] Fruit Ethanol extract Observed significant reduction in GSH and an increase in malondialdehyde (MDA) production. [53] Neuroprotective activity Fruit Methanol and aqueous extract Methanol and aqueous extract of fruit pulp (100 mg/kg and 200 mg/kg) had neuroprotective activities. [55] Antiallergic activities Seed Alcoholic extract The antiallergic activity of extract in mice was observed. [56] Not specified Alcoholic extract Found its efficacy to inhibit passive cutaneous anaphylaxis in mouse and rat. [57] Antiulcer activity Fruit Ethanol extract Decreased the level of H + -K + ATPase, volume of gastric juice, and acid output. Gastric wall mucus, p H and catalase enzyme were increased significantly. Antioxidant enzyme levels of superoxide dismutase were decreased. [58] Fruit Hydro alcohol extract Gastroprotective and ulcer healing activities were observed. [59] Anticancer activity Root Methanol extract The growth inhibitory index (%) of -spinasterol-3-o--D-glucopyranoside was shown to be 50%, at the dose of 4 g/mL while testing on cancer cell (L1210). [31] Antimicrobial activity

Fruit
Methanol, aqueous extract Found methanolic extract had more promising antimicrobial activity. [47] Root, Leaf Ethyl acetate extract  Fruit Methanol extract Exhibited a significant therapeutic effect at a dose of 400 mg/kg administered for 7 days in rat. [72] Fruit n-butanol extract Observed significant lowering of liver cholesterol and triacylglycerol levels in rats. Moreover, n-butanol extract caused a significant reduction in the pancreatic lipase activity in vitro. [73] Antifertility activity Root Ethanol, aqueous extract Found moderate estrogenic activity including significant increase in uterine weight and abortifacient activity. [74] Fruit Ethanolic extract Found antifertility activities of female rats but no male antifertility activity at the dose of 250 mg/kg [75] Antiedemic activity Root Alcoholic extract Showed significant reduction of carrageenan-induced paw edema. [45] Insecticidal activity Seed Seed oil Alkaloid momordicin in seed oil was responsible for 100% mortality at 4% conc. in 24 hours. [76] Grain protectant activity Seed Seed oil Seed oil was grain protectant against Callosobruchus chinensis [77] Antifeedant activity Fruit Hexane and ethyl acetate extract Showed antifeedant activity against Spodoptera litura [78,79] Allelopathic activity Leaf Aqueous extract Leaf extract has allelopathic activity on seedling growth and seed germination of P. aconitifolius [80] sources against disease is frustrating. Because continuous reports of antibiotic resistance as well as the side effects of synthetic drugs all over the world are indicating a global health alert. The higher occurrence rate of worldwide diabetes, cancer, obesity, hypertension, and neurodegenerative diseases becomes alarming to all. Huge researches are carried out to find the causes and remedies of them. Therefore, to search for a better alternative than synthetic drug becomes the demand of time.
Medicinal plants may be a good option to play pivotal role against such complications. But, before that their previous use and curability should be justified. Medicinal plants are the source of enormous secondary metabolites. The diverse role of secondary metabolites may provide a key of the door Evidence-Based Complementary and Alternative Medicine 9 of undiscovered remedy against diseases. In that case, long term research on medicinal plant is essential to justify their potential. Moreover, the use of medicinal plants is important for its ecofriendly significance as well as its fewer side effects than other synthetic drugs. Additionally, it will be comparatively safer and cheaper than man-made drugs formulation.
South Asia, as one of the highest sources of medicinal plant in the world, provides enormous medicinal plants including kakrol, having several significant folk uses but not clinically evaluated till now. Therefore, vast chances have been created to justify the dynamic ethnobotanical and phytotherapeutical roles of several plants for future researchers. This paper has mainly focused on the phytotherapeutical and pharmacological potential of Momordica dioica. As it contains significant amount of antioxidant, vitamin, secondary metabolites, and other important ingredients, these may be helpful to fight against several diseases including diabetes, cancer, and neurodegenerative diseases. For example, ethyl acetate and ethanol extract of kakrol containing steroids, tritepenoids etc. have potential role in alloxan-induced diabetic rats and broadly type 2 diabetes. Similarly, methanol and aqueous extract of its fruit pulp have neuroprotective activities.
Therefore, this paper will be fruitful if it stimulates the researcher's emphasis to justify the unrevealed but potential therapeutic properties of Momordica dioica against diabetes, cancer, neurodegenerative disease, and other life threatening disorders.