Winter melon

Winter melon also known as Benincasa hispida, wax gourd, ash gourd, white gourd, winter gourd, tallow gourd, ash pumpkin, winter melon, Chinese preserving melon, kundur fruit, chalkumra, and (alu) puhul, is a fruit the family Cucurbitaceae that is eaten as a vegetable when mature ¹. The taste is rather bland but sweet ². Winter melon fruit is covered in a fuzzy coating of fine hairs when young. The immature melon has thick white flesh that tastes sweet. The mature fruit sheds its hairs and forms a waxy white coating, giving the name of “wax gourd.” The gourd wax coating increases the long shelf life of it. Winter melon can grow of a length up to 80 cm and also have broad leaves and yellow flowers  ³.

Winter melon is a native of South and Southeast Asia. However, it is commonly grown all over Asia, including Japan, China, Korea, Burma, Ceylon, Sri Lanka, Indonesia, and Australia ², ⁴, ⁵.

Winter melon fruit contains 93–96% water and is rich in nutrients such as vitamin C, vitamin B2 (riboflavin), sodium (Na), and calcium (Ca) ⁶, ⁷, ⁸. Phenolic compounds such as astilbin, catechin, and naringenin have been isolated from winter melon fruit ⁹. Other bioactive compound constituents include triterpenes (alnusenol, multiflorenol, isomultiflorenol), sterols (lupeol, lupeol acetate, β-sitosterol), glycosides, saccharides, carotenes, β-sitosterin, tannins, and uronic acid ¹⁰, ¹¹. However more studies are needed to be done to isolate and identify the bioactive chemical components contained in winter melon ¹².

Several lab animal and test tube studies on the functionality of winter melon fruit extracts have reported their antioxidant, anti-inflammatory, anti-ulcerogenic, antidiabetic, and anti-Alzheimer’s efficacy (see Figure 2 below) ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ². However, there have been no randomized studies on the effect of ash gourd (winter melon) on the prevention of diseases in human ²¹. In Chinese medicine, winter melon crust is used to treat urinary dysfunction, and the fruits are used to treat fever ²¹. In Ayurveda, winter melon fruits are also used to treat epilepsy, lung diseases, asthma, cough, and urinary retention ²¹.

Figure 1. Winter melon

Figure 2. Winter melon uses

Footnotes: Diagram with different parts (aerial parts, flower, fruit pulp unripe, fruits, fruit pulp mature, and seeds) of Benincasa hispida (Thunb.) Cogn, traditional uses, and its most important pharmacological properties.

Abbreviations: PPARγ = peroxisome proliferator-activated receptor gamma; C/EBPα = CCAAT enhancer-binding protein alpha; CAT = catalase; SOD = superoxidase dismutase; GSH = reduced glutathione; LPO = lipid peroxidations.

[Source ²¹ ]

Winter melon nutrition facts

Winter melon fruit contains 93–96% water, proteins (0.30-0.70/100 g), carbohydrates (1.10-4.00/100 g), fat (0.02-0.20/100 g), fiber (0.50-2.10/100 g), and ash (0.27-0.70/100 g).

Vitamins present in the edible portion (per 100 g) of winter melon are vitamin C (13 mg), thiamin (vitamin B1) (0.04 mg), riboflavin (vitamin B2) (0.11 mg), niacin (vitamin B3) (0.4 mg), and vitamin E. Major minerals in the edible portion (per 100 g) include sodium (Na) (111 mg), potassium (K) (6 mg), calcium (Ca) (19 mg), iron (Fe) (0.4 mg), and phosphorus (P) (19 mg) ²², ²³, ²⁴, ²⁵. The fruit contains water-soluble polysaccharides ²⁶, such as arabinogalactans ²⁷.

The fruit pulp contains homogalacturonan, β-(1 → 4)-D-galactan, acidic arabinan ²⁸ and natural sugars (e.g., glucose and fructose) ²⁹. The mature fruit also contains organic acids such as malic and citric acid. The fruit also contain many volatile compounds, including (E,E)-2,4-nonadienal, (E)-2-hexenal, n-hexanal, n-hexyl formate, (E,E)-2,4-heptadienal, (Z)-3-hexenal, (E)-2-heptenal, 1-octen-3-ol, 2,5-dimethylpyrazine, 2-methyl pyrazine, 2-ethyl-5-methyl pyrazine, and 2,6-dimethylpyrazine, 2,3,5-trimethylpyrazine ³⁰.

Winter melon seeds contain proteins ³¹, carbohydrates, phenolic compounds, amino acids, flavonoids, sterols ³², glycosides, alkaloids, fixed oils and fats, phenolic compounds, steroids ³³ and unsaturated fatty acids ³⁴. The peel contains alkaloids, saponins, steroids, carbohydrates, flavonoids ³⁵, tannins, carotenoids, oxalates, and phytate ²⁵.

The root contains proteins ³¹.

Table 1. Winter melon, ash gourd, wax gourd, chinese preserving melon (raw per 100 gram)

Name	Amount	Unit
Water	96.1	g
Energy	13	kcal
Energy	54	kJ
Protein	0.4	g
Total lipid (fat)	0.2	g
Ash	0.3	g
Carbohydrate, by difference	3	g
Fiber, total dietary	2.9	g
Calcium (Ca)	19	mg
Iron (Fe)	0.4	mg
Magnesium (Mg)	10	mg
Phosphorus (P)	19	mg
Potassium (K)	6	mg
Sodium (Na)	111	mg
Zinc (Zn)	0.61	mg
Copper (Cu)	0.023	mg
Manganese (Mn)	0.058	mg
Selenium (Se)	0.2	µg
Vitamin C (ascorbic acid)	13	mg
Thiamin (vitamin B1)	0.04	mg
Riboflavin (vitamin B2)	0.11	mg
Niacin (vitamin B3)	0.4	mg
Pantothenic acid (vitamin B5)	0.133	mg
Vitamin B6	0.035	mg
Folate, total	5	µg
Folic acid	0	µg
Folate, food	5	µg
Folate, DFE	5	µg
Vitamin B12	0	µg
Vitamin A, RAE	0	µg
Retinol	0	µg
Vitamin A, IU	0	IU
Vitamin D (D2 + D3), International Units	0	IU
Vitamin D (D2 + D3)	0	µg
Fatty acids, total saturated	0.016	g
SFA 16:0	0.011	g
SFA 18:0	0.005	g
Fatty acids, total monounsaturated	0.037	g
MUFA 18:1	0.037	g
Fatty acids, total polyunsaturated	0.087	g
PUFA 18:2	0.087	g
Fatty acids, total trans	0	g
Cholesterol	0	mg
Tryptophan	0.002	g
Lysine	0.009	g
Methionine	0.003	g

Abbreviations: SFA = saturated fatty acid; MUFA = monounsaturated fatty acid; PUFA = polyunsaturated fatty acid; SFA 16:0 = palmitic (hexadecanoic acid); SFA 18:0 = stearic (octadecanoic acid); MUFA 18:1 = oleic acid; PUFA 18:2 = linoleic acid

[Source ²² ]

Winter melon bioactive compounds

Winter melon is rich in phenolic compounds. Several other bioactive compounds present in it are isomultiflorenyl acetate, isovitexin, 1-sinapoylglucose, multiflorenol, 5-gluten-3-β-ylacetate, alnusenol, and benzylalcolcohol-O-α-l-arabinopyranosyl-(1-6)-β-d-glucopyranoside ³⁶. The most representative phytochemicals present in winter melon is shown Table 2.

Table 2. Winter melon chemical phytoconstituents

Compounds	Plant parts	Locality/country	References
E-2-hexenal, n-hexanal and n-hexyl formate; however, 2,5-dimethylpyrazine, 2,6-dimethylpyrazine, 2,3,5-trimethylprazine, 2-methylpyrazine, 2-ethyl-5-methylpyrazine	Fruit	Taipei, Taiwan/China	30
Cucumisin-like protease	Sarcocarp	Kagoshima/Japan	37
Triterpenes, sterols, flavonoid C-glycoside, benzyl glycoside, alnusenol, multiflorenol	Fruit	Kyoto/Japan	38
Osmotin-like protein	Seeds	New York/USA	39
Chitinase	Seeds	New York/USA	40
Astilbin, catechin, naringenin	Fruit	Hainan/China	36
Di-2-ethylhexyl phthalate	Fruit	Hainan/China	41
W-sitosterol, V-amyrin, quercetin	Stem	Visakhapatnam/India	42
β-Carotene	Fruit	Faisalabad/Pakistan	24
Tryptophan	Fruit	Gwalior/India	43
Linoleic, palmitic, oleic, and stearic acids	Fruit	Temerloh, Pahang/Malaysia	44
Acetoin, octanal, nonanal	—	Mumbai/India	45
α-Tocopherol, δ-tocopherol, linoleic acid, β-sitosterol, campesterol, stigmasterol, Δ5-avenasterol	Fruit	Serdang, Selangor/Malaysia	46
Galactose, glucose, xylose, sorbose	Peel	Karnataka/India	47
Linoleic acid, linolenic acid	Seeds	Serdang, Selangor/Malaysia	48
Myristic acid, palmitoleic acid, oleic acid, linoleic acid, stearic acid, α-linolenic acid, palmitic acid, other saturated and unsaturated fatty acids	Seed oil	Serdang, Selangor/Malaysia	49
3α,29-O-di-trans-cinnamoyl-D:C-friedooleana-7,9(11)-diene, oleanolic acid 28-O-β-D-xylopyranosyl-[β-D-xylopyranosyl-(1 → 4)]-(1 → 3)-α-L-rhamnopyranosyl (1 → 2)-α-L-arabinopyranoside, oleanolic acid 28-O-β-D-glucopyranosyl-(1 → 3)-β-D-xylopyranosyl-[β-D-xylopyranosyl-(1 → 4)]-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranoside, multiflorenol, isomultiflorenyl acetate, stigmasterol, stigmasterol 3-O-β-D-glucopyranoside, α-spinasterol, α-spinasterol 3-O-β-D-glucopyranoside, β-sitosterol, daucosterol, arbutin, nicotinic acid, (+)-pinonesinol, ethyl β-D-glucopyranoside	Fruit	Jinghong/China	50
Phloem lectin-like protein	Exudate	Fukuoka/Japan	51
Linoleic acid, palmitic acid, oleic acid, stearic acid	Seeds	Rambagh, Allahabad/India	52
Gallic acid	Fruit	Kota Bharu/Malaysia	53
Lupeol	Seeds	Mumbai/India	33
Gallic acid, linoleic acid	Seeds	Serdang, Selangor/Malaysia	34
β-Sitosterol	Seeds	Mumbai/India	54
Ascorbic acid	Fruit	Kubang Kerian, Kelantan/Malysia	55
β-Carotein, ascorbic acid	Peel	Mysore/India	25
Polysaccharides	Fruit	Guangzhou/China	56
Gallic acid, catechin, epicatechin, rutin, quercetin, quercetin-3-D-galactoside, trans-ferrulic acid, oleanolic acid, ursolic acid	Fruit	Buzau/Romania	19

[Source ²¹ ]

Winter melon uses

Scientific reports suggest that winter melon possesses many important nutritious substances, including vitamins, natural sugars, amino acids, organic acids, and mineral elements ⁵⁷, ²³, ⁵⁸. Winter melon fruit contains 93–96% water and is rich in nutrients such as vitamin C (ascorbic acid), vitamin B2 (riboflavin), sodium (Na), and calcium (Ca) ⁶, ⁷, ⁸. Phenolic compounds such as astilbin, catechin, and naringenin have been isolated from winter melon fruit ⁹. Other bioactive compound constituents include triterpenes (alnusenol, multiflorenol, isomultiflorenol), sterols (lupeol, lupeol acetate, β-sitosterol), glycosides, saccharides, carotenes, β-sitosterin, tannins, and uronic acid ¹⁰, ¹¹.

In India, winter melon is used as a winter season vegetable for a wide variety of diseases. Its medicinal properties have been also recognized in the Ayurvedic system of medicine, spiritual traditions of India and Yoga ²¹. In Vietnam, its soup (cooked with pork short ribs) is traditionally used by breastfeeding mothers ²¹. In north India and almost all regions in Bangladesh, it is added with pulses like as moong which usually crushed, along with wax gourd, makes a dish locally called bori, which after sun drying is used in curry dishes and eaten with rice or chapati ⁵⁹. To make wax gourd soup in China, it is used in stir-fries or added into pork or pork/beef bones, which often served in the scooped-out gourd, carved by scraping off the waxy coating. It is also cut into pieces, candied and normally eaten during the time of New Year festivals, or used as filling in Sweetheart cake. For the Moon Festival, the Chinese and Taiwanese also used it in moon cakes as a base filling. It is candied by the people of the Philippines and is used as a pastry filling for bakpia. In some savoury soups and stir-fries, it also acts as an ingredient. In Nepal, India, and Bangladesh, the tendrils, shoots, and leaves of the plant are consumed as green vegetables ²³.

Winter melon is widely used in Chinese medicine, in the treatment of fever, cough accompanied by thick mucus and urinary disorders, it is used especially in bark with a very good diuretic effect ²¹. The fruit is recommended for overweight people who want to follow diets ²¹. In Ayurvedic medicine, it is used in the treatment of epilepsy, cough, lung disease, hiccups, asthma, internal bleeding, and urinary retention. In India, a fruit compote called Petha Cubes is made from the pulp of the fruit, which is recommended for vegetarians ⁶⁰.

Winter melon fruit is also used in peptic ulcer, and it is also used in diabetes mellitus, urinary infection, hemorrhages from internal organs, insanity, epilepsy, and other nervous disorders in Ayurveda ⁶¹. The fruit is sweet and traditionally used as a cooling, styptic, antiperiodic, laxative, diuretic, tonic, aphrodisiac, and cardiotonic, and also in jaundice, dyspepsia, urinary calculi, blood disease (e.g., hemorrhages from internal organs), insanity, epilepsy, asthma, diabetes, vitiated conditions of pitta, fever, menstrual disorders, and balancing the body heat ⁵³.

Antioxidant effects

Antioxidants are man-made or natural substances that may prevent or delay some types of cell damage ⁶². Antioxidants are found in many foods, including fruits and vegetables ⁶². Antioxidants are also available as dietary supplements. Table 3 shows the antioxidant effects of various parts of winter melon.

The body’s trillions of cells face constant threat from chemicals called free radicals. In very high levels, free radicals are capable of damaging cells and genetic material. The body generates free radicals as the inevitable byproducts of turning food into energy. Free radicals are also formed after exercising or exposure to cigarette smoke, air pollution, and sunlight ⁶². Oxidative stress is a term used for free radical diseases ⁶³, ⁶⁴. It is defined as the imbalance between free radicals and antioxidants, given that oxidants (free radicals) are more and have a destructive potential on the human body ⁶⁵, ⁶⁶.

The methanolic ash gourd seed extract showed a concentration-dependent (25-200 μg/mL) 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide radical scavenging effects ⁶⁷. Another study revealed that the ethanolic winter melon seed extract shows better DPPH and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging along with total phenolic content (TPC) than its ethyl acetate and n-hexane extracts ⁴⁸. The seed oil (0.1 mg/mL) also showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging capacity ⁶⁸. This study also determined the total phenolic content in seed oil. The aqueous extract of ash gourd plant reduced reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) ⁶⁹.

Polysaccharides of fruit extract showed 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals scavenging activity with an EC50 (half-maximal effective concentration) value of 0.98 mg/mL ⁵⁶. The seed oil also showed DPPH and ABTS radical scavenging capacity. However, the antioxidant activity was lower than the catechin and BHT at the same concentration (0.1 mg/mL) ⁴⁹. Petroleum ether and methanol fruit extracts increased in catalase (CAT) levels in gastric ulcer rats ⁷⁰. Hispidalin isolated from this herb also showed DPPH radical scavenging and inhibition of lipid peroxidation capacity ⁷¹. The aqueous fruit extract significantly increased the antioxidant status as well as levels of vitamin C concentration in gastric juice of rats ⁷².

Antioxidant effects of various parts of winter melon on various test models have been also observed by several authors ⁶⁸, ³⁵, ⁷³, ⁴⁹, ⁷⁴, ²⁵, ³⁴, ⁵⁶.

Table 3. Antioxidant properties of winter melon parts

Extract/isolated compounds	Test system	Results	References
Crude oil from seeds	DPPH ABTS TPC	DPPH: EC50 = 0.1 mg/mL ABTS: EC50 = 0.1 mg/mL Significant antioxidant effect Standards: methyl ether, fatty acids	68
Seeds extract	DPPH, ABTS, total phenolic content	EC50 = 10 − 100 μg/mL Significant antioxidant effect Standards: methyl ether, fatty acids
Methanolic and aqueous peel extracts	DPPH	EC50 = 10 − 100 μg/mL Concentration-dependent radical scavenging activity The methanolic extract exhibited a better antioxidant effect Standard: DPPH	35
Aqueous seeds extract	TPC, TFC DPPH, ABTS, H2O2, linoleic acid oxidation nitrite scavenging assay	TPC: EC50 = 81.3 ± 1.4 μg gallic acid/g TFC: EC50 = 486.8 ± 4.1 μg catechin/g dry mass DPPH: EC50 = 0.6 − 3 mg/mL Concentration-dependent antioxidant activity Standards: catechin 0.05-0.5 mg/mL, BHT, ascorbic acid 10 mg/mL	73
Seed oil	DPPH ABTS radical scavenging assay	DPPH: EC50 = 0.1 mg/mL The antioxidant activity of the seed oil was lower than the catechin and BHT at the same concentration. Standard: FAME	49
Hispidalin	DPPH Lipid peroxidation assay	DPPH: EC50 = 2 − 40 μg/mL EC50 = 40 μg/mL Significant DPPH radical scavenging and inhibition of lipid peroxidation capacity Standard: methyl ether	74
Methanol, ethanol, aqueous peel extracts	DPPH Reducing power assay	Significant antioxidant effect Standard: acarbose 20, 40, 60, 80, 100 μg/mL	25
Seed extract	DPPH ABTS	Significant antioxidant effect Standard: FAME	34
Polysaccharides of fruit extract	DPPH	EC50 = 0.98 mg/mL Significant antioxidant effect Standard: glucose	56

Abbreviations: TPC = total phenolic contents; TFC = total flavonoid contents (TFC); ABTS = 2, 2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid); DPPH = 2,2-diphenyl-1-picrylhydrazyl free radical-scavenging ability; BHT = antioxidant butylated hydroxytoluene; FAME = fatty acid methyl ester; EC50 = the half-maximal effective concentration.

[Source ²¹ ]

Antibacterial, antihelmintic, and larvicidal effects

Due to the excessive use of antibiotics that can lead to the development of antibiotic resistance of various strains of bacteria ⁷⁵, ⁷⁶, attempts have been made to use natural antibiotic alternatives ⁷⁷. Most of these options include plants with antiviral and antibacterial properties that can be effective against gram-negative and gram-negative germs, which are often difficult to eradicate ⁷⁸. The methanolic ash gourd whole plant extract (500 μg/disc) was found to act against Pseudomonas aeruginosa and Vibrio parahaemolyticus ⁷⁹. In the latter case, the zone of inhibition was 6 mm only. Hispidalin, an isolated compound from winter melon seeds, was found to act against several bacteria (e.g., Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella enterica) and fungi (e.g., Aspergillus flavus, Penicillium chrysogenum, Fusarium Solani, and Colletotrichum gloeosporioides) ⁷¹. In this case, the minimum inhibitory concentrations (MIC = the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation) were 30-120 and 100-200 μg/mL for bacterial and fungal strains, respectively. Moreover, the aqueous, methanol, and petroleum extracts of winter melon seeds showed significant therapeutic efficacy with methanol extract being the best comparable to the antibiotic ciprofloxacin. In other study, the aqueous peel extract showed strong antibacterial activity against S. aureus (MIC = 14.5 μg/mL), Micrococcus luteus (MIC = 8.6 μg/mL), E. coli (MIC = 6.1 μg/mL), and Klebsiella pneumoniae (MIC = 13.4 μg/mL) ²⁰. The herb shows prebiotic activity ⁸⁰. Table 4 shows the antibacterial, antihelminthic and larvacidal effects of various parts of winter melon.

Ethanolic ash gourd seeds extract (20, 40 and 60 mg) showed a dose-dependent anthelmintic activity on Pheretima posthuma ⁸¹. The phloem lectin-like protein from the exudate of ash gourd exerted an inhibitory effect on the Samia ricini larvae ⁵¹.

Table 4. Antimicrobial, anthelmintic, and larvicidal effects of winter melon parts

Extract/isolated compounds	Dose/concentration model (in vitro/in vivo)	Results/mechanisms	References
Antibacterial effects
Methanolic whole plant extract	Pseudomonas aeruginosa Vibrio parahaemolyticus In vitro Standard: DMSO	IC50 = 500 μg/disc Zone of inhibition = 6 mm	82
Hispidalin	Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Salmonella enterica; Fungi: Penicillium chrysogenum, Fusarium solani, Aspergillus flavus, Colletotrichum gloeosporioides In vitro Standard: acetoin (0.01–20 μg/μl)	Antibacterial: MIC = 30 − 120 μg/mL, Antifungal: MIC = 100 − 200 μg/mL	74
Aqueous peel extract	Staphylococcus aureus, Micrococcus luteus, Escherichia coli, Klebsiella pneumoniae In vitro Standard: DMSO 150 μL	Antibacterial: MIC = 6.1 − 14.5 μg/mL	20
Anthelmintic effect (antiparasitic to treat infections with parasitic worms)
Ethanolic seed extract	Pheretima posthuman/in vitro Standard: phenytoin sodium	IC50 = 20, 40, and 60 mg Dose-dependent anthelmintic effect	81
Larvicidal effect (insecticide that is specifically targeted against the larval life stage of an insect)
Phloem lectin-like protein from the exudate	Samia ricini larvae/in vitro Standards: Precision Plus Protein™, serum albumin	↑ inhibitory activity against the larvae Dose: 70 μg/g	51

Abbreviations: IC50 = value concentration that inhibits cell growth by 50%; MIC = minimum inhibitory concentration.

[Source ²¹ ]

Anti-inflammatory effect

The methanolic ash gourd seeds extract (100-300 mg/kg, orally) showed dose-dependent anti-inflammatory effects on carrageenan-induced paw oedema rat (n = 6) model ⁶⁷. The winter melon fruit peel methanolic extract showed an anti-inflammatory effect on egg albumin-induced inflammation in rats ⁸³. The petroleum ether and methanolic fruit extract of winter melon (300 mg/kg, oral) showed a dose-dependent anti-inflammatory effect on cotton pellet-induced granuloma models in rats, carrageenan-induced paw oedema, and histamine-induced paw edema ⁷⁴.

Anticancer effects

The winter melon fruit, seed, and root proteins (10-1000 μg/mL) exerted a concentration-dependent cytotoxic effect on Artemia salina (a species of brine shrimp) ²¹. The median lethal concentration (LC50) values of ash gourd fruit, seed, and root extract were 44, 41, and 50 μg/mL, respectively ³¹. In this study, the ash gourd root proteins inhibited the proliferation of HeLa and K-562 cells by 28.50 and 36.60%, respectively ³¹. Another study reveals that the whole winter melon plant methanolic extract (5-50 μg/mL) exerted a cytotoxic effect on Artemia salina (a species of brine shrimp) (LC50: 45.187 μg/mL) ⁷⁹. Moreover, the aqueous winter melon seed extract (20-800 μg/mL) did not exert cytotoxic effects on HUVECs and normal fibroblast (NIH/3T3) cells. On male C57BL/6 mice, the extract showed a potent inhibitory effect on basic fibroblast growth factor- (bFGF-) induced angiogenesis ⁸⁴. The aqueous extract (1–20 μg/mL) also reduced cell adhesion molecules activation by inhibiting monocyte adhesion, ROS, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) on high glucose (25 mM) induced HUVECs cells ⁸⁵.

Table 5 shows the cytotoxic (toxic to cells) and anti-cancer effects of various parts of winter melon.

Table 5. Anticancer effects of various parts of winter melon

Extract/isolated compounds	Model dose/concentration	Results/mechanisms	References
Aqueous seed extract	HUVECs, NIH/3T3 cells/in vitro Male C57BL/6 mice/in vivo IC50 = 20 − 800 μg/mL Standard: NNGH	No cytotoxicity on HUVECs, NIH/3T3 cells decrease bFGF-induced angiogenesis in mice	84
Fruit, seed, root proteins	HeLa, K-562 cells/in vitro IC50 of fruit, seeds root extract = 44, 40-50 μg/mL IC50 = 10 − 1000 μg/mL in Artemia salina IC50 = 10–50 μg/mL on HeLa, K-562 cells Standards: lysozime, tyrosine, carbonic anhydrase, ovalbumin, albumin	Decrease cell proliferation by 28.50-36.80%	31
Aqueous extract	HUVECs cells/in vitro IC50 = 1–20 μg/mL on high glucose (25 mM) Standards: glucose 25 mM, glucose and ABH 5 μg/ml, 20 μg/ml	Decrease cell adhesion molecules activation, Decrease ROS, NF-κB Decrease inhibiting monocyte adhesion	85
Methanolic/whole plant extract	Artemia salina/in vitro IC50 = 45.186 μg/mL Standard: DMSO, vincristine sulphate 0.91 μg/mL	Increase cytotoxic effect concentration-dependent	79

Abbreviations:  IC50 = value concentration that inhibits cell growth by 50%; bFGF = basic fibroblast growth factor; ROS = reactive oxygen species; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; NNGH = N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid.

[Source ²¹ ]

Gastrointestinal protective effects

Fresh ash gourd juice (1-4 mL/animal, orally), ethanol (12, 24 and 48 mg/kg, orally), and petroleum ether extract (0.75, 1.5 and 3 mg/kg, orally) in swimming stress, aspirin plus restraint, serotonin-induced ulcers, and indomethacin plus histamine displayed a dose-dependent anti experimental ulcers effect in rats and mice ⁶⁰.

The petroleum ether and methanol winter melon fruit extracts (300 mg/kg, orally) significantly reduced ulcer index, vascular permeability, and malondialdehyde (MDA) content, while an increase in CAT levels in comparison to the control group in pylorus ligated gastric ulcers, ethanol-induced gastric mucosal damage, and cold restraint stress- (CRS-) induced gastric ulcer rat models ⁷⁰. The winter melon fruit extract (1 mL/kg, orally) also decreased ulcer index as well as malondialdehyde (MDA), superoxide dismutase (SOD), and vitamin C levels in indomethacin-induced gastric ulcer in rats ⁸⁶.

The hydromethanol, ethyl acetate, and aqueous ripe winter melon fruit extracts (20 mg/kg, orally/alternative days) were treated for 14 days in ranitidine (5 mg/kg, orally) induced hypochlorhydria in rats ⁷². The aqueous extract showed better effects on the test animals. It increased the antioxidant status as well as levels of pepsin, vitamin C, and gastric juice chloride concentration than the other extracts ⁷². On the other hand, the extract of winter melon fruits with the whole plant of Fumaria vaillantii Loisel (earthsmoke) (1 : 1) (20 mg/kg, orally) was administrated in ranitidine (5 mg/kg) induced hypochlorhydria in rats as pre-and cotreatment manners. The extract significantly enhanced the concentration of pepsin, iron levels in serum, chloride level in gastric juice, and liver along with blood hemoglobin level in experimental animals ⁸⁷.

A prospective pilot study on dyspeptic patients (n = 20) (baseline between 30 days and 45 days) aged between 18 and 45 years with only single dose of 200 mL winter melon fruit juice every morning in empty stomach for thirty days suggests that a significant improvement of pain, nausea, belching, retrosternal burning, and bowel habits among the patients ⁸⁸. Table 6 shows the gastrointestinal -protective effects of various parts of winter melon.

Table 6. Gastrointestinal protective effects of various parts of winter melon

Gastroprotective	Model/dose/concentration	Mechanisms	References
Antiulcer effect
Fresh juice, petroleum ether, alcoholic/fruits extract	Aspirin plus restraint, serotonin-induced ulcers, indomethacin plus histamine Swimming stress Mice/in vivo Dose: 1 ml/mouse	↓ulcer index formed by several ulcerogenic	60
Fresh juice, ethanol, petroleum ether extracts (5% v/v)	Aspirin plus restraint, swimming stress, indomethacin plus histamine, and serotonin-induced ulcers Rats and mice/in vivo Fresh juice (1-4 mL/animal, p.o.), Dose: ethanol extract 12, 24, and 48 mg/kg, p.o. Dose: petroleum ether extract 0.75, 1.5, 3 mg/kg, p.o.	Dose-dependent anti-ulcerogenic effect The fresh juice treatment for 3 months did not change the indices (i.e., WBC, RBC counts HCT, HB, MCV, MCH urea, and sugar) No behavioural changes in experimental animals.	60
Petroleum ether, methanol/fruits extract	Pylorus ligated (PL) gastric ulcers, ethanol-induced gastric mucosal damage, cold restraint-stress- (CRS-) induced gastric ulcer Rats/in vivo Dose: 300 mg/kg, p.o.	↓ulcer index ↓MDA ↓vascular permeability ↑ CAT	70
Fruit extract	Indomethacin-induced gastric ulcer Rats/in vivo Dose: 1 mL/kg, p.o.	↓ulcer index, ↓MDA ↓SOD, ↓vitamin C	89
Hydromethanol, aqueous ripe fruit, ethyl acetate extracts	Ranitidine (5 mg/kg) induced hypochlorhydria Rats/in vivo Dose: 20 mg/kg, p.o./alternative days for 14 days	The aqueous extract showed better effects: ↑antioxidant status, ↑pepsin, ↑vitamin C, ↑chloride in gastric juice	72
Fruit extract with the whole plant of Fumaria vaillantii Loisel (1 : 1)	Ranitidine (5 mg/kg) induced hypochlorhydria Rats/in vivo Dose: 20 mg/kg, p.o.	↑iron levels in serum, ↑pepsin, ↑gastric juice chloride level and liver ↑blood haemoglobin level	87
Fruit juice	Prospective pilot study Dyspeptic patients (n = 20) (baseline between 30-45 days); age 18-45 years; 200 mL single-dose every morning in empty stomach for thirty days	↓pain ↓belching retrosternal burning ↓nausea ↓bowel habits	88
Antidiarrheal effect
Methanolic fruit extract	Castor oil-induced diarrheal, PGE2-induced, enter pooling and charcoal meal models Rats/in vivo Dose: 200, 400, and 600 mg/kg, orally by gavage	Dose-dependent antidiarrheal effect ↓PGE2- induced, enter pooling ↓gastrointestinal motility	90
Methanolic fruit extract	Castor oil, charcoal meal, and antienter pooling models in rats/in vivo Dose: 200, 400, 600 mg/kg, p.o.	↓ activity against castor oil-induced diarrhoea; ↓PGE2 induced enter pooling ↓gastrointestinal motility	90

Abbreviations: ↑(increased); ↓(decreased); WBC = white blood cells; RBC = red blood cells; HCT = hematocrit; HB = hemoglobin; MCV = mean corpuscular volume; MCH = mean corpuscular haemoglobin concentration; MDA = malondialdehyde; CAT = catalase; SOD = superoxide dismutase; PGE2 = prostaglandin E2.

[Source ²¹ ]

Antidiarrheal effect

The winter melon fruit methanolic extract displayed potential antidiarrheal activity on the castor oil-induced diarrheal rat model ⁹⁰. It was also seen to inhibit induced PGE2, enter pooling, and reduce in the motility of gastro-intestine in charcoal meal rats ⁹⁰. The same extract also possessed a significant inhibitory activity against castor oil-induced diarrhoea and induced PGE2, enter pooling and gastrointestinal motility at 200, 400, and 600 mg/kg (orally) in castor oil, charcoal meal, and antienter pooling models in rats ⁹⁰.

Antidiabetic effects

The methanolic winter melon
stem extract (50,100, 200 mg/kg, orally) dose-dependently lowered the blood glucose level in alloxan-induced diabetic rats ⁴². The chloroform fruit extract (250 and 500 mg/kg, orally) dose-dependently ameliorated the derangements in lipid metabolism in alloxan-induced diabetic albino rats after 14 days of treatment ⁹¹. The study reveals that the methanol, ethanol, and aqueous winter melon peel extracts showed significant α-amylase inhibition activity ²⁵. The ethanol and ethyl ethanoate winter melon leaf extracts lowered the blood glucose level of the diabetic mice in a dose-dependent manner ⁹². Antidiabetic effects of various parts of winter melon have been shown in Table 7.

Table 7. Winter melon antidiabetic, antiobesity, lipid-lowering and neuroprotective effects

Extract/isolated compounds	Model dose/concentration	Results/potential mechanisms	References
Lipid-lowering effect
Hexane, chloroform, ethyl acetate/aqueous fruit extract	3T3-L1 cells/in vitro	Hexane extract: ↓adipocyte differentiation, ↓PPARγ, ↓C/EBPα, ↓leptin gene expression, ↓lipids accumulation, ↑releasing of glycerol, ↑ triglycerides	93
Antidiabetic effect
Methanolic/stem extract	Alloxan-induced diabetes Rats/in vivo Dose: 50,100, 200 mg/kg p.o.	↓blood glucose level dose-dependent	42
Chloroform/fruits extract	Alloxan-induced diabetes Rats/in vivo Dose: 250, 500 mg/kg p.o.	Dose-dependently ameliorated the disorders in the metabolism of lipids in diabetic mice	91
Ethanol, hexane, ethyl ethanoate/leaf extract	STZ-induced diabetes Mice/in vivo Dose: 0.2-1 g/kg, i.p	Ethanol, ethyl ethanoate extracts: ↓blood glucose level	92
Antiobesity effect
Methanolic fruit extract	Mice/in vivo Dose: 0.2-1 g/kg, i.p.	Anorexic activity ↓food intake	94
Antiageing of skin
Petroleum ether, chloroform, ethyl acetate, methanol/dried fruit pulp extract	Stratum corneum of human skin and dansyl chloride fluorescence models In vitro	Cream prepared from the fruit extract showed the significant antiageing effect	95
Effects on other diseases
Fruit methanol extract	Antigen-antibody induced reaction in rats exudate cells/in vitro	↓histamine release, anti-inflammatory effect Triterpenes, sterols, multiflorenol, alnusenol exerted better inhibitory effects	[38
Methanolic fruits extract	Histamine and acetylcholine-induced bronchospasm Guinea pigs/in vivo Dose: 50, 200, 400 mg/kg, p.o.	Bronchodilator effect: dose-dependent protection against histamine and acetylcholine-induced bronchospasm	96
Petroleum ether, methanolic/fruits extract	Histamine stimulated paw oedema carrageenan- stimulated paw oedema cotton pellet stimulated granuloma Rats/in vivo Dose: 300 mg/kg, p.o.	↓histamine release Anti-inflammatory effect	70
Juice	Isolated rat aortic ring/in vitro Cultured porcine endothelial cells/in vitro Rats/in vivo Dose: 0.4–1.6 mL/kg, i.v.	Antihypertensive effect dose-dependent ↓blood pressure ↑relaxation, ↓contraction of isolated rat aortic ring ↑NO in cultured porcine aortic endothelial cells	97
Methanolic fruit extract	Renal ischemia/reperfusion injury model Rats/in vivo Dose: 500 mg/kg/day, p.o. for 5 days	Nephroprotective ↓MDA, ↑SOD, CAT, ↑GSH	98
Ethanolic seeds extract	Ethylene glycol induced chronic Hyperoxaluria model Rats/in vivo Dose:250, 500 mg/kg, p.o. for 35 days	Nephroprotective ↓ urinary oxalate, ↓endogenous oxalate synthesis; ↓urinary protein excretion, ↓kidney oxalate and calcium; ↓elevated serum levels of sodium, creatinine, calcium, phosphorus	99
Neuroprotective effects
Fruit juice	Morphine addiction model Mice/in vivo Dose: 1 mL/mouse, p.o.	The development of morphine addiction prevented along with the suppression of opioid withdrawal symptoms	100
Methanolic fruit extract	Spontaneous motor, muscle relaxant, antihistaminic effect and barbiturate induced hypnosis models Mice, rats, and guinea pigs/in vivo Dose: 200-3000 mg/kg, p.o.	↑ barbiturate induced hypnosis ↑ antihistaminic activity	101
Fruit methanol extract	Pentylenetetrazole, strychnine, picrotoxin, and maximal electro seizures model Rats/in vivo Dose: 0.2-1 g/kg, p.o.	Dose-dependent anticonvulsant activity	102
Methanolic fruit extract	Acetic acid-induced writhing and hot plate Model Mice/in vivo Dose: 200, 400, 600 mg/kg, p.o.	Dose-dependent analgesic effect	103
Aqueous pulp extract	Colchicine-induced Alzheimer’s model Rats/in vivo Dose: 100-450 mg/kg, p.o.	↑SOD, ↑CAT, ↑GSH, ↓LPO dose-dependent	24
Ethanolic seed extract	Rats/in vivo Dose: 250, 500 mg/kg, p.o.	Dose-dependent analgesic and antipyretic effects	104
Methanolic fruit extract	Marble-burying and motor coordination tests Mice/in vivo Dose: 200, 400, 600 mg/kg, p.o.	Significant dose-dependent anticompulsive effect	105
Methanolic leaf extract	Acetic acid-induced writhing Mice/in vivo Dose: 50, 100, 200, 400 mg/kg, p.o.	Dose-dependent analgesic effect	106
Fruit peel methanolic extract	Egg albumin-induced inflammation in rats; acetic acid-induced writhing, formalin-induced pain, hot plate-induced, and pentylenetetrazol-induced convulsions Mice/in vivo Dose: 50, 100, 200, 400 mg/kg, p.o.	Dose-dependently (0.25-1.5 g/kg) inhibited acetic acid-induced writhing, formalin-induced pain licking, and hot plate-induced pain in mice. Significantly inhibition of egg albumin-induced inflammation in rats and pentylenetetrazol-induced convulsion in mice	83
Ethanolic seed extract	Anticonvulsant activity Mice/in vivo Dose: 250, 500 mg/kg, p.o.	Dose-dependent anticonvulsant effects	81
Methanolic fruit extract	TST and FST model Mice/in vivo Dose: 50, 100, 200 mg/kg, p.o.	Dose-dependent antidepressant effect possibly through GABAergic involvement.	107
Petroleum ether, methanolic, aqueous/fruit extracts	Motor coordination, locomotor, cognitive behaviour, anxiolytic, haloperidol-induced catalepsy, and anticonvulsant models Mice/in vivo Dose: 100, 200, 400 mg/kg, p.o.	Dose-dependent anxiolytic, analgesic, and nootropic activity	108

[Source ²¹ ]

Antiobesity and lipid-lowering effect

Lipids are fatty organic substances that are the largest source of energy for the body. The vast majority of fats are stored in solid form in various organs or skin, and a small part circulates in the blood in liquid form ¹⁰⁹. Imbalances in lipid metabolism lead to pathophysiological changes and the appearance of chronic diseases such as cardiovascular disease, fatty liver, endocrine disorders, and diabetes ¹¹⁰. Methanolic fruit extract (0.2-1 g/kg) reduced food intake, suggesting anorectic activity in mice ⁹⁴. Hexane fraction from the aqueous winter melon fruit extract inhibited adipocyte differentiation by blocking leptin gene expression, peroxisome proliferator-activated receptor gamma (PPARγ), and CCAAT enhancer-binding protein alpha (C/EBPα), resulting in the reduction of lipid accumulation, increased releasing of glycerol and intracellular triglycerides in 3T3-L1 cells ⁹³.

Effects on Alzheimer’s disease

The winter melon fruit extract at a dose of 400 mg/kg (orally) showed a protective effect on colchicine-induced Alzheimer’s disease in rats, possibly through the presence of both vitamin E and β-carotene protecting rat neurons against oxidative stress ²⁴. On the other hand, the aqueous fruit pulp extract (100-450 mg/kg, p.o.) dose-dependently increased SOD, CAT, and GSH, while reduced in LPO levels in the colchicine-induced Alzheimer’s rat model ²⁴.

Effects on memory and cognitive behavior

The methanolic winter melon fruit extract (200, 400, or 600 mg/kg, orally) showed a significant dose-dependent anticompulsive effect in marble-burying and motor coordination test models in mice ¹⁰⁵. The petroleum ether, methanolic, and aqueous winter melon fruit extracts (100, 200, and 400 mg/kg, p.o.) showed a dose-dependent nootropic activity in the cognitive behaviour mouse model ¹⁰⁸. Kumar and Nirmala ¹¹¹ also studied the possible nootropic (enhance memory or other cognitive functions) effects of the winter melon fruit on experimental animals.

Anticonvulsant effects

The winter melon fruit methanol extract (0.2-1 g/kg, orally) showed a dose-dependent anticonvulsant activity in pentylenetetrazole, strychnine and picrotoxin, and maximal electro seizures model ¹⁰². On the other hand, winter melon fruit peel methanolic extract exerted a dose-dependent (0.25-1.5 g/kg) anticonvulsant effect on pentylenetetrazol-induced convulsion in mouse models ⁸³. Ethanolic winter melon seed extract (250 and 500 mg/kg, p.o.) showed a dose-dependent anticonvulsant effect in anticonvulsant activity in Swiss albino mice ⁸¹.

Antidepressant and anxiolytic effects

Methanolic winter melon fruit extract (50, 100, and 200 mg/kg, p.o.) showed a dose-dependent antidepressant-like effect in TST and FST models possibly through GABAergic involvement in Swiss mice ¹⁰⁷.

Petroleum ether, methanolic, and aqueous winter melon fruit extracts (100, 200, and 400 mg/kg, p.o.) confirmed a dose-dependent anxiolytic activity in mice ¹⁰⁸. Effects of various parts of winter melon on the nervous system are shown in Table 7 above.

Analgesic and antifever effects

The methanolic winter melon fruit extract (200, 400, and 600 mg/kg, orally) showed a dose-dependent analgesic effect in acetic acid-induced writhing and hot plate model in mice ¹⁰³. The ethanolic winter melon seed extract (250 and 500 mg/kg, p.o.) exerted a dose-dependent analgesic and antipyretic effect in Wistar albino rats ¹⁰⁴. Winter melon fruit peel methanolic extract also dose-dependently (0.25-1.5 g/kg) inhibited acetic acid-induced writhing, formalin-induced pain licking, and hot plate-induced pain in mice ⁸³.

In another study, the methanolic winter melon seed extract (100-300 mg/kg, p.o.) also showed a dose-dependent analgesic effect on the rats (n = 6) model ⁶⁷. The methanolic leaf extract (50-400 mg/kg, p.o.) exerted a dose-dependent analgesic effect in an acetic acid-induced writhing mouse model ¹⁰⁶. Petroleum ether, methanolic, and aqueous winter melon fruit extracts (100, 200 and 400 mg/kg, p.o.) showed a dose-dependent analgesic effect in the mouse model ¹⁰⁸. The ash gourd juice juice (1 mL, p.o.) prevents morphine addiction development along with the suppression of opioid withdrawal symptoms in mice ¹⁰⁰. In experimental animals such as rats, mice, and guinea pigs, the methanolic winter melon fruit extract (200-3000 mg/kg, p.o.) significantly potentiated the barbiturate stimulated hypnosis ¹⁰¹.

Bronchodilatator effect

Winter melon fruit methanol extract inhibited histamine release ³⁸. The methanolic extract (50, 200, and 400 mg/kg, orally) of winter melon exhibited significant protection in guinea pigs against the histamine and acetylcholine-induced bronchospasm ⁹⁶. The methanolic winter melon fruit extract (200-3000 mg/kg, p.o.) showed significant antihistaminic activity on experimental animals (e.g., rats, mice, and guinea pigs) ¹⁰¹.

Antihypertensive effect

The ACE inhibitory effect of the winter melon plant may show the pharmacological basis in the treatment of high blood pressure for its long time uses in traditional Chinese medicine. The winter melon fruit juice (0.4 – 1.6 mL/kg, i.v.) dose-dependently lowered blood pressure, concentration-dependently showed relaxation of isolated rat aortic rings and produced nitric oxide (NO) from the cultured porcine aortic endothelial cells ⁹⁷. Polysaccharides of winter melon fruit extract showed an antiglycation effect ⁵⁶.

Kidney protective effects

Methanolic winter melon fruit extract (500 mg/kg/day, orally) for five days reduced the MDA content, while the increase in SOD, CAT, and GSH levels in renal ischemia/reperfusion injury in female Wistar albino rats ⁹⁸. Winter melon seed ethanolic extract (250 and 500 mg/kg, orally) for 35 days significantly lowered the increased urinary oxalate, presenting a regulatory action on endogenous oxalate synthesis; decreased in the urinary excretion and kidney retention levels of protein, oxalate, and calcium; and reduced the increased serum levels of sodium, calcium, phosphorus, and creatinine levels in ethylene glycol induced chronic hyperoxaluria in Wistar albino rat ⁹⁹.

Effects of various parts of winter melon on the kidney are shown in Table 7 above.

Antiageing of skin

A cream prepared from the dried ash gourd fruit pulp extract (petroleum ether, chloroform, ethyl acetate, and methanol) showed a significant antiageing effect on the stratum corneum of human skin and dansyl chloride fluorescence models ⁹⁵.

Winter melon safety and side effects

The fresh ash gourd juice (5% v/v) treatment for 3 months did not change the total white blood cells (WBC), red blood cells (RBC), hemoglobin (HB), mean corpuscular haemoglobin (MCH), hematocrit (HCT), mean corpuscular volume (MCV), sugar, and urea levels in rats and mice ⁶⁰. The treatment also caused no behavioural changes in experimental animals ⁶⁰. The methanolic extract of winter melon fruit was nontoxic and did not cause the death of mice, rats, and guinea pigs in doses up to 3.0 g/kg ¹⁰¹. Other studies, performed in female and male rats, concluded that the standardized hydroalcoholic (70% ethanol) extract of the fruit pulp of winter melon administered orally was relatively safe when to female and male rats ¹¹². Up to oral dose (1000 mg/kg body weight/day) level, no-observe-adverse-effect-level (NOAEL) was obtained for the extract in the 90-days toxicity study. The ethanolic seed extract up to 5000 mg/kg (orally) did not exert toxicity in rats ¹⁰⁴. There is a report of Di-2-ethylhexyl phthalate (DEHP), a popularly used plasticizer, contaminated winter melon fruit collected from southern and northern provinces in China and is harmful to human health ⁴¹.

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