1. Introduction

2. Nutritional composition, bioactives’ content and associated health benefits of watermelon and its y-products

2.1. Nutritional composition, bioactives’ content and associated health benefits of watermelon

Watermelon is characterized by a chunky rind and a fleshy middle with various colors. According to Oberio and Sogi [26], watermelon fruits yield 55.3% juice, 31.5% rind, and 10.4% pomace. The nutrition composition of flesh, juice, rind/peel, rind powder, and seeds of watermelon, has been evaluated through a number of studies. The flesh and rind portion are low in fat while seeds are high in crude fat content whereas, crude fiber content was found high in the rind portion as compared to other parts (Table 1).

Table 1. Proximate composition of watermelon and its by-products (g/100g) [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44].

Table 1. Proximate composition of watermelon and its by-products (g/100g) [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44].

	Fruit			By-products
	Flesh	Juice	Pulp	Seed	Peel	Rind
Compounds	Quantity g/100g			Quantity g/100g
Moisture	91.45	90.1-92.42	11.5	3.39-8.5	8.78	5.12-94.62
Ash	0.25	0.1-0.37	3.66	2.48-4.9	5.31	0.46-20
Protein	0.61	0.4-0.84	3.33	17.75-49.7	2.88	0.63-21
Crude fat	0.15	0.05-0.027	0.5	13.7-50.5	2.33	0.08-15
Carbohydrates	7.55	7.55	73.35	6.06-46.3	70.04	4.2-80.75
Crude fiber	0.4	0.4-0.7	7.66	2.1-40.75	10.66	2.6-23

The sweetness of the watermelon is mainly attributed to a combination of sucrose, glucose, and fructose [17]. Sucrose and glucose make up 20-40% of the total sugars in a ripe watermelon, while fructose makes up 30-50% [17]. Nevertheless, watermelon has a low energy density and is hence advised for weight management [13]. Watermelon is a good source of nutrients, minerals and vitamins [45], such as phosphorus, magnesium, calcium, and iron, as well as thiamine, riboflavin, niacin, folate and A, C and E vitamins [14,16,46]. It is also a source of several amino acids (Figure 1) and especially of citrulline, a non-essential amino acid that helps muscle relaxation [47].

Figure 1. Structures of the most important micronutrients in watermelon (adopted from Jebir and Mustafa [48] (a) Arginine, (b) Citrulline, (c) Aspartic acid, (d) Ascorbic acid, (e) Beta-carotene, (f) Citrulline, (g) Lycopene, (h) Leucine and (i) Glutamic acid. Structures were obtained from https://molview.org/ (accessed on the 21st of September 2023).

Figure 1. Structures of the most important micronutrients in watermelon (adopted from Jebir and Mustafa [48] (a) Arginine, (b) Citrulline, (c) Aspartic acid, (d) Ascorbic acid, (e) Beta-carotene, (f) Citrulline, (g) Lycopene, (h) Leucine and (i) Glutamic acid. Structures were obtained from https://molview.org/ (accessed on the 21st of September 2023).

Thus, watermelon is a nutrient-dense, thirst-quenching fruit with few calories [49] and its consumption may also be advantageous in maintaining acid-base balance in the body, which is crucial in normal physiology, hunger, and digestion [15]. Its vitamin content makes it beneficial for normal vision and skin health, cholesterol control, normal appetite, and nervous system function, and it may be involved in normal muscle contraction [50,51].

On the other hand, the leading organic acids that contribute to the peculiar watermelon flavor are malic, citric, and oxalic acids [52]. Watermelon flesh is red, yellow, and pink due to the presence of carotenoids such as β-carotene and its acyclic isomer, lycopene, lycopene [53]. The content of watermelons’ microconstituents varied since it depends on cultivar, level of maturity, and provenance [54,55,56,57]. These carotenoids possess antioxidant, anti-inflammatory, and hypotensive beneficial effects for human health [58,59], while they can scavenge free radicals with therapeutic impact in several manifestations, including cancer and CVD, too [60,61,62]. Lycopene is also shown to have analgesic and anti-inflammatory properties [63,64], anti-ulcerative properties [65,66], and antibacterial properties [63,67]. Overall, lycopene is a primary bioactive compound present in watermelon, contributes several health benefits such as, antioxidant, anti-inflammatory antiproliferative, antihyperglycemic antidiabetic and cardio-preventing and protecting properties [8,57,68,69].Watermelon juice's lycopene-rich nature and health benefits, according to Kim et al. and Jumde et al. [13,69], make it a good choice for preparing additional functional foods to increase utilization.

On the other hand, vitamins, minerals and specific amino acids, watermelon also contains a variety of other bioactive compounds, including phenolic compounds and alkaloids are distributed and concentrated differently in the flesh, rind, leaves, and seeds, as depicted in Figure 2 [10,70,71,72]. Some of these phytochemicals could prevent diseases like hypertension and arthritis [11], while according to Bailey et al. watermelon juice supplementation improves vascular health in hypertensive people [73]. Watermelon contains comparably more antioxidants than popular fruits like tomatoes, strawberries, and guavas [15]. Nevertheless, apart from the antioxidant protection, watermelon bioactive compounds demonstrate numerous health benefits, including reduced risk of CVD, aging-related ailments, obesity, diabetes, and various cancer-fighting effects [10,74,75,76,77], suggesting that incorporating watermelon in the diet can effectively reduce such chronic disease [8,14].

Watermelon has been considered an excellent dietary source of bioactive phenolics. Phenolic compounds can be found in great numbers in the seeds [78] and higher in all portions except flesh [77]. Abu-Reidah et al. reported that 23 compounds of watermelon flesh belong to the flavonoid families [79]. Mushtaq et al. found myricetin and quercetin in rind [80] while apigenin, naringenin-7-O-glycoside, rutin, amentoflavone, quercetin, quercitrin, kaempferol and luteolin in seeds were determined by Jimoh et al. and Sultana & Ashraf [78,81]. Major bioactive compounds present in watermelon and by-products such as peel, rind, and seed are depicted in Figure 2. Watermelon fruits contain other phytochemical compounds too, like cucurbitacins and their glycoside derivatives, which have a unique medicinal significance due to their potential biological activities like hepatoprotection, anti-inflammatory, anti-tumor, antimicrobial, and anti-helminthic effects (Figure 3) [82,83].

Thus, watermelon’s health benefits are greatly linked to its nutrient composition and its high content in a number of bioactive compounds, mostly phytochemicals, with anti-inflammatory, antioxidant and anti-cancer properties that contribute to health and the prevention of chronic diseases [82,84,85,86,87,88]. Because of these qualities, and due to its watermelon is a desirable functional food high lycopene, vitamin A, vitamin C, antioxidant and anti-inflammatory bioactives’ content, watermelon is a great functional food [39,63,89].

2.2. Nutritional composition, bioactives’ content and associated health benefits of watermelon by-products

Watermelon by-products are usually its rind, peel, seeds and pulp. Watermelon rind (WR) is an integral part of watermelon. It is a thick white flesh between the outer green skin and the interior-colored flesh that contributes to about one-third of the total fruit mass mostly discarded despite being comestible. Watermelon rind contains starch, non-starch polysaccharides, sugars, resistant starch, oligosaccharides, and pectin [90]. Nutrition composition of watermelon and by-products is given in Table 1. Fresh WR has 95% moisture, but dry WR powder contains water (9-17%), crude protein (6-21%), fat (0.66-15%), dietary fiber (12-23%), ash (12-20%), and total carbohydrates (42-65%) including sugars, pectin, cellulose, lignin and hemicellulose [14,35,42,91]. The minerals content of rind are reported as; Fe (0.28mg/kg), Na (1.16mg/kg), K (4.83mg/kg), P (5.17mg/kg), Mg (8.22mg/kg), Zn (19.80mg/kg), and Ca (28.70mg/kg) [43,92]. Watermelon rind is also a rich source of citrulline, flavones, saponin, sterols, terpenoids and phenolic compounds, which are bioactives compound providing antioxidant properties and other health promoting effects [93].

Figure 2. Major bioactive compounds in watermelon and its by-products. Structures were obtained from https://molview.org/ (accessed on the 21^st of September 2023). Bioactives numbered as 1-11 are mostly found in watermelon fruit, while bioactives 12-23 are mostly found in its by-products (rind, peel and seed).

Figure 2. Major bioactive compounds in watermelon and its by-products. Structures were obtained from https://molview.org/ (accessed on the 21^st of September 2023). Bioactives numbered as 1-11 are mostly found in watermelon fruit, while bioactives 12-23 are mostly found in its by-products (rind, peel and seed).

Figure 3. Chemical structure of the main cucurbitacins (adopted from Zamuz et al. [24]). Structures were obtained from https://molview.org/ (accessed on the 21st of September 2023).

Figure 3. Chemical structure of the main cucurbitacins (adopted from Zamuz et al. [24]). Structures were obtained from https://molview.org/ (accessed on the 21st of September 2023).

Watermelon seeds are abundant in protein, minerals (including magnesium, potassium, iron, zinc, sodium, phosphorus, copper, and manganese), B vitamins, lipids and unsaturated fatty acids like stearic, palmitic, linoleic, and oleic acid, as well as several bioactive phytochemicals [94]. It also contains a lot of carbohydrates, including glucose, sucrose, and fructose, as well as carotenoids like carotene [95]. Watermelon seeds contain also a significant amount of arginine, contributing to their therapeutic properties [96], as this amino acid can decrease ulcerative colitis symptoms, but also it increases antioxidant capacity [97,98]. Due to the existence of many nutritious benefits, watermelon seeds have applications in a variety of culinary products. Sola et al. found that watermelon seed extracts contain antimicrobial capabilities [99]. Furthermore, roasted watermelon seeds are used by customers as an appetite stimulant and to alleviate constipation [83]. Nutrients and valuable bioactive compounds are given in Table 2.

Table 2. Nutrients and other valuable and bioactive compounds of watermelon and its by-products [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44].

Table 2. Nutrients and other valuable and bioactive compounds of watermelon and its by-products [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44].

Parts	Carbohydrates	Anti-nutrients	Vitamins	Minerals	Amino acids	Phenols	Fatty acids
WMR	Galactose Xylose Arabinose Glucose Glucoranic acid Mannose Rhamnose Glucuronic acid	Oxalates Alkaloids Phytates Saponin Tanin Flavonoids Phenols	A B1 B2 B3 B6 C	Fe Mn P Ca Na Zn Cu K Mg	Citrulline phenylalanine Valine Leucine Tyrosine Lysine	Gallic acid, Synapic acid, Hydroxycinnamic acid, Quercetin, m-Coumaric acid, Chlorogenic acid, Syringic acid, p-coumaric acid, myricetin, caffeic acid, vanillic acid, 4-hydroxybenzoic acid, p-anisic acid.	Saturated Myristic acid, Palmitic acid, Margeric acid, Stearic acid, Arachidic acid, Behenic acid, Lignoceric acid. Unsaturated Elaidic acid, Linolenic acid, Linoleic acid, Vaccenic acid Oleic acid, Docosahexaenoic acid, Eicosadienoic acid, eicosenoic acid, hypogeic acid, vaccenic acid, gondoic acid.
Seed	Galactose Arabinose Glucose Sucrose Mannose Fructose Xylose	Oxalates Alkaloids Phytates Saponin Tannin Phenols Flavonoids	A B1 B2 B3 B6 B12 D E K	Fe Mn P Ca Na Cu Zn Cr K Mg Pb	Arginine Phenylalanine Lysine Leucine Iso-leucine Aspartic acid Glutamicacid, Serine Valine Cysteine Glycine Histidine Threonine Alanine Proline Methionine	Gallic acid, Caggeic acid, Syringic acid, Sinapic acid, Rosmarinic acid, Vanillic acid, Prochatechuic acid, Leuteolin, Flavonoids, Flavone, Chlorogenic acid, Apigenin, Phenolic acid, 4-hydroxybenzoic acid, Ferulic acid, Coumaric acid.	Saturated Myristic acid, Arachidic acid, Pentadecyclic acid, Margeric acid, Behenic acid, Stearic acid, Lignoceric acid. Unsaturated Palmitoleic acid, Gadoleic acid, Linolenic acid, Linoleic acid, Oleic acid, Erucic acid.
Peel	Galactose Xylose Arabinose Glucose Glucoranic acid Mannose Rhamnose Glucuronic acid	Alkaloids Saponin Tanin Flavonoids Phenols	A B1 B2 B3 B6 C	Fe Mn P Ca Na Zn Cu K Mg	Citrulline Phenylalanine Valine Leucine Tyrosine Lysine	Gallic acid, Synapic acid, Hydroxycinnamic acid, Quercetin, m-Coumaric acid, chlorogenic acid, syringic acid, p-coumaric acid myricetin caffeic acid vanillic acid 4hydroxybenzoic acid, p-anisic acid.	Saturated Myristic acid Palmitic acid Margaric acid Stearic acid Arachidic acid Unsaturated Linolenic acid Linoleic acid Oleic acid
Pulp	Fructose Sucrose Glucose	Flavonoids Glycosides Tannins Phenols Saponins Tannins	A B1 B6 C E	Ca Fe Mg Zn Na K	Citrulline Leucine Glutamic acid, Aspartic acid Arginine	Carotenoids Quercetin, Luteolin Gallic acid Coumarin Aviprin	Linoleic acid Oleic acid Palmitic acid Stearic acid Linolenic acid

*WMR= watermelon rind.

2.3. Molecular-Biochemical-Cellular Mechanisms of Action of of the most Bioactive Compounds present in Watermelon and Its By-Products: A Molecular Perspective

The most abundant bioactive constituents of watermelon and its by-products are several subclasses of cucurbitacins and polyphenols. Cucurbitacins are tetracyclic triterpenoids, derived from Cucurbitaceae family plants, while more than 100 species of such micro-constituents have been found in about 30 different species of Cucurbitaceae family [100]. Some of the different species of Cucurbitaceae family are the Bryonia [101], Cucumis [102] and Momordica [103], while cucurbitacins have also been identified, in lower amounts, in Polemoniaceae [104], Scrophulariaceae [105], and Thymelaeaceae species [106], too. From a chemical standpoint, cucurbitacins have a signature highly oxidized tetracyclic nucleus, since containing several of oxygen-containing groups at different positions [107]. Structurally, cucurbitacins are categorized into 12 primary forms, namely, cucurbitacin A to T [108]. It is reported that cucurbitacins demonstrate potential biological activities, based on the target cells, such as, anti-oxidant, anti-inflammation, anti-microbial, anti-diabetic, anti-rheumatic, anti-tumor, and so on [109,110,111].

Considering the bioactivity of cucurbitacins, their low water solubility and lipophilicity contribute to enhanced antitumor effectiveness. This effect is facilitated by increased solubility and targeting following local and systemic administration, especially in their glycosylated forms, which have demonstrated the ability to prevent free radical and oxidative damage [110]. In terms of their anti-inflammatory activity, cucurbitacins have been found to block the activity of tumor necrosis factor alpha (TNFα) in lymphocytes and macrophages; simultaneously, they inhibit the function of nuclear factor-kappa-B (NF-κB) [112,113,114,115]. For instance, cucurbitacin R, has been proven effective against pain and inflammation in several different studies [116].

In addition to the aforementioned activities, several derivatives of cucurbitacins derivatives, namely, cucurbitacin B, D, E, and I, have been found to manifest anti-multiplication effects on various human cancer cell lines and tumor xenografts, including those associated with breast, brain, liver, lung, skin, prostate and uterine cervix cancers [109,110,117,118,119]. Noteworthy, cucurbitacin glycosylated derivatives (B and E) extracted from Citrullus colocynthis have demonstrated antigrowth effects on human breast cancer cells, through the conglomeration of cells in the phase II of growth/mitotic phase (G2/M phase) of the cell cycle and the induction of apoptosis, simultaneously [109]. Moreover, cucurbitacin R and 23, 24-dihydrocucurbitacin B extracted from the roots of Cayaponia tayuya were found to suppress cellular proliferation and/or initiate apoptosis in colon cancer cell lines [115,120]. Other studies suggest that, the simultaneous intake of cucurbitacins and anti-cancer medication led to improved results; the co-intake of doxorubicin and cucurbitacin E led to marked cytotoxicity towards tumor cells in vivo and in vitro resulting in diminished tumor dimensions and mass [121]. A similar trend was observed when comparing single medication with the simultaneous intake of cucurbitacin B with medication (docetaxel), on human laryngeal cancer cell line (Hep-2) [122].

On the other hand, polyphenols are products of plant secondary metabolism, found within the nucleus, the mesophyll cells and other regions where the generation of the reactive oxygen species (ROS), take place [123]. Polyphenols, including flavonoids, are produced through the phenylpropanoid pathway have been shown to exhibit several health promoting activities [124,125]. The functional hydroxyl group of polar phenolics give them the ability to scavenge free radicals and bind metal ions [126,127,128]; metal chelation is a key factor in preventing radical generation that could lead to the biomolecular damage [129]. In addition, many studies have demonstrated that polar phenolics have the capability to activate several protective enzyme systems in the human body, while simultaneously are able to manifest protective impacts against numerous human diseases, including, cancer, cardiovascular diseases and bacterial and viral infections [130,131].

Polar phenolic compounds have several different activities, with their distinctive trait being their ability to function as antioxidants. This behavior is attributed to the arrangement of functional groups surrounding the nucleus; the substitution and the configuration of the hydroxyl groups in the B ring, also significantly affect the antioxidant activity mechanisms, including chelating metal ions like iron and copper, and scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS) [132,133]. Additionally, the position, structure, and number of sugars in flavonoids (glycosylated forms) significantly affect their antioxidant properties with aglycone forms generally exhibiting better antioxidant efficacy than their respective glycosylated counterparts [134].

The mechanisms through which antioxidants, i.e., polyphenols, act, include the reduction of the ROS formation, either by binding to compounds involved in the production of the free radicals or by inhibiting enzymes, the scavenging of ROS and the enhancement of the human organism’s antioxidant defense [135]. As for the enzyme inhibition, polyphenols exhibit inhibitory effects against the ones responsible for ROS generation, such as glutathione and monooxygenase, while enzymes such as NADH oxidase and mitochondrial succinoxidase are also implicated in such processes [136]. In addition, flavonoids serve as potential protective compounds against lipids oxidation through several different pathways [137].

For instance, epicatechin and rutin have been proven as stable, robust molecules that may effectively inhibit lipid peroxidation in vitro [138]. Additionally, quercetin has been demonstrated to chelate and stabilize iron [139]; the ethanol extract of winery by-products containing epicatechin and quercetin exerts a potent anti-platelet effect [140].

During oxidation on the B ring of flavonoids possessing a catechol group, they form a stable radical known as orthosemiquinone, rendering them potent scavengers. In contrast, flavones lacking the catechol group tend to be weaker scavengers due to their tendency to form unstable radicals [141].

It should also be mentioned that apart from their general antioxidant capacity, specific phenolic compounds have also been found to possess potent anti-inflammatory activities with several health promoting properties [142]. For instance some phenolic compounds have shown anti-cancer potency through inhibiting the synthesis of potent thrombo-inflammatory mediators implicated in cancer growth and metastasis [2], while they have also shown strong antiplatelet activities [140,143] and a general anti-inflammatory potency in renal cells and blood cells that contribute in the reduction of risk for developing several disorders related to the inflammatory manifestations of these cells [144,145].

Figure 4. The biochemical mechanisms of (A) Cucurbitacins and (B) Polyphenols, of watermelon and its by-products. TNFα: tumor necrosis factor alpha; NF-κB: nuclear factor-kappa-B; ROS: reactive oxygen species; PNS: reactive nitrogen species; GSH: glutathione; MOG: monooxygenase; GPX: glutathione peroxidase; NOXs: NADPH oxidases.

Figure 4. The biochemical mechanisms of (A) Cucurbitacins and (B) Polyphenols, of watermelon and its by-products. TNFα: tumor necrosis factor alpha; NF-κB: nuclear factor-kappa-B; ROS: reactive oxygen species; PNS: reactive nitrogen species; GSH: glutathione; MOG: monooxygenase; GPX: glutathione peroxidase; NOXs: NADPH oxidases.

Figure 4. The biochemical mechanisms of (A) Cucurbitacins and (B) Polyphenols, of watermelon and its by-products. TNFα: tumor necrosis factor alpha; NF-κB: nuclear factor-kappa-B; ROS: reactive oxygen species; PNS: reactive nitrogen species; GSH: glutathione; MOG: monooxygenase; GPX: glutathione peroxidase; NOXs: NADPH oxidases. .

3. Health promoting effects associated with watermelon and its by-products bioactives

3.5. Other health promoting effects

3.5.1. Hepatoprotective properties

The rich content of watermelon and its by-products in phytochemicals and lycopene seems to also prevent liver-related disorders [63,83,181]. Oyenihi et al. reported that WJ had an antioxidant and hepatoprotective effect in ethanol-induced oxidation in the liver of rats [224]. Watermelon seed and seed oil also showed hepatoprotective activity in CCl₄ induced hepatotoxicity in rats, as it improved the serum enzymatic activities of hepatic enzymes and the histopathology of liver tissues [64,155].

3.5.1. Antimicrobial properties

Several studies have shown that watermelon extracts have antimicrobial activities against bacteria as well as fungi [67,225,226,227]. Ethanol extract of watermelon seeds showed great potential of antimicrobial activities against four bacterial strains (2 Gram-negative and 2 Gram-positive) were studied for their limited direct anti-fungal effects against four fungal species, primarily influencing bacterial-fungal interactions and susceptibility patterns in specific contexts [228]. Moreover, crude extracts of watermelon seeds, using cold and hot water, ethanol, and methanol showed antimicrobial activities against bacteria and fungi [94,229,230]. The observed antimicrobial activities of chloroform extracts were attributed to watermelon secondary metabolites such as flavonoids, tannins, and saponins [67], while lycopene also seem to possess antimicrobial activity [67].

3.5.1. Analgesic properties

Watermelon rich content in lycopene has an analgesic effect [63]. Moreover, Wahid, et al. observed analgesic activities of ethanol extracts from watermelon seeds in an in vivo study in rats [184], while aqueous extracts of watermelon peel showed in vivo analgesic properties too [231]. Thus, extracts of watermelon by-products have the potential to be used as a functional ingredient for the development of analgesics [179,184]. The highest concentration of alkaloids found in seeds, in comparison to all the other parts of watermelon, have also showed several therapeutic effects as secondary metabolites, including analgesic properties, as well as anti-bacterial, and antispasmodic effects [232].

Table 3. Health promoting properties of watermelon and its by-products.

Table 3. Health promoting properties of watermelon and its by-products.

Heath Promoting Properties	Watermelon Part	Compound/ component	Study type	Specific effects	References
Antioxidant	Seed	Aqueous extract	In-vivo		[179]
	Seed	Extract	In-vitro		[182]
	Seed	Extract (chloroform, ethyl acetate, and methanol)	In-vitro		[178]
	Seed	Extract	In-vitro		[182]
	Rind& Seed	Extract	In-vivo		[183,191,194,188]
	Peel	Extract	In-vitro		[192]
	Pulp & Seed	Lycopene	In-vitro		[233]
	Seed	Extract	In-vitro		[234]
	Whole watermelon powder		In-vivo	Ingestion	[186]
	Fruit	Bioactive compounds	In-vitro		[10]
Cardioprotective	Pulp	Extract	In-vivo	Anti- atherosclerotic activity	[174]
	Seeds	Phytochemicals	In-vivo	Anti- hypertensive	[40]
	Rind	Extract of polysaccharides	In-vivo	Anti- hypertensive	[14]
	Seeds	Extract	In-vivo	Decrease serum Cholesterol	[235]
	Pulp	Carotene	In-vitro	Heart health	[236]
	Pulp	Lycopene	In-vitro	heart health	[74]
	Rind	Phytochemicals	In-vitro In-vivo	Hypocholesterolemic effect	[215]
	Seed	Extract,	In-vitro In-vivo	Hypolipidemic effect anti- inflammatory and antioxidant properties	[182] [235]
	Seeds	Kernel	In-vivo	Hypolipidemic efficiency	[83]
	Whole watermelon powder		In-vivo	Improvement of lipid profiles	[186]
	Rind and peel	Powder	In-vivo	LDL Control anti- inflammatory reduces atherosclerosis	[174]
	Pulp	Juice; L-Citrulline	In-vivo In-vitro	Recovery heart rate and muscle soreness	[201]
	Seeds	Extract	In-vivo	Reduction in creatine kinase, triglycerides, LDL, and sodium	[161]
	Flesh, Seeds, Rind	L-citrulline and Arginine	In-vivo	Regulation of blood pressure and vascular health	[237]
	Seeds	Extract	In-vivo	Cardioprotective potential	[203]
	Seeds	Extract	In-vivo	Cardiovascular benefits, Anti-hypertension, reduce blood pressure	[174,200]
	Seed	Sitosterol, campesterol, and stigmasterol in seed oil.	In-vitro	Cardiovascular health	[238,239]
	Rind	Citrulline	In-vitro	Cardiovascular health	[75]
	Rind	l-citrulline and l-arginine	In-vivo	Cardiovascular health	[240]
	Pulp		In-vivo	Cardiovascular Protective	[187,241]
	Pulp	Juice	In-vivo	Control serum lipid profile	[242]
Antidiabetic	Flesh, seed, rind	Extract and Juice	In-vivo		[72,93,180,220,243,244]
	Rind	Citrulline	In-vitro		[215,216,245,246]
	Seeds	Extract	In-vivo		[218]
	Flesh and Rind	Extract and powder	In-vivo		[213]
	Pulp	Juice	In-vivo	Inhibitory activity against -glucosidase and -amylase that is dosage dependent.	[242]
	Pulp	Juice, extract (containing alkaloids, flavonoids, and saponins)	In-vivo	Stimulate insulin release during pancreatic-cell regeneration and hinder intestinal glucose absorption.	[247]
	Rind	Extract	In-vivo		[211,248]
	Rind and Peel	Pomace	In-vivo		[171]
Gastrointestinal tract diseases	Seed	Seed extract	In-vivo	Anti-ulcer activity	[65]
	Pulp	Juice	In-vino	Anti-secretary activity	[249]
	Pulp	Juice	In-vivo	Anti-secretory effects	[249]
	Rind	Hydro-methanolic extracts	In-vivo	Anti-ulcer	[193]
	Seeds	Extract	In-vivo	Antiulcer and gastroprotective	[66]
	Seed	Seed extract	In-vivo	Anti-ulcer action in pyloric ligated and water immersion stress generated ulcer models.	[65,66]
	Seeds	Methanolic extract	In-vivo	Anti-ulcerogenic	[65]
	Pulp	Pulp extract	In-vivo	Gastroprotective Laxative Activity in Indomethacin-Induced Ulcer Model	[250]
	Pulp	Pulp extract	In-vivo	Loperamide-induced constipation decreases in a dose-dependent manner by laxative activity.	[250]
	Pulp	Extract	In-vivo	Laxative Activity	[250]
	Pulp		In-vivo	Ameliorate the gastrointestinal discomforts	[171]
Hepatoprotective	Pulp	Juice	In-vivo		[251]
	Seeds	Extract	In-vivo		[252]
	Seed	Seed oil	In-Vivo	Oral, estimate serum hepatic enzyme level	[64]
	Seeds	Oil	In-vivo		[64]
	Seeds	Extract	In-vivo		[155] [253]
Anti-inflammatory	Seed	Seed Oil	In-vivo & In-Vitro		[64]
	Seed	Aqueous extract	In-vivo		[179]
	Seeds	Extract	In-vivo		[184]
	Seed	Oil, extract	In-vitro		[254,255,256]
	Rind	Methanolic extract	In-vivo		[184,193]
	Pulp	Juice	In-vivo	α-glucosidase and α-amylase inhibitory action in a dose-dependent manner	[242]
	Seed	Seed oil	In-vivo & In-vitro	Carrageenan-induced paw edema in a rat model	[64,257]
	Seed	Seed Oil,	In-vitro and In-vivo		[64]
	Whole watermelon powder		In-vivo	Ingestion	[186]
	Pulp	l-citrulline and l-arginine	In-vivo		[258]
Antimicrobial	Seed	Seed extract	In-vitro	cup-plate and disc diffusion method	[229,230]
	Rind	Extract	In-vitro		[259]
	Seed	Extract	In-vitro		[99,228,260]
	Seed	Oil, extract	In-vitro		[254,255,256]
	Seed	Seed extract	In-vitro		[94,261]
	Seeds	Extract	In-vitro		[229]
	Pulp	Extract	In-vitro		[67]
	Seeds	Extract	In-vitro		[229]
	Seed	Seed extract	In-vitro		[225]
	Pulp	Juice	In-vivo		[8,224]
Role in oxidative stress	Pulp	l-citrulline & l-arginine	In-vivo		[258]
	Peel	Extract	In-vivo		[231]
Analgesic and antipyretic	Seed	Aqueous extract	In-vivo		[179]
	Rind	Methanolic extract	In-vivo		[184,193]
	Pulp	Lycopene	In-vitro		[74]
Anticancer	Rind	Extract	In-vivo		[262]
	Rind	Extracted polysaccharides	In-vivo		[262]
	Pulp	Extract	In-vivo In-vitro	U Anti- urolithiatic and diuretic activities	[71]
Urinary tract disorders	Fruit	Aqueous extract	In-vivo	U Kidney health	[263]
	Flesh and Rind	Extract	In-vivo	Uterine Contractility	[264]
	Seeds	Extract	In-vivo	Anti-Prostatic Hyperplasia activity	[265]
Miscellaneous Effects	Seeds	Methanolic extract	In-vivo	Nephroprotective effects	[253,266]
	Seeds	Extract	In-vivo	Neuroprotective	[267,268]
	Seeds	Extract		Male Sexual enhancement	[252]
	Seeds	Extract	In-vivo	Weight loss and hematological benefits	[269]

4. Potential applications of watermelon by-products that improve bio-functionality and health promoting effects of food and cosmetics products

5. Limitations – Future Perspectives

6. Conclusions

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