molecules

Review
Versatile Nutraceutical Potentials of
Watermelon—A Modest Fruit Loaded with
Pharmaceutically Valuable Phytochemicals
Abinaya Manivannan , Eun-Su Lee, Koeun Han, Hye-Eun Lee and Do-Sun Kim *
Vegetable Research Division, National Institute of Horticultural and Herbal Science, Rural Development
Administration, Jeonju 55365, Korea; [email protected] (A.M.); [email protected] (E.-S.L.);
[email protected] (K.H.); [email protected] (H.-E.L.)
* Correspondence: [email protected]; Tel.: +82-63-238-6670

Academic Editors: Ryszard Amarowicz and Adriano Costa de Camargo




Received: 16 October 2020; Accepted: 9 November 2020; Published: 11 November 2020

Abstract: Watermelon (Citrulus lantus) is an important horticultural crop which belongs to the
Curcubitaceae family. The nutraceutical potential of watermelon has been illustrated by several
researchers, which makes it a better choice of functional food. Watermelon has been used to treat
various ailments, such as cardio-vascular diseases, aging related ailments, obesity, diabetes, ulcers,
and various types of cancers. The medicinal properties of watermelon are attributed by the presence
of important phytochemicals with pharmaceutical values such as lycopene, citrulline, and other
polyphenolic compounds. Watermelon acts as vital source of l-citrulline, a neutral-alpha amino
acid which is the precursor of l-arginine, an essential amino acid necessary for protein synthesis.
Supplementation of l-citrulline and lycopene displayed numerous health benefits in in vitro and
in vivo studies. Similarly, the dietary intake of watermelon has proven benefits as functional food in
humans for weight management. Apart from the fruits, the extracts prepared from the seeds, sprouts,
and leaves also evidenced medicinal properties. The present review provides a comprehensive
overview of benefits of watermelon for the treatment of various ailments.

Keywords: anti-cancer; anti-diabetic; functional food; l-citrulline; lycopene; obesity; polyphenols

1. Introduction
Consumption of fruits and vegetables in regular diet provides several health benefits. The wide
occurrence of phytochemicals such as carotenoids, lycopenes, anthocyanins, phenols, and flavonoids
along with vitamins and minerals makes the choice of plant based diet healthier. It lowers the risks
of various dreadful diseases such as cancer, cardiovascular diseases, neurodegenerative disorders
and aging associated ailments. Plants, being the wide source of pharmaceutically valuable secondary
metabolites, provide diverse products in the form of fruits and vegetables loaded with nutraceutical
potential. In general, the major role of secondary metabolites in plants are pertained to the protection
against diverse abiotic and biotic stresses. In addition, secondary metabolites also acts as an
antimicrobial agents and antioxidants to combat stresses.
Watermelon is a notable horticultural crop belonging to the Cucurbitaceae family cultivated
widely for its delicious fruits. Asian countries contribute approximately 81% of total production
of watermelon worldwide [1]. According to the Food and Agricultural Organization of the United
Nations, a cultivation area of 3.2 million hectares was employed for the production of 103 million
tons of watermelon worldwide in 2018 [1]. The watermelon fruits are used for the preparation
of smoothies, jams, sauces, candies, and juices. Watermelon serves as a vital natural source of
l-citrulline (0.9 to 5 mg/kg of fresh fruit) [2]. The refreshing taste, high water content, and its attractive

Molecules 2020, 25, 5258; doi:10.3390/molecules25225258 www.mdpi.com/journal/molecules

Molecules 2020, 25, 5258 2 of 15

colors ranging from red, yellow, and pink increases the consumption of watermelon. The diverse
colors of watermelon are due to the presence of carotenoids especially, lycopene and β-carotene [2].
The sweet taste of watermelon is contributed by the combination of sugars such as glucose, sucrose,
and fructose. Moreover, watermelon, acts as a vital reservoir of valuable phytochemicals with high
nutrition and pharmaceutical potentials. In particular, watermelon can be considered as an excellent
functional food due to its rich lycopene, vitamin A, vitamin C contents and antioxidant potentials [3,4].
Bioactive compounds present in watermelon render numerous health benefits, such as decreasing
the risk of cardio-vascular disease, aging related ailments, obesity, diabetes, and various cancer
alleviating effects have been reported [5–10]. In 1930, Wada [11] determined and isolated citrulline,
a non-essential amino acid from watermelon which is involved in the synthesis of arginine. The amino
acid arginine is vital for the endogenous synthesis of nitric oxide, a crucial signaling molecule involved
in various neurological and immune responses in animals and humans [12]. Watermelon acts as a
vital dietary supplement to enhance the arginine content. In watermelon, citrulline aid in the tolerance
against stresses such as drought [13]. Moreover, the seeds of watermelon are enriched with protein,
fat, and moderate levels of iron and zinc. Watermelon seeds are consumed as snacks, fat binder,
soup thickener, condiments, and also for the extraction of cooking oil [14–16]. The occurrence of high
arginine content in the seeds of watermelon adds its medicinal benefits [17]. Due to the presence of
various nutritious benefits the seeds of watermelon possess application in the field of several food
products. Recently, Sola et al. [18] identified and quantified the phytochemicals in the methanol extracts
derived from the seeds of watermelon. Furthermore, the report [18] evidenced the anti-bacterial
property of watermelon seed extracts.
The present review deals with various nutraceutical potentials of watermelon and its importance
as an antioxidant, anti-cancerous, cardiovascular protectant, anti-inflammatory properties evidenced
by in vitro and in vivo studies.

2. Cardiovascular Protection by Watermelon

Cardiovascular diseases are the leading cause of increasing death rate worldwide. Moreover, the cost
of treating cardiovascular disease are high. Therefore, adapting a lifestyle with cardio-friendly diet
would decrease the risk factors associated with the disease. Fruits and vegetables can combat the
negative effects of cardiovascular diseases. l-citrulline and l-arginine possess the capacity to alleviate
the inflammation and oxidative stress [19,20]. However, direct intake of l-citrulline and l-arginine could
lead to gastro-intestinal discomforts such as nausea and diarrhea [21,22]. Therefore, the consumption of
fruits rich in l-citrulline (precursor of l-arginine, an essential amino acid for protein synthesis)—such as
watermelon—is important to obtaining the necessary nutrition. Supplementation of whole watermelon
in powder form improved the lipid profiles, antioxidant status, and anti-inflammatory properties
of high fat fed rats [23]. Moreover, the ingestion of watermelon regulated the expression of genes
associated with lipid metabolism [23]. In detail, the augmentation of watermelon and l-arginine
enhanced the regulation of hepatic gene expression of endothelial nitric oxide synthase. Nitric oxide
(NO) is a ubiquitous signaling molecule vital for the relaxation of blood vessels and it also reduces
the atherosclerosis by influencing the lipid metabolism [23–25]. On the other hand, watermelon
supplementation down-regulated the genes involved in lipid metabolism such as fatty acid synthase
(FAS), 3-hydroxy-3methyl glutaryl-coA reductase (HMGCR), sterol regulatory element binding protein
(SERB) 1, SERB 2, cyclooxygenase-2 (COX2), and nuclear factor-kB (NF-κB) in rats [23]. Among the
above enzymes, FAS plays an important role in the denovo synthesis of fatty acids, whereas HMGCR
acts as a rate limiting enzyme in cholesterol synthesis [26]. Similarly, both SREBP-1 and SREBP-2
regulate the transcription of genes involved in fatty acid and cholesterol synthesis respectively [27].
Oxidative stress and inflammation are the key players in the onset of atherosclerosis. The serum
C-reactive protein levels are utilized as the indicators of systemic inflammation which leads to cardiac
dysfunction [28,29]. Watermelon intake significantly reduced the levels of C-reactive protein levels in
the serum of high fat fed rats [30]. Moreover, watermelon also down-regulated the expression of Cox-2
Molecules 2020, 25, 5258 3 of 15

enzyme responsible for the synthesis of pro-inflammatory prostaglandins. Furthermore, Hong et al. [30],
illustrated that the watermelon supplementation exhibited similar mechanism to non-steroidal
anti-inflammatory drugs that inhibits the activity of Cox-2 and reduces the inflammatory response.
A recent study has demonstrated the ability of watermelon to reduce the risk factors of cardiovascular
disorder in human [31,32]. According to Connolly et al. [32], consumption of watermelon in daily
basis for a period of four weeks resulted in significant reductions in body weight, body mass index,
waist-to-hip ratio, and blood pressure. In addition, the report also claims that the watermelon
supplementation lowered the levels of triglyceride, low density lipoprotein cholesterol, thiobarbituic
acid reactive substance, and increased the antioxidant capacity in obese adults [32]. Overall, it has
been evident that the consumption of watermelon in regular basis reduces the risk factors associated
with chronic illnesses such as cardiovascular diseases.

3. Watermelon as a Functional Food in Obesity Management and Anti-Diabetic Snack

Obesity is an alarming public health issue worldwide which is linked to crucial metabolic ailments
including diabetes and lifestyle-related diseases. Modern lifestyle and un-healthy food habits including
several fast foods and processed food with higher levels of sugar in routine diet are major contributing
factors for obesity. According to the National Diabetics Statistics Report (2020) published by Centers
for Disease Control and Prevention (CDC), 45.8% of adults in USA are obese, among which 10.5% of the
population suffer with diabetes [33]. Diabetes can be classified into two types (1 and 2) depending on
the etio-pathogenesis. Type 1 diabetes is characterized by the destruction of pancreatic B cells due to the
autoimmune response of the body leading to the insulin deficiency, whereas type 2, the most common
form of diabetes involving resistance to insulin [34]. The chronic hyperglycemia resulting from the
diabetes leads to retinopathy, neuropathy, nephropathy, peripheral vascular diseases, cerebrovascular
diseases, and ischemic heart diseases [35–37]. However, the oxidative stress level and inflammatory
responses in the body play a vital role in the development of the abovementioned complications.
The prominent symptom of non-insulin-dependent diabetes is the reduction in endothelial NO
synthesis and bioavailability, increase in glucose concentration in plasma, free fatty acid, homocysteine,
and methylarginines [38]. Numerous studies suggest that the regulation of energy substrate oxidation,
sensitivity to insulin and hemodynamics are influenced by NO in humans [24]. For the synthesis of
NO, l-arginine acts as the precursor which is converted by tetrahydrobiopetrin (BH4 )-dependent NO
synthase [9]. Based on the results of various in vivo and in vitro studies, it has been demonstrated that
the dietary intake of l-arginine decreased the glucose level in diabetic and obese rats [39–41]. In addition,
the l-arginine enhanced the vascular reactivity in animal models [38,42,43] and hypercholesterol
patients [44]. Thus, owing to the numerous health benefits of l-arginine, it has been recommended to
alleviate the risk of obesity and diabetes. However, direct intake of l-arginine displayed gastro-intestinal
problems therefore diets enriched with l-arginine have become the alternative.
Consumption of watermelon significantly increased the plasma l-arginine levels. According to
Wu et al. [12], supplementation of watermelon juice in Zucker diabetic fatty rats (a widely used animal
model for non-insulin dependent diabetes) elevated the l-arginine levels, decreased the amount of
glucose, free fatty acid, homocysteine, and methylarginines [12]. On the other hand, it enhanced the
activity of GTP cyclohydroxylase-1 and tetrahydrobiopterin levels in heart and acetylcholine-mediated
vascular relaxation. In addition, Wu et al. [12] recommended the consumption of watermelon pomace
juice as a functional food to combat diabetes and obesity based on their results in animal models.
In humans, the oral administration of watermelon juice can act as an effective alternative for
the supplementation of arginine. Watermelon juice effectively aided in the regulation of whole
body metabolism, and enhanced the cardiovascular and immune response in humans. A study by
Figueroa et al. [45] in obese middle-aged adults with pre-hypertension revealed that the watermelon
intake improved the arterial function and reduced the ankle blood pressure, brachial blood pressure,
and carotid wave reflection. Similarly, consumption of watermelon elicited the satiety response,
and reduced the body weight, body mass index (BMI), and waist to hip ratio in obese adults.
Molecules 2020, 25, 5258 4 of 15

Furthermore, Lum et al. [46] suggested that watermelon can effectively reduce the appetite and aid in
the weight management on comparison to the conventional refined carbohydrate snacks.

4. Anti-Ulcerative Colitis Property of Watermelon

Ulcerative colitis is one of the inflammatory bowel disease occurring broadly which causes the
mucosal inflammation in the entire bowel system [47]. The characteristic feature of ulcerative colitis is
the destruction of goblet cells, crypts, and development of ulcers [48]. In addition, ulcerative colitis in
the chronic stages can develop into the deadly colorectal cancer, which is the second leading cancer
with high death rate [49]. Apart from colorectal cancer, ulcerative colitis is also associated with the
onset of other related ailments such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis [50].
The reduction in the absorption of l-arginine by colonocytes is one of the symptoms of ulcerative
colitis [51,52]. According to Coburn et al., [53] the patients with ulcerative colitis displayed lesser
content of l-arginine which influenced the histology of colon and normal mucosal permeability.
Furthermore, the supplementation of l-arginine alleviated the symptoms of ulcerative colitis by
increasing the activity of antioxidants, lowering the pro-inflammatory cytokine levels, and also by
improving other allied clinical parameters [54,55]. The abundance of l-citrulline, precursor of l-arginine
in the watermelon can aid in the treatment of ulcerative colitis. A recent study by Hong et al. [30]
demonstrated that the watermelon supplementation mediated improvement of the micro-architecture
of colon crypts, cellular kinetics, and an increase in the endogenous levels of nitric oxide. Hong et al. [30]
hypothesized that the upregulation of NO levels by watermelon would synergistically enhance the
expression of peroxisome proliferator-activated receptor–γ (PPAR-γ) which in turn alleviated the
inflammation and oxidative stress. Previous studies suggested the direct influence of NO and
l-arginine on the up-regulation of PPAR-γ whereas ulcerative colitis leads to the reduction in the
levels of PPAR-γ [56,57]. The important enzymes such as COX-2, iNOS, and NF-κB involved in the
generation of reactive oxygen species are inhibited by PPAR-γ; on the other hand, the activities of
antioxidant enzymes are enhanced by PPAR-γ [58].
In addition, the watermelon augmentation decreased the levels on cyclin D1, a vital protein in the
Wnt signaling pathway in the high fat fed mice with ulcerative colitis [30]. Elevated expression of cyclin
D1 is widely observed in ulcerative colitis and colon carcinogenesis [59]. The Wnt signaling pathway
triggers the cellular proliferation rather than cellular differentiation, leading to carcinogenesis [59].
Previous reports suggested the endogenous NO mediated inhibition of Cyclin D1 regulation via
β-catenin pathway [59,60], therefore the increase in the NO level by watermelon could decrease the
expression of Cyclin D1.
One of the major factor that increases the pathogenesis of ulcerative colitis is the generation of
excess reactive oxygen species resulting in oxidative stress which is lethal to the macromolecular
components of the cells and also leads to DNA damage [61]. In particular, the oxidative stress
causing DNA damages leads to the promotion of carcinogenesis. For instance, the generation of
8-hydroxydeoxyguanosine (8-OHdG), an oxidized derivative of deoxyguanosine formed by the reaction
between reactive hydroxyl radical and DNA nucleobase facilitates the onset of colorectal cancer via the
down-regulation of tumor suppressor genes [62,63]. Hong et al. [30] have identified the elevated levels
of 8-OHdG in rats treated with DSS, whereas supplementation of watermelon reduced the 8-OHdG
content. The abundant antioxidant property of watermelon can be responsible for the suppression of
8-OHdG levels by alleviating the oxidative stress and thus protecting the DNA from damage.

5. Anti-Oxidant Properties of Watermelon

Several cascades of biochemical reactions are continuously undergoing in the cells and organelles
of a human body. The constant metabolic reactions generate highly reactive free radicals in the system
as inevitable by-products. These free radicals have the tendency to react with the macromolecules such
as proteins, lipids, and also with the DNA molecules and affects their normal functions [64]. The cellular
redox reactions generate reactive oxygen species which can act as beneficial secondary signaling
Molecules 2020, 25, 5258 5 of 15

molecules, but in excess cause oxidative stress in the cells. The oxidative stress potentially damages the
cellular organelles, which in the long term can result in various life-threatening ailments, such as cancers,
cardiovascular, and other neurodegenerative diseases [64]. However, diets enriched with antioxidants
can prevent the oxidative damages caused by the ROS. Plant-based diets are the major source of
antioxidants. In particular, phytochemicals such as phenols, flavonoids, alkaloids, and terpenoids
are the vital antioxidant molecules with several nutraceutical benefits [65]. These phytochemicals are
termed as secondary metabolites which are observed in lower abundance in plants in comparison with
primary metabolites and distributed in specialized cells or organelles [66]. Secondary metabolites plays
a vital role in the interaction between the plant and environment. It aids in the protection against abiotic
and biotic stresses in plants and also provides colors and aroma to plants and plant products [66].
The primary antioxidant potential of a secondary metabolite is acclaimed by the ability of the
compound to detoxify the toxic ROS by scavenging or by the prevention of oxidation of low-density
lipoproteins. In recent times, various health benefits rendered by plant-based polyphenolic compounds
have become the focus of several researchers. Similarly, pigments such as lycopene and β-carotene
present in watermelon also displayed antioxidant properties. Reports suggested that the consumption
of lycopene and β-carotene protects the architecture of plasma lipoprotein from oxidative stress,
suppresses the macular degeneration, prevents cataracts, and decreases the bioavailability of nitrogen
oxide [67–69]. In addition, the pigments aided in the improvement of immune system and prevented
the progression of tumors [70]. Among the carotenoids, lycopene consists of strong antioxidants,
for instance, the free radical scavenging rate of lycopene is higher in comparison with carotenoids such
as β-carotene and tocopherol. According to previous reports, the capability of lycopene to quench
the singlet oxygen is ten times higher than tocopherol and two-fold higher than β-carotene [71,72].
Among the fruits, watermelon consists of higher contents of bioavailable lycopene (1:12 of carotene)
followed by tomato [70]. However, the content of lycopene differs among the different cultivars of
watermelon as well as being determined by the growing environment [72,73]. The abundance of
lycopene in watermelon makes it as an excellent choice of functional food. The consumption of a
lycopene-rich diet can effectively improve the detoxification of free radicals which pose a threat to
DNA and cellular membrane and also regulates the lipid biosynthesis by influencing the enzymes in
the cholesterol biosynthesis pathway [74–76].
Polyphenolic compounds are vital antioxidants classified into phenolic acids, flavonoids, lignans,
and stilbenes. The polyphenol structure contains a minimum of two hydroxyl groups attached to an
aromatic ring. In fruits and vegetables, the majority of the antioxidant properties are attributed by the
polyphenolic compounds. According to Tilili et al. [7], in watermelon, the occurrence of polyphenols
is responsible for the hydrophilic antioxidant activity, and the fresh juice of watermelon is reported
to have 16.94–20.23 mg Gallic acid equivalent (GAE)/100 mL of polyphenols. Therefore, the intake
of watermelon as a dietary snack or in beverage form can induce the antioxidant potentials in the
human body and helps in the improvement of cell signaling, adhesion, and other biological activities.
However, the structure, level, absorption, and bioavailability of polyphenols determine the antioxidant
potentials [77]. Several polyphenols have been encompassed in the watermelon and few studies have
attempted to identify the polyphenolic contents (Table 1). Abu-Reidah et al. [78], have characterized
phytochemicals present in the methanolic extracts of watermelon using high-performance liquid
chromatography coupled to electrospray ionization–quadrupole time-of-flight mass spectrometry
(HPLC–ESI–QTOF–MS).
Apart from the direct consumption, watermelon can be added into food products, for instance the
augmentation of watermelon rind powders as a component in cake enhanced the free radical scavenging
activity and beta-carotene levels. Supplementation of watermelon rind powder along with wheat flour
during the preparation of cake increased the moisture, fat, protein, and carbohydrate contents [79].
In addition, the watermelon rind powder consisted of different polyphenolic substances such as
4-hydroxybenzoic acid, vanillin, and coumaric acid [79]. The presence of polyphenolic compounds
in watermelon rind powder significantly increased the efficiency of 1, 1-diphenyl-2-picryIhydrazyl
Molecules 2020, 25, 5258 6 of 15

(DPPH) radical scavenging [79]. The antioxidant capacity resulting from the addition of watermelon
rind in the cakes can also improve the shelf life along with the enhancement of the functional
components like polyphenols. Similarly, the inhibition of DPPH radicals by watermelon extracts was
reported by Tita et al. [80]. The report has analyzed the antioxidant ability and other health promoting
biological functions of pulp and rind extracts of various watermelon cultivars. Similarly, the study
led by Choudhary et al. [81], evidenced the presence of health promoting phytochemicals and
antioxidant potentials of various watermelon cultivars using in vitro assays. The results suggested
that the mean antioxidant activity determined using cupric reducing antioxidant capacity assay of
different watermelon cultivars ranged between 40.13 to 84.05 µmol Trolox equivalents (TE)/100 g FW.
Moreover, the report also estimated the phytochemicals such as total phenol (16.77 to 21.41 mg/g DW),
total flavonoids (55.60 to 100.93 mg/100 g DW), tannin (35.07 to 60.83 mg/100 g DW) and carotenoids
(4.90 to 8.06 mg/100 g), and lycopenes (3.74 to 6.80 mg/100 g) with well-known antioxidant ability [81].
According to the results observed in different cultivars, a higher amount of phytochemicals with
antioxidant capacity has been determined in the red-fleshed watermelons [81]. Similarly, the red
fleshed watermelon consisted of higher levels of ascorbic acid (86.32 mg/kg) and lycopene (9.50 mg/kg)
in comparison with the yellow fleshed watermelon (ascorbic acid: 52.05 mg/kg; lycopene: (0.04 mg/kg),
which correlated with the antioxidant capacity [82]. The antioxidant capacity of the watermelon has
been evaluated using the DPPH radical scavenging potential and ferrous ion chelating activity.
In addition to the rind and flesh, watermelon peels also exhibited the antioxidant capacity.
The investigation of phytochemicals and mineral components in the rind and peel of watermelon can
promote the utilization of low-cost agricultural by products for commercial use in small and large scale
food and allied industries. For instance, the report by Feizy et al. [83] has determined the presence of
protein, fat, ash, fiber, sodium, potassium, calcium, copper, magnesium, iron, phosphorus, and zinc in
the watermelon peel. Furthermore, the peel tissue consisted of significant amounts of polyphenols
which aided in the scavenging of free radicals. In general, the synthetic antioxidants such as butylated
hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are supplemented to increase the shelf
life and stability of the processed food and food products [83]. These synthetic antioxidants consists
of several potential disadvantages which needs a natural replacement. Therefore, the application of
fruits and vegetable by-products could render a possibility for an effective substitute. Taken together,
the consumption of watermelon as both direct dietary supplement or as indirect food supplement can
aid in the improvement of antioxidant potentials.

Table 1. Phytochemicals profiled in watermelon with antioxidant property.

S. NO Compound Name Class Reference

1. 3-O-Feruloylsucrose Hydroxycinnamic acid derivatives [84]
2. Ajugol Iridoid [78]
3. Apigenin-O-hexoside I Flavonoid [78]
4. Apigenin-O-hexoside II Flavonoid [78]
5. Aviprin I Coumarin [78]
6. β-carotene Carotenoid [2]
7. Caffeoylhexose I Hydroxycinnamic acid derivatives [78]
8. Catalposide Iridoid [78]
9. Chrysoeriol-O-hexoside I Flavonoid [78]
10. Chrysoeriol-O-hexoside II Flavonoid [78]
11. Cimifugin Phenol [78]
12. Citrulline Amino acid [4]
13. Coumarin Coumarin [78]
14. Decaffeoylacetoside Hydroxycinnamic acid derivatives [78]
15. Dicaffeoylshikimic acid II Hydroxycinnamic acid derivatives [85]
Molecules 2020, 25, 5258 7 of 15

Table 1. Cont..

S. NO Compound Name Class Reference

16. Dihydrophilonotisflavone Flavonoid [78]
17. Eriodictyol 7-glucoside Flavonoid [78]
18. Ferulic acid hexoside I Hydroxycinnamic acid derivatives [78,86]
19. Glehlinoside C Phenol [78]
20. Hydroquinone glucuronide Phenol [78]
Isolariciresinol
21. Lignan [78]
90 -β-d-glucopyranoside I
22. Isoorientin Flavonoid [78]
23. Isovitexin Flavonoid [87,88]
Kaempferol
24. Flavonoid [78]
rhamnoside–hexoside I
25. Leachianol G Phenol [78]
26. Lucenin-2-methyl ether Flavonoid [78]
27. Luteolin-O-hexoside I Flavonoid [89]
28. Lycopene Carotenoid [2]
29. Naringenin 7-rutinoside I Flavonoid [78]
30. O-Feruloylquinide Hydroxycinnamic acid derivatives [86]
31. Obtusoside Coumarin [78]
32. p-Coumaric acid glucoside I Hydroxycinnamic acid derivatives [78,90]
33. p-Coumaric acid glucoside II Hydroxycinnamic acid derivatives [78,90]
34. Phloroglucinol glucuronide Hydroxybenzoic acid derivative [78]
35. Picroside Iridoid [91]
Protocatechuic acid
36. Hydroxybenzoic acid derivative [92]
glucoside I
Protocatechuic acid
37. Hydroxybenzoic acid derivative [92]
glucoside II
38. Quercitin Flavonoid [78]
39. Rutin Flavonoid [78,93]
40. Salicylic acid-O-hexoside I Hydroxybenzoic acid derivatives [94]
41. Salicylic acid-O-hexoside II Hydroxybenzoic acid derivatives [94]
42. Saligenin glucopyranoside Phenol [78]
43. Shikonine Phenol [78]
44. Sinapic acid glucoside Hydroxycinnamic acid derivatives [78]
45. Taxifolin-O-hexoside I Flavonoid [78]
46. Tri-O-caffeoylshikimic acid I Hydroxybenzoic acid derivatives [85]
47. Vanillic acid hexoside Hydroxybenzoic acid derivatives [78]
48. Vanillin hexoside I Hydroxybenzoic acid derivatives [78]
49. Vanillin hexoside II Hydroxybenzoic acid derivatives [78]
50. Vanillin hexoside III Hydroxybenzoic acid derivatives [78]

6. Anticancer Properties of Watermelon

Cancer is a dreadful disease with high fatality rate in many nations worldwide. The association
between the active components of diet with the expression of genes in several metabolic pathways can
influence the molecular mechanism of carcinogenesis in biological system. For instance, the lycopene,
an active component in watermelon can indulge in the modulation of cancer development by the
inhibition of DNA mutation and acting against the metastasis of the tumor [95]. According to Nahum
Molecules 2020, 25, 5258 8 of 15

et al. [95], lycopene induces modulations in the cell cycle machinery, particularly by the inhibition of G1
phase in human breast and endometrial cancer. The administration of lycopene resulted in a reduction
in cyclin-dependent kinase (CDK) 1 and 3 activities in cancer cells. Moreover, the antioxidant property
of lycopene reduces the oxidative stress and aids in the anti-proliferative effects against cancerous cells.
Several studies have demonstrated the anti-cancerous potential of lycopene in vitro and in vivo [96].
However, the in-depth molecular rationale behind the lycopene-mediated regulation of interaction
between genes are still in study.
Among the cancers, the colon cancer is the second major deadliest cancer worldwide affecting
humans. Colon cancer can occur due to the disturbance of the balance between the cellular proliferation
and the programmed cell death (apoptosis). However, studies suggested that the proper dietary
intervention can prevent most of the colon cancers. The supplementation of watermelon in rats with
colon cancer decreased the cellular proliferation but no significant effects on apoptosis have been
observed [97]. The tumoricidal property of the watermelon can be due to various factors, but the vital
one could be the occurrence of abundant l-citrulline and its function in the synthesis of endothelial
nitric oxide (NO). According to Glen et al. [98], the addition of watermelon powder in the diets of
male Sprague-Dawley rats induced with colon cancer reduced the risks by alleviating the formation
of aberrant crypt foci via reducing the oxidative damages and inflammation to DNA. In addition,
an increase in the production of endogenous nitric oxide added the alleviation of cancerous effects and
the watermelon supplementation also modulated the expression of DNA repair enzymes to combat
the cancer.
In women, breast and cervical cancers are the two most major cancers with high fatality rate.
The anti-proliferative effects of watermelon leaf extracts have been investigated on both breast
and cervical cancer cell lines [99]. Leaf extracts from six cultivars of watermelon were tested in
cervical cancer cell lines (C33A, HeLa and SiHa) and breast adenocarcinoma cell lines (MDA-MB-231
and MCF-7) [99]. The in vitro MTT assay and the microscopic observation of cells evidenced the
anti-proliferative property of watermelon leaf extracts in both cancer cell lines on comparison with
normal cells. However, the cervical cancer cell lines, in particular the C33A, displayed high sensitivity
to the extracts. Among the cancer cell lines, the microscopic observations elucidated the reduction in
the number of cells and cellular size in C33A, MCF-7, and MDA-MB-231 lines [99]. The report also
suggested the cultivar dependent anti-cancer property of watermelon leaf extracts.
Leukemia is caused by the abnormal proliferation of blood cells in the bone marrow. Various parts
of watermelon have the anti-cancer potential due to the presence of the vital pharmaceutically valuable
phytochemicals. The phytochemical ‘phytol’ extracted from the sprouts of watermelon inhibited the
excessive proliferation of human T-cell leukemia line Jurkat cell and human lung adenocarcinoma
epithelial cell line A549—xenograft mice model [100]. In addition, the molecular mechanism behind
the phytol-mediated cell death included the activation of intercellular reactive oxygen species via
NADPH oxidase, which resulted in the arrest of cell cycle in S-phase. The expressions of vital proteins
such as cyclin A, cyclin D, mitogen activated protein kinase (MAPK) and phosphatidylinositol-3-kinase
(PI3K)/protein kinase b (Akt) were downregulated which resulted in the S-phase arrest [100]. The protein
cyclin A is vital for the synthesis of DNA molecules and for the advancement of S-phase in the cell
cycle by binding to Cdk2 protein [101,102]. Furthermore, the transition of G1 to S phase in the cell
cycle is mediated by cyclin D; for instance, the cyclin D phosphorylates the retinoblastoma tumor
suppressor protein by docking directly to Cdk4 or Cdk6 [103,104]. Moreover, the report suggested
that the regulation of cyclin A and D proteins was mediated by the ROS which prevented the cell
cycle in S-phase [100]. Similarly, several reports have illustrated the regulation of cyclin A and D
expressions mediated by the MAPKs and PI3K/Akt [105–109]. Both MAPKs and PI3K/Akt are involved
in numerous functions of cells such as proliferation, movement, differentiation, elongation, survival,
growth, and death [110]. However, the apoptosis mechanism was not significantly related to the
phytol-induced cell death in the cancer cell lines. Similar observation of non-apoptosis mediated cell
death primarily triggered by the intercellular ROS in cancer cell lines by phytochemicals have been
Molecules 2020, 25, 5258 9 of 15

reported [111]. Overall, the secondary metabolites present in watermelon tissues can effectively reduce
the proliferation of cancer cells. Further studies related to the identification and extraction of the
potential phytochemicals with efficient anti-cancer activity can aid in the search for drug candidates
for several dreadful cancers. Intake of watermelon displayed potential health benefits against several
life-threatening diseases. The phytochemicals present in the different tissues of watermelon combat
the harmful oxidative stress and also influenced vital metabolic pathways (Figure 1). Most of the
molecules targeted by the phytochemicals in watermelon are involved in diverse metabolic networks,
therefore, the molecular rational behind the disease alleviation by watermelon have to be studied in
detail by considering the isolation of active components in the extract.
Molecules 2020, 25, x FOR PEER REVIEW 9 of 15

Figure 1. A schematic representation of various mechanisms induced by the phytochemicals present

Figure 1. A schematic representation of various mechanisms induced by the phytochemicals present in
in watermelon extracts. The figure has been conceived based on the interpretation of the literatures
watermelon extracts. The figure has been conceived based on the interpretation of the literatures cited
cited in sections (2-6). ACC, acetyl-coA carboxylase; ACLY, ATP-citrate lyase;
in sections (2-6). ACC, acetyl-coA carboxylase; ACLY, ATP-citrate lyase; COX1/2,cyclooxygenase; Akt,
COX1/2,cyclooxygenase; Akt, alpha serine-threonine protein kinase; HMGCS, 3-hydroxy-3-
alphamethylglutaryl-CoA
serine-threonine protein kinase;
synthase; HMGCR, HMGCS, 3-hydroxy-3-methylglutaryl-CoA
3-hydroxy-3-methylglutaryl-CoA reductase;synthase; HMGCR,
FAS, fattyacid
3-hydroxy-3-methylglutaryl-CoA reductase; FAS, fattyacid synthase; MUFA,
synthase; MUFA, monounsaturated fatty acid; NO, endogenous nitric oxide; NOS, nitric oxidemonounsaturated
fatty synthase;
acid; NO, endogenous
PPAR-γ, peroxisome nitric oxide; NOS, nitric
proliferator-activated oxide
receptor–γ; synthase;
PUFA, PPAR-γ,fatty
polyunsaturated peroxisome
acid;
proliferator-activated receptor–γ;
PGH2, prostaglandin-H 2; ROS, PUFA,
reactivepolyunsaturated fatty acid;
oxygen species, SERB, sterolPGH2, prostaglandin-H
regulatory element binding2 ; ROS,
proteins;
reactive oxygenTCA, tricarboxylic
species, SERB, acetic
sterolacid cycle. element binding proteins; TCA, tricarboxylic acetic
regulatory
acid cycle.
6. Conclusions
7. Conclusions
Watermelon encompasses a diverse amounts of phytochemicals with vital pharmaceutical
importance majority
Watermelon of which
encompasses have been
a diverse attributed
amounts of by the abundant occurrence
phytochemicals with vital of citrulline,
pharmaceutical
importance majority of which have been attributed by the abundant occurrence ofvarious
lycopenes, and polyphenols. The supplementation of watermelon extracts under citrulline,
pathological ailments aids in the convalescence of diseases as well as from their inevitable negative
lycopenes, and polyphenols. The supplementation of watermelon extracts under various pathological
side effects. Secondary metabolites with nutraceutical potential present in different tissues of
ailments aids in the convalescence of diseases as well as from their inevitable negative side effects.
watermelon—such as leaves, sprouts, seeds, rinds, and fruits—act on different potential drug targets
Secondary metabolites with nutraceutical potential present in different tissues of watermelon—such as
involved in diseases such as diabetes, cancer, inflammation, and obesity. However, further studies
leaves,
dealing withseeds,
sprouts, rinds, and
the extraction fruits—act
of the on different potential
active phytochemical drug targets
and investigation involved
of molecular in diseases
regulatory
such mechanisms
as diabetes,ofcancer, inflammation,
the bioactive compoundsand obesity. However,
in watermelon are requiredfurther
to extendstudies dealingofwith
the utilization the the
extraction of the active
phytochemicals phytochemical
in nutraceutical and investigation
industries. In addition,ofthemolecular regulatory
phytochemical mechanisms of the
and pharmacokinetic
interpretation
bioactive compounds of vital secondary metabolites
in watermelon in watermelons
are required to extendcanthefacilitate the drug
utilization designing
of the process in
phytochemicals
to combat dreadful diseases. Moreover, being the functional food intake of watermelon
nutraceutical industries. In addition, the phytochemical and pharmacokinetic interpretation of vital can prevent
the onset
secondary of various in
metabolites disorders in humans.
watermelons canTaken together,
facilitate to accelerate
the drug designingthe discovery
process toofcombat
several plant
dreadful
based drug candidates with minimal side effects, the knowledge gained from the phytochemicals
diseases. Moreover, being the functional food intake of watermelon can prevent the onset of various
present in the fruits and vegetables can be a valuable asset.
Author Contributions: A.M. designed the manuscript outline, collected literature, and wrote the manuscript.
E.-S.L., K.H., H.-E.L., and D.-S.K. reviewed and edited the manuscript. E.-S.L. and K.H. participated in literature
collection and figure designing. D.-S.K. proofread and finalized the manuscript. All authors have read and
agreed to the published version of the manuscript.

Funding: This study was supported by the National Institute of Horticultural & Herbal Science, Rural
Molecules 2020, 25, 5258 10 of 15

disorders in humans. Taken together, to accelerate the discovery of several plant based drug candidates
with minimal side effects, the knowledge gained from the phytochemicals present in the fruits and
vegetables can be a valuable asset.

Author Contributions: A.M. designed the manuscript outline, collected literature, and wrote the manuscript.
E.-S.L., K.H., H.-E.L., and D.-S.K. reviewed and edited the manuscript. E.-S.L. and K.H. participated in literature
collection and figure designing. D.-S.K. proofread and finalized the manuscript. All authors have read and agreed
to the published version of the manuscript.
Funding: This study was supported by the National Institute of Horticultural & Herbal Science, Rural Development
Administration, Republic of Korea (Project No. PJ01417301). Abinaya Manivannan was supported by
the RDA Research Associate Fellowship Program of National Institute of Horticultural and Herbal Science,
Rural Development Administration, Republic of Korea.
Conflicts of Interest: These authors have declared no conflict of interest.

References
1. Assefa, A.D.; Hur, O.S.; Ro, N.Y.; Lee, J.E.; Hwang, A.J.; Kim, B.S.; Rhee, J.H.; Yi, J.Y.; Kim, J.H.; Lee, H.S.; et al.
Fruit Morphology, Citrulline, and Arginine Levels in Diverse Watermelon (Citrullus lanatus) Germplasm
Collections. Plants 2020, 9, 1054. [CrossRef]
2. Perkins-Veazie, P.; Davis, A.; Collins, J.K. Watermelon: From dessert to functional food. Isr. J. Plant Sci. 2012,
60, 395–402.
3. U.S. Department of Agriculture ARS. USDA National Nutrient Database for Standard Reference, Release 27;
Service, A.R., Ed.; Department of Agriculture: Washington, DC, USA, 2015.
4. Rimando, A.M.; Perkins-Veazie, P.M. Determination of citrulline in watermelon rind. J. Chromatogr. A 2005,
1078, 196–200. [CrossRef] [PubMed]
5. Rao, A.V.; Agarwal, S. Role of antioxidant lycopene in cancer and heart disease. J. Am. Coll. Nutr. 2000,
19, 563–569. [CrossRef] [PubMed]
6. Romero, M.J.; Platt, D.H.; Caldwell, R.B.; Caldwell, R.W. Therapeutic use of citrulline in cardiovascular
disease. Cardiovasc. Drug Rev. 2006, 24, 275–290. [CrossRef]
7. Tlili, I.; Hdider, C.; Lenucci, M.S.; Riadh, I.; Jebari, H.; Dalessandro, G. Bioactive compounds and antioxidant
activities of different watermelon (Citrullus lanatus (Thunb.) Mansfeld) cultivars as affected by fruit sampling
area. J. Food Compos. Anal. 2011, 24, 307–314. [CrossRef]
8. Tomes, M.L.; Johnson, K.W.; Hess, M. The carotene pigment content of certain red fleshed watermelons.
Inproc. Am. Soc. Hortic. Sci. 1963, 82, 460–464.
9. Wan, X.; Liu, W.; Yan, Z.; Zhao, S.; He, N.; Liu, P. Changes of the contents of functional substances including
lycopene, citrulline and ascorbic acid during watermelon fruits development. Sci. Agric. Sin. 2011,
44, 2738–2747.
10. Tarazona-Díaz, M.P.; Viegas, J.; Moldao-Martins, M.; Aguayo, E. Bioactive compounds from flesh and
by-product of fresh-cut watermelon cultivars. J. Sci. Food Agric. 2011, 91, 805–812. [CrossRef]
11. Wada, M. Uber Citrullin, eine neue Aminosaure im PreBsaft der Wassermelone, Citrullus vulgaris schrad.
Biochemische Zeitschrift 1930, 224, 420–429.
12. Wu, G.; Collins, J.K.; Perkins-Veazie, P.; Siddiq, M.; Dolan, K.D.; Kelly, K.A.; Heaps, C.L.; Meininger, C.J.
Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the
metabolic syndrome in Zucker diabetic fatty rats. J. Nutr. 2007, 137, 2680–2685. [CrossRef] [PubMed]
13. Yokota, A.; Kawasaki, S.; Iwano, M.; Nakamura, C.; Miyake, C.; Akashi, K. Citrulline and DRIP-1 protein
(ArgE homologue) in drought tolerance of wild watermelon. Ann. Bot. 2002, 89, 825–832. [CrossRef]
[PubMed]
14. El-Adawy, T.A.; Taha, K.M. Characteristics and composition of different seed oils and flours. Food Chem.
2001, 74, 47–54. [CrossRef]
15. Stafford, W.; Oke, O.L. Protein isolate from lesser known oilseeds from Nigeria. Nutr. Rep. Int. 1977,
16, 813–820.
16. King, R.D.; Onuora, J.O. Aspects of melon seed protein characteristics. Food Chem. 1984, 14, 65–77. [CrossRef]
17. Kaul, P. Nutritional potential, bioaccessibility of minerals and functionality of watermelon (Citrullus vulgaris)
seeds. LWT-Food Sci. Technol. 2011, 44, 1821–1826.
Molecules 2020, 25, 5258 11 of 15

18. Sola, A.O.; Temitayo, O.O.; Olufunke, A.; Shittu, F. Chemical composition, nutritional values and antibacterial
activities of watermelon seed (Citrullus lanatus). Int. J. Biochem. Res. Rev. 2019, 27. [CrossRef]
19. Suliburska, J.; Bogdanski, P.; Krejpcio, Z.; Pupek-Musialik, D.; Jablecka, A. The effects of l-arginine, alone and
combined with vitamin C, on mineral status in relation to its antidiabetic, anti-inflammatory, and antioxidant
properties in male rats on a high-fat diet. Biol. Trace Elem. Res. 2014, 157, 67–74. [CrossRef]
20. Alam, M.A.; Kauter, K.; Withers, K.; Sernia, C.; Brown, L. Chronic l-arginine treatment improves metabolic,
cardiovascular and liver complications in diet-induced obesity in rats. Food Funct. 2013, 4, 83–91. [CrossRef]
21. Evans, R.W.; Fernstrom, J.D.; Thompson, J.; Morris, S.M., Jr.; Kuller, L.H. Biochemical responses of healthy
subjects during dietary supplementation with l-arginine. J. Nutr. Biochem. 2004, 15, 534–539. [CrossRef]
22. Wu, G.; Meininger, C.J. Arginine nutrition and cardiovascular function. J. Nutr. 2000, 130, 2626–2629.
[CrossRef] [PubMed]
23. Hong, M.Y.; Hartig, N.; Kaufman, K.; Hooshmand, S.; Figueroa, A.; Kern, M. Watermelon consumption
improves inflammation and antioxidant capacity in rats fed an atherogenic diet. Nutr. Res. 2015, 35, 251–258.
[CrossRef] [PubMed]
24. Jobgen, W.S.; Fried, S.K.; Fu, W.J.; Meininger, C.J.; Wu, G. Regulatory role for the arginine–nitric oxide
pathway in metabolism of energy substrates. J. Nutr. Biochem. 2006, 17, 571–588. [CrossRef] [PubMed]
25. Jobgen, W.; Fu, W.J.; Gao, H.; Li, P.; Meininger, C.J.; Smith, S.B.; Spencer, T.E.; Wu, G. High fat feeding
and dietary l-arginine supplementation differentially regulate gene expression in rat white adipose tissue.
Amino Acids 2009, 37, 187–198. [CrossRef] [PubMed]
26. Jensen-Urstad, A.P.; Semenkovich, C.F. Fatty acid synthase and liver triglyceride metabolism: Housekeeper
or messenger? Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2012, 1821, 747–753. [CrossRef]
27. Baenke, F.; Peck, B.; Miess, H.; Schulze, A. Hooked on fat: The role of lipid synthesis in cancer metabolism
and tumour development. Dis. Models Mech. 2013, 6, 1353–1363. [CrossRef]
28. Iantorno, M.; Campia, U.; Di Daniele, N.; Nistico, S.; Forleo, G.B.; Cardillo, C.; Tesauro, M. Obesity,
inflammation and endothelial dysfunction. J. Biol. Regul. Homeost. Agents 2014, 28, 169–176.
29. Zaiss, A.K.; Zuber, J.; Chu, C.; Machado, H.B.; Jiao, J.; Catapang, A.B.; Ishikawa, T.O.; Gil, J.S.; Lowe, S.W.;
Herschman, H.R. Reversible suppression of cyclooxygenase 2 (COX-2) expression in vivo by inducible RNA
interference. PLoS ONE 2014, 9, e101263. [CrossRef]
30. Hong, M.Y.; Tseng, Y.T.; Kalaba, M.; Beidler, J. Effects of watermelon powder supplementation on colitis in
high-fat diet-fed and dextran sodium sulfate-treated rats. J. Funct. Foods 2019, 54, 520–528. [CrossRef]
31. Shanely, R.A.; Zwetsloot, J.J.; Jurrissen, T.J.; Hannan, L.C.; Zwetsloot, K.A.; Needle, A.R.; Bishop, A.E.; Wu, G.;
Perkins-Veazie, P. Daily watermelon consumption decreases plasma sVCAM-1 levels in overweight and
obese postmenopausal women. Nutr. Res. 2020, 76, 9–19. [CrossRef]
32. Connolly, M.; Lum, T.; Marx, A.; Hooshmand, S.; Kern, M.; Liu, C.; Hong, M.Y. Effect of Fresh Watermelon
Consumption on Risk Factors for Cardiovascular Disease in Overweight and Obese Adults (P06-102-19).
Curr. Dev. Nutr. 2019, 3. [CrossRef]
33. Center for Disease Control and Prevention. National Diabetes Statistics Report; Centers for disease control and
prevention, US Department of Health and Human Services: Atlanta, GA, USA, 2020.
34. Johnson, J.A.; Pohar, S.L.; Majumdar, S.R. Health care use and costs in the decade after identification of type
1 and type 2 diabetes: A population-based study. Diabetes Care 2006, 29, 2403–2408. [CrossRef] [PubMed]
35. Kahn, R.; Buse, J.; Ferrannini, E.; Stern, M. The metabolic syndrome: Time for a critical appraisal. Diabetologia
2005, 148, 1684–1699. [CrossRef]
36. Inzucchi, S.E.; Matthews, D.R.; Buse, J.B.; Diamant, M.; Ferrannini, E.; Nauck, M.; Peters, A.L.; Tsapas, A.;
Wender, R.; Matthews, D.R. Response to Comments on Inzucchi et al. Management of Hyperglycemia in Type
2 Diabetes, 2015: A Patient-Centered Approach. Update to a Position Statement of the American Diabetes
Association and the European Association for the Study of Diabetes. Diabetes Care 2005, 28, 2289–2304.
37. Marliss, E.B.; Chevalier, S.; Gougeon, R.; Morais, J.A.; Lamarche, M.; Adegoke, O.A.; Wu, G. Elevations of
plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover.
Diabetologia 2006, 49, 351–359. [CrossRef]
38. Pieper, G.M. Review of alterations in endothelial nitric oxide production in diabetes: Protective role of
arginine on endothelial dysfunction. Hypertension 1998, 31, 1047–1060. [CrossRef]
39. Míguez, L.; Marino, G.; Rodriguez, B.; Taboada, C. Effects of dietary l-arginine supplementation on serum
lipids and intestinal enzyme activities in diabetic rats. J. Physiol. Biochem. 2004, 60, 31–37. [CrossRef]
Molecules 2020, 25, 5258 12 of 15

40. Mendez, J.D.; Balderas, F. Regulation of hyperglycemia and dyslipidemia by exogenous l-arginine in diabetic
rats. Biochimie 2001, 83, 453–458. [CrossRef]
41. Kohli, R.; Meininger, C.J.; Haynes, T.E.; Yan, W.; Self, J.T.; Wu, G. Dietary l-arginine supplementation
enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. J. Nutr. 2004, 134, 600–608.
[CrossRef]
42. Fu, W.J.; Haynes, T.E.; Kohli, R.; Hu, J.; Shi, W.; Spencer, T.E.; Carroll, R.J.; Meininger, C.J.; Wu, G. Dietary
l-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. J. Nutr. 2005, 135, 714–721.
[CrossRef]
43. Popov, D.; Costache, G.; Georgescu, A.; Enache, M. Beneficial effects of l-arginine supplementation in
experimental hyperlipemia-hyperglycemia in the hamster. Cell Tissue Res. 2002, 308, 109–120. [CrossRef]
[PubMed]
44. Creager, M.A.; Gallagher, S.J.; Girerd, X.J.; Coleman, S.M.; Dzau, V.J.; Cooke, J.P. l-arginine improves
endothelium-dependent vasodilation in hypercholesterolemic humans. J. Clin. Investig. 1992, 90, 1248–1253.
[CrossRef] [PubMed]
45. Figueroa, A.; Sanchez-Gonzalez, M.A.; Perkins-Veazie, P.M.; Arjmandi, B.H. Effects of watermelon
supplementation on aortic blood pressure and wave reflection in individuals with prehypertension: A pilot
study. Am. J. Hypertens. 2011, 24, 40–44. [CrossRef] [PubMed]
46. Lum, T.; Connolly, M.; Marx, A.; Beidler, J.; Hooshmand, S.; Kern, M.; Liu, C.; Hong, M.Y. Effects of fresh
watermelon consumption on the acute satiety response and cardiometabolic risk factors in overweight and
obese adults. Nutrients 2019, 11, 595. [CrossRef]
47. Machiels, K.; Joossens, M.; Sabino, J.; De Preter, V.; Arijs, I.; Ballet, V.; Claes, K.; Verhaegen, J.; Van Assche, G.;
Rutgeerts, P.J.; et al. 187 Bacterial Dysbiosis in Ulcerative Colitis Patients Differs From Crohn’s Disease
Patients. Gastroenterology 2012, 142, S-46. [CrossRef]
48. Danese, S.; Fiocchi, C. Ulcerative colitis. N. Engl. J. Med. 2011, 365, 1713–1725. [CrossRef]
49. Clapper, M.L.; Cooper, H.S.; Chang, W.-C.L. Dextran sulfate sodium-induced colitis-associated neoplasia:
A promising model for the development of chemopreventive interventions 1. Acta Pharm. Sin. 2007,
28, 1450–1459. [CrossRef]
50. Ghosh, S.; Mitchell, R. Impact of inflammatory bowel disease on quality of life: Results of the European
Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA) patient survey. J. Crohn’s Colitis 2007,
1, 10–20. [CrossRef]
51. Hatoum, O.A.; Binion, D.G.; Otterson, M.F.; Gutterman, D.D. Acquired microvascular dysfunction in
inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation. Gastroenterology 2003, 125, 58–69.
[CrossRef]
52. Hong, S.K.; Maltz, B.E.; Coburn, L.A.; Slaughter, J.C.; Chaturvedi, R.; Schwartz, D.A.; Wilson, K.T. Increased
serum levels of l-arginine in ulcerative colitis and correlation with disease severity. Inflamm. Bowel Dis. 2010,
16, 105–111. [CrossRef]
53. Coburn, L.A.; Horst, S.N.; Allaman, M.M.; Brown, C.T.; Williams, C.S.; Hodges, M.E.; Druce, J.P.; Beaulieu, D.B.;
Schwartz, D.A.; Wilson, K.T. l-arginine availability and metabolism is altered in ulcerative colitis. Inflamm.
Bowel Dis. 2016, 22, 1847–1858. [CrossRef]
54. Ren, W.; Yin, J.; Wu, M.; Liu, G.; Yang, G.; Xion, Y.; Su, D.; Wu, L.; Li, T.; Chen, S.; et al. Serum amino acids
profile and the beneficial effects of l-arginine or L-glutamine supplementation in dextran sulfate sodium
colitis. PLoS ONE 2014, 9, e88335. [CrossRef]
55. Coburn, L.A.; Gong, X.; Singh, K.; Asim, M.; Scull, B.P.; Allaman, M.M.; Williams, C.S.; Rosen, M.J.;
Washington, M.K.; Barry, D.P.; et al. l-arginine supplementation improves responses to injury and
inflammation in dextran sulfate sodium colitis. PLoS ONE 2012, 7, e33546. [CrossRef]
56. Ptasinska, A.; Wang, S.; Zhang, J.; Wesley, R.A.; Danner, R.L. Nitric oxide activation of peroxisome
proliferator-activated receptor gamma through a p38 MAPK signaling pathway. FASEB J. 2007, 21, 950–961.
[CrossRef]
57. Liu, Y.; Huang, J.; Hou, Y.; Zhu, H.; Zhao, S.; Ding, B.; Yin, Y.; Yi, G.; Shi, J.; Fan, W. Dietary arginine
supplementation alleviates intestinal mucosal disruption induced by Escherichia coli lipopolysaccharide in
weaned pigs. Br. J. Nutr. 2008, 100, 552–560. [CrossRef]
Molecules 2020, 25, 5258 13 of 15

58. Cai, W.; Yang, T.; Liu, H.; Han, L.; Zhang, K.; Hu, X.; Zhang, X.; Yin, K.J.; Gao, Y.; Bennett, M.V.; et al.
Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair.
Prog. Neurobiol. 2018, 163, 27–58. [CrossRef]
59. Hulit, J.; Wang, C.; Li, Z.; Albanese, C.; Rao, M.; Di Vizio, D.; Shah, S.; Byers, S.W.; Mahmood, R.;
Augenlicht, L.H.; et al. Cyclin D1 genetic heterozygosity regulates colonic epithelial cell differentiation and
tumor number in ApcMin mice. Mol. Cell. Biol. 2004, 24, 7598–7611. [CrossRef]
60. Warboys, C.M.; Chen, N.; Zhang, Q.; Shaifta, Y.; Vanderslott, G.; Passacquale, G.; Hu, Y.; Xu, Q.; Ward, J.P.;
Ferro, A. Bidirectional cross-regulation between the endothelial nitric oxide synthase and β-catenin signalling
pathways. Cardiovasc. Res. 2014, 104, 116–126. [CrossRef]
61. Roessner, A.; Kuester, D.; Malfertheiner, P.; Schneider-Stock, R. Oxidative stress in ulcerative colitis-associated
carcinogenesis. Pathol. Res. Pract. 2008, 204, 511–524. [CrossRef]
62. Valavanidis, A.; Vlachogianni, T.; Fiotakis, C. 8-hydroxy-20 -deoxyguanosine (8-OHdG): A critical biomarker
of oxidative stress and carcinogenesis. J. Environ. Sci. Health 2009, 27, 120–139. [CrossRef]
63. Yasui, M.; Kanemaru, Y.; Kamoshita, N.; Suzuki, T.; Arakawa, T.; Honma, M. Tracing the fates of
site-specifically introduced DNA adducts in the human genome. DNA Repair 2014, 15, 11–20. [CrossRef]
[PubMed]
64. Ijah, U.J.; Ayodele, H.S.; Aransiola, S.A. Microbiological and some sensory attributes of water melon juice
and watermelon-orange juice mix. J. Food Resour. Sci. 2015, 4, 49–61.
65. Luckner, M. Secondary Metabolism in Microorganisms, Plants and Animals; Springer Science & Business Media:
Berlin, Germany, 2013.
66. Rhodes, M.J. Physiological roles for secondary metabolites in plants: Some progress, many outstanding
problems. Plant Mol. Biol. 1994, 24, 1–20. [CrossRef] [PubMed]
67. Kulczyński, B.; Gramza-Michałowska, A.; Kobus-Cisowska, J.; Kmiecik, D. The role of carotenoids in the
prevention and treatment of cardiovascular disease–Current state of knowledge. J. Funct. Foods 2017,
38, 45–65. [CrossRef]
68. Lemos, Á.T.; Ribeiro, A.C.; Fidalgo, L.G.; Delgadillo, I.; Saraiva, J.A. Extension of raw watermelon juice
shelf-life up to 58 days by hyperbaric storage. Food Chem. 2017, 231, 61–69. [CrossRef]
69. Kehili, M.; Kammlott, M.; Choura, S.; Zammel, A.; Zetzl, C.; Smirnova, I.; Allouche, N.; Sayadi, S.
Supercritical CO2 extraction and antioxidant activity of lycopene and β-carotene-enriched oleoresin from
tomato (Lycopersicum esculentum L.) peels by-product of a Tunisian industry. Food Bioprod. Process. 2017,
102, 340–349. [CrossRef]
70. Oberoi, D.P.; Sogi, D.S. Utilization of watermelon pulp for lycopene extraction by response surface
methodology. Food Chem. 2017, 232, 316–321. [CrossRef]
71. Naz, A.; Butt, M.S.; Sultan, M.T.; Qayyum, M.M.; Niaz, R.S. Watermelon lycopene and allied health claims.
EXCLI J. 2014, 13, 650.
72. Kyriacou, M.C.; Leskovar, D.I.; Colla, G.; Rouphael, Y. Watermelon and melon fruit quality: The genotypic
and agro-environmental factors implicated. Sci. Hortic. 2018, 234, 393–408. [CrossRef]
73. Soteriou, G.A.; Kyriacou, M.C.; Siomos, A.S.; Gerasopoulos, D. Evolution of watermelon fruit physicochemical
and phytochemical composition during ripening as affected by grafting. Food Chem. 2014, 165, 282–289.
[CrossRef]
74. Oberoi, D.P.; Sogi, D.S. Prediction of lycopene degradation during dehydration of watermelon pomace
(cv Sugar Baby). J. Saudi Soc. Agric. Sci. 2017, 16, 97–103. [CrossRef]
75. Srivastava, S.; Srivastava, A.K. Lycopene; chemistry, biosynthesis, metabolism and degradation under
various abiotic parameters. J. Food Sci. Technol. 2015, 52, 41–53. [CrossRef]
76. Elumalai, M.; Karthika, B.; Usha, V. Lycopene-role in cancer prevention. Int. J. Pharma Bio Sci. 2013,
4, 371–378.
77. Sharma, S.; Sarvesh, P.; Dwivedi, J.; Amita, T. First report on laxative activity of Citrullus lanatus.
Pharmacologyonline 2011, 2, 790–797.
78. Abu-Reidah, I.M.; Arráez-Román, D.; Segura-Carretero, A.; Fernández-Gutiérrez, A. Profiling of phenolic
and other polar constituents from hydro-methanolic extract of watermelon (Citrullus lanatus) by means of
accurate-mass spectrometry (HPLC–ESI–QTOF–MS). Food Res. Int. 2013, 51, 354–362. [CrossRef]
79. Al-Sayed, H.M.; Ahmed, A.R. Utilization of watermelon rinds and sharlyn melon peels as a natural source of
dietary fiber and antioxidants in cake. Ann. Agric. Sci. 2013, 58, 83–95. [CrossRef]
Molecules 2020, 25, 5258 14 of 15

80. Tit, a, B.; Statti, G.A. Nutraceutical properties and health-promoting biological activities of fruits of watermelon
cultivars with different origins. Farmacia 2020, 68, 4.
81. Choudhary, B.R.; Haldhar, S.M.; Maheshwari, S.K.; Bhargava, R.; Sharma, S.K. Phytochemicals and
antioxidants in watermelon (Citrullus lanatus) genotypes under hot arid region. Indian J. Agric. Sci. 2015,
85, 414–417.
82. Choo, W.S.; Sin, W.Y. Ascorbic acid, lycopene and antioxidant activities of red-fleshed and yellow-fleshed
watermelons. Adv. Appl. Sci. Res. 2012, 3, 2779–2784.
83. Feizy, J.; Jahani, M.; Ahmadi, S. Antioxidant activity and mineral content of watermelon peel. J. Food
Bioprocess Eng. 2020. [CrossRef]
84. Kujala, T.S.; Vienola, M.S.; Klika, K.D.; Loponen, J.M.; Pihlaja, K. Betalain and phenolic compositions of four
beetroot (Beta vulgaris) cultivars. Eur. Food Res. Technol. 2002, 214, 505–510. [CrossRef]
85. Gouveia, S.; Castilho, P.C. Characterisation of phenolic acid derivatives and flavonoids from different
morphological parts of Helichrysum obconicum by a RP-HPLC–DAD-(−)–ESI-MSn method. Food Chem.
2011, 129, 333–344. [CrossRef]
86. Bellés, J.M.; López-Gresa, M.P.; Fayos, J.; Pallás, V.; Rodrigo, I.; Conejero, V. Induction of cinnamate
4-hydroxylase and phenylpropanoids in virus-infected cucumber and melon plants. Plant Sci. 2008,
174, 524–533. [CrossRef]
87. Krauze-Baranowska, M.; Cisowski, W. High-performance liquid chromatographic determination of flavone
C-glycosides in some species of the Cucurbitaceae family. J. Chromatogr. A. 1994, 675, 240–243. [CrossRef]
88. Pikulski, M.; Brodbelt, J.S. Differentiation of flavonoid glycoside isomers by using metal complexation and
electrospray ionization mass spectrometry. J. Am. Soc. Mass Spectrom. 2003, 14, 1437–1453. [CrossRef]
89. Siciliano, T.; De Tommasi, N.; Morelli, I.; Braca, A. Study of flavonoids of Sechium edule (Jacq) Swartz
(Cucurbitaceae) different edible organs by liquid chromatography photodiode array mass spectrometry.
J. Agric. Food Chem. 2004, 52, 6510–6515. [CrossRef]
90. Billett, E.E.; Grayer-Barkmeijer, R.J.; Johnson, C.B.; Harborne, J.B. The effect of blue light on free and esterified
phenolic acids in etiolated gherkin tissues. Phytochemistry 1981, 20, 1259–1263. [CrossRef]
91. Hong, J.L.; Qin, X.Y.; Shu, P.; Wu, G.; Wang, Q.; Qin, M.J. Analysis of catalpol derivatives by characteristic
neutral losses using liquid chromatography combined with electrospray ionization multistage and
time-of-flight mass spectrometry. Rapid Commun. Mass Spectrom. 2010, 24, 2680–2686. [CrossRef]
92. Rodríguez-Medina, I.C.; Segura-Carretero, A.; Fernández-Gutiérrez, A. Use of high-performance liquid
chromatography with diode array detection coupled to electrospray-Qq-time-of-flight mass spectrometry
for the direct characterization of the phenolic fraction in organic commercial juices. J. Chromatogr. A 2009,
1216, 4736–4744. [CrossRef]
93. Cai, J.; Wang, W. Study on content of total flavonoids in leaves of cucumber. Shipin Kexue (Beijing, China).
Food Sci. 2005, 8, 194–197.
94. Zhang, P.Y.; Wang, J.C.; Liu, S.H.; Chen, K.S. A novel burdock fructo oligosaccharide induces changes
in the production of salicylates, activates defence enzymes and induces systemic acquired resistance to
Colletotrichum orbiculare in cucumber seedlings. J. Phytopathol. 2009, 157, 201–207. [CrossRef]
95. Nahum, A.; Hirsch, K.; Danilenko, M.; Watts, C.K.; Prall, O.W.; Levy, J.; Sharoni, Y. Lycopene inhibition of cell
cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and
retention of p27 Kip1 in the cyclin E–cdk2 complexes. Oncogene 2001, 20, 3428–3436. [CrossRef] [PubMed]
96. Giovannucci, E. Tomatoes, tomato-based products, lycopene, and cancer: Review of the epidemiologic
literature. J. Natl. Cancer Inst. 1999, 91, 317–331. [CrossRef] [PubMed]
97. Fesseha, M.; Hong, M.Y. Effects of Watermelon Consumption on Cellular Proliferation, and Apoptosis in Rat
Colon (P05-019-19). Curr. Dev. Nutr. 2019, 3, 3–5. [CrossRef]
98. Glenn, K.; Klarich, D.S.; Kalaba, M.; Figueroa, A.; Hooshmand, S.; Kern, M.; Hong, M.Y. Effects of
Watermelon Powder and l-arginine Supplementation on Azoxymethane-Induced Colon Carcinogenesis in
Rats. Nutr. Cancer 2018, 70, 938–945. [CrossRef]
99. Sueakham, T.; Chantaramanee, C.; Iawsipo, P. Anti-proliferative effect of Thai watermelon leaf extracts on
cervical and breast cancer cells. NU. Int. J. Sci. 2018, 15, 89–95.
Molecules 2020, 25, 5258 15 of 15

100. Itoh, T.; Ono, A.; Kawaguchi, K.; Teraoka, S.; Harada, M.; Sumi, K.; Ando, M.; Tsukamasa, Y.; Ninomiya, M.;
Koketsu, M.; et al. Phytol isolated from watermelon (Citrullus lanatus) sprouts induces cell death in human
T-lymphoid cell line Jurkat cells via S-phase cell cycle arrest. Food Chem. Toxicol. 2018, 115, 425–435.
[CrossRef]
101. Pagano, M.; Pepperkok, R.; Verde, F.; Ansorge, W.; Draetta, G. Cyclin A is required at two points in the
human cell cycle. EMBO J. 1992, 11, 961–971. [CrossRef]
102. Yam, C.H.; Fung, T.K.; Poon, R.Y. Cyclin A in cell cycle control and cancer. Cell. Mol. Life Sci. 2002,
59, 1317–1326. [CrossRef]
103. Diehl, J.A. Cycling to cancer with cyclin D1. Cancer Biol. Ther. 2002, 1, 226–231. [CrossRef]
104. Giacinti, C.; Giordano, A. RB and cell cycle progression. Oncogene 2006, 25, 5220–5227. [CrossRef] [PubMed]
105. Cuenda, A.; Rousseau, S. p38 MAP-kinases pathway regulation, function and role in human diseases.
Biochim. Biophys. Acta Mol. Cell Res. 2007, 1773, 1358–1375. [CrossRef] [PubMed]
106. Maddika, S.; Ande, S.R.; Wiechec, E.; Hansen, L.L.; Wesselborg, S.; Los, M. Akt-mediated phosphorylation of
CDK2 regulates its dual role in cell cycle progression and apoptosis. J. Cell Sci. 2008, 121, 979–988. [CrossRef]
107. Seifrtova, M.; Havelek, R.; Chmelarova, M.; Cmielova, J.; Muthna, D.; Stoklasova, A.; Zemankova, S.;
Rezacova, M. The effect of ATM and ERK1/2 inhibition on mitoxantrone-induced cell death of leukaemic
cells. Folia Biol. 2011, 57, 74–81.
108. Yang, T.Y.; Chang, G.C.; Chen, K.C.; Hung, H.W.; Hsu, K.H.; Sheu, G.T.; Hsu, S.L. Sustained activation of
ERK and Cdk2/cyclin-A signaling pathway by pemetrexed leading to S-phase arrest and apoptosis in human
non-small cell lung cancer A549 cells. Eur. J. pharmacol. 2011, 663, 17–26. [CrossRef]
109. Liu, P.; Begley, M.; Michowski, W.; Inuzuka, H.; Ginzberg, M.; Gao, D.; Tsou, P.; Gan, W.; Papa, A.; Kim, B.M.;
et al. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 2014,
508, 541–545. [CrossRef]
110. Zhang, X.; Tang, N.; Hadden, T.J.; Rishi, A.K. Akt, FoxO and regulation of apoptosis. Biochim. Biophys. Acta
Mol. Cell Res. 2011, 1813, 1978–1986. [CrossRef]
111. Rastogi, N.; Gara, R.K.; Trivedi, R.; Singh, A.; Dixit, P.; Maurya, R.; Duggal, S.; Bhatt, M.L.; Singh, S.;
Mishra, D.P. (6)-Gingerolinduced myeloid leukemia cell death is initiated by reactive oxygen species and
activation of miR-27b expression. Free Radic. Biol. Med. 2014, 68, 288–301. [CrossRef]

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional
affiliations.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).