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 [67,68,69]. In addition, the pigments aided in the improvement of immune system and prevented the progression of tumors . 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 . 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 [74,75,76].
Ulcerative colitis is one of the inflammatory bowel disease occurring broadly which causes the mucosal inflammation in the entire bowel system . The characteristic feature of ulcerative colitis is the destruction of goblet cells, crypts, and development of ulcers . 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 . Apart from colorectal cancer, ulcerative colitis is also associated with the onset of other related ailments such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis . 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.,  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.  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.  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 .
These authors have declared no conflict of interest.
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 . 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 . 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 . Similarly, several reports have illustrated the regulation of cyclin A and D expressions mediated by the MAPKs and PI3K/Akt [105,106,107,108,109]. Both MAPKs and PI3K/Akt are involved in numerous functions of cells such as proliferation, movement, differentiation, elongation, survival, growth, and death . 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 reported . 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.
Consumption of watermelon significantly increased the plasma l -arginine levels. According to Wu et al. , 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 . 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.  recommended the consumption of watermelon pomace juice as a functional food to combat diabetes and obesity based on their results in animal models.
4. Anti-Ulcerative Colitis Property of Watermelon
Watermelon encompasses a diverse amounts of phytochemicals with vital pharmaceutical importance majority of which have been attributed by the abundant occurrence of citrulline, lycopenes, and polyphenols. The supplementation of watermelon extracts under various pathological ailments aids in the convalescence of diseases as well as from their inevitable negative side effects. Secondary metabolites with nutraceutical potential present in different tissues of watermelon—such as leaves, sprouts, seeds, rinds, and fruits—act on different potential drug targets involved in diseases such as diabetes, cancer, inflammation, and obesity. However, further studies dealing with the extraction of the active phytochemical and investigation of molecular regulatory mechanisms of the bioactive compounds in watermelon are required to extend the utilization of the phytochemicals in nutraceutical industries. In addition, the phytochemical and pharmacokinetic interpretation of vital secondary metabolites in watermelons can facilitate the drug designing process to combat dreadful diseases. Moreover, being the functional food intake of watermelon can prevent the onset of various 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.
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 . 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 . The chronic hyperglycemia resulting from the diabetes leads to retinopathy, neuropathy, nephropathy, peripheral vascular diseases, cerebrovascular diseases, and ischemic heart diseases [35,36,37]. However, the oxidative stress level and inflammatory responses in the body play a vital role in the development of the abovementioned complications.
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