Plants have supplied many essential human needs, including a variety of therapeutic medications (Alagawany et al., 2020, 2021a, b; Dhama et al., 2021). Therefore, deliberate efforts towards cultivation are crucial for the continuous availability of those plant species. Medicinal plants have been used in healthcare for a long time, and their use to prevent and treat illness is expanding worldwide (Dhama et al., 2018; Bilal et al., 2021; Reda et al., 2021; Saeed et al., 2021). The medicinal properties of plants are due to the natural chemicals/compounds they contain (Saeed et al., 2019; Alagawany et al., 2021c; Garg et al., 2021; Zhang et al., 2021). Plants are a source of food and act as raw materials from which a variety of drugs are synthesized (Hassan, 2012). Citrullus colocynthis is a desert plant and a source of several bioactive compounds such as essential oils, glycosides, flavonoids, alkaloids, and fatty acids. Medicinal plants improve the immune system. The dried fruit pulp of C. colocynthis has been used to treat gastrointestinal disorders like indigestion, gastroenteritis, and intestinal parasites. C. colocynthis also has excellent pharmacological properties, such as being a laxative and purgative; it is anti-diabetic, anti-inflammatory, anthelmintic, and anti-cancerous. The fruit has been studied extensively for its antimicrobial, antioxidant, and anti-inflammatory activities (Hussain et al., 2014). C. colocynthis seed powder (CCSP) has been used as an emulsifier, fat binder, and flavoring (De Smet., 1997). C. colocynthis has also long been utilized in popular cuisine. Some of its medicinal characteristics include antioxidant, anti-inflammatory, anti-diabetic, and antibacterial activities (Kamran et al., 2018). Its pharmacological properties include antioxidative, hypoglycemic, antibacterial, anti-cancerous, anti-inflammatory, analgesic (Sanafi et al., 2006). C. colocynthis has antidiabetic, hypolipidemic, antineoplastic, profibrinolytic, antiallergic, antimicrobial, pesticidal, and immune-stimulatory effects. It also affects the reproductive system and fertility (Meybodi, 2020). C. colocynthis acts as an antioxidant and anesthetic in humans (Hyderi et al., 2015); its oil can be used to treat constipation (Qureshi et al., 2010), while an extract showed anti-tumor activity on cancerous cells (Abdulridha et al., 2020) and its leaves are anti-cancerous and anti-adipogenic (Perveen et al., 2020). Phytochemical screening of C. colocynthis fruit extract revealed anti-diarrheal properties (Dhakad, 2017). The irregular use of antimicrobials results in drug resistance in animals and humans, adversely affecting their health. Therefore, in 2006, the European Union prohibited antibiotics as growth promoters (Milanov et al., 2016). Due to this restriction, many alternative antimicrobials are being used, and preferences trend towards photogenic products extracted from herbs and spices with known antimicrobial properties (Bajagai et al., 2020). Many other products have been selected as alternatives to antibiotic growth promoters; these include probiotics, prebiotics, enzymes, organic acids, acidifiers, antioxidants, and phytogenic additives (Perić et al., 2009).

In Pakistan, the poultry industry is a key sub-sector of the livestock industry, with current investment of >750 billion and a growth rate of 7.5% per annum. Pakistan is the 11th largest poultry producer globally, with an estimated population of 64.01 million layers, 1,407.73 million broilers, and 14.34 million breeders (Pakistan economic survey, 2020). This indicates the strong growth and importance of, as well as prospects for broiler farming in Pakistan. The antimicrobial growth promoters boost feed conversion and body weight gain as they change the composition and activity of gut microflora (Al Dobaib and Mousa, 2009). The focus of broiler production is growth and performance, and the latter and health depend on the microflora present in the lower gastrointestinal tract (GIT) of broiler chicken (Rinttilä and Apajalahti, 2013). Change or imbalance in gut microbiota can adversely affect nutrient utilization and gut health (Choct., 2009). Phytobiotics are natural, less toxic, and residue-free. Growth promoters improve digestive capacity and growth, increase nutrient availability, and reduce potential pathogens in the GIT (Yitbarek, 2015). These additives also improve feed intake, thus improving the feed conversion and weight gain of broiler chickens (Ertas et al., 2005). Phytobiotics are added to poultry feed and are considered an antimicrobial substitute. These compounds can be used as replacements for antibiotic growth promoters because of their antibacterial, antifungal, antiparasitic, and immune stimulatory attributes, resulting in improved product performance of chickens (Abd El Ghany and Yazar Soyadı, 2020). Ten bioactive components were isolated from C. colocynthis seeds (CCS). CCS are anti-microbial, immune-stimulating, and enhance growth. CCSP improves production performance and alleviates immune suppression (Alzarah et al., 2021). CCS contains 13.5% protein, is rich in methionine and cysteine, and is limited in lysine. The in vitro digestibility of seed protein is 75.9% (Sawaya et al., 1986).

Previous research has reported multiple benefits of C. colocynthis for humans, livestock, and poultry. This literature, from various sources, has been reviewed. As the literature on the use of C. colocynthis in poultry and its importance in humans is limited, we recommend further research on it and its extract in manufacturing poultry and human medicine. We aim to broaden the scope of C. colocynthis use and increase the awareness of scientists and veterinarians regarding the benefits of this plant for human and poultry health.

C. colocynthis is a perennial plant with perennial roots and angular, tough, rough, and vine-like stems that spread on the ground and may climb up from there. They produce a single yellow flower at leaf axils. They are monoecious and have long peduncles and tuberous rootstock sprouting long trailing or climbing stems (Pravin et al., 2013) (Table 1).

The plant is native to the arid sandy areas of West Asia, Arabia, tropical Africa, and the Mediterranean (Pravin et al., 2013). It is also widely distributed in the desert area of Pakistan (Kamran et al., 2018). C. colocynthis originated in Asia and the Mediterranean Basin, particularly Turkey and Nubia, to the western coastal regions of Africa, the Sahara, and Egypt in the east. It is also found in India and the northern coastal regions of the Caspian and Mediterranean seas. C. colocynthis belongs to the Cucurbitaceae family, and its common names are shown in Table 2.

C. colocynthis can be used to treat gastrointestinal conditions and pulmonary, skin, and bacterial infections (Hameed et al., 2020); constipation; edema, cancer, and diabetes (Kumar et al., 2008). The dried pulp of the fruit of C. colocynthis is used as a remedy for gastrointestinal disorders like indigestion, gastroenteritis, and intestinal parasites (Hussain et al., 2014). The plant is also used to treat diabetes, liver problems, weak bowel movements, and obstruction or paralysis of the intestine (Rahimi et al., 2012). The fruit extract is used as an analgesic (Heydari et al., 2015). The vital pharmacological effects of C. colocynthis are shown in Figure 2.

C. colocynthis contains several bioactive compounds like cucurbitacin, flavonoids, and polyphenols, which impart medicinal properties (Bhasin et al., 2020). The phytochemical constituents of C. colocynthis are shown in Table 4.

Three flavone glucosides–isovitexin, isosaponarin, isoorientin, and the two cucurbitacin glucosides 2-glucopyranosyl-cucurbitacin L and glucopyranosyl cucurbitacin were extracted from the fruits of the locally growing C. colocynthis and identified. The flavonoids were shown to have considerable antioxidant effects, which is a key characteristic for treating various disorders because reactive oxygen species play an important role in inflammation, cancer, tissue damage, and a variety of diseases (Delazar et al., 2006). Phytochemical screening also revealed the presence of tannins, flavonoids, alkaloids, saponins, and glycosides in C. colocynthis. The chemical components of the ethanolic extract of C. colocynthis, including alkaloids, glycosides, and flavonoids, could have a strong antibacterial effect (Najafi et al., 2010). Terpenoids, steroids, alkaloids, flavonoids, glycosides, phenols, tannins, flavones, and saponins were found in crude extracts of C. colocynthis (Ahmed et al., 2019). Carbohydrates, proteins, tannins, distinct amino acids, steroids, phenolic compounds, alkaloids, glycosides, terpenoids, and cucurbitacins A, B, C, D, E, J, and L were also all found in various preparations of C. colocynthis (Mazher et al., 2020).

The bitter and spicy C. colocynthis fruit is used to treat colds, diarrhea, parasitic worms, the expulsion of wind, tumors, ascites, leukoplakia, ulcers, asthma, bronchitis, diabetes insipidus, jaundice, splenomegaly, neck tuberculosis, constipation, anemia, throat diseases, elephantiasis, and joint pain; it is also used as an antipyretic. The root can be used to treat jaundice, ascites, urinary disorders, rheumatism; in children, and it can be used against enlarged abdomens, coughs, and asthma attacks. A root plaster can also be used to treat breast inflammation. An application of the fruit or root with a mixture of water and/or Nux vomica can treat papules and acne (Pravin et al., 2013). Different studies on C. colocynthis have been summarized in Table 5.

C. colocynthis has many therapeutic uses and has also been studied for its various pharmacological effects. It is considered an excellent therapeutic agent for the trachea, gut, and cardiovascular system (Hussain et al., 2014).

CCS was fed to 144-day-old straight-run chicks as a potential source of protein in feed, in place of soybean meal. The feeding experiment revealed that including up to 15% of the whole seed in the feed resulted in the normal growth of the chicks. However, the inclusion of 15% unprocessed meals depressed growth and showed a poor feed conversion ratio (FCR) (Sawaya et al., 1986).

CCSP was fed to 360-day-old Ross strain broiler chickens as a 0, 2, 4, and 6% supplement in feed. The result of the study showed that the 6% supplement in feed improved live body weight and dressing percentage while decreasing feed intake and FCR (Ali et al., 2012).

C. colocynthis fruit powder was fed to 100 broiler chickens, among which 100 chicks were given this on the sixth day after inoculation with Eimeria tenella. The power was supplemented in feed at 0.05, 0.01, 0.15, and 0.00%. The result showed that the 0.15% C. colocynthis fruit powder supplement was the most efficient at preventing coccidiosis (ALamery and ALsaeq, 2011). The effects of CCS meal (CCSM) on 270-day-old male Cobb broiler chickens were studied. CCSM was supplemented through feed at 0, 2, and 4%, and results showed that supplementation at 4% improved carcass weight, dressing percentage, and live body weight. As the dietary level of CCSM increased, feed intake decreased, and FCR was impaired (Ali et al., 2012). In another study, C. colocynthis was fed to 240-day-old Ross broiler chicks to check the effects of the former on growth performance and intestinal morphology. Here, C. colocynthis was supplemented at 0, 0.2, 0.4, and 0.6% of bitter cucumber feed with 0 and 0.01% protein. The results showed that supplementation at 0.6% improved feed intake, body weight gain, breast meat, and carcass yield while reducing FCR. Villus height, crypt depth, and intestinal mucosal muscle also increased (Hashemi et al., 2016).

In a different study, C. colocynthis fruit pulp was fed to replace antibiotic growth promoters with 400-day-old Ross broiler chicken chicks. Here, C. colocynthis fruit pulp was supplemented at 1 g/kg feed and 1.5 g/kg. The result showed that supplementation of C. colocynthis fruit pulp at the latter rate could replace antibiotic growth promoters (Kamran et al., 2018). In a separate study, CCS was fed via feed to 300 Cobb 21-day-old broiler chickens subjected to chronic heat stress at the rate of 0.1%. The result showed that this supplementation rate improved immune response and production performance in the heat-stressed group but had no effect on a control (thermo-neutral) group (Alzarah et al., 2021). The promising effects of C. colocynthis for poultry nutrition are shown in Figure 5.

At 4 g/day, a polyherbal combination including C. colocynthis modified gene expression to promote growth and health from the pre-ruminant to weaning phase. Some gene expression research indicates that polyherbal therapy enhanced lipid, protein, carbohydrate, and immune response metabolism. These findings support using plant chemicals in animal feed (Díaz Galván et al._, 2021). Supplementation with C. colocynthis fruit showed potential to minimize methanogenesis and improve rumen fermentation. However, in vivo testing on ruminants is required to evaluate the persistence of benefits as well as health issues (Hundal et al., 2020). De-oiled CCS cake was added to dairy cow feed and showed no effect on milk yield (Khatri et al., 1993).

Ten sheep were fed fresh C. colocynthis fruits and leaves. The sheep developed poisoning symptoms and died within 4–25 days after being dosed. They showed symptoms of dyspnea, diarrhea, loss of condition, and anorexia (Elawad et al., 1984). C. colocynthis fruits oral dosing with Rhazya stricta leaves proved deadly within 26 days, resulting in ataxia, profuse diarrhea, loss of condition, dehydration, and recumbency prior to death (Adam et al., 2000). A trial of the ingestion and metabolism of C. colocynthis was undertaken in 12 yearlings Najdi sheep to investigate the consumption of crude protein in CCS meal as this was shown to be a good partial substitute for soybean meal in sheep diets (Bhattacharya, 1990). After reviewing the literature, we found that there is currently a lack of research-based data on the use of C. colocynthis in veterinary science. More research is needed to determine its importance and note effective inclusion levels in the diet of animals.

The methanolic extract of C. colocynthis leaves and its two fractions, ethyl acetate, and chloroform possess notable anti-cancerous effects. Bioassays showed a significant reduction in the multiplication and growth of treated cells compared to untreated cells. Owing to the expression of cyclin-CDK inhibitors, C. colocynthis arrests the cell cycle in human breast tumor cells (Perveen et al., 2021). C. colocynthis is used for treating colorectal cancer in humans. Cucurbic acid present in C. colocynthis extract is believed to stop the multiplication of cancerous cells. The anti-tumor activity of C. colocynthis can be attributed to different pathways and effects, such as apoptotic pathways, antioxidant and anti-inflammatory effects, inhibition of Wnt/ß-catenin signaling pathway, and anti-metastatic effects (Abdulridha et al., 2020). CCSP lowers the cholesterol level in non-diabetic patients (Rahbar and Nabipour, 2010). The C. colocynthis plant acts as a good anti-diabetic agent in humans with type II diabetes as it reduces glucose and cholesterol levels (Youshan et al., 2015; Chenghe et al., 2014). C. colocynthis fruit pulp of mature seed can also be used to treat tuberculosis, and it was found to have active anti-bacterial properties against various strains of normal and drug-resistant mycobacterium (Archana et al., 2013). The methanolic extract of C. colocynthis fruit is also active against several food-borne bacteria hazardous to human health (Kim et al., 2014). C. colocynthis also shows excellent potential as an anti-cancerous agent for treating human breast cancer via the modulation of lipid metabolism (Perveen et al., 2020). Consumption of C. colocynthis for a long time could lead to anti-fertility issues in both males and females (Chaturvedi et al., 2003; Amal et al., 2016). C. colocynthis fruit extract shows anti-tumor activity on drug-resistant cancerous cell lines (Saeed et al., 2019). C. colocynthis oil can be used for treating constipation in humans (Qureshi et al., 2010). C. colocynthis fruit has shown promising results in treating diabetic patients. A dose of 300 mg/day given to patients showed no adverse effects on their health (Huseini et al., 2009). An extract of C. colocynthis leaves can be used to treat skin infections, and a paste of C. colocynthis roots can be applied to treat joint problems (Upadhyay et al., 2007). C. colocynthis has also been used to treat edema, cancer, constipation, bacterial infections, and diabetes and has been used as an abortifacient (Delazar et al., 2006). C. colocynthis is a desert shrub with a long history as a valuable oil source and medicinal plant. During the first 4 weeks of ripening, yield and size of fruit, seed output, and overall oil yield were all at their peak. C. colocynthis has the potential to be grown as a source of edible oil. The oil has a laxative effect and contains between 80 and 85 percent unsaturated oleic and linoleic fatty acids, making it a high-quality oil for human consumption (Schafferman et al., 1998).

The health benefits of C. colocynthis are shown in Figure 6.

The chemical cucurbitacin, found in colocynth, irritates mucous membranes, especially those in the stomach and intestines. Colocynth is extremely dangerous to use. The Food and Drug Administration (FDA) prohibited it in 1991. Even tiny doses of colocynth can induce severe stomach and gut lining irritation, bloody diarrhea, kidney damage, bloody urine, and inability to pee. Convulsions, paralysis, and death are some of the other adverse effects. Colocynth dosage is determined by a number of factors, including the user’s age, health, and other circumstances. There is insufficient scientific evidence to define a suitable dosing range for colocynth. Keep in mind that natural products aren’t always safe and that doses are crucial. Before using, be sure to read the product label and consult your pharmacist, physician, or another healthcare expert. According to reports, ingestion of merely 1-1/2 tablespoons of the powder has resulted in death. Colocynth is unsuitable for use during pregnancy and breastfeeding. Ingestion of less than 2 gm of the powder has been reported to result in death. In clinical studies, as little as 300 mg of colocynth powder was found to cause moderate diarrhea.

Oral administration of C. colocynthis fruits 0.25 g/kg/day with Rhazya stricta leaves proved deadly within 26 days, resulting in dehydration, loss of condition, profuse diarrhea, ataxia, and recumbency before death (Adam et al., 2000). The treatment regimen having 10% of C. colocynthis fruits was once checked for rats. The outcomes characterized by C. colocynthis treatment were depression, ruffled hair, low physique weight, low feed efficiency, and entero-hepato-nephropathy (Al-Yahya et al., 2000). Chickens fed a 10% Citrullus diet developed reversible lesions in the liver, small intestine, and kidney (Bakhiet and Adam, 1995). 60 ml of decoction of the plant fruit taken by a 48-year old man to treat constipation resulted in watery diarrhea, hypotension and hypoglycemia, and hepatic injury (Rezvani et al., 2011). C. colocynthis being stimulant laxatives can cause the body’s potassium levels to drop. Low potassium levels might exacerbate digoxin side effects. Lanoxin: Colocynth can induce diarrhea in some patients who are taking Warfarin. Diarrhea can make Warfarin less effective and raise the risk of bleeding. Taking colocynth with water pills may cause the body’s potassium levels to drop too low.

The biological activity of the extracts and isolated compounds have been discovered, particularly in antidiabetic, anticancer, anti-inflammatory, antioxidant, insecticidal, and antibacterial areas. Interestingly, the plant has been demonstrated to have a high nutritional value since it is a strong source of protein, has edible seed oil, and contains certain vital minerals such as calcium, potassium, and magnesium, all of which are known to have medical benefits. Despite the fact that growing interest has driven greater research on C. colocynthis’ phytochemistry and pharmacology, there are still many areas where existing understanding might be improved. Furthermore, there is a scarcity of information concerning its mode of action and dosing rate. In recent pharmacological investigations, various traditional applications of the C. colocynthis fruit have been verified; however, some of these studies were only examined in vitro. As a result, in vivo experiments should be used to evaluate further the efficacy and safety of C. colocynthis fruit extracts and isolated chemicals. In previous studies, C. colocynthis has been shown to have many roles in people, cattle, and fowl. The aforementioned system’s literature has been evaluated from a variety of sources. Because there is limited research on the use of C. colocynthis in poultry, veterinary medicine, and human medicine, it is the forward reassessment to advocate C. colocynthis plant and extract for use in poultry and human medicine manufacturing.

In the present assessment, the nutrient composition and medicinal qualities of C. colocynthis have been evaluated based on various previous studies. This review strongly indicates that C. colocynthis is a fruit crop that could benefit the treatment of a range of diseases. Although C. colocynthis has high dietary value, it is not widely known. More investigations are required to spotlight the utility of such fruit crops as a dietary supplement that can enhance fitness. This review demonstrates that C. colocynthis is a medicinal plant with a wide variety of pharmacological properties that might make it useful and effective in numerous medical applications. To date, no review article has published comprehensive literature about its uses in poultry, veterinary and human areas. This review gives a thorough insight into its phytochemistry along with the structure-activity relationship of some bioactive compounds, pharmacology, beneficial effects, limitations, and drug interaction. The study compiles the most recent data present on C. colocynthis. So, the objective of this review is to provide comprehensive data about the benefits and limitations of C. colocynthis, as the data about inclusion levels and its use and possible side effect are still not precise and need to be validated by pharmacological investigations against various disorders in vivo. C. colocynthis has many vital health-promoting effects like neurological, physiological as well as biological functions, but still, their mechanism of action behind these properties in different species is not known and needs to be exploited. The future avenues for the veterinary and pharmaceutical researchers would be to identify more of these demanding areas and document reliable markers (bio and molecular) which are responsible for a vast array of C. colocynthis’s benefits.