Papaya, scientifically known as Carica papaya or Carica Papaya Linn is the only edible member of the Caricaceae family. Papaya is a large herbaceous plant exploited for its biological activities. Papaya's wide range of uses and activities are attributed to its abundance of enzymes, minerals, nutrients, and phyto-constituents. Its applications range from adding it to one's diet regularly to treating minor illnesses and even serious conditions like cancer. All of the papaya plant's parts; bark, flowers, fruit, latex, leaves, peel, roots, seeds, and stem have therapeutic and medical uses. The use of papaya as a food and traditional medicine is as old as mankind. Presently, to overcome antibiotic-resistant microbes, C. papaya is a natural source with far more advantages. C. papaya plant is used in commercial, industrial, medicinal, and therapeutic applications owing mainly to its anti-inflammatory, antioxidant, and anti-microbial properties. This review aims to provide a concise review of the applications of C. papaya.

 Fruits are a necessary part of an individual’s daily diet, not only they are good in taste and nutrition but they also confer numerous other health and nutrition advantages. C. papaya is one of the most beneficial fruits, regarding its nutritional value as well as its therapeutic and medical uses (Sharma et al., 2020). For ages, papaya has been used as a culinary ingredient as well as for traditional medicine in many cultures across the world. In most countries, Papaya is grown as a food-crop (Nafiu et al., 2019). All the parts of the papaya plant including bark, blooms, flowers, fruit, latex, leaves, peel, roots, seeds, squash, and stem have medicinal and therapeutic benefits (Ikram et al., 2015). Despite being grown as a food-crop, it is used for numerous biological and commercial applications such as; (1) industrial, (2) nutritional, and (3) medicinal and therapeutic (Niklas & Marler, 2007). Industrial applications of C. papaya include the production of processed foods which can later be sold for commercial benefits such as jams and pickles, the use of papaya in cosmetic products such as creams and ointments for reducing acne and blemishes, and lastly for the production of alcohol. Moreover, papaya can be used as a dietary additive for animal feed or a supplement for humans. These benefits conferred by C. papaya are attributed to the large number of enzymes, nutrients, vitamins, minerals, and phytoconstituents that are present in it (Alara et al., 2020). The papaya plant parts possess different bioactive compounds in each of its parts including alkaloids, carotenoids, flavonoids, and vitamins, all of which confer exceptional therapeutic advantages (Gayosso-García Sancho et al., 2010; Fabi et al., 2012; Abdullah et al., 2023; Din et al., 2023; Hamid et al., 2023). Medicinal and therapeutic uses of papaya include its use as an abortifacient, antibacterial, antifungal, anti-diabetic, anti-inflammatory, antifertility, anthelmintic, antihypertensive, antiprotozoan, antitumor, and antiviral agent. Among the most notable applications of C. papaya is its antiinflammatory and anti-oxidant property which allows it to be used for a range of purposes including the treatment of fatal diseases such as cancer, as well as neurodegenerative diseases, diabetes, and skin aging (Srivastava & Singh, 2015; Anitha et al., 2018; Bashir et al.,2022; Sami et al., 2023). Furthermore, C. papaya also exhibits immunomodulatory properties which are especially useful in the treatment of diseases that suppress the human immune system (Anjana et al., 2018). Anatomy and morphology The papaya plant is usually a herbaceous, laticiferous, single-stemmed, semi-woody perennial, large plant with a rapid, unpredictable growth rate. It grows up to 10m (20-30 feet) in height and is not very woody in texture, lacking a proper bark (Nafiu et al., 2019). The colors of papaya stems range from light green to tanbrown, which are hollow (Adiaha & Adiaha, 2017). J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 2 Despite its semi-woody nature and no proper bark, it is usually considered a tree (Jiménezet al., 2007). 1. Leaves: The leaves crowning the papaya plant are extremely large, sometimes measuring up to more than 60 cm (2-2.5 feet), palmately lobed (5-9 lobes) with deep incisions and complete margins. They are subtended by hollow petioles which are about (30-150 cm) 1-3 feet in length, and their stems are light green to tan brown, having a diameter of approximately 20 cm (Posse et al., 2009; Leal-Costa et al., 2010; Aravind et al., 2013). The leaves are hypo-stomatic containing stomata with either no subsidiary cells (anomocytic) or asymmetric guard cells (anisocytic). The cellular composition of the papaya leaves consists of single layers of epidermis and palisade parenchyma and four to six layers of spongy mesophyll tissue (Carneiro & Cruz, 2009). 2. Flower: Reproductively, the flowers of papaya plants naturally are monoecious (true hermaphrodite), dioecious (containing male and female organs on separate plants), or gynodioecious (with hermaphrodite and female organs) (Ming et al., 2007; Nafiu et al., 2019). However, occasionally papaya plants may also be “trioecious” meaning that the male, female, and hermaphroditic flowers are present on separate plants (Niklas & Marler, 2007; Yogiraj et al., 2014). The flowers occur in small groups of three, known as cymes or solitarily. Both hermaphroditic and female flowers have waxy petals of ivory-white color attached to short peduncles on leaf axils, along the main stem. The flowers measure 0.10–0.30m in diameter and 0.15–0.45m in length (Aravind et al., 2013). In terms of shape and structure, papaya flowers fall under six different categories including (1) typical female, (2) typical male, (3) hermaphrodite elongated, (4) hermaphrodite immediate and (5) hermaphrodite sterile (Alara et al., 2020). The hermaphroditic flowers consist of both the female reproductive organs (ovaries) and the male reproductive organs (pollen sac), they are self-pollinating and produce the best fruits; thus, they are chosen over male or female plants for cultivation. Female flowers usually have a conical top and a rounded base. They have a conical appearance while closed, and five petals grow out from the circular base when they open. Another type of female flower has five petals with five anthers corresponding to each petal (Anitha et al., 2018). Plants with smaller flowers attached to longer stalks are generally regarded as male papaya plants. They possess a long, thin corolla composed of anthers in two sets of five, where the series are different in length, one short and one long (Adiaha & Adiaha, 2017). 3. Fruit: Papaya fruits are large and oval, with salmoncolored (pink-orange) flesh encircling a central seed hole matching that of melons. The only portion of the fruit that can be eaten is the meat (Panzarini et al., 2014). Though they can sometimes show up in little groups, the fruits are usually affixed to the main stem separately. The weight of each papaya fruit ranges from 0.2 to 9 kg (0.5 to 20 pounds), and as it ripens, its colour changes from green to yellow to red-orange (Aravind et al., 2013). The melon-like fruit can be pyriform, obovoid, globose, or ovoid in shape. The fruit's typical dimensions are 0.15 to 0.50 m in length and 0.10 to 0.20 m in thickness (Crane, 2005; Anitha et al., 2018). Species of papaya C. papaya from the small angiosperm family, namely Caricaceae consisting of 6 genera and 43 species, all of which can be found listed on the Plant List (http://www.theplantlist.org), among these species the most commonly cultivated and economically important is C. papaya and the only species to grow fruits on its tree (Evans & Ballen, 2012; Carvalho & Renner, 2015; Basalingappaet al., 2018). The species are listed in table 1. Karyotype and sex expression The genomic studies of C. papaya have revealed that the fruit possesses a total of 18 chromosomes (2n = 18), an experiment conducted by Hague in 2004 led to the conclusion that regardless of the sex of the plant, the general cytological condition of the plant has a total of 18 chromosomes (Haque, 2004; Somsri & Bussabakornkul, 2008’ Araújo & Carvalho 2010; Rockinger et al., 2016). The sex determination genomics system has revealed that C. papaya exists in three sex forms; male, female, and hermaphrodite. Several studies have demonstrated that the XY chromosome system specifies the sex of C. papaya, just like it does for many other organisms. Inverted repeats, transposable elements, and nucleotide modifications in the small non-recombinant region and autosomal chromosome sections between the X and Y chromosomes are also thought to have influenced the development of the X and Y chromosomes (Liu et al., 2004). The expression of the male (XY) and hermaphrodite (XYH) types is controlled by a tiny specific region and always occurs in the heterozygous form. On the other hand, allfemale plants occur as XX forms (Ming et al., 2007). Cultivation, origin and global distribution The exact origin of C. papaya is rather obscure and not exactly known, though it is known to be cultivated in tropical and sub-tropical regions. Various places of origin of the papaya fruit are mentioned in texts; the earliest evidence of the existence of C. papaya dates back to 1525, when papaya seeds were found in the Dominican Republic and Panama. It was then that the cultivation of papaya spread to central and tropical America in regions like Bahamas, Bermuda, and southern Mexico (Morton, 1987). In the 1950s, C. J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 3 papaya was introduced into Miami, New York Santa Marta (Colombia), and Puerto Rico. In 1959, an Italian entrepreneur known as Albert Santo brought papaya to Cuba. It is also believed that the Spanish might have carried the papaya seed to Malacca and the Philippines, which then became the cause of their spread to India and the Kingdom of Naples in 1626. Later, C. papaya was introduced as a plantation crop across all the tropical and subtropical regions of the world (Nakasone & Paull, 1998). Presently, papaya is cultivated commercially and for personal use all around the world including countries such as Australia, Ceylon, India, Hawaii, Malaya, Philippines, and tropical Africa. The currently present variety of papaya is thought to be the fusion of two or more different varieties of papaya that originally belonged to central America and Mexico (Nafiu et al., 2019). In Pakistan, varieties of papaya seeds are sowed to establish nursery plants in March and transplanting takes place in April. Regardless, the fruit is available all year long (Zhou et al., 2000; Singh et al., 2014). Plant growth and habitat C. papaya seeds germinated in well-drained, sandy, loam soils under appropriate environmental conditions including sufficient water, oxygen, light, and appropriate humidity levels, pH, and temperature (Adiaha & Adiaha, 2017). Appropriate conditions for the ideal growth of C. papaya include; low rainfall of around 32 inches (0.80 m) in summer and spring, temperature between 21 and 32 °C (70–90 °F), and a pH of 6.5-7.0 (Crane, 2005). Under tropical conditions and proper manure, the papaya tree grows very rapidly (Anitha et al., 2018). Adequate rainfall required for papaya fruit growth is relatively lesser than that of most other plants, requiring rainfall only four times a month. In well-drained soils, the plant needs to be watered on alternate days, while in loamy soils watering the plant once in 3-4 days is sufficient (Sara et al., 2015). C. papaya plants require an environment packed with nutrients and minerals; the macronutrients required include Potassium > Nitrogen > Calcium > Phosphorus > Sulfur > Magnesium and micronutrients include Chloride > Iron > Manganese > Zinc > Boron > Copper > Molybdenum (Jiménez et al., 2007). After plantation under appropriate conditions, C. papaya plant takes approximately 8-10 months before ripe fruits are produced by the plant. However, in warm regions, the same plant takes from 6-9 months for proper and complete growth, while in temperate regions the growth period ranges from 9-11 months. The papaya plant is also able to survive in colder winters, however, it may not produce fruits (Crane, 2005). The emergence of the papaya plant from the seeds takes about 2–3 weeks (Fisher, 1980). Papaya plants usually grow speedily; they reach the juvenile phase, or flowering stage, 3–8 months after seed germination and are ready for harvest in 9–15 months (Paterson et al., 2008). Nutritional value and composition Papaya plants can live for 20 years on average, but because of their large height and disease susceptibility, their commercial lifespan is just two to three years (Alara et al., 2020). Once the tree blossoms, it requires around 5-8 months before the fruits on the plant are ripe and ready for harvesting (Sara et al., 2015). The papaya plant grows flowers and fruits all year long (Alara et al., 2020).

C. papaya is a fruit that is high in vitamins, minerals, enzymes, and non-vitamin substances. High in calcium, iron, potassium (including folate), niacin, thiamine, vitamins A, C (ascorbic acid), and riboflavin, it has a low-calorie count and a high nutritional value. Alkaloids, sugars, flavonoids, glycosides, saponins, steroids, terpenoids, and tannins are also present in extracts of unripe C. papaya (Aravind et al., 2013; Vij & Prashar, 2014).

Phytochemistry and phytoconstituents

The chemical composition varies depending on the agricultural environment, cultivar, exposure to sunlight, location, level of ripeness, and post-harvest handling (Wall, 2006; Gayosso-Garcıa Sancho et al., 2011; Ikram et al., 2015). The fruit portion of C. papaya comprises an endosperm, sarcotesta, seed coat, an outer pericarp, and an inner pericarp (Table 2). Each of these regions contains different types of J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 4 molecules and has a different chemical composition. The endosperm mainly has oils and some protein content, while the pericarps are rich in proteins. The sarcostesta contains high amounts of ascorbic acid (Adesuyi & Ipinmoroti, 2010; Syed et al., 2011; Saran & Choudhary, 2013).

As mentioned earlier, the chemical composition changes with the stages of ripening of the fruit, and the biochemical and physiological properties of the fruit change with the growth and ripening stages. As a result of these changes, the fruit loses its rigidness and softens, which indicates ripening and makes the fruit suitable for commercial and edible uses (Pereira et al., 2009). C. papaya fruit contains carbohydrates, fat, fiber, minerals, vitamins, citric acid, malic acid, and a variety of commercially important compounds The unripe fruit is especially rich in a variety of phytochemicals and volatile compounds, such as alkaloids, carbohydrates, flavonoids, glycosides, saponins, steroids, and terpenoids, as well as a variety of health-promoting bioactive compounds and phytochemicals, including β-cryptoxanthin and carotenoids (β-carotene and lycopene), Additionally, papaya also contains several enzymes that confer several health benefits (Corral-Aguayo et al., 2008; Gayosso-García Sancho et al., 2010; Fabi et al., 2012; Aravind et al., 2013; Vij & Prashar, 2014; Fabi & Do Prado, 2019). Carotenoids The color of the papaya fruit significantly changes with its ripening and maturation; starts with a lightgreen color and changes until it reaches an amber, orange to red colorReduced synthesis of chlorophyll and increased production of esterified carotenoids (which embraces β-carotene, β-cryptoxanthin, and lycopene) are the biological causes of this colour shift. Carotenoids rapidly integrate into the membranes and build up more densely in the chromoplasts during ripening, giving the fruit its orange-red colour (Andersson et al., 2009; Yahia & Ornelas-Paz, 2010). The coloration of the fruit is dependent upon the varieties of carotenoids (Ikram et al., 2015; GayossoGarcía Sancho et al., 2017). β-carotene, and lycopene are the main carotenoids found in C. papaya fruit; lycopene alone accounts for 65% of the carotenoid content of papayas (Marelli de Souza et al., 2008; Güilcin, 2012). Known for their extraordinary antioxidant qualities, carotenoids are lipophilic substances composed of eight isoprenoid units. They are essential to human health and nutrition because they efficiently capture singlet oxygen molecules and neutralize radicals like peroxyl (Al-Duais et al., 2009). Carotenoids are unique because of their vast network of doubleconjugated bonds, which alternate between single and double carbon-to-carbon bonds. A polyenic chain, a resonance structure, stabilises these connections. Because of this polyenic chain, also known as the chromophore, carotenoids can operate as photoreceptors, absorbing light and offering scavenging and antioxidant qualities against reactive oxygen species (ROS) (Yahia & Ornelas-Paz, 2010). Structurally, carotenoids are divided into two major groups; (1) carotenes, those which are linked hydrocarbons, and (2) xanthophylls, those that contain at least one or more oxygen molecules. These carotenoids possess double bonds which allow them to act as photoprotectors that in turn protect the lipid membrane against peroxidation by quenching reactive oxygen species (ROS) (Tanaka et al., 2008; RiveraPastrana et al., 2010). The antioxidant capacities of carotenoids are dependent upon and vary with the structure of the carotenoids. Numerous investigations have shown that distinct carotenoids have a range of abilities, which are listed in the order: Zeaxanthin > lutein > β-cryptoxanthin > α-carotene > β-carotene > lycopene (Gayosso-García Sancho et al., 2013). Β-carotene Because of its antioxidant qualities, β-carotene is essential for photoprotection. But occasionally, its purported prooxidant effects can outweigh this protective function (Nimal et al., 2022). Certain carotenoids behave similarly to provitamin A; they are known to lower the chances of coronary heart disease and cancer (Yahia & Ornelas-Paz, 2010). lycopene J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 5 as lycopene's presence in plasma and serum has been inversely linked to the risk of cancer, it has gained a lot of attention recently (Nimal et al., 2022). Additionally, it is also known to quench singlet oxygen and scavenge other free radicals (Mein et al., 2008). Additionally, lycopene is a useful substance in lowering the risk of obesity, osteoporosis, cardiovascular disease, and cognitive decline. Additionally, because bell peppers contain vitamin C and β-carotene, they may help prevent cataracts (Stahl and Sies, 2003). PhenolicsPhenolic compounds are aromatic, containing at least one or more aromatic rings with a hydroxyl group that enables them to act against ROS and mitigate oxidative stress. They are produced as a result of secondary metabolism in plants (Wojdyło et al., 2009). The phenolic compound content has been studied in several varieties and stages of papayas and it has been found that the most ripened papaya contains the lowest of phenolic compounds (Mahattanatawee et al., 2006; Corral-Aguayo et al., 2008). Compounds of phenolic may or may not act as antioxidants, depending on their structure. It is assumed that the antioxidant capabilities of phenolic compounds depend upon the number of hydroxyl groups present in their structure (Wang et al., 2008). Moreover, phenols are also crucial in determining the color and taste of C. papaya fruit. (Al-Duais, 2009; Gorinsteinetal.,2009.Fruits and vegetables contain va rying levels of phenolic compounds, which are essen tial in protecting against oxidative stress caused by R OS and free radicals. Phenolic compounds confer health benefits in more than one way; they are capable of preventing oxidative damage caused by ROS and oxygen free radicals which in turn prevent several disorders (Valko et al., 2007). Various studies have also demonstrated that the consumption of foods rich in phenolic acids is inversely proportional to the incidence of various diseases (Gayosso-García Sanchoet al., 2017). Saponified papaya extracts mostly contain hydroxycinnamic acid sugar derivatives as phenolic compounds, but non-saponified extracts only contain trace levels of acylated versions of these compounds. Phenolic acids found in C. papaya include caffeic acids, ferulic acids, and p-coumaric acids (RiveraPastrana et al., 2010; Gayosso-García Sancho et al., 2011). Phenolic compounds protect the plant from damage caused by UV-radiations and possess anticarcinogenic, antimutagenic, and antiradical properties (Hounsome et al., 2008; Cantin et al., 2009). Many studies have proved the anticarcinogenic mechanisms carried out by phenolic compounds by stimulating the production and cytoprotective effect of various enzymes (Gayosso-García Sancho et al., 2017). Caffeic acid Caffeic acid, a key component of several fruits, vegetables, and coffee usually occur in and esterified form, in combination with quinic acid known as chlorogenic acidStrong antioxidants with notable anti-inflammatory qualities are caffeic acid and its derivatives, including octyl caffeate and caffeic acid phenethyl ester (CAPE) (Da Cunha et al., 2004). Herein, among natural compounds we focused on caffeic acid (CA), the major representative of hydroxycinnamic acids and phenolic acid, produced through the secondary metabolism of several vegetables, including olives, coffee beans, fruits, potatoes, carrots and propolis. It is usually found as various simple derivatives such as glycosides, amides, esters and sugar esters (Reddy et al., 2010; Alam et al., 2022). Several studies have been performed to investigate the total antioxidant capacity (TAC) of caffeic acid, its TAC is dependent upon its structure, the number of hydroxyl groups and its concentration in the fruit (Jaikang & Chaiyasut, 2010; GayossoGarcía Sancho et al.., 2013) Ferulic acids Ferulic acids are found in conjugation with glycoproteins and insoluble carbohydrate biopolymers anchored to the cell membranes. Among the benefits of ferulic acids are their antiinflammatory and anti-oxidant effects. By inhibiting choline acetyltransferase's enzymatic activity by electron donation from the 3-methoxy and 4-hydroxyl groups on the benzene ring, the anti-inflammatory action is accomplished (Itagaki et al., 2009). P-coumaric acid P-coumaric acid, another phenolic compound forms as an intermediate during phenylpropanoid synthesis; it has conferred several benefits such as antioxidant activity, the ability to reduce cholesterol levels and prevent atherosclerosis. It has also been shown that a regular oral intake of 370mg p-coumaric acid for 30 days significantly reduced cholesterol levels by preventing the oxidation of low-density lipids (LDL), without interfering with the levels of high-density lipids (HDL). The mechanism of action of p-coumaric acid depends upon its ability to remove ROS and exert antioxidant effects (Rodriguez et al., 2022). vitamin C Vitamin C also known as ascorbic acid has been known for ages for its exceptional antioxidant properties and its role in mitigating oxidative stress. It is found in several fruits, vegetables, and other foods and demonstrates high sensitivity towards environmental conditions and factors (Comunian et al., 2020). By nature, vitamin C is a hydrosoluble antioxidant capable of trapping hydroxyl and superoxide radicals. Furthermore, it plays a part in the production of collagen (Odriozola-Serrano et al., J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 6 2008). An intake of 200-250mg of vitamin C or ascorbic acid can significantly reduce oxidative stress and damage (Tariq, 2007). In C. papaya fruit, vitamin C is found in both the skin and the pulp; it occurs either as L-ascorbic acid or as isoascorbic acid. The vitamin C content increases with the stage of ripeness of the fruit (Gayosso-García Sancho et al., 2011). Cultural and traditional uses C. papaya is a common edible fruit used by several cultures (Table 3) and nations for a variety of purposes (Nayak et al., 2007; Anuar et al., 2008). In most Asian countries, C. papaya is used in the production of processed foods such as cocktails, canned and sugar-coated in syrups, ice-creams, jams, and soft drinks (Ezike et al., 2009). In other countries, papaya is also used to make pickles, salads, sweetmeat and is commonly eaten with rice (Table 4) (Ikram et al., 2015).

Table 3. Traditional uses of C. papaya fruit in various countries.

Table 4. Common Uses of C. papaya

Medicinal and therapeutic properties 

Anthelmintic activity 

Helminthiasis is a disease where an organ in the body becomes infested with worms like pinworms, roundworms, or tapeworms. These worms usually inhibit the gastrointestinal tract (GIT) or the liver in some cases and cause adverse effects on human host health by depriving them of blood, food, and by the secretion of toxins. C. papaya effectively acts against parasites and parasitic worms (Dwivedi et al., 2011; Shrivastava & Singh, 2015). In recent years, latex, seeds, and other parts of papaya have been used for the removal of parasitic worms from the GIT. Most research related to the anthelmintic effect of C. papaya has been carried out on the Indian earthworm (Pheretima posthuman) since it is easily available and closely resembles other parasitic worms. The use od papaya extract alongside honey is also very effective as an anthelmintic treatment (Ortega, 2011; Kanthal, 2012). Anti-diabetic property The use of C. papaya has been a traditional use for ages. More recently, scientific reports of animal models have also supported the antidiabetic effects of C. papaya; it lowers blood sugar levels (hyperglycemia), proposing regenerative capacity J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 7 (Gbolade, 2009; Sasidharan et al., 2011; Juárez-Rojop et al., 2012; Maniyar & Bhixavatimath, 2012). Further studies on diabetic animal models have also shown that papaya extracts can restore basal insulin levels, this ability is attributed to beta cell regeneration. Additionally, it has also been shown that C. papaya may also affect anti-glucosidase activity (Loh & Hadira, 2011; Oboh et al., 2014). Studies on humans have also assessed C. papaya's antidiabetic potential, and it has been determined that this potential stems from its hypoglycemic effect (Somanah et al., 2012). Anti-diarrheal activity Chloroform extracts from raw C. papaya fruits combined with acetone extract from ripe C. papaya fruits are proven to be effective anti-diarrheal agents as they possess antimicrobial activity against gut pathogens, Plesiomonas shigelloides in particular (Prabhu et al., 2017). Other parts of C. papaya used for the treatment of diarrhea include aqueous leaf and root extracts (Akindele et al., 2011; Zanna et al., 2017). Anti-hypertensive property Only a small number of scientific investigations have demonstrated C. papaya's antihypertensive ability; evidence indicates that intravenous (IV) injection of C. papaya reduces mean arterial pressure in renal and deoxycorticosterone acetate-induced hypertension in animal models (Santana et al., 2019). Other studies have also suggested that the antihypertensive effect of papaya is exerted via adrenoceptor antagonism (Brasil et al., 2014). Anti-fertility activity C. papaya causes infertility in both males and females, however, the effect on females is far more severe and if consumed by pregnant females, it may lead to abortion. Experiments have been carried out on pregnant rodents with each part of the plant and it has been shown that the unripe fruit interferes with the estrous cycles in pregnant rodents and removes the instigated fetus (Memudu & Oluwole, 2022). When consumed by males, it causes infertility, and in pregnant females, C. papaya acts as pessary to increase blood flow in the pelvic region to induce abortion (Krishna et al., 2008; Yogiraj et al., 2015 Hainida et al., 2015). However, ripe papaya fruit does not pose any significant dangers during pregnancy, the unripe contains latex which causes uterine contractions (Budama-Kilincet al., 2018). Anti-inflammatory property Inflammation, which is associated with pain, redness, and swelling brought on by the release of prostaglandin mediators, is one of the body's most natural defense mechanisms against infections (Chen et al., 2017). The pathophysiology of inflammation is initiated by tissue injury, followed by antigenpresenting cells (APCs) and macrophage activation. Vascular events, or repercussions in the microvasculature, usually happen minutes after tissue damage or microbial infection, especially when other inflammatory stimuli are present. The ROS are produced to eliminate invaders, consequently, ROS also causes the activation of nuclear factor kappa-B (NF-kB) which induces the inducible enzyme iNOS and thus the production of NO. Excessive ROSupregulated prostaglandin (PGE2) promotes the expression of cyclooxygenase-2 (COX-2) and worsens inflammation (Morgan & Liu,2011; Hussain et al., 2016; Kanda et al., 2017). Other studies have suggested that ROS enhances the inflammation reaction by causing an increase in the expression of genes that code for inflammatory proteins such as activator protein 1 (AP-1), NF-kB, and peroxisome proliferator activator receptor gamma (PPAR-γ). Other inflammatory chemokines and cytokines also increase ROS production via several signaling molecules and pathways such as mitogen-activated protein kinase (MAPK), NADPH oxidase 2 (NOX), polymorphonuclear neutrophils (PMN), protein kinase C (PKC), and c-Jun-N-terminal kinase (JNK) pathways (Chatterjee, 2016). Several research studies have shown that C. papaya extracts contain phytochemicals such as benzyl isothiocyanate (BiTC), β-carotene, lycopene, and vitamin C that exert protective effects by attenuating ROS production and by causing a reduction in the release of pro-inflammatory cytokines secretion of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and TNF-α. Additionally, these phytochemicals also upregulate enzyme activity and reduce oxidative stress (Somanah et al., 2017). Moreover, polyphenols present in C. papaya also play a role in the scavenging of free radicals and upregulation of antioxidant enzymes (Od-ek et al., 2020). Anti-malarial activity Petroleum ether extract of raw C. papaya fruit demonstrates antimalarial activity (Krishna et al., 2008; Vij & Prashar, 2015). Papaya plant has traditionally been used as an antimalarial agent in a lot of cultures and even currently, in several cultures such as Africa, India, and South America, malarial patients are suggested to consume papaya herbs as an allopathic medication in combination with antimalarial drugs. It is assumed that C. papaya extracts enhance the efficacy of antimalarial drugs while being safe and cost-friendly (Onaku et al., 2011; Kovendan et al., 2012). Anti-microbial activity The antimicrobial effects of C. papaya have been long known and exploited. Over time, most pathogenic strains of bacteria and fungi have developed J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 8 resistance against several treatments and antibiotics. Additionally, antibiotics and synthetic treatments have side effects thus, natural remedies from medicinal plants can be considered as a safer alternate option (Tambekal et al., 2012; Lohidas et al., 2015). Several published studies have shown tremendous evidence supporting the chemo-preventive activity of different parts of C. papaya. However, seeds, latex, leaves, and roots have greater antimicrobial potentials than the fruit on its own (Abdullah et al., 2011; Alabi et al., 2012; Baskaran et al., 2012; Ghosh et al., 2017; Callixte et al., 2020). C. papaya plant exhibits antifungal activity but the fruit in particular does not demonstrate any antifungal activities, rather the antifungal activity is attributed to the latex (Vij & Prashar, 2015). The use of plants as medicines is a common practice in many cultures and nations. Plants have been used as a primary remedy against several diseases owing to their exceptional pharmaceutical properties. Presently, even with the advent of modern and synthetic medications, the use of plants as medicine is common in Asia, Africa, and Latin America. Not only the C. papaya fruit but also other parts of the plant are proven to be beneficial in several health conditions. Additionally, plants such as C. papaya can also be used for the pharmaceutical production of drugs. Extracts from papaya fruits have shown evidence by acting as antimicrobial agents against fever, gastroenteritis, otitis media, typhoid, and urethritis. Pseudomonas aeruginosa, Shigella flexneri, Staphylococcus aureus, Escherichia coli, and Bacillus cereus have all been shown to exhibit bactericidal action (Oloyede, 2005; Doughari et al., 2007; Krishna et al., 2008; Sasirekha et al.,2018). Anti-neoplastic property Unripe fruit extract of C. papaya contains hydroethanol, which when concentrated exerts anti-neoplastic activity. This was proven by a study conducted on animal models. (Sasidharan et al., 2011; Ranasinghe et al., 2012; Praveena et al., 2017). Antioxidant properties Oxidative stress, a persistent issue, is described as an imbalance between antioxidants, pro-oxidants, ROS, and free radicals. It is characterized by either an excess of pro-oxidants or a lack of the body's inherent antioxidant defense system (Kong et al., 2021). Free radicals are continuously produced within cells and play important roles in aging and the etiology of several degenerative diseases because of their ability to disrupt and change the structure and function of biomolecules, including proteins, lipids, carbohydrates, and nucleic acids. ROS are produced via both endogenous and exogenous sources (Genestra, 2007). Oxidative damage caused by free radicals and ROS leads to inflammation which in turn is linked to several health conditions and diseases including Alzheimer’s disease (AD), asthma, atherosclerosis, cancers, cataracts, cardiovascular diseases (CVDs), rheumatoid arthritis and skin conditions such as wrinkling (Silva et al., 2010; Park et al., 2016). Molecular oxygen and nutrients are constantly processed throughout the body by enzymes involved in complex metabolic activities, these processes are necessary for yielding oxidants that have a positive impact on the body. However, oxidants must be produced at a basal level and cause no harm to human health or nutrition. Under normal conditions, the human body’s endogenous antioxidant defense system contains antioxidant enzymes including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), all of which scavenge free radicals and inhibit the generation of oxidative stress (Kong et al., 2021). Diet, environment, and exposure to sunlight are common sources of free radicals (Sies, 2015; Pizzino et al., 2017). The production of excess oxidants and free radicals such as ROS, reactive nitrogen species (RNS), hydroxyl, and peroxides occur under several health conditions and diseases that alter tissue metabolism including chronic wound healing, diabetes mellitus, inflammation-associated diseases, and microbial infections. Conditions such as the above mentioned alter the mechanism of tissue metabolism suppress the endogenous antioxidant defense system and lead to oxidative damage/stress. When endogenous defense systems fail, exogenous antioxidants find relevance (Nafiu et al.,2019). Antioxidants, as the name suggests are compounds that inhibit oxidation, prevent the formation of and scavenge free radicals. Several compounds, nutritional components, and phytochemicals present in the fruit C. papaya are proven to have antioxidant activities (Chakrabirty et al., 2015; Somanah et al., 2017). Phytoconstituents of C. papaya with antioxidant roles include carotenoids, flavonoids, flavonols and polyphenols, and traditional antioxidants vitamins such as vitamins C and E. Additionally, adding selenium to this antioxidant regime exerts a far greater synergistic effect (Maisarah et al., 2013; Nafiu et al., 2019). Several clinical and epidemiological studies have shown that C. papaya extracts have significantly reduced oxidative stress in several health conditions, these conditions are discussed below. Alzheimer’s disease (AD) The relationship between oxidative stress and the onset and development of AD is well-established and well-acknowledged. Aggregation of β-amyloid peptides and the formation of neurofibrillary tangles in the brain are the most typical characteristics of AD (Gella & Durany, 2009). The accumulation of β- J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 9 amyloid in the brain leads to the generation of ROS which causes lipid and protein peroxidation and results in neurotoxicity in the brain. AD generally results in the impairment of defense mechanisms against oxidative stress characterized by low glutathione levels. Moreover, it is also discovered that ROS in the brain inhibits α-secretase activity, and promotes the activity of β-secretase and γ-secretase by generating neurotoxic β-amyloid 40 and 42. Another proposed mechanism of AD pathophysiology suggests that β-amyloid impedes and interferes with mitochondrial function in the neuronal cells. Studies have also proven that β-amyloid causes impairment of the antioxidative stress mechanism by interfering with the expression of uncoupling proteins (UCPs) which mainly function in reducing the ROS generated (Zhao & Zhao, 2013). FPP is one of the most commonly used papaya products which acts as a source of exogenous antioxidants and free radical scavengers (Zhang et al., 2006). Cancer There is currently no proven cure for the longstanding illness known as cancer. Some cancers are incurable, but others can be managed or cured to a certain degree. Both the development and possible eradication of malignancy are influenced by reactive oxygen species (ROS), which originate from mitochondrial metabolic activities. The two main processes that cause the progression of tumors and cancers are angiogenesis and metastasis, increased oxidative stress caused by ROD diminishes the body’s anti-oxidant defense mechanisms against angiogenesis and metastasis thereby promoting the growth of cancer cells (Nourazarian et al., 2014). In basal and tolerable concentrations of ROS, cancers in the body result from alterations and mutations in the genomic DNA, which in turn interfere with the normal physiological signaling pathways; pathways such as the cycling D, JNK, ERK, and MAP-K are all thought to have roles in the progression of cancer (Saha et al., 2017). Normal cells have a lower tolerance for ROS and eventually undergo cellular damage or death in high concentrations of ROS. Unlike normal cells, cancer cells have a higher resistance and tolerance towards ROS; however, after a certain limit, ROS reduces the growth and progression of cancer cells (Sosa et al., 2013). Additionally, it is also proposed that ROS causes the induction of carcinogenesis by interfering with the activities of tumor-suppressor genes (Saliasi et al., 2018). Certain studies have shown that FPP was able to impede DNA fragmentation, otherwise caused by free H2O2 and free radicals (Aruoma et al., 2006). The anti-cancer activity of FPP is owed to its ability to trigger cellular signaling mechanisms that cause apoptosis (Garcia-Solis et al., 2009). As already known, C. papaya is enriched with flavonoids which confer chemo-preventive and chemotherapeutic properties; the underlying preventive mechanisms include; (1) activation of tumor-suppressor genes, (2) deactivation of oncogene products, (3) decreasing oxidative stress by free radical scavenging and by preventing lipoxygenase action via chelating agents, 4) elevation of anti-oxidant enzyme levels such as and (5) preventing DNA from any structural damage that may be caused by free radicals or genotoxins (Waly et al., 2014; Murakami et al., 2014; Pathak et al., 2016; Somanah et al., 2016). Diabetes With advancements in the age and duration of diabetes, there is a gradual tendency for the level of blood sugar to rise along with a subsequent increase in the HbA1c as well as in the fasting insulin level (Skyler et al., 2017). It is evident from numerous researches that oxidative stress plays a role in the progression of diabetes Reactive oxygen species (ROS) generation is increased in diabetes, according to a wealth of experimental and clinical data, oxidative stress is closely associated with the progression of diabetes (Leisegang, 2022). There is an overwhelmingly high amount of evidence that uncontrolled hyperglycemia is correlated to the promotion of ROS and weakening of antioxidant defense systems; the defense systems are weakened by glucose oxidation, induction of lipid peroxidation of low-density lipoprotein (LDL), and glycation of proteins. Advanced glycation end products (AGEs), which are produced when glucose and proteins interact non-enzymatically, increase the creation of reactive nitrogen species (RNS), such as nitric oxide (NO). This oxidative stress and resultant free radicals hinder the functionality of β-cells in the islets of Langerhans, potentially leading to diabetes (King et al., 2004; Rolo et al., 2006). Antioxidants are therefore essential for the treatment of diabetes. Studies have demonstrated that the antioxidants in fermented papaya preparation (FPP) aid prevent atherosclerotic plaque, reduced lipid peroxidation, and raise superoxide dismutase (SOD) levels, among other diabetes problems (Raffaelli et al., 2015). Periodontal disease Periodontal disease is a condition characterized by the infection and inflammation of the gums, which is very likely to be related to oxidative damage and stress (Highfield, 2009). Periodontal inflammation is triggered and augmented by the production of unnecessary ROS and leukocytes. Epidemiological trials on humans have shown that the application of standardized fermented papaya gel (SFPG) significantly improves gum health, bleeding, and inflammation by decreasing the levels of inflammatory cytokines, nitrate (NO3 - ), and nitrite J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 10 level (NO2 - ) (Saliasi et al., 2018). SFPG also inhibits the activity of bacterial catalase and thereby reduces infection (Kharaeva et al., 2016). Skin aging The degradation of the extracellular matrix (ECM) is the main process that leads to the aging of the skin; it makes the skin drier, thinner, unevenly pigmented, and wrinkled. For ages the skin damage has been attributed to ROS; ROS is also known to cause premature aging of the skin as a result of oxidative stress and inflammation. ROS are also generated as a result of exposure to ultraviolet (UV) radiations, which activate signaling molecules and pathways such as AP-1, extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), MAP-K, nuclear factor kappa B (NF-κB). These factors and pathways are responsible for the induction of matrix metalloproteinase (MMP) 1, 3, 9 expression and collagen production in keratinocytes and fibroblasts which eventually lead to ECM damage and thus, aging (Rinnerthaler et al., 2015). Another phenomenon induced by ROS is melanogenesis mediated by an increase in melanogenic factors such as tyrosinase-related protein 1 (TYRP-1) and tyrosinase that eventually cause pigmentation of the skin. Furthermore, UV also increases the amount of cholesterol hydroperoxides, oxidized lipids, and triglyceride hydroperoxides which cause infections like acne vulgaris Propionibacterium acnes, which eventually leads to further generation of ROS (Masaki, 2010). C. papaya is used for its anti-aging properties due to its anti-inflammatory and antioxidant properties. Extracts of unripe C. papaya have been shown to prevent H2O2-induced endothelial cell death; these extracts alter the defense mechanisms by attenuating NF-κB and upregulating CAT and SOD activities. ROS leads to the depletion of the natural anti-oxidants and promotes aging while using papaya extracts maintains redox homeostasis and thus prevents aging (Jarisarpurin et al., 2019; Sanchez et al., 2019). Wound healing Wound-healing is a complex and well-coordinated biological process that has several stages; inflammation, homeostasis, proliferation, and modeling (Guo & Dipietro, 2010; Janis & Harrison, 2016). The process and rate of wound-healing can significantly be affected and altered by oxidative stress; oxidative stress and redox signaling play crucial roles in normal healing of wounds by facilitating (1) angiogenesis, (2) development and maturation of ECM, (3) granulation, (4) hemostasis, (5) inflammation, (6) tissue formation and (7) wound closure (Sen & Roy, 2010; Gonzalez et al., 2016; Cano Sanchez et al., 2018). Though lower concentrations of ROS prevent infection, higher concentrations of ROS can be cytotoxic and impair skin lipids, reduce their fluidity, and damage cellular membranes, DNA, and tissues thereby promoting inflammation (Suntar et al., 2012; Gonzalez et al., 2016; Lephart, 2016; Cano Sanchez et al., 2018; Robinson et al., 2022). In vivo research with FPP has shown that FFP inhibits hydroxyl radicals, superoxide and reduces the general content of ROS (Nafiu & Rahman, 2015). C. papaya extracts and topical applications enhance and speed up the process of wound-healing by reducing inflammation, producing antioxidant enzymes, and causing arginine metabolism (Leitao et al., 2022). Oral administration of FPP has also been proven to enhance wound closure in diabetic wounds (Collard & Roy, 2010). Anti-sickling activity Sickle cell disease (SCD) is a fatal genetic hematological disorder characterized by the presence of abnormally shaped red blood cells (RBCs) (Dash et al., 2013). The search for natural anti-sickling agents and plants has been a long struggle. The anti-sickling potential of C. papaya has been long recognized, it was first recognized in 1987 (Thomas & Ajani, 1987). After the discovery of the anti-sickling potential of papaya, FPP was used in sickle cell and thalassemic patients showing an improvement in the RBC sensitivity towards hemolysis (Amer et al., 2008; Fibach & Rachmilwitz, 2010; Nurain et al., 2016). Hepatoprotective effect Aqueous and ethanol extracts of C. papaya confer and possess exceptional hepatoprotective activity, especially against carbon tetrachloride (CCl4) induced hepatoxicity. It is also concluded that C. papaya extracts along with vitamin E further enhance the hepatoprotective effect. Nevertheless, the exact underlying mechanisms and principles by which the hepatoprotective effects are conferred are yet to be elucidated (Adeneye et al., 2009; Sadeque et al., 2012; You et al., 2017). Immunomodulatory properties Immune system strengthening is crucial for avoiding infections in diseases like HIV and immunosuppressed states (Yogiraj et al., 2015; Pandey et al., 2016). Recent research has shown that C. papaya extracts increase leukocyte, lymphocyte, monocyte, and platelet count in bone marrow cells in rat animal models (Jayasinghe et al., 2017). Additionally, high doses of C. papaya extract also significantly decrease the levels of pro-inflammatory cytokines. The most commonly exploited parts of C. papaya used for their immunomodulatory effects are the leaf and the seed (Anjana et al., 2018). Papaya extracts dramatically increased the cytotoxic activity and immunomodulatory effects of human peripheral blood mononuclear cells (PBMC) against cancer cells, according to a different study. Additionally, the J. Phys. Biomed. Biol. Sci. 2024; Volume, 3: 34 Ahmad et al., (2024) 11 study indicated that C. papaya extracts might be employed in vaccination therapy as an immunoadjuvant (Otsuki et al., 2010). Other uses Alcohol production Among the current challenges faced by the world’s biofuel industries is the production of a low-cost, environment-friendly method of ethanol production. Traditional petroleum-based methods of ethanol via fermentation are highly toxic to the environment. One of the alternate approaches is the production of ethanol and other alcohols by using agro-waste. C. papaya fruit extracts are proven to be a good alternate source of ethanol production as they have a high content of energy, nutrients, and phytochemicals (Saeed et al., 2014). Animal feed Seeds of C. papaya are added to animal feed to enhance animal health, nutrition, and production. There are several advantages of doing so; (1) animals feed more and gain more nutrients, (2) enzymes and phytochemicals are added to their diet which protect the animal against microorganisms of the GIT, (3) increased rate of ovulation, (4) increase production of milk and (5) bloating intestinal parasitic load is reduced (Farrag et al., 2014; Hainida et al., 2015). When added to a broiler diet, C. papaya containing diets are cost-friendly and reduce the amount of fecal ammonia produced (Bolu et al., 2009). Cosmetics Other than its application as a food, papaya can be used in cosmetics and topical creams. One of the earliest uses of C. papaya was to reduce acne and pimples and diminish blemishes and scars on the skin. In cosmetics, papaya is used as either peeled or mashed forms (Hainida et al., 2015; Lim, 2012). The peels of papaya contain vitamin A, which has antioxidant properties and therefore is even more suitable for its use in cosmetics (Aravind et al., 2013). Culinary C. papaya is known for its culinary uses and its use as a fruit to be eaten regularly. In various countries, papaya is consumed on its own or it is cooked, fermented, or processed to make commercially available food products. Papaya is eaten raw in some countries as one of the daily nutrients, and is made into deserts, jams, pickles salads, and sweet dishes (Aruoma et al., 2014). Other parts of the plant such as leaves are cooked as soup and used as a medicinal herb. In some other regions such as India, papaya seeds are used to replace black pepper seeds (Krishna et al., 2008; Hainida et al., 2015).

The health benefits of C. papaya are far too many to be counted; it contains enzymes, minerals, nutrients, and vitamins which not only are necessary for the normal diet of an individual but also provide numerous health and nutritional benefits. The fruit on the plant grows throughout the year and all of its parts can be used for their potential bioactivities. Enzymes present in C. papaya such as chymopapain and papain aid the digestion process and ease dyspepsia. Vitamins A, C, and E present in papaya confer antioxidant activities and prevent human health from several diseases such as aging of the skin, cancer, and high levels of cholesterol. Additionally, phytochemicals including alkaloids, carotenoids, flavonoids, and phenols also contribute to the many advantages conferred by C. papaya. Therefore, it can be concluded, that the papaya plant is a safe and natural option to improve human health and nutrition.