A Mini-Review on the Phytochemistry and Pharmacology of the Plant Carica Papaya L. (Caricaceae)

Medicinal plant is an important element of indigenous medical systems all over the world. The ethno botany provides a rich resource for natural drug research and development. Carica papaya is used in Traditional Medicine since a long time. Our investigations started by a search of relevant literature on the plant species. Databases such as Science direct, PubMed, Google Scholar and Scopus were used successively to retrieve the articles on C. papaya. The chemical structures of isolates compounds from this plant were drawn using ChemBioDraw Ultra 12.0 software package. Finally, bibliographical references were made using bibliographical software "Mendeley". Results show that the plant C. papaya contains various secondary metabolites, minerals and vitamins. The plant species is reported to possess various pharmacological properties like anti-oxidant, antiinflammatory, antibacterial, anti-diabetic, anti-hyperlipidemic, larvicidal effects, etc. These pharmacological activities could due to the presence of various phytochemicals present in this plant species. The present review can therefore help inform future scientific research towards the development of novel drugs of relevance from C. papaya to combat various ailments including Sickle cell disease.


I. Introduction
Medicinal plant is an important element of indigenous medical systems in all over the world. The ethno botany provides a rich resource for natural drug research and development [1]. Natural products have played an important role throughout the world in treating and preventing human diseases [2]. According to the World Health Organization (WHO), 80% of the population living in developing countries relies on traditional medicine for their primary health care needs [3 -5]. In Democratic Republic of Congo (DRC), medicinal plants represent the key product for both urban and rural populations for their health care needs because the costs of conventional drugs are often unaffordable. These medicinal plants have found to have therapeutic value for fighting against major health problems [6][7][8][9]. C. papaya is a tropical tree, native to Central America and now widely cultivated in all tropical and sub-tropical regions for its edible fruits and its latex. [10] The medicinal properties of C. papaya are well documented in traditional systems of medicine [11] Many phyto-constituents were identified from different parts of C. papaya like saponnins, alkaloids, flavonoids, phenolic acid, terpenoids, carbohydrates, reducing sugars, phytosterols, cardiac glycosides, tannins and anthraquinnon, amino acids and proteins [12 -19]. It possesses as well antioxidant, antimicrobial; ant sickling, anthelminthic, antimalarial, anti -inflammatory, antidiabetic, antipyretic, anti-hyperglycemic activities were reported.
The main aim of the present study was to review the literature on the nutritional value, phytochemistry and pharmacology of Caraca papaya. These data would allow this species to be used as a multifunctional and low toxicity phyto-drug candidate for the management of various diseases.

II. Research Method
In this study, our investigations started by a search of relevant literature on the plant species. Databases such as Science direct, PubMed, Google Scholar and Scopus were used successively to retrieve the articles on C. papaya. The chemical structures of isolates compounds from this plant were drawn using ChemBioDraw Ultra 12.0 software package. Finally, bibliographical references were made using bibliographical software "Mendeley".

Botany
Asha et al. [20] reported C. papaya is a polygamous species and it is difficult to identify a plant whether it is male, female or hermaphrodite. It is a tree reaching 3-10 m in height, with the habit of a palm; the fleshy stem marked by scars where leaves have fallen off, is surmounted by a terminal panache of leaves on long petioles and with 5-7 lobes. Flowers fragrant, trimorphous, usually unisexual-dioeciously, male flowers in lax many-flowered, densely pubescent cymes at the tips of the pendulous, fistular rachis; female flowers large, solitary or in few flowered racemes, with a short thick rachis, fruit a large berry, varying widely in size, elongate to globose with a large central cavity, seeds black, tuberculous and enclosed in a transparent aril. Its flowers are mostly dioeciously and resemble each other until they start to develop sexual organs [21]. The fruit bearing trees are less than 18 month old. The leaves and unripe fruit contain milky juice in which the protein ferment papain is present. The fruit is ripe when it feels soft (like a ripe avocado or a bit softer) and its skin has attained amber to orange hue. The melon-like fruit varies in size and shape, and hangs from short, thick peduncles at the leaf axil.
This species is a large tree-like plant, with a single stem growing with spirally arranged leaves confined to the top of the trunk. The lower trunk is conspicuously scarred where leaves and fruit were borne. The leaves are large, 50-70 centimeters (20-28 in) diameter. The tree of this plant is usually unbranched, unless lopped. They appear on the axils of the leaves, maturing into the large 15-45 centimeters (5.9-18 in) long, 10-30 centimeters (3.9-12 in) diameter fruit.

Origin and Geographic Distribution
The survey of literature reveals that this species is native to Central America, formerly from southern Mexico, and now widely cultivated in all tropical and sub-tropical countries because of its high yield, nutritional value, functional properties, and year-round fruit production, the importance of this crop around the world is undeniable [19,20,22,23] .

Ethnobotany
In Asia regions, particularly in Pakistan, India and Sri Lanka the green fruit of papaya is used for contraceptive purposes by traditional healers [24]. Krishna et al. [11] reported that C. papaya leaves are being used specifically for fever, beriberi, asthma, colic in India. Other reports in the same country suggest that different parts of C. papaya such fruits, seeds, bark, leaves, roots and latex has been used for treatment of several diseases like jaundice, stomach problem, dengue, blood pressure, wound dressing and snake bite [25,26]. Amenta et al. [27] reported that latex of C. papaya is employed to treat eczema and psoriasis in Cambodia and Vietnam. The seeds have been used to heal vermifuge, thirst quencher, or pain alleviator [11] In Jamaica, Hewitt et al. [28] reported the ripe fruit has been used as topical ulcer dressings to promote desloughing, granulation, healing, and reducing odor in chronic skin ulcers. C. papaya leaves are used for heal cancer in Australia [29]. In Nigeria, the green fruit has been used for various human and veterinary diseases such as malaria, hypertension, diabetes mellitus, jaundice, intestinal helminthiasis [24].

Biological Activities a. Anti-amoebic Activity
The anti-amoebic activity of C. papaya seeds was evaluate against Entamoeba histolytica infection compared with metronidazole by using mice models. The result show that a single oral dose of C. papaya seeds water extracts of up to (0.1 mL∕mice∕day) reduced parasite appearance in feces and disappear completely at the 8th day compared with metronidazole the cysts parasite continued till 10th day. The histomorphological study findings showed in the group which was given C. papaya seeds the majority of tissue intestine return to normal shape [50]. Okeniyi et al. [41] reported that air-dried C. papaya seeds are efficacious in treating human intestinal parasitosis.

b. Gastro-protective Activity
Gastro-protective effects of aqueous C. papaya seed extract on ethanol induced gastric ulcer were investigated in male rats. Thirty two male's rats weighing between 180 and 250 g were randomly divided into four groups. Group 1 served as the negative control (distilled water), groups 2 and 3 received 50 mg/kg and 100 mg/kg C. papaya seed extract respectively, while group 4 received 200 mg/kg cimetidine (positive control). After two weeks, the results showed that the extract protected the gastric mucosa against ethanol effect. C. papaya extract significantly reduced the gastric juice volume and gastric acidity (p<0.05) in dose dependent manner when compared with the control. The percentage ulcer inhibition was significantly high (p<0.05) in rats treated with the extract when compared with the control and the effect is similar to that of rats treated with cimetidine.

c. Antibacterial and Antifungal Activities
Jyotsna et al. [52] demonstrated the antibacterial activity of C. papaya extracts. The results of this study revealed that the aqueous and methanolic extracts of seeds were effective to inhibit the bacterial pathogens but chloroform extract did not show any inhibition against the bacteria. Different solvent extracts of C. papaya were tested against Gram positive (Staphylococcus aureus and Bacillus cereus) and Gram negative (E. coli, P. aeruginosa and Shield Flexner) bacterial strains by observing the zone of inhibition. The ethanol, chloroform and benzene extracts of C. papaya showed activity against bacteria, the chloroform extract of this plant showed stronger activity against E. coli and P. aeruginosa. The ethanol extract showed stronger activity on B. cereus and E. coli. Chloroform extract in bacteria showed a varying degree of inhibition to the growth of tested organism [12].
In another study, Baskaran et al. [15] investigated the antimicrobial activity of various extracts of C. papaya. Their result showed these extracts have antibacteria and antifungal activities. The chloroform extract of C. papaya showed more activity against Micrococcus luteus, zone of diameter 15.17±0.29 mm and acetone extract C. papaya showed more activity against -669-Candida albicans, zone diameter 11.23±0.25 mm compared to other solvent extracts. In papaya, absolute ethanolic extract showed highest antibacterial activity [53].

d. Anti-diabetic Activity
Sobia et al. [54] investigated the antidiabetic activity of the C. papaya leaves ext racts in mice. The results of this study indicates that hyperglycemic level in diabetic mice was normalized after administration of various doses (50,150and300mg/kg bw) of ethanolic leaves extracts to diabetic mice. Similarly leaves extracts of C. Papaya have also shown pronounced effects on plasma insulin, triglyceride, and cholesterol and HDL cholesterol levels. The levels of liver enzymes (ALT, AST and ALP), bilirubin and blood cells (Red cells, white cells and platelets) were improved on dose depended manner. It is assumed that biologically active components of papaya leaf extracts are helpful in decreasing secondary complications of diabetes and improved insulin sensitivity to uptake glucose by cells.

e. Anti-hyperglycemic Activity
Antidiabetic effect of the ethanol extracts of C. papaya on streptozotocin-induced diabetic mice was investigated. The results of this study indicated that there was no significant difference in the body weight of the treated groups when compared to diabetic control. Whereas, there was significant decrease in the blood glucose level of the plant treated groups compared to the diabetic control. Histologically the pancreas of the treated groups indicated significant regeneration of the β-cells when compared to the diabetic control. The liver tissues of the treated group indicated a reduction in fatty changes and pyknotic nucleus. The kidney tissues of the treated groups indicated significant recovery in the cuboidal tissue. The antidiabetic effect of C. papaya observed in the present study may be due to the presence of these phytochemicals [17].

f. Anti-inflammatory, Antipyretic and Antinociceptive Activities
Anti-inflammatory, antipyretic and antinociceptive activities of aqueous extract of C. papaya seeds were demonstrated in animal models. These activities were done using 15% suspension of Brewer'syeast in Wistar rats (Antipyretic activity), using writhing method in mice and tail immersion method in Wistar rats (anti-nociceptive) and done using the xylene-induced ear oedema test and Carrageenan-induced paw oedema (anti-inflammatory activity).
The results showed there was a significant decrease in temperature after 120 mins for both extract groups. For the antinociceptive activity, there was no analgesia with tail immersion test while the writhing test produced 4.5% and 17.4% inhibition for groups 3 and 4 respectively. In the Carrageenan-induced paw oedema, the extract test did not have significant effect while the xylene-induced ear oedema test showed inhibitions of 27.72% and 34.97% for groups 3 and 4 respectively [55]. Owoyele et al. [34] investigated the anti-inflammatory activity of an ethanolic extract of C. papaya leaves in rats using carrageenan induced paw oedema, cotton pellet granuloma and formaldehyde induced arthritis models. Experimental animals received 25-200 mg/Kg (orally) of the extracts or saline (control group) and the reference group received 5 mg/Kg of indomethacin. The ulcerogenic activity of the extract was also investigated. The results show that the extracts significantly (p <0.05) reduced paw oedema in the carrageenan test. Likewise the extract produced significant reduction in the amount of granuloma formed from 0.58 ±0.07 to 0.22±0.03 g. In the formaldehyde arthritis model, the extracts significantly reduced the persistent oedema from the 4th day to the 10th day of the investigation.

g. Antisickling Activity
Imaga et al. [13] examined methanolic leaf extracts of C. papaya for possible in vitro antisickling and membrane-stabilizing activities involving the use of positive (p-hydroxybenzoic acid 5 mg/mL) and negative (normal saline) controls for the antisickling experiments and osmotic fragility test on Hbss red blood cells obtained from non-crisis state sickle cell patients. Fragiliograms indicated that the plant extract reduced hemolysis and protected erythrocyte membrane integrity under osmotic stress conditions. Pretreatment of SS cell suspensions with C. papaya leaf extract inhibited formation of sickle cells under severe hypoxia, with only 0 -5% sickle cells at 40 min compared with untreated SS cell suspensions which had over 60% sickle cells. The amino acids, phenylalanine, tyrosine and glycine already reported in the unripe fruit of Carica papaya, which are the possible antisickling components and responsible for their antisickling activity [53].

h. Antioxidant Activity
The antioxidant activity has been reported by Srikanth et al. [56] In this study, the free radical scavenging activity of the aqueous leaf extraction of C. papaya was studied by using different antioxidant models of screening e.g lipid peroxide (rat brain and liver), 1,1 -diphenyle hydrazyl (DPPH),2,2-azinobis -(3-ethyle benzothiazoline -6-sulphonate) (ABTS), nitric oxide, super oxide and hydroxyl radical model. The extract showed good dose dependent free radical scavenging activity in all the in vitro models. IC50 values were found to be 198,141,185,244, 323, 461 and 922 µg/ml respectively in DPPH, ABTS, nitric oxide, superoxide, hydroxyl ion, lipid peroxidation (liver and brain) inhibition assays. However the extract showed only moderate scavenging activity of hydroxyl radical and anti-lipid peroxidation potential, which was performed using rat liver and brain homogenate.
The antioxidant results revealed that the extract of unripe pawpaw peel had higher ferric reducing antioxidant property (112.35mg AAE/100g) compared to the unripe papaya seed extract (102.78 mg AAE/100 g) [57]. In papaya peel, highest TPC and reducing activity was shown by water extract while, TFC and radical scavenging activity was given by 80% ethanolic extract [53].

i. Antimalarial Activity
Bhat and Surolia [58] reported the petroleum ether extract of the rind of raw papaya fruit exhibits significant antimalarial activity. There may be significant commercial potential in extracting the active element from this plant, which grows abundantly throughout the tropics and the rind of which is discarded as waste, can be exploited for antimalarial activity. In another study, C. papaya extracts showed moderate to good antiparasitic effects. These four concentrations (25, 50,100 and 150 μg/mL) of ethanol leaf extracts exhibited promising inhibitory activity against the CQ sensitive strain with (IC50) values 40.75%, 36.54%, 25.30%, and 18.0% and in CQ resistant 50.23%, 32.50%, 21.45%, and 23.12% against P. falciparum [30].

j. Anti-tumor Activity
Nariko et al. [59] reported that aqueous extract of C. papaya leaves exhibits anti -tumor activity and it has been reported. In PBMC, the production of IL-2 and IL-4 was reduced following the addition of C. papaya extract, where as that of IL-12p40, IL-12p70, IFN-γ and TNF-α was enhanced without growth inhibition.

k. Antihyperlipedimic
The antihyperlipedimic activity of ethanol root extract of C. papaya was demonstrated in wistar rats. The results of this study suggested that (ERCP) possessed potent anti-hyperlipidemic activity. In poloxamer-407 induced hyperlipidemia In Wistar rats, as was evident from the reduced levels of TC, TG, LDL and VLDL [60].

l. Anti-helminthic Activity
Satrija et al. [61] indicated that the latex of this species has anthelmintic efficacy against Heligmosomoides polygyrus in experimentally infected mice, which suggests its potential role as an anthelmintic against potent intestinal nematodes of mammalian hosts. It also has anthelmintic activity against natural infection of Ascaris suum in pigs and found to be 100% effective at the dose of 8 g/kg body weight [62]. Another study indicates that the plant extracts of papaya possesses a dose dependent significant effect on the egg, infective larvae and adult worms of Trichostrongylus colubriformis. Alcoholic extracts of papaya shows potential in vitro antiparasitic action, which affects eggs, infective larvae and adult Haemonchus contortus [63].
By combining C. papaya with Anthocleista schweinfurtii, we can formulate an antisickling polyherbal drug which can be fortified with Moringa oleifera to manage sickle cell anemia and malnutrition [64,65].

IV. Conclusion
The African tropical region is characterized by the endemicity of many diseases for which population face many difficult to access to conventional medicines. It is therefore important to search for alternative solutions, especially from medicinal plant species. The aim of this study was to do bibliographic research on the bioactivity and phytochemistry of Carica papaya. The results revealed that this plant species possesses various pharmacological properties (like anti -oxidant, anti-inflammatory, antibacterial) which can be useful in the management of Sickle cell disease.