Phytomedicinal Chemistry and Pharmacognostic Value of Carica papaya L., Leaf

Carica papaya L. leaves contain potent secondary metabolites, such as alkaloids, phenolics, flavonoids, saponin, tannins, glycosides, and other crucial phytochemicals. The leaf is a source of several vitamins conferring it an anti-oxidant property. The leaf is also rich in dietary minerals and essential fatty acid. The fresh leaf extracts are used as a possible remedy for dengue viral infections in Asian countries. This review compiles the knowledge about the physiochemicals, phytochemicals, and biochemicals of Carica papaya L. leaves. This includes the identified chemical structures of alkaloids, phenolic, flavonoids, linoleic, and linolenicacids. Additionally, it covers up-to-date information on in-vitro anti-cancer and anti-gout and in-vivo anti-microbial properties, anti-oxidant, anti-sickling, hepatoprotective, hypolipidemic, hypoglycemic, and anti-gout effects.

Carica papaya L. is commonly known as pawpaw tree. It is a nutraceutical plant. All plant parts have vital immunostimulative and antioxidant effects. The Indian traditional medicinal system prescribes its leaf extract to control dengue viral infections. In other Asian countries, it is also used as a remedy for the same 1 . The leaf contains a mixture of chemicals, which can be described broadly as physiochemical, phytochemicals and biochemicals.

Physiochemicals
The physiochemical nature of the dried leaf has following contents in % w/w: Total Ash

Phytochemicals
It contains alkaloids, phenols, flavonoids, saponin, tannins, and glycosides. They could be described as follows:

Carpaine
Its molecular formula is C 28 H 50 N 2 O 4 ( Figure 1), which accounts for a molecular mass of 478.70g/Mol. It is used to reduce cardiovascular problems, act as amebicide and was found to inhibit Mycobacterium tuberculosis under in-vitro assay condition 4 .

p, m, o-Coumaricacids and caffeicacid
Coumaric acids are hydroxyl derivatives of cinnamic acid ( Figure 3). p-Coumaric acids possess anti-oxidant property, which results in the inhibition of the low density lipoprotein oxidation 7 .

Chlorogenic acid
It is a polyphenol compound, belongs to the family of esters of hydroxyl cinnamic acids, and has antioxidant effects.The molecular formula is C 16 H 18 O 9 ( Figure 4). Molecular mass is 354.31g mol -1 . This can form an ester linkage with caffeic acid and quinic acid.

Coumarin
Its molecular formula is C 11 H 10 O 4 ( Figure  5) and the molecular weight is 206.19gmol-1.

Fatty acids
Linoleic (Figure 7) acid is an unsaturated omega-6 fatty acid. Linolenic acid (Figure 8) is an omega-3 fatty acid. These two compounds were found to show anti-malarial property in in-vitro biological assay conditions 10 .

Pharmacognostics properties of the leaves Antibacterial activity
The in-vitro activity against clinical pathogens such as Klebsiella pneumonia, K.oxytocin, Enterococcus faecalis, Proteus mirabilis 11 , Escherichia coli, Pseudomonas aeruginosa 12 , Salmonella typhi 13 , Salmonella paratyphi A, Shigella flexneri 14 , Streptococcus pyogenes, Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus has been detected in the leaf extract using agar and disk diffusion methods.

Anti-helminthic
The leaf extract at 5% concentration caused paralysis to the Pheretima posthuma, an Indian adult earthworm 21 .The healthy leaves were used to cure ascariasis infection caused by a pathogenic form of Ascaridia galli 22 and Ancylostoma caninum in an in-vivo mouse animal model 23 .

Antitumor activity
The leaf extracts can block the proliferative responses in cervical carcinoma, breast adenocarcinoma, hepatocellular carcinoma, lung adenocarcinoma, and pancreatic epithelial carcinoma. Apart from these, the leaf extracts also help in protecting the vascular systems and functional systems. It mediated Th1 type shift in human and acted as a potent anti-tumor agent in an in-vitro assay 24 .

Immunostimulant activity during DENV viral infection
In a study, a leaf extract was orally administered to the patients to reduce the dengue viral symptoms. It increased the thrombocyte 25 and platelet count in a mouse model infected with dengue virus. During the dengue viral infection, a crushed leaf extract was found to improve the body immunity 1 .

Antioxidant effect
The leaf contains flavonoids (quercetin), phenols, tannins 26 and vitamins as the source of natural anti-oxidants. It has a potent hydroxy radical scavenging activity as found in some invitro conditions. It reduced acrylamide induced oxidative stress in stomach, liver, and kidney in an in-vivo animal model 27 . In an in-vitro assay, it scavenged1,1-diphenylehydrazyl (DPPH), 2,2azinobis-(3-ethyle benzothiazoline-6-sulfonate) (ABTS), nitric oxide, superoxide, and lipid peroxide in rat brain and liver 28 . It inhibited nitric oxide and TNF-a production in in-vitro conditions 29 . It reduced alcohol-induced acute gastric damage and blood oxidative stress in Sprague-Dawley rats 30 .

Hepatoprotective effect
The fresh leaves of the plant are traditionally used to cure liver associated problems. The leaf extracts help regularize liver enzyme during cirrhosis, hepatitis, and jaundice conditions. Carbon tetrachloride-induced liver damage was rectified by the aqueous extracts of C. papaya leave in in-vivo animal models 31 . The freeze-dried leaf extracts considerably protected hepatic cells from oxidative injury caused by tert-butyl hydroperoxide in in-vitro conditions. This chemical induced free radicals were scavenged by the anti-oxidants, phenolic and flavonoids, which are present in the leaves 32 .

Anti-inflammatory effects
The leaves also act as analgesic. It can reduce carrageenan induced paw oedema, cotton pellets induced granuloma, and formaldehyde induced arthritis in in-vivo models 33 . It could reduce Salmonella typhi infection induced inflammation in albino rats 34 .

Hypoglycemic effect
The extracts showed a significant hypoglycemic effect in in-vivo rat animal models 35 , where diabetes was induced by streptozotocin 36 .

Anti-sickling effect
The methanolic extracts of the leaves protected the membranes and reduced the sick cell formation under in-vitro conditions 37 .

Anti-gout effect
Xanthine oxidase enzyme is primarily involved in gout. The dry leaf extracts are the source of xanthine oxidase inhibitors, which can act as an anti-gout agent 38 .

Toxicity
The leaf extracts showed no pathological differentiation forms in the tissues and there were no contrary effects on the major functional organs like liver, kidney, and bone marrow by its aqueous extracts in in-vivo animal models.Thus the leaf extracts were found to be safe.

CONClusION
Carica papaya L. leaves contain chemicals that are multi-functional and of a great medicinal importance. Several in-vitro and in-vivo studies have approved its therapeutic efficacy and attainable mechanisms against newly emerging infectious diseases. However, further research is required for the development of potential anti-viral drugs from this leaf. The immunity development mechanisms during dengue viral infections have confirmed the anti-viral efficacy of Carica papaya L. leaves. The further exploration of dengue viral control mechanism is required and it may lead to the development of several anti-viral therapies. The toxicity level of pawpaw leaves is less and it doesnot hinder the medicinal beneficial effect. Therefore, the ethanomedicinal usage of these leaves is much safer than any other synthetic drugs.

ACKNOwlEDgEMENT
Our special thanks to Prof. Naoki Yamamoto, ID lab, Department of Microbiology, Yong Loo Lin School of Medicine, the National University of Singapore for anti-DENV studies.