Title: Treatment of dengue fever through the extraction of other part

of Carica papaya instead of its leaves

2.0 LITERATURE REVIEW

2.1 Overview on Carica Papaya and its properties

Papaya or scientifically named as Carica papaya L., is one of the major fruit crops
cultivated in tropical and sub-tropical zones. Papaya is from a short-term crop family
with a life expectancy of 1-4 years depending on the management. The papaya tree
is a soft, fast-growing tree and easily been seen especially in Malaysia.The economic
life of this plant is 2 years. Oval-shaped papaya usually is hermaphrodite fruit while
the round one is female papaya. Worldwide over 6.8 million tonnes (Mt) of fruit
were produced in 2004 on about 389,990 Ha. Of this volume, 47% was produced in
Central and South America (mainly in Brazil), 30% in Asia, and 20% in Africa. The
papaya industry in Brazil is one of the largest worldwide that continues to show
rapid growth. Although papaya is mainly grown (>90%) and consumed in developing
countries, it is fast becoming an important fruit internationally, both as a fresh fruit
and as processed products.

Nowadays, papaya is considered as neutraceutical fruit since it has multi-faceted

medicinal properties. Every single part of the papaya has their own benefits toward
the world. Carica papaya is a herbaceous plant whose fruits, leaves, seeds and latex
are used medicinally. The fruit has a juicy taste rich in antioxidant nutrients like
carotene, vitamin C, vitamin B, flavonoids, folate, pantothenic acids and minerals
such as potassium and magnesium. The prominent medicinal properties of papaya
include anti-fertility, uterotonic, diuretic, anti-hypertensive, hypolipidemic, anti-
helmintic, wound-healing, anti-fungal, anti-bacterial, anti-tumor and free radical
scavenging activities.

The biologically active constituents of papaya include chymopapain and papain

which are used in the treatment of arthritis and digestive disorders. Extracts of the
ripe fruits are used for a variety of medicinal purposes ranging from treatment of
ringworm, malaria and hypertension. The extract is also known to have antioxidant
properties. Despite the wide and historical use of Carica papaya in the traditional
management of many diseases, the scientific validation of its use as antioxidant is
lacking. While extracts of unripe fruit have been used in treatment of diabetes.
Traditionally, the leaf extract was used as a tonic for the heart, analgesia and
treatment for stomach ache. Meanwhile, its leaves and seeds are known to contain
proteolytic enzymes such as papain and chymopapain, alkaloids such as carpain,
carpasemine, Sulfurous compounds such as benzyl isothiocyanate, flavonoids,
triterpenes, organic acids and oils. Whole fruit extract also is said to contain ferulic,
p-coumaric acid, caffeic acid, carotenoids, and vitamin C. Leaves extract contains
folic acid, vitamins B12, A, and C, alkaloids, saponins, glycosides, tannins, and
flavonoids. Seeds extract contains different phenolic compounds, vanillic acid, and
vitamin C. (Phytochemical Analysis of Papaya Leaf Extract: Screening Test)

Figure1 Anatomy of papaya plant

2.2 Flavonoids as bioactive component that can treat dengue (behaviour)

2.2.1 Possible Mechanism of action of Papaya extract in dengue because of

some bioactive component.
 A study reported that papaya leaf extract could be useful in patients with dengue
infection due to the presence of flavonoids and other phenolics compound in the
papaya leaves. The papaya plant possibly brings about its effect in dengue by
treating the thrombocytopenia associated with the condition. The study reported
that the papaya leaf extracts have membrane stabilizing properties in in-vitro studies
and the C. papaya leaf extracts inhibited heat-induced and hypotonicity-induced
hemolysis obtained from both healthy individuals and individual with dengue
infection, the effect was observed at the lower concentrations of the extracts. Thus,
the extracts are likely to possess membrane-stabilizing properties and protect blood
cells against stress-induced destruction. This property may be useful in patients with
dengue infection where the leaf extract could be due to the presence of flavonoids
and other phenolics compounds in the papaya leaves (Sarala & Paknikar, 2014).

2.2.2 Flavonoid in papaya fruit can treat dengue fever

Flavonoids is a natural compound that are valuable resources in drug discovery

and are safe for human consumption. Besides, the interest on these compounds has
been increased tremendously in the recent years. Flavonoids are one such natural
compound found in almost all fruits and vegetables. Flavonoids are one of the
largest groups of phytonutrients well known for their antioxidant property. In
addition, they also possess anticancer, anti-inflammatory, antimicrobial,
neuroprotective, cardioprotective, vasoprotective and hepatoprotective properties.
The important thing is flavonoids are reported to have antiviral activities against
viruses such as herpes simplex virus, polio-virus, respiratory syncytial virus, sindbis
virus, influenza virus, parainfluenza virus, human immunodeficiency virus, dengue
virus, hepatitis C virus, chikungunya virus and zika virus(Kumar & Pandey, 2013).

Basically, the basic skeleton of flavonoids has 2 benzene rings linked by a

heterocyclic pyran ring. There are many types of flavonoids including compounds
from four subclasses: flavones, flavonols, flavanones and biflavonoids and their
Inhibitory Concentration values (IC50), are in a range from 0.16 µM to 80 µM. Based
on IC50 values, flavonoids are grouped into highly active (IC50 ≤ 5 µM), moderately
active (IC50 = 5-20 µM) and less active/ inactive (IC50 ≥ 20 µM). All the compounds
in the dataset have a ketone group in 4th position and an alcoholic group in 5th
position. Flavones, flavonols and biflavonoids have a double bond in between
position 2 and 3, whereas flavanones have a single bond.

Figure 2. General structure of (a) flavonols (b) flavones and (c) flavanones.

The structural basis of flavonoids can act as dengue polymerase inhibitors.

Basically, polymerase has two different conformations which are open and closed
conformations. When replication is initiated, polymerase has to shift its
conformation from closed to open. In this case, flavonoids act as non-nucleoside
inhibitors toward the polymerase. Non-nucleoside inhibitors are allosteric inhibitors
which upon binding produce a conformational change that makes the polymerase
inactive. The non-nucleoside inhibitors such as flavonoids retain the polymerase in
closed conformation and thus prevent replication of the virus of the dengue(Anusuya
& Gromiha, 2019).

2.2.3 Different part of papaya plant that also contain flavonoid

Papaya has widely used as traditional medicine and used as alternative

medication due to its low side effects. All parts of the papaya plant can be used as
medicine; the fruit flesh, flowers, seeds and the flowers. Many scientific
investigations have been conducted to evaluate the biological activities of various
part of C. papaya including their fruits, shoots, leaves, rinds, seeds, roots or latex.
Papaya leaves and fruits contain flavonoids that can be used as anti-bacterial, anti-
fungal and anti-cancer. Flavonoid is one of secondary metabolite products.
Flavonoids are ubiquitous in photosynthesis cells. Flavonoid content can be affected
by enzyme which arranged from protein, meanwhile difference formation of gene
can affect protein content.

In a study showed that different part of papaya also contains flavonoids that said can
treat dengue fever. Figure 3 shows the amount of total flavonoids content in
different part of papaya plant which are ripe papaya fruit, unripe papaya fruit,
papaya seed and papaya leaves(Maisarah, Amira, Asmah, & Fauziah, 2013).

Figure 3

Usually, papaya shoot is used in order to increase the number of red blood cell
on dengue patient. Normally, this alternative treatment went well by increasing the
patient’s platelet but they need to drink the papaya leaves that are blended and in
the form of juice which taste bitter. In fact, the highest phytochemicals in C.
papaya leaves other than flavonoids were also saponins, which make up to 0.022 ± 
0.10% of all the phytochemicals tested present in the same part. Although it bears
the potential as a cure or medicine for many ailments, commercially available
medicinal products from papaya leaf extracts have hindered its potential due to its
bitterness, greatly believed to be caused by saponins (Amran, Abidin, Hashim, &
Zubairi, 2018). Thus, this research is carried out in order to know if the leaves can be
substitute with their fruit, so that the patient can recover from the disease without
the taste of bitter from saponins since the papaya fruits also contain flavonoids.

References

1. Amran, S. N. S., Abidin, N. Z., Hashim, H., & Zubairi, S. I. (2018). Saponin
Bitterness Reduction of Carica papaya Leaf Extracts through Adsorption of
Weakly Basic Ion Exchange Resins. Journal of Food Quality, 2018.
 https://doi.org/10.1155/2018/5602729
2. Anusuya, S., & Gromiha, M. M. (2019). Structural basis of flavonoids as
dengue polymerase inhibitors: insights from QSAR and docking studies.
Journal of Biomolecular Structure and Dynamics, 37(1), 104–115.
https://doi.org/10.1080/07391102.2017.1419146
3. Kumar, S., & Pandey, A. K. (2013). Chemistry and biological activities of
flavonoids: An overview. The Scientific World Journal. ScientificWorld Ltd.
https://doi.org/10.1155/2013/162750
4. Maisarah, A. M., Amira, N., Asmah, *, & Fauziah, O. (2013). Antioxidant
analysis of different parts of Carica papaya. International Food Research
Journal (Vol. 20).

5. Sarala N., Paknikar SS. 2014. “Papaya Extract to Treat Dendue: A Novel
Therapeutic Option?”. Ann Med Health Sci Res.