How to Cope with Dengue in Developing Countries Like Pakistan?
Gazi Mahabubul Alam,
Rizwan Rasul Khan
A viral disease like dengue lacking a specific form of treatment is a high menace to human health. Situation becomes worse in developing countries like Pakistan because of poor health care services and facilities. Using data from earlier works and analyzing them, this review aims to explore the disease epidemiology. Dengue Virus (DENV) destroys the immune system and causes health problems like headache, inflammation, bleeding, hypertension and mental disorders. Death also can be caused through dengue because of its adverse effects on liver which also may result in hepatitis. Dengue spread can be controlled through many ways like modulating the environment and devastating its vector. Biological control appears as potential approach to control its vector, especially the use of Wolbachia. Currently, no vaccines are available against this virus and antiviral drugs are also not significantly effective. Phytochemical studies revealed that apple, papaya and lemon are rich source of carotenoids, esters, flavonoids, phenolic acid, terpene and vitamins. Apple was found to have a number of antiviral compounds like phytoestrogens, procyanidins and rosmarinic acid. Although there are few reports of antiviral compound obtained from papaya but it has been reported to have evocative beneficial effects on immune system. The phytochemicals behave as strong anti-oxidant and anti-inflammatory agents which can help the body against dengue-induced inflammation and oxidation stresses. Several other features are also found in these reviewed phytochemicals that can protects the human body from the adverse effects of dengue infection. In nutshell, the consuming of papaya and apple should be incorporated in daily routine life especially during the season when this disease appears in its epidemic form.
Received: May 01, 2011;
Accepted: September 13, 2011;
Published: October 15, 2011
During last ten years, the total number of dengue patients has been doubled
(Bigongiari, 2010). WHO (World Health Organization) in
2010 also reported a graver concern is that about 100 million cases of dengue
are not administrated by medical staff and 0.5-2.5% of these suffers with severe
harmful consequences of virus (Deen et al., 2006).
Dengue is a vector born virus and has four different types DENV-1, DENV-2, DENV-3
and DENV-4 called serotypes (Jahan, 2011). Its four
serotypes originated approximately 1000 years ago and from past few hundred
years, it starts infecting humans (Holmes and Twiddy, 2003).
Dengue has large distribution due to its low entomological threshold level and
it is mainly transmitted by the biting of infected Aedes aegypti and
Stegomyia albopicta (Scott and Morrison, 2010;
Cecilio et al., 2009). Many other dengue transmitting
vectors are also known but several studies on A. aegypti describes its
major significant role in transmitting the virus (Anderson
and Rico-Hesse, 2006; El-Badry and Al-Ali, 2010;
Focks et al., 2000; Harrington
et al., 2005; Mohammed et al., 2008;
Phongsamart et al., 2008). A. aegypti
extensively favors the dengue dispersal due to its diverse distribution in phytotelmata
and peridomestic environments like earthen pots, containers, tyres etc. (Adebote
et al., 2006; Adebote et al., 2008;
Bashar et al., 2005).
In Pakistan, Dengue may be observed throughout the year but high dengue inflectional
period is from October to December (Khan et al.,
2010; Tahir et al., 2010). According to a
report on tertiary care hospital, in Pakistan large number of dengue infections
is mostly detected during winter season (Wasay et al.,
2008). Pakistan is one of the developing nations where approximately, one
fourth of its population lives below the line of poverty (The World Bank). It
is thus basic health care facilities are not readily available for most of the
people resulting use of alternate medicines is a much common phenomenon (Qureshi
et al., 2001; Khan et al., 2003;
Karim et al., 2011; Sohail
et al., 2011). Since last couple of years, dengue has emerged as
an epidemic disease and use of papaya, apple and lemon extracts to treat dengue
fever was found to be very common. But, there are not much scientific studies
available to support the use of these extracts for the treatment of this disease.
So literature was reviewed to find the potential beneficial activity of these
plants against dengue on the basis of their reported phytochemicals. In addition
a brief look at disease symptoms and approaches to control it has been provided
under the lights of previous studies.
EFFECTS ON HUMAN BODY
Symptoms caused by dengue may be in overlap with other diseases. These symptoms
are fever, headache, nausea, skin rash and ocular pain (Ali
et al., 2011; Humayoun et al., 2010).
Dengue patients suffer from gastrointestinal bleeding, headache and several
neurological problems. It is also observed that 100% of the dengue patients
have significantly lower values of platelets in their body while the lower number
of neutrophils and leukocyte were also recorded in 58 and 88% of the patients,
respectively (Hakim et al., 2011). Dengue also
disturbs the liver by increasing the concentrations of alanine transaminase
(ALT) and aspartate transaminase (AST), liver enzymes. There are chances of
mild-severe hepatitis on infection with dengue, which increases the complications
like gastrointestinal bleeding, hypertension, mental disorders and inflammation
of gall bladder and ultimately leads to the death of patients (Almas
et al., 2010; Parkash et al., 2010;
Souza et al., 2008). Dengue also affects the
muscle cells by causing inflammation, which may be due to the increased intracellular
Ca2+ concentrations (Salgado et al., 2010).
The development of disease symptoms directly correlates with the presence of
IgM antigen of dengue (Tang et al., 2008). While
the presence of viral RNA does not play any role in dengue caused symptoms,
the disease severity could increase if patient again come into contact with
different serotype of dengue virus (Sierra et al.,
2010). This severity may be due to increased imbalance in immune system
regulation. The dengue virus also harms its mosquito vector; it cause apoptosis
in mosquito tissues during its life cycle (Shafee and AbuBakar,
2006a). The observed apoptosis was not the part of metamorphic programmed
cell death as the apoptosis was directly proportional to the number of virus
antigen positive cells.
HUMAN IMMUNE RESPONSES TO VIRUS
Todays vulnerable environmental and poor human health conditions make
the global spread of dengue rapidly (Guzman and Isturiz,
2010). Therefore, the understanding of significant features of human immune
system in relation to viral attacks may help to reduce the severity of this
disease. The human immune system is of two types called innate and adaptive
immune system (Cooper and Herrin, 2010; Smith
and Weyrich, 2010). The immunity against pathogen and injury is governed
by both innate (e.g., through platelets) and induced (through a variety of lymphocytes
e.g., T and B cells) immune systems. The T and B cells have antigen recognizing
complex to identify the harming pathogens. On the other hand, platelets stabilize
the disturbed homeostasis and translocate the information among immunity responsive
T, B and neural cells (Varga-Szabo et al., 2008;
Wannemacher et al., 2011). Monocytes (type of
white blood cells) are the source of innate and adaptive immunity responses
(Auffray et al., 2009; Serbina
et al., 2008). As they take part in the development process of dendritic
cells and macrophages, healing and clearance of pathogens. Moreover, these are
also an important tool against DENV (Klomporn et al.,
2010). Any pathogen like virus affects the various immune responses; it
targets the antigen identification complex, apoptosis and hormonal immune responses
(Tortorella et al., 2008). Virus causes the abnormality
in the function of B cells, which may be due to some kinds of association developed
between virus and B cells (Stamataki et al., 2009).
CD4+ (primary immune response) and CD8+ (secondary immune
response) are the types of T cells and stop the invasion of virus (Jiang
and Chess, 2004; Strowig et al., 2009) and
number of these cells indicates the severity of disease (Ahasan
et al., 2004; Kagone et al., 2011).
The absence of these T cells in body can negatively increase viral-mediated
diseases, as was observed in mouse infected with Epstein-Barr virus. The dengue
virus receives more prevalent situation in mice depleted with CD8+
T cells while CD4+ T cells depletion didnt show any kind of
effect (Yauch et al., 2009; Yauch
et al., 2010). But the T and B cells are not the major inhibitors
of virus particles instead macrophages play major role in the inhibition of
virus (Blackley et al., 2007; Kou
et al., 2008). Thus for a successful infection virus has to kill
the macrophages but the T and B cells do have some antiviral effects.
Upon viral infection the CD8+ T cells enhanced the expression of
Programmed Death 1 (PD1) responses with the help of CD4+ T cells
(Barber et al., 2006; Petrovas
et al., 2006). Virus triggers the expression of T regulatory cells
(CD4+CD25+ T cells) and these cells suppress the proliferation
of virus specific CD4+ T and CD8+ T immune cells (Boettler
et al., 2005; Weiss et al., 2004).
Thus CD4+CD25+ T cells are responsible for the pathogenic
effects of virus in the body but its activity may be suppressed over time as
observed in HCV recovered patients (Pearson et al.,
2008). The platelet can destruct the virus by engulfing it (Torre
and Pugliese, 2008; Youssefian et al., 2002).
But if virus bound with platelet through specific ligands, it may alter the
platelets activity (Flaujac et al., 2010).
The altered platelets activity can disseminate the virus within the body as
Hantavirus causes the change in the platelets activity to favor its dissemination
(Gavrilovskaya et al., 2010). Nitric oxide concentration
plays a significant role in different body functions (Najati
et al., 2008; Moazedi et al., 2010).
Dengue virus elevates the nitric oxide (NO) levels, which inhibit the adhesion
of platelets and cause bleeding (Mendes-Ribeiro et al.,
2008). NO toxicity may be the main reason of dengue caused health problems
(Chaturvedi and Nagar, 2009). Some dengue proteins e.g.
Non-Structural Protein 1 (NS1) are homologue of coagulatory proteins (Lin
et al., 2011). The resultant antibody produced against these viral
proteins cross react with coagulatory proteins and damage the platelets. The
homologue responsible portion of NS1 is the C-terminal and if C-terminal is
removed, this viral protein would be unable in affecting the platelets (Chen
et al., 2009). The antibodies produced against NS1 also cause severe
damages to liver, which may be due the elevated levels of AST and ALT enzymes
(Lin et al., 2008a). The infection of dengue
can be minimized by strengthening the immune responses.
As DENV does not affect the single cell type or organ of the body, it can be concluded that dengue has complex mechanisms of action. This may also be due to the reason that its infection in one type of cell can severely effects whole body health. For example, the T cells, which recognize any antigen of pathogen upon dengue-caused reduction, would be unable to recognize other antigens. Likewise, dengue caused reduction in platelets not only affects the coagulatory responses but also results in reduce signaling between other immune cell. Thus, there is not only the need to reduce the dengue infections but also to treat the other complications that originate as consequences of this disease.
CONTROL OF DENGUE
Viral diseases such as rabies, herpes, influenza, hepatitis and HIV have always
remained as important discourse amongst health scientists in order to have better
understanding of these diseases (Farooq et al., 2006;
Oguntibeju et al., 2007; Ilboudo
et al., 2009; Movahed and Shoaa, 2010; Shabahang,
2010; Hassanzadeh et al., 2011). Studies
based on the prevalence of these diseases helps to identify the geological distribution
and factors responsible for their spread (Moghim et al.,
2007; Ilboudo et al., 2007; Talaie
et al., 2007; Daryani et al., 2009;
Sagna et al., 2010). The non-preventive measures
for urbanization, globalization, modern air transport, water and waste management
cause the rapid infestation of environment with dengue and its vector (Barboza
et al., 2008; Gubler, 2010; Kyle
and Harris, 2008; Ooi and Gubler, 2008; Ooi
and Gubler, 2009). This huge spread of dengue can be minimized by modulating
our environment like managing the cool air supply in the houses, use of insecticide
treated materials and frequent distance from neighboring houses (Reiter
et al., 2003; Vanlerberghe et al., 2011).
There are two fundamental types of controls. They are (1) before infection
and (2) after infection (Fig. 1). Before
infection control is based on preventive measures to avoid disease e.g.,
vector control and vaccination. After infection control consists
of efforts that are focused on suppression of virus attack and its related complications.
|| A schematic diagram describing the general layout of dengue
REDUCED DISSEMINATION OF VIRUS
The best way to control a virus is to control its vector; A. aegypti
is the main vector of dengue virus and control of this vector will definitely
result in the reduced spread of this disease. Thus, the spread of dengue can
be controlled by elimination of its vector A. aegypti; many studies have
been conducted in this regard (Morrison et al., 2008;
Paulraj et al., 2011; Raghavendra
et al., 2011). The control of A. aegypti is necessary as it
also causes another important lethal disease, malaria (Yasinzai
and Kakarsulemankhel, 2003). Synthetic insecticides are not much effective
against A. aegypti population as many of its strains have obtained the
resistance against the commonly used insecticide and insects are only susceptible
to the insecticide at specific life stage (Ahmad et al.,
2007; Ocampo et al., 2011). Moreover, the
use of these synthetic insecticides is also harmful for environment and causes
stern health issues (Al-Jahdali and Bisher, 2007). So
environment friendly and effective method like biological control of A. aegypti
appears as more suitable approach. There are many approaches to biologically
control the viruss vector e.g. Bacillus thuringiensis israelensis
(Alam et al., 2008). Its Cry proteins
have potential to control A. aegypti but these are sensitive to heat;
heat suppresses the proteins activity. The marine environment also offers
biological control against this mosquito species in the form of sponges like
Clathria gorgonoids, Callyspongia diffusa, Haliclona pigmentifera, Sigmadocia
carnosa etc. (Sujatha and Joseph, 2011). Among
these C. gorgonoids and C. diffusa showed the significant larvicidal
activity at V instar larvae stage. The marine algae also showed larvicidal activity
against A. aegypti (Manilal et al., 2011).
The potentially important larvicidal activity was found in Lobophora variegata.
Another important biological control of A. aegypti is Wolbachia.
It causes alternations in host reproductive organs and modulates the host genomic
expression to confirm its establishment in the host body (Hussain
et al., 2011; Saridaki and Bourtzis, 2010).
The Wolbachia strains cause viral transmission reducing phenomenon in
mosquito like shortened life-span and cytoplasmic incompatibility (McMeniman
et al., 2009; Yeap et al., 2010).
It also lessened the feeding success of mosquito on human body which may be
due to the tissue damage caused by Wolbachia (Moreira
et al., 2009a; Turley et al., 2009).
Less feeding eventually result in less transmission of virus. The potential
of Wolbachia to infect the mosquito depends upon the Wolbachia
strain type; establishment of genetically different Wolbachia strains
may cause more promising effects (Walker et al.,
2011; Xi et al., 2005).
The spread of dengue can also be limited by the use of nanoparticles. The nanoparticles
of silver upon exposure to UV radiations show the efficient ability to kill
A. aegypti larvae, in a concentration dependant manner (Sap-Iam
et al., 2010). The virus transmission can also be controlled, if
the immune system of A. aegypti is strong enough to reject the virus
infection (Sanchez-Vargas et al., 2009; Xi
et al., 2008). Ahmed et al. (2008)
observed that the application of Nigella sativa derived thymoquinone
strengthen the immune responses of A. aegypti. In later studies
it was observed that Wolbachia can provide strength to anti-dengue immune
responses of A. aegypti (Bian et al.,
2010; Frentiu et al., 2010; Moreira
et al., 2009b). It enhances the expression of immune genes of A.
aegypti against dengue infection and it strongly reduces the number of
virus particles in the mosquito tissues. Among all the vector control methods,
Wolbachia mediated biological control appears to be the prominent option.
VACCINES FOR DENGUE
Dengue has different mechanism of actions depending upon the type of cell line
and in humans the immunity responses are highly dependent on their genetic polymorphism
(Chaturvedi et al., 2006; Shafee
and AbuBakar, 2011). Todays approach is to obtain anti-dengue vaccines
but these vaccines are still under development due to their adverse effects
and short-lived immunity responses (Guirakhoo et al.,
2006; Kanesa-Thasan et al., 2001; Guzman
et al., 2010; Murphy and Whitehead, 2011).
The virus particles based vaccine can be used to develop the immunity against
dengue (Mota et al., 2005; Shafee
and AbuBakar, 2006b). Tambunan and Parikesit (2011)
provide the in silico design of E DENV vaccines for dengue-2 and 3, E
DENV are the virus proteins which facilitate the attachment of virus on the
host cell. But the functionality of these vaccines also depends upon the genetic
system of human being so there is need of more computational power to fully
express the efficiency and establishment of these vaccines. The intramuscularly
applied plasmid of DEN-2 non-structural protein 1 (NS1) in mice causes decrease
in morbidity and ultimately leads to the increased chances of survival (Wu
et al., 2003). The immunity in the newborn of this NS1-treated mouse
was more pronounced. But the increasing demand of DNA derived vaccines has increased
the need of large quantities of pure DNA plasmid and the extraction of DNA plasmid
is an important and difficult procedure (Duarte et al.,
2007; Li et al., 2008a). Moreira
et al. (2007) found the PEG 400 (20/20% w/w) system as the best PEG/phosphate
system for the extraction of dengue 2 plasmid DNA vaccines from the lysate cells
of E. coli. It can extract 37% of DNA plasmid. Thus this can be concluded
that the development of vaccines to cure dengue has many limitations and there
is need of more research on their efficiency and production.
In nature many compounds are present that can be employed against viral diseases
(Baranisrinivasan et al., 2009; Momtaz
and Abdollahi, 2010; Vignesh et al., 2011).
Squalamine, a compound obtained from dogfish shark and sea lamprey has the potent
antiviral activity against many viruses including dengue (Zasloff
et al., 2011). In vitro it has concentration dependent protective
effects on human endothelial cells against dengue. Nearly thirty seven licensed
antiviral drugs are present today, yet no reliable anti-dengue drug is present
(De Clercq, 2004; Czeizel et
al., 2006). But, dengue proliferation can be controlled by targeting
the vulnerable sites of dengue life cycle using the small drug molecules (Wilder-Smith
et al., 2010). According to Schul et al.
(2007) the use of antiviral drugs even after acute dengue infection can
significantly cause the reduction in virus particles and virus-caused disease.
They further proposed that AG129 mice model is an appropriate object to study
the anti-dengue drugs. Another chemical compound NITD008, which is the analogue
of adenosine, also showed the potential antiviral activity against many vector-borne
viruses especially dengue (Yin et al., 2009).
It shows the dengue virus titer and virus-caused disease reducing ability in
both in vitro and in vivo studies. But the significance of any
anti-dengue drug is needed to check in human trials. Moreover the antiviral
drug should also be checked on the basis of its origin, cost, cytotoxicity,
purification etc. (Selisko et al., 2007). As many
natural anti-dengue drugs derived from plants were rejected in past due to their
difficult extraction and cytotoxic effects. Thus the development of anti-dengue
drugs has many hurdles, but their development should be checked on critical
PHYTOCHEMICAL STUDY OF APPLE, LEMON AND PAPAYA FOR THE TREATMENT OF DENGUE FEVER AND ITS RELATED COMPLICATIONS
The daily intake of 400-600 g of fruits and vegetables prevents from many diseases
(Heber, 2004). The phytochemicals found in these plants
have many therapeutic effects on human body (Garba et
al., 2006; Musa et al., 2008; Yang
et al., 2008a; Prakash and Gupta, 2009; Hussein
et al., 2010; Karthishwaran and Mirunalini, 2010;
Asmawi et al., 2011).
|| Some reported phytochemicals of apple, lemon and papaya
These are also responsible for the protective effects against inflammation,
oxidation, neural-degenerations, etc. hence these chemicals inhibits the metabolic-dysfunctioning
(Ekor et al., 2006; Oloyede
et al., 2008; Nirmala et al., 2008;
Potchoo et al., 2008; Wahab
et al., 2009; Sivabalan and Anuradha, 2010;
Hasani-Ranjbar et al., 2010; Patil
and Patil, 2011; Lawal et al., 2011). The
papaya leaf extract, apple and lemon juice have been recommended by the folks
to treat dengue fever but there is very little scientific literature available
to support the use of these plant remedies. So in next section some of the important
phytochemicals have been explored with reference to their potential therapeutic
attributes (Table 1).
PHYTOCHEMICAL SIGNIFICANCE OF APPLE
Apple is from one of the major fruits of Northern areas of Pakistan and has
many medicinal uses (Sher et al., 2010). The
methanolic and acetonic extracts of apple pomace have antioxidant and antiviral
activity against some viruses (Suarez et al., 2010).
One of apples phytochemicals phytoestrogens has the potential
anti-dengue property, it is also found in other fruits and have strong antiviral
actions (Torres-Sanchez et al., 2000; Martin
et al., 2007; Ogbuewu et al., 2010).
Sialic acid is an essential requirement of eukaryotic cells and accounted for
the normal development (Schwarzkopf et al., 2002;
Balcan and Sahin, 2006; Senthil
et al., 2007; Pavana et al., 2008; Mathur
et al., 2010). Dengue causes the oxidative stress in the body by
oxidating the plasma proteins and lowering the sialic acid concentration (Rajendiran
et al, 2008). Thus antioxidants can help in maintaining the protein
structure disturbed by oxidative stress. Apple contains many strong antioxidants
like catechin and phloridzin (Boyer and Liu, 2004; Gilani
et al., 2006; Beg et al., 2008; Gupta
et al., 2008; Falah et al., 2008;
Lelono et al., 2009; Rivas-Arreola
et al., 2010; Kaur and Saraf, 2011), which
can reduce the oxidative stress. The strong antioxidant like reduced glutathione
(GSH) has the capability to inhibit the dengue production in the body and hence
reduce the virulence of dengue (Tian et al., 2010).
The apple juice has the excellent antioxidant ability; also promote the expression
of anti-oxidating glutathione enzyme genes (Kujawska et
al., 2011; Soyalan et al., 2011). The
peels of unripe apple have oligomeric procyanidins, which simulate the innate
immunity responses in DENV-infected cells (Kimmel et
al., 2011). Many other procyanidins e.g. B1, B2, C1 etc. are also found
in apple and procyanidin B2 was also detected in the human serum after the intake
of procyanidin-rich food (Sano et al., 2003;
Shoji et al., 2003). Procyanidins may have antiviral
activities e.g., procyanidin B1 inhibits the hepatitis C virus by suppressing
its RNA synthesis (Li et al., 2010; Zhuang
et al., 2009). In Huh-7 cells procyanidin B1 showed concentration
dependant effect against virus. Depending on this information this can be said
that the procyanidins found in apple might have some antiviral activity. Thus
apples not only directly can reduce the dengue infections but it also possesses
indirect beneficial effect on dengue affected persons.
Catechin, the most active antioxidant flavonoid is found in apples and results
based on HPLC and GC/MS studies showed its concentration 1.01 mg/kg w/w of apples
(Sim et al., 2010). According to Pignatelli
et al. (2006) catechin only in combination with quercetin can cause
the recruitment of platelets. This recruitment of platelets was resulted by
the inhibition of PKC-dependent NADPH oxidase activation. Coumaric acid is another
medicinally known compound found in apple. p-Coumaric acid (isomeric form of
coumaric acid) has antioxidant, anti-coagualtory and hepato-protective activity
with high absorption in the rats gut (Choi et al.,
1998; Lee et al., 2008; Luceri
et al., 2007; Zhang et al., 2007).
It can reduce the ethanol caused oxidation and can inhibit the ADP-induced platelets
aggregation by enhancing the plasma antioxidant activity. In addition it also
reduces the thromboxane B2 production, which occurs during ADP-induced aggregation
but it doesnt showed any effect on platelet count and mean platelet volume.
Coumaric acid contents of apple may be beneficial in reducing the oxidation
and inflammation problems caused by dengue infections.
A gas chromatography-mass spectrometry study on apple skin confirms the presence
of an anti-oxidant compound called rosmarinic acid (Amzad
et al., 2010; Koroch et al., 2010).
Rosmarinic acid has a potential antiviral activity against Japanese Encephalitis
Virus and HIV-1 (Dubois et al., 2008; Swarup
et al., 2007). It inhibits the replication of both of these viruses.
It also possesses the antithrombotic effect in the wistar rats vena cava,
which may be due to the inhibition of collagen induced platelets aggregation
(Zou et al., 1993). Thus this can be said that
apple is a rich source of phenolic and polyphenolic compounds which are of significant
medicinal importance. Some of these compounds have antiviral effects, which
may play role in controlling the dengue virus but further investigation is still
PHYTOCHEMICAL SIGNIFICANCE OF LEMON
Lemon is a common cultivated plant in Pakistan, where in some areas its fruits
are used commonly to treat the teeth problems (Hussain and
Ishtiaq, 2009; Hussain et al., 2010). But
many other characteristics can also be ascribed to this plant due to the presence
of a range of important phytochemicals (Table 1). Scoparone
is a phytoalexin; an immunoregulatory compound of lemon, which induce the reduction
in NO levels by suppressing the expression of iNOS genes (Kim
et al., 2007; Ortuno et al., 2011;
Yang et al., 2008b; Yang
et al., 2009). Thus immunoregulatory activity of scoparone could
be considered as positive role in treating the dengue caused immunological problems.
The other biologically important antioxidant compound of lemon is Vicenin-2,
a flavonoid, which may has the anti-inflammatory activity (Aquila
et al., 2009; Barreca et al., 2010;
Ramful et al., 2010). Another medicinally important
compound, limonene is the natural terpene found in different plants including
lemon, has low toxicity; it reduces the heart burn and gastroesophageal reflux
in dosage dependant manner (Al-Howiring, 2003; Talei
and Meshkatalsadat, 2007; Gattuso et al., 2007;
Meshkatalsadat and Mirzaei, 2007; Yoon
et al., 2009; Di Vaio et al., 2010;
Sun, 2007). It cause an increase in the concentrations
of cytosolic calcium and cAMP and proteins kinase activity, which may energize
the antiviral and anti-inflammatory immune responses (Hirota
et al., 2010; Park et al., 2010; Romeilah
et al., 2010). The curative properties of lemon can also be enjoyed
by utilizing its essential oils, which have the excellent antioxidant property
(Campelo et al., 2011). The other compounds of
lemon with antioxidant property are neral, neryl acetate and geraniol (Tansi
and Nacar, 2000; Vekiari et al., 2002; Meftahizade
et al., 2010; Kadri et al., 2011).
Thus lemon has many phytochemicals which can support the immune responses against
virus caused problems, especially through its anti-oxidant agents.
PHYTOCHEMICAL SIGNIFICANCE OF PAPAYA
Carica papaya is an important plant with significant medicinal properties
e.g. anti-inflammatory, antimicrobial and wound management (Rahmat
et al., 2002; Saeed and Tariq, 2006; Raji
et al., 2006; Zakaria et al., 2006;
Oladunmoye and Osho, 2007; Idu and
Onyibe, 2007; Oladimeji et al., 2007; Goyal
et al., 2009; Ajlia et al., 2010;
Ansari et al., 2011; Osadolor
et al., 2011). It is also an important source of many phytochemicals
(Table 1). On administration of papaya in its powder form
at the rate of 5 mg kg-1 of body weight, it can significantly increase
the platelet count of dengue infected patients (Sathasivam
et al., 2009). In another research it is found that its leaf aqueous
extracts are responsible for a significant increase in platelets count, white
blood cells and neutorphils in dengue infected patient (Ahmad
et al., 2011). The fermented preparations of this fruit have antioxidant
activity; it increases the reduced glutathione concentration in red blood cells
and decreases the reactive oxygen species (Fibach et
al., 2010). The papaya extracts also shows the positive effects on other
immune responsive cells like macrophages; its extracts have a positive effect
on the macrophage antiviral properties (Lidbury and Mahalingam,
2000; Rimbach et al., 2000; Ishikawa
and Miyazaki, 2005; Mahbub-E-Sobhani et al.,
2011; Du et al., 2011). The macrophages upon
viral infection are responsible to produce antiviral antibodies. So this can
be said that papaya may have many healthy effects on dengue infected patients
due to its positive regulation of macrophages and platelets.
The medicinal importance of papaya phytochemicals is elucidated here to make
an awareness of its remedial uses against dengue caused problems. Anthraquinone
an important photochemical of may plants also found in papaya either in free
or in bound form and many studies reported that various anthraquinones have
antiviral property against different viruses (Semple et
al., 2001; Li et al., 2007; Kumar
et al., 2007; Hassan et al., 2007;
Imaga et al., 2010a; Sonibare
et al., 2011; Xiong et al., 2011).
The anthraquinone derivatives also possesses the anti-coagulatory activity,
its derivatives have the potency to reduce the thrombin, arachidonic acid, collagen
and platelet-activating factor-induced platelet aggregation (Baqi
et al., 2009; Gan et al., 2008). These
derivatives have potential to activate the CD34+ dendritic cells,
which is important for immunological responses (Van de Ven
et al., 2011). The anthraquinone derivatives are also important in
stimulating the proliferation of resting human peripheral blood mononuclear
cells and lymphocyte (Cherng et al., 2008). Another
therapeutic compound of papaya is myricetin, which possess the in vitro anti-inflammatory
activity and can reduce the acetic acid-induced capillary permeability (Miean
and Mohamed, 2001; Wang et al., 2010). It
also has the sedative activity against chemical (acetic acid and formalin) caused
neural problems; it may also have the anti-platelet activity (Tong
et al., 2009). So both of these compounds have anti-inflammatory
effects and can modulate the immunological anti-dengue responses.
Another flavonoid kaempferol present in papaya, which showed antimicrobial
(Taechowisan et al., 2008) and strong anti-inflammatory
activity by reducing the NO levels (Hamalainen et al.,
2007). It is responsible for dose dependent reduction in NO levels, which
was governed by the reducing in iNOS proteins and mRNA expression. Papaya is
an important source of some vitamins like vitamin A, B12 and Folic acid, which
might have some contribution in its therapeutic properties (Iyawe
and Onigbinde, 2006; Wall, 2006; AL-Sowyan,
2009; Imaga et al., 2010b; Jiao
et al., 2010). Vitamin B 12 deficiency can cause abnormalities in
central nervous system, which may increase the complications in dengue patients
with already affected nervous system (Bordignon et al.,
2008; Scalabrino, 2009; Yauch
and Shresta, 2008). Thus the presence of vitamin B 12 may has healthy impact
on dengue infected patients. Deficiency of vitamin A may also contribute to
immune defects and can increase the prevalence of several diseases (Saeed
et al., 2005; Lin et al., 2008b; Sommer,
2008; Uboh et al., 2008; Uboh
et al., 2009; Qiu et al., 2010; Iribhogbe
et al., 2011). Dengue virus causes aplastic anemia which can be inhibited
by the application of folic acid (Albuquerque et al.,
2009; Ganji and Kafai, 2009). Iron-folic acid can
decrease the rate of anemia especially in women; by the increasing the haemoglobin
levels (Casey et al., 2010). It also protects the
endothelial cells from the oxidative stress by increasing the expression of
dihydrofolate reductase (Gao et al., 2009). Dihydrofolate
reductase regulates the tetrahydrobiopterin and NO superoxide production to
suppress the oxidative stress (Crabtree et al., 2011).
Ferulic acid a form of phenolic acid is an important subject of antioxidant
activity and so can protect the body from many health problems including neural
disorders (Kanski et al., 2002; Srinivasan
et al., 2007). Its antioxidant property is basically due to its functional
hydroxyl and phenoxy groups. Lycopene is another anti-oxidant compound of papaya.
It has the potential antioxidant property and thus inhibits the liver from oxidative
stress (Seren et al., 2008) and might be helpful
to reduce the HCV related complications. Bignotto et
al. (2009) studied the anti-inflammatory effects of lycopene in two
rat models. It was observed that lycopene impose a strong anti-inflammatory
activity at 25 and 50 mg kg-1 concentrations in both paw oedema and
ischaemia-reperfusion models of rat. Herzog et al.
(2005) noted that lycopene administration causes a decrease in inflammation
causing agents like interleukin-1β, CXC chemokines, etc. Thus lycopene
is an efficient anti-inflammatory agent and it also showed preventive effect
on chromosomal aberrations (Aslanturk and Celik, 2005).
Another phenolic acid named vanillic acid is also present in papaya
and some other plants (Mehboob et al., 2000;
Tajuddin et al., 2002; Shaukat
et al., 2003; Jazayeri et al., 2007;
Zhou et al., 2011). Vanillic acid possesses a
strong hepatoprotective activity, as it decreases the activity of transaminase
enzyme and disorganized hepatic sinusoids (Itoh et al.,
2009). In addition, it also protects the liver from immune-induced liver
injuries by decreasing the concentration of inflammatory cytokines, interferon
(IFN)-gamma and other liver infecting agents. This investigation of papaya properties
shows that papaya has many therapeutic properties and it is a rich source of
highly protective biological compounds, which can treat many health problems.
SHARED PHYTOCHEMICALS AND THEIR SIGNIFICANCE
The three studied fruits have some common curative phytochemicals like ascorbic
acid (vitamin C) and quercetin (Akhila et al., 2009;
Bari et al., 2006; Ghasemi
et al., 2009; Li et al., 2008b; Sultana
and Anwar, 2008; Ramful et al., 2011; Wach
et al., 2007). The curative antioxidant ascorbic acid is an important
coagulatory nutrient, which may reduce the severity of oxidation and anticoagulation
problems of dengue infection (Fromberg et al., 2011;
Savini et al., 2007; Padayatty
et al., 2003). It has other remedial properties, which may able to
treat dengue caused problems. Like, it has hypotensive property and can reduce
the vascular tension in Stroke-Prone Spontaneously Hypertensive Rats (SHRSP)
(Chen et al., 2001; Sato
et al., 2011a). It can strongly reduce the oxidative stress in mice
liver caused by high iron diets but it did not play any role in maintaining
the physiological processes under low iron concentrations (Premkumar
et al., 2007). Ascorbic acid also have anti-inflammatory responses,
it significantly reduce the amount of inflammation causing C-reactive protein
(Black et al., 2004; Block
et al., 2009; Du Clos and Mold, 2004). Thus
ascorbic acid in the presence of physiologically enough iron may be an important
candidate of antioxidant properties. Quercetin is a strong antioxidant candidate
(Cibin et al., 2006; Jun
et al., 2007) and can modulate the memory impairments (Sternberg
et al., 2008; Naseri et al., 2008;
Ebrahimzadeh et al., 2009; Bahri-Sahloul
et al., 2009; Tota et al., 2010).
It also acts as an anti-inflammatory agent and protects the body from kinase
activity of platelet, which cause coagulation (Bischoff,
2008; Navarro-Nunez et al., 2010; Van
der Meijden and Heemskerk, 2010). It doesnt has direct effect on coagulation
causing stimulus (like thrombin) instead it interfere with the signaling pathway
and stops the platelets aggregation (Nunez et al.,
Caffeic acid and chlorogenic acid are the two phenolic acids shared by the
papaya and apple (Bouayed et al., 2007; Boyer
and Liu, 2004; Chinnici et al., 2004; Canini
et al., 2007; He and Liu, 2008; Rivera-Pastrana
et al., 2010). Caffeic acid has the antiviral property, its application
before the infection can effectively reduce the replication of herpes simplex
virus type 1 (Ikeda et al., 2011). The caffeic
acid esters have noteworthy antioxidant properties, it possess negative effect
on the collagen-induced platelet aggregation (Bakasso
et al., 2008; Hsiao et al., 2007; Jayaprakasam
et al., 2006). Its ester causes the direct inhibition of collagen
binding to the platelet by binding to the platelets collagen receptor.
Hence it reduces the collagen induced platelet aggregation, which may help to
cope with heart problems of coagulation. Caffeic acid is also produced in intestine
by the hydrolyzation of chlorogenic acid; chlorogenic acid is an antioxidant
polyphenol (Sato et al., 2011b). But caffeic
acid has more pronounced antioxidant effects than chlorogenic acid. The chlorogenic
acid plays role in anti-inflammatory reactions by inhibiting the neutrophil
locomotion and adhesion (Hebeda et al., 2011).
All studied fruits are good source of important phytochemicals, which possesses
different biological properties. The phenolic compounds of these studied fruits
have chief antioxidant property, which is important for treating many health
problems. The variety of phytochemicals provides variety of benefits to health
as the phytochemicals have positive effects on immune-responsive cells. They
also provide benefits to memory impairments.
Dengue is a vector born disease with a complex mechanism of action, as it can directly or indirectly destroy the activity of many immune cells. Its adverse effects are due to highly suppressed immune responses through IgM antigen of dengue. Figure 1 shows a general layout scheme for the approaches to deal with dengue virus. Its vector control appears to be the best approach because antiviral drugs are not much successful for this disease. Vaccines for dengue could be another preventive measure but these vaccines are still in developmental phase. In addition, these antiviral drugs and vaccines are not much common in developing countries where this disease is transforming into an epidemic. After viral infection treatment totally concentrates either in the suppression of viral particles or reduction in the severity of related complications. Papaya and apple both comprised of phytochemicals that have potential antiviral activities but lemon was only found useful in dealing with secondary complication issues. All of these three plants have significant antioxidant activities which might be helpful in reducing the indirect oxidant effects of this virus on different human tissues. After dengue infection the best approach seems to be the improvement of patients immune response, especially the platelets count in body. Papaya and apple both have been reported for their ameliorating effects on immune system. On the basis of reviewed literature it can be concluded that both papaya and apple have their potential use in the treatment of dengue. There is future need of clinical studies to deeply investigate the phytochemistry of papaya and apple to identify their best possible use in the treatment of dengue fever. In a developing country like Pakistan with weak health care system the use of medicinal plant (such as apple and papaya) should be promoted as cheaper and easily available alternate medicine source to deal with epidemic diseases like dengue.
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