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Review

Protective Mechanisms of Carica papaya Leaf Extract and Its Bioactive Compounds Against Dengue: Insights and Prospects

by
Tanvir Zaman Shoyshob
1,2,†,
Irin Amin Heya
1,†,
Nusrat Afrin
1,
Mansura Akter Enni
1,
Israt Jahan Asha
1,
Akhi Moni
1,
Md. Abdul Hannan
2 and
Md. Jamal Uddin
1,*
1
ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh
2
Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh 2200, Bangladesh
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Immuno 2024, 4(4), 629-645; https://doi.org/10.3390/immuno4040037
Submission received: 15 July 2024 / Revised: 31 October 2024 / Accepted: 10 December 2024 / Published: 12 December 2024
(This article belongs to the Special Issue Effects of Malnutrition of Immune Response)
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Abstract

Dengue fever is currently a major global issue, especially in tropical and subtropical countries. The absence of specific antiviral medications supports alternative dengue treatment strategies. South Asian countries have been using Carica papaya leaves as a traditional remedy for dengue for many years. Carica papaya possesses several biological features, including anti-inflammatory, antiviral, cancer-fighting, anti-diabetic, and antioxidant qualities. Additionally, numerous studies have demonstrated that bioactive compounds found in papaya leaf extracts, including carpaine, dehydrocarpaine I and II, chymopapain, and papain, significantly influence platelet counts, while phenolic compounds, such as chlorogenic acid, kaemferol, protocatechuic acid, quercetin, and 5,7-dimethoxycoumarin significantly inhibit viral replication in dengue patients, with negligible side effects. Carica papaya may be considered a viable pharmacological candidate with several targets for treating dengue. It has been shown to prevent infections, reduce oxidative stress, control cytokine storms and the immune system, lessen thrombocytopenia, and increase the body’s protein and hemoglobin levels. This literature review highlights the pathophysiological mechanism of dengue, as well as the pharmacological action of Carica papaya, both of which combat this debilitating disease. Despite these findings, additional investigation, including clinical studies, is necessary to confirm the effectiveness and safety of papaya-based treatments. It is necessary to address issues like standardizing papaya extracts, figuring out the best dosages, and assessing any drug interactions.

1. Introduction

Dengue fever is a viral disease that can be transmitted to millions of individuals via infected mosquito bites. As reported by the World Health Organization, dengue is widespread in over 100 countries situated in tropical and subtropical regions globally [1]. The global prevalence of dengue fever has increased in recent decades, with an estimated 390 million dengue infections occurring annually [2]. Dengue is one of the main contributors to severe illness and economic burden, especially in the eastern south part of Asia and the Indian subcontinent [1]. Although dengue fever is widespread in Bangladesh, the present dengue surge shows an abrupt spike compared to previous years. A total of 69,483 dengue cases were confirmed and 327 deaths were associated with the disease from 1 January to 7 August 2023, according to the Bangladeshi Ministry of Health and Family Welfare [3].
Dengue fever can be caused by four different types of viruses (DENV1 to DENV4), which are primarily transmitted via infected female Aedes mosquito bites [4,5]. Dengue illness takes 4–7 days to incubate [1,6]. From asymptomatic or mild fever to severe forms such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), dengue infection can trigger a variety of clinical symptoms. Augmented vascular permeability, bleeding, plasma leakage, and organ failure from thrombocytopenia are the indicators of severe dengue [1,6]. In most cases, the immune system eventually clears viruses. However, severe dengue can lead to life-threatening complications with thrombocytopenia symptoms if not managed properly [7]. Thrombocytopenia, or lower levels of platelet, is a typical hematological manifestation of dengue fever that can vary from moderate to serious, with severe thrombocytopenia being connected with an increased chance of bleeding complications [8].
Despite ongoing efforts to control dengue through vector control measures and vaccine development [9], no antiviral treatment exists for the disease. Consequently, researchers have been exploring alternative approaches to alleviate the severity of dengue symptoms and improve patient outcomes [7,10].
One such approach involves the utilization of medicinal plants and their extracts, which have been utilized for centuries in conventional therapies to treat various ailments. Among these, Carica papaya (Linn.), commonly called papaya, has gained attention for its probable therapeutic properties in managing dengue. Papaya leaves have gained attention for their potential health benefits, including cancer-fighting, antioxidant, anti-inflammatory, immune system support, liver protection, digestive health, and diabetes management activities [11,12].
Papaya leaves in particular have been investigated for their effects on dengue patients due to their ability to raise platelets and alleviate symptoms. Papaya leaf extract has been traditionally used in some tropical regions, such as India and Malaysia, to help raise platelet counts in dengue patients [13,14]. It is believed that compounds in papaya leaves such as papain, chymopapain, and carpaine may contribute to the increase in platelets [15,16,17]. Papaya leaf extract has also exhibited antiviral activities against dengue [18]. The phenolic compounds of papaya leaf extract (chlorogenic acid, kaemferol, protocatechuic acid, quercetin, and 5,7-dimethoxycoumarin) restricted viral replication of DENV [19].
This review will provide an in-depth exploration of the existing scientific literature on the effects of Carica papaya leaf extract on dengue, including both in vitro and in vivo research. By examining the biochemical constituents of papaya leaves, the mechanism of action, and the clinical outcomes associated with their use, we aim to shed light on the potential role of Carica papaya leaf in terms of treatment for dengue.

2. Methods

The literature was collected from published online databases and homepages that included various published data, reviews, and research findings. The protective mechanisms of Carica papaya against dengue were extracted using databases such as Google Scholar, Google, and PubMed, using the keywords “dengue infection”, “bioactivated compound” and “Carica papaya on dengue disease”, or “extract” in all fields. Adobe Illustrator was used to create every figure.

3. Pathophysiological Mechanisms of Dengue

The progression and severity of DENV infection are attributed to intricate interactions among the host genes, virus, and the immune response of the host [20]. The pathophysiological spectrum of DENV includes mild febrile disease (dengue fever) and asymptomatic infection, as well as more severe manifestations encompassing dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [21]. The majority of research has focused on immune response markers of critical dengue infections, such as interleukins (IL-7, IL-8, IL-10), tumor growth factor-ß, tumor necrosis factor -α (TNF- α), interferon- γ (IFN-γ), etc. [22].
The main targets of DENV infection and replication are lymphocytes, macrophages, and monocytes [23]. According to a recent study, the DENV NS1 antigen disrupts the stability of the monolayer of endothelial cells within blood arteries through activation of toll-like receptor 4 by triggering human peripheral blood mononuclear cells and macrophages. Pro-inflammatory cytokines released by NS1-mediated immune cells lead to hyperpermeability of endothelial cells and to plasma leakage [24]. DENV can inhibit type 1 IFN response and pattern recognition receptor signaling by targeting nucleotide-binding oligomerization domain (NOD)-like receptors, retinoic acid-inducible gene-I (RIG-I), and toll-like receptors (TLRs) [25,26,27]. DENV may stimulate complement via the alternative pathway, targeting liver cells and stimulating inflammatory cytokines. This causes plasma leakage as well as fluid accumulation in the third space, which ends up in the DSS [28].
Again, upon entering the DENV, anti-DENV NS1 antibodies are produced and anti-NS1 antibodies bind to glycosylphosphatidylinositol-anchored NS1 proteins on the cell membranes, activating signal transduction mechanisms and tyrosine phosphorylating proteins in the process. The release of different inflammatory mediators can be induced by DENV NS1 antibodies in a nuclear factor kappa B-dependent way. IL-6, IL-8 and Monocyte chemoattractant protein-1 (MCP-1) are a few of them. Leukocyte transmigration is facilitated by MCP-1-mediated upregulation of intercellular adhesion molecule-1 expression, which eventually leads to cell damage and cell death [29,30,31].
Through the formation of aggregates involving endothelial cells or leukocytes, or directly through cross-reactive antibodies, substantial damage to platelets can take place. The primary cause of this damage is thought to be the molecular resemblance that exists between host blood clotting components, endothelial cells, platelets, and virus proteins such as E, NS1, and prM [32,33]. Coagulation deficits, macrophage activation, platelet dysfunction, and endothelial cell death can be triggered by antibodies generated against these virus proteins that are cross-reactive [34]. Furthermore, immunoglobulin M antibodies generated against NS1 viral proteins can lead to peripheral platelet death as well as hindering platelet aggregation [29,34,35].
The body produces antibodies after contracting a first infection with a DENV serotype; such antibodies can neutralize a subsequent infection with the same variant. However, a secondary heterotypic infection could result in a worsening of the condition. Although they can attach to the virus, the antibodies produced during the initial infection are unable to neutralize it. These cross-reactive antibodies generate contagious virus–antibody complexes that can attach to and move into cells that have crystallizable fragment (Fcγ)-receptors, which include dendritic cells, monocytes, and macrophages, increasing viral output and viral loads [36]. Antibody-dependent augmentation is the term for the phenomenon that happens when antibodies produced in response to a previous heterotypic infection attach to the viral proteins but are unable to counteract a subsequent infection of a different subtype [37]. Afterward, cells phagocytose the virus–antibody pairing through Fcγ receptors, leading to elevated viremia and disease due to the upregulation of platelet destruction [38,39].
In DHF or DSS, immunological mediators, and cytokines such as IL-1, IL-2 and IL-10, IFN-γ and IFN-α, TNF-α, chemokine (C–C motif) ligand 2, vascular endothelial growth factor, and C-X-C Motif Chemokine Ligand 10, are elevated compared to mild dengue fever. Also, the cytokine storm phenomenon is produced mostly by increased Th2 cell activation in comparison to Th1 cell activation [40,41,42,43,44,45,46]. IL-10 overproduction blocks IFN signaling, resulting in increased DENV replication and virus titers in severe dengue infections in DHF [47]. These severe versions are marked by increased vascular permeability, platelet dysfunction, and bleeding tendencies.
DENV-1 triggers apoptosis by activating the transcription factor NF-κB and exerting stress on the PrM and C proteins, which affect mitochondria, and the p53 protein in DENV-1 has a role in inducing apoptosis [48]. In DENV-2, the Caspase-3 protein is activated through another protein called XAF-1, which leads to apoptosis [49]. It can also activate the “Intrinsic Apoptotic Pathway” by activating the Caspase-3 and Caspase-9 proteins [50,51,52]. Along with caspase 3 and in addition to caspase 9 activation, it causes mitochondrial depolarization in platelet cells, which may contribute to thrombocytopenia [53]. Additionally, DENV-2 affects a protein called p53 and reduces another protein called Bcl-2, both of which are related to the control of apoptosis [54].
Additionally, DENV employs the NS2B3 protease complex to specifically target nuclear factor erythroid 2-related factor 2, resulting in a gradual elevation of oxidative stress, inflammation, and cell death within infected cells [54]. The mannose-binding lectin (MBL) pathway provides a neutralizing defense against DENV. MBL attaches to surfaces that contain mannose glycans, recognizing the DENV surface and triggering bacterial cell lysis by activating the complement cascade, thereby inducing inflammation [55,56]. These are summarized in Figure 1.

4. Pharmacological Effects of Papaya Against Dengue

The pharmacological potential of papaya leaves extract against some plausible factors such as oxidative stress, cytokine storm and interferons, immune cells, microRNA and exosomes, complement activation, platelets and thrombocytopenia, endothelial cell dysfunction, and other pathologies responsible for the dengue infection, as shown in (Figure 2) and (Table 1 and Table 2), are summarized in this section.

4.1. Oxidative Stress

Oxidative stress arises because of variations in the amount of oxidants or reactive oxygen species (ROS), encompassing hydrogen peroxide (H2O2), hydroxyl radicals (HO), and superoxide anions (O2−). Oxidative stress results from a discrepancy between oxidants and antioxidants that disrupts redox equilibrium [72]. Excessive ROS production intensifies this imbalance, which adversely affects the pathogen as well as the host [73]. For example, while viral components are targeted, host cell damage is caused by ROS. During the period of viral infection, the immunological system of the host uses phagocytic cells to engulf the virus and releases cytokines TNF and IL-1 that produce ROS; this process contributes to mutations and produces a virulent virus [74]. Virus replication further amplifies ROS production by disrupting host compartmentalization, resulting in oxidative stress [75]. At the time of DENV infection, the unbalanced ratio of oxidants to antioxidants disrupts homeostasis, leading to serious illness [76]. Numerous studies have confirmed the antioxidative properties of Carica papaya in protecting against cellular damage. Carica papaya contains alkaloids such as carpain and nicotine, flavonols, tannins, and terpenes as well as proteolytic enzymes such as papain. Phenolic compounds offer protection against free radicals, while flavonoids exhibit antioxidant activity, thereby reducing oxidative stress within cells [76,77].

4.2. Cytokine Storm and Interferons

Cytokine storm is a type of physiological reaction that is observed in both humans and animals. It is caused by the innate immune response triggering an uncontrolled release of an excessive amount of pro-inflammatory signaling molecules known as cytokines. While cytokines are essential components of the body’s immune response to infection, their unanticipated large-scale release can lead to multiple-organ failure and even death [78]. IFNs represent a prominent class of cytokines, serving as signaling proteins produced and released by host cells upon encountering various viruses. Typically, IFNs are released by a viral-infected cell, causing neighboring cells to enhance their antiviral defenses [79]. Fruits and vegetables hold therapeutic potential due to their ability to mitigate inflammation by suppressing cytokines [80]. Moreover, they are associated with minimal known adverse effects, and being whole foods, they may have additive along with synergistic benefits. Consumption of Carica papaya may trigger a Treg (regulatory T cells)-mediated anti-inflammatory reaction, presenting promise in reducing inflammatory ailments [81]. Freeze-dried Carica papaya leaf juice reduced cytokine production in DENV-2-induced AG129 mice by downregulating GM-CSF, GRO-alpha (chemokine), IL-6, MCP-1 (chemokine), Macrophage inflammatory protein-1 beta (chemokine), IL-1 beta, IFN-γ, TNF-α and Chemokine (C-C motif) ligand 6/multidrug resistance-associated protein 1 (CCL6/MRP-1), CCL8/MCP-2, CCL12/MCP-5, CCL17/Thymus and activation-regulated chemokine, IL-1 receptor type, IL-1 receptor antagonist, Nicotinamide phosphoribosyl transferase/pre-b-cell colony-enhancing factor 1, PF4/CXCL4 genes which encodes cytokines [6,58]. A study showed that the standardized Carica papaya leaf aqueous extract in Cyclophosphamide-induced thrombocytopenic rats significantly inhibited the production of TNF-α [61]. Carica papaya mature leaf concentrate downregulates the cytokines IFNγ, IL-6, and TNF-α in Wistar rats [62].

4.3. Immune Cell Infiltration

Immune cells, including both innate and adaptive components, play a significant role in protecting the body from invasive pathogens with their wide spectrum of functions. Among the most common immune cells are lymphocytes (including B cells, T cells, and NK cells), macrophages/monocytes, and neutrophils, all of which belong to the category of white blood cells. Clinical studies showed that papaya leaf juice can lead to a rise in white blood cell (WBC) counts within 24 h [82]. Carica papaya leaf juice’s probable immunomodulatory effects were observed in mice with AG129 infection, where there was an increase in both total WBC and neutrophil counts [58]. An experiment that mimicked the administration of mature leaf concentrate of Carica papaya by mouth against hydroxyurea-induced thrombocytopenic mice effectively increased WBC and red blood cells (RBCs) [59]. A study showed that the oral administration of standardized Carica papaya leaf aqueous extract in cyclophosphamide (CP)-induced thrombocytopenic rats increased both whole and differential leucocyte counts [61]. When supplied orally, the mature leaf concentrate is considered safe, exhibiting non-toxicity and oral activity, while regulating the immunological response efficiently. Also, the mature leaf concentrate’s impact on the ex vivo growth of bone marrow cells and splenocytes, and the in vitro phagocytotic activity of peritoneal macrophages, was evaluated [62].

4.4. Platelets and Thrombocytopenia

A condition known as thrombocytopenia is marked by decreased formation of platelets in the bone marrow, often resulting in lower-than-normal platelet counts. This condition is frequently multifactorial in nature. Thrombocytopenia possesses several established mechanisms, such as hematological malignancies, aplastic anemia, an immune system malfunction, and loss by splenic destruction [83]. There are very few scientific reports published discussing Carica papaya leaf extract’s impact on platelet number [84]. A study showed that mice administered Carica papaya leaf extract exhibited a notable increase in platelet as well as RBC counts with a dosage of 2 g/kg and suggested that the leaf extract of Carica papaya had the potential to enhance hematopoiesis and thrombopoiesis [57]. The study of hydroxyurea-induced thrombocytopenic Wistar rats reiterated that the concentrate of mature leaf, irrespective of whether it was obtained from mature or immature leaves of Carica papaya, had the potential for further investigation to treat thrombocytopenia. For the very first time, this study scientifically claimed that concentrate prepared by the mature leaves of Carica papaya was safe for three days and that it was orally active, efficiently increasing platelets [59]. The same results were shown in Wistar rats, in which counts of rat platelets were notably increased by oral gavage of the mature leaf concentrate [62]. In CP-induced thrombocytopenic rats, it is proved that Carica papaya can impede the destruction of platelets in the bloodstream, consequently prolonging the lifespan of platelets in circulation [60]. Studies on herbal medicines to increase platelets are consistently increasing. One such study revealed that Carica papaya showed the highest potential in platelet augmentation [63]. According to several studies, Carica papaya leaves contain carpaine, flavonoids, and phenolic acids which potentially enhance animal platelet counts [65,66]. The juice of the mature leaf of Carica papaya from Sri Lankan wild type cultivars has been shown to stimulate megakaryocytes and increase platelet counts in thrombocytopenic rats through the modulation of thrombopoietic cytokines, including thrombopoietin [67].

5. Nutrition and Bioactive Compound of Papaya Against Dengue

Infections of dengue can accelerate platelet destruction, which in turn causes thrombocytopenia and can result in mucocutaneous bleeding. These infections cause a decrease in platelet count [12,85]. It was suggested that the nutritional status of individuals is associated with DENV infection [86].
Papaya extract alleviates dengue thrombocytopenia due to membrane-stabilizing properties of flavonoids and phenolic chemicals, which repress viral assembly protease, increasing the white blood cell and platelet count [73,74,87]. When the fresh extract of Carica papaya leaf (0.2 mL) per mouse, was used for 21 days, there was a substantial increase in platelet count, which was almost four times higher on day 21 (11.3 × 105/mL), and at the final point of treatment, the RBC count of test group increased from 6 × 106/mL to 9 × 106/mL [12]. Papaya leaf extract is a potent antimicrobial and antioxidant agent due to its high content of phenolic and non-phenolic compounds [15]. The functional bioactive elements in papaya leaves can increase the blood’s total antioxidant capability. Papaya leaves contain various chemical compounds, including alkaloids such as carpaine, flavonoids, various glycosides, phenols, saponins, tannins, and terpenoids [76,88,89,90]. It has been determined that papain extracted from papaya leaves can stop immune-mediated platelet degradation [91]. Carpaine, one of the most vital and potent bioactive substances present in papaya leaves, could sustain platelet counts without acute toxicity [92]. In another study, various phytochemicals including 15-tetracosenoic acid, decylene, farnesyl cyanide, heneicosanoic acid, hexadecanoic acid, methyl behenate, methyl erucate, methyl heptacosanoate, myristic acid, oleic acid, palmitic acid, stearic acid, trans-13-docosenoic acid, and trans-geranylacetone were identified in papaya leaf extract using n-hexane and methanol as solvents [93]. Using the LLC-MK2 cell line, the leaf chloroform extract showed inhibitory activities against DENV2 with a selectivity index value of ±>1 [85]. Nine compounds, 1-Hydroxy-2-propanone, 2-methyl-propanoic acid, Baicalein, 2-methyl-butanoic acid, Epigallocatechin, Fisetin, Genistein, Catechin, and protocatechuic acid, were found to inhibit DENV NS2B, NS3 and NS5 proteins, after in vivo studies were conducted on these compounds [94]. Another in silico study found that papaya leaf extracts, including quercetin, kaempferol, and chlorogenic acid, have potential inhibitory properties against the NS3 as well as NS5 proteins of DENV2 [95]. In molecular docking research, coumarin was discovered to block the DENV2 NS2B/NS3 protease found in DENV [96]. The vitamins, minerals (including manganese, copper, cadmium, iron, cobalt, and zinc), and amino acids present in papaya leaves are very beneficial for boosting the body’s overall levels of hemoglobin, proteins, and immunity [93,97].
Several studies reported that the severity of dengue is lower in malnourished people. Malnourished children have lower circulating leptin concentrations, which are linked to the production of TNF-α via the TLR 7/8 pathway [98]. However, overweight people have a higher chance of developing dengue complications. Patients with obesity have a higher chance of developing dengue complications, since they have more adipose tissue, which increases the production of IL-6, IL-8, and TNF-α, potentially causing plasma leakage [99,100]. According to a different study, obese dengue patients exhibited higher levels of leukocytes, creatinine, and lactate dehydrogenase (LDH) and lower platelet counts compared to non-obese individuals [101]. The amount of total serum cholesterol was found to be lower in dengue-infected patients, possibly as a result of liver damage. Lower total cholesterol and LDL levels are correlated with severe dengue [102]. Obesity was found to be an indication of severe adverse dengue infection outcomes in another investigation [103]. Undernourishment provided defense against the development of severe dengue [104,105]. Another study, however, found no connection between dengue and nutritional status and suggested that undernutrition may cause a weakened immune response, which slows the spread of symptomatic infections [106].
Carica papaya contains bioactive compounds and nutrients which is beneficial to malnourished individuals. These nutrients include carbohydrates, lipids, proteins, vitamins, and minerals. Though the amount of protein is low in Carica papaya leaves, it can be used as a supplement for malnourished children [107,108]. Vitamins A, C, E, and beta-carotene in Carica papaya show antioxidant, anti-inflammatory, and immunological properties, and vitamins B1 and B2 are involved in metabolism and in producing energy from carbohydrates, fats, and proteins [107,109,110]. A study showed that vitamin E treatment decreased thrombocytopenia in dengue patients [111]. Carica papaya contains minerals essential to the immunological response, glucose transportation, cell function, and other processes. These minerals, including calcium, iron, magnesium, potassium, phosphorus, and sodium, might help the body manage dengue by boosting immunity [107,112]. Research hypothesized that Carica papaya leaves have the potential to treat obesity, which exacerbates dengue [113]. In addition, the protective effects of papaya leaf extract against dengue pathogenesis in cell models have been shown in Table 2.

6. Clinical Trials of Carica papaya Leaf Extract in Dengue Patients

Since primitive times, ordinary plant species have been part of the invention and promotion of significant medicines in most therapeutic categories [114]. Besides Carica papaya’s use as a fruit, its leaves have been used in making traditional medicines and are mostly used to treat dengue fever. Dengue virus is susceptible to binding with platelets and its clearance, which is the prerequisite of having thrombocytopenia ≤100 × 103 /mL, a critical phase of the illness [115]. A randomized open-label study of 285 pediatric subjects was evaluated to determine the safety of extract from the leaf of Carica papaya for treating dengue fever-related thrombocytopenia. Leaf extract syrup from Carica papaya was administered to children; those aged 1 to 5 years received 275 mg three times a day, while those older than 5 years were given 550 mg three separate times for five days. The primary outcome that was assessed was a spike in the number of platelets, starting on day three. The average platelet count was 89,739.31 on day three, 120,788.96 on day four, and 168,922.75, on day five. At the same time, the accessory outcome assessment, average increasing RBC count, as well as the WBC were analyzed. It was noted that the average rise in RBC count was cabalistic statistically on day five, with a mean of 3.89 × 106 /µL, and day 3, day 4, and day 5 saw statistically significant increases in the average WBC count, with mean values of 4.74 × 103 /µL, 5.42 × 103 /µL, and 6.65 × 103 /µL, respectively [7]. A study reported the safety and efficacy of Carica papaya leaf extract in increasing the platelet counts of several dengue patients, where 51 dengue patients took 11 mg Carica papaya leaf extract tablets three times on five consecutive days. The group with Carica papaya leaf extract treatment showed a more rapid growth in platelet counts [16]. Various case reports have shown that the administration of Carica papaya leaf extract in different dosages increases platelet count in dengue in humans. A study reported that 25 mL of watery Carica papaya leaf extract administered to a dengue patient twice a day for five successive days caused their platelet count to rise from 55 × 103/ µL to 168 × 103/ µL [82]. Another case series of 80 dengue patients narrated that 12 capsules (550 mg each of Carica papaya capsule containing 70% ethanol extract of Carica papaya leaves) were administered twice daily for 2–7 days to dengue fever patients. The results showed that Carica papaya capsules significantly increased platelet count, maintained the stability of hematocrit at the normal level, and shortened hospitalization in dengue fever patients [116]. An open-label randomized controlled trial involving 228 patients who received standard treatment for dengue investigated the effect of juice from 50 g of fresh Carica papaya leaf daily for three days continuously and showed a significant enhancement in platelet count at 40 h and 48 h in the intervention group compared to standard of care alone [117]. These outcomes of Carica papaya leaf extract against dengue in clinical trials are summarized in Table 3.

7. Conclusions and Future Prospects

The current study shows that Carica papaya leaf extract mediates several benefits related to dengue prevention by boosting the platelet count, lowering oxidative stress, and regulating the immunological response in preclinical experimental models. By lowering the amount of intracellular ROS, these results highlight the extraordinary potential of Carica papaya leaf extract. According to some studies, Carica papaya leaf extract reduces TNF and IL-1 levels in mice, which decreases the amount of oxidative stress caused by ROS. The results of this study offer more proof in favor of papaya’s possible therapeutic use in the control of cytokine storm by reducing the production of chemokines and other cytokines. Dengue fever reduces the number of immunological cells in the body. The administration of Carica papaya leaf extract increased the activity of immune cells, and the number of neutrophils, WBC, and RBC. The study also found that Carica papaya leaf extract prevents platelet breakdown, which is important in thrombocytopenia, but instead enhances platelet count. The phenolic compounds of Carica papaya leaf extracts have inhibitory properties against DENV. Additionally, Carica papaya leaf extract protects dengue patients by increasing platelet count in some clinical trials. Because of its wide-ranging effects, Carica papaya leaf extract is a potentially useful candidate for further study for treating dengue disease.
Carica papaya leaf extract also demonstrates some limits. It has been observed that Carica papaya leaf extract shows adverse effects such as allergic reactions, interactions with medications, and interference with the body’s ability to absorb essential nutrients. The fact that larger doses of Carica papaya leaf extract are required to achieve the desired therapeutic effects may hinder its efficacy. Studies showed that adults can safely consume Carica papaya leaves for a brief amount of time, while pregnant women and those with liver impairment should exercise caution [118]. The extract of Carica papaya leaves shows interesting potential in inhibiting thrombocytopenia, as found in different preclinical models. The lack of comprehensive clinical trials that accurately evaluate Carica papaya leaf extract’s efficacy in treating dengue infections represents another limitation. Even though several preclinical studies have demonstrated its antiviral, antioxidant, and immunomodulatory properties, further study is required to validate these results in human subjects. Additionally, the adulteration of botanical extracts is a serious issue because it significantly affects human health. Adulterated Carica papaya leaf extract can cause ineffective treatment and adverse reactions. Strict quality controls, including sophisticated testing methods, should be implemented to address the issue of adulteration. Research revealed that the flavonoids present in Carica papaya leaf extract have a high excretion time [119,120] and further study is needed to provide us with a more detailed understanding of these mechanisms. High-quality and standardized extracts must be used to increase their efficacy, safety, and bioavailability for human usage [120]. Despite these constraints, prospects for the future suggest that Carica papaya leaf extract may be useful in the fight against dengue. Administering Carica papaya leaf extract in combination with other substances or drugs may increase its efficacy. Synergistic effects have been observed when Carica papaya is used in conjunction with standard medications or other naturally occurring substances that have antiviral capabilities [117]. The implementation of this strategy may increase the effectiveness of conventional antiviral drugs while reducing dosage and side effects. Further research, including carefully designed clinical studies, is needed to fully understand the effectiveness as well as safety of the medication against dengue infections.

Author Contributions

This was a collaborative work among all the authors. M.J.U. outlined the manuscript. The first draft of the manuscript was written by T.Z.S., I.A.H., N.A., M.A.E. and I.J.A. The scientific information included in the manuscript was examined by A.M., M.A.H. and M.J.U. All authors have read and agreed to the published version of the manuscript.

Funding

No specific grant was obtained for this research from governmental, private, or nonprofit funding organizations.

Conflicts of Interest

The authors declare that they have no competing interests.

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Figure 1. The pathophysiological mechanism of dengue. Infected cells and platelets are destroyed by DENV-induced immune system activation (anti-NS1 antibody, IgM, cross-reactive antibodies, Caspase-3, and Caspase-9). Apoptosis results from blood artery damage caused by TLR4 and macrophage activation. Macrophages and monocytes that possess the Fcγ receptors’ phagocytose virus–antibody complexes, which are created by cross-reactive antibodies, cause viremia, which leads to thrombocytopenia. The NS2B3 protease complex induces cell death by activating Nrf2, which causes both inflammation and oxidative stress. DENV-activated MBL pathway-mediated cell death is caused by inflammation. DENV activates P53 genes and suppresses BCL2 genes, leading to cell death. Activation of NF-κB by DENV causes ER stress, which leads to cell death. Inflammatory cytokines released by DENV-infected liver cells and DHF cause DSS, which increases the number of Th2 cells. Th2 cell-mediated cytokine storm release inhibits IFN response. DENV restricts IFN response and, by targeting PRRs RIG I, also inhibits NOD-like receptors, TLRs and NF-κB. Inhibition of IFN response upregulates viral replication. DHF—dengue hemorrhagic fever; DSS—dengue shock syndrome; ER—endoplasmic reticulum; ICAM-1—intercellular adhesion molecule 1; IFN—interferon; IgM: immunoglobulin M; MBL—mannose-binding lectin; NF-κB—nuclear factor kappa B; NOD—nucleotide-binding oligomerization domain; Nrf2—nuclear factor erythroid 2-related factor 2; PBMCs—peripheral blood mononuclear cells; PRR—pattern recognition receptor; RIG I—retinoic acid-inducible gene-I; Th2—type 2 helper T cell; TLR4—toll-like receptor 4; TLRs—toll-like receptors.
Figure 1. The pathophysiological mechanism of dengue. Infected cells and platelets are destroyed by DENV-induced immune system activation (anti-NS1 antibody, IgM, cross-reactive antibodies, Caspase-3, and Caspase-9). Apoptosis results from blood artery damage caused by TLR4 and macrophage activation. Macrophages and monocytes that possess the Fcγ receptors’ phagocytose virus–antibody complexes, which are created by cross-reactive antibodies, cause viremia, which leads to thrombocytopenia. The NS2B3 protease complex induces cell death by activating Nrf2, which causes both inflammation and oxidative stress. DENV-activated MBL pathway-mediated cell death is caused by inflammation. DENV activates P53 genes and suppresses BCL2 genes, leading to cell death. Activation of NF-κB by DENV causes ER stress, which leads to cell death. Inflammatory cytokines released by DENV-infected liver cells and DHF cause DSS, which increases the number of Th2 cells. Th2 cell-mediated cytokine storm release inhibits IFN response. DENV restricts IFN response and, by targeting PRRs RIG I, also inhibits NOD-like receptors, TLRs and NF-κB. Inhibition of IFN response upregulates viral replication. DHF—dengue hemorrhagic fever; DSS—dengue shock syndrome; ER—endoplasmic reticulum; ICAM-1—intercellular adhesion molecule 1; IFN—interferon; IgM: immunoglobulin M; MBL—mannose-binding lectin; NF-κB—nuclear factor kappa B; NOD—nucleotide-binding oligomerization domain; Nrf2—nuclear factor erythroid 2-related factor 2; PBMCs—peripheral blood mononuclear cells; PRR—pattern recognition receptor; RIG I—retinoic acid-inducible gene-I; Th2—type 2 helper T cell; TLR4—toll-like receptor 4; TLRs—toll-like receptors.
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Figure 2. Protective effects of papaya against dengue pathophysiology. Papaya inhibits the release of chemokines, cytokines, viral assembly protease, DENV2, and IgM-induced platelet destruction. In order to inhibit thrombocytopenia, papaya upregulates WBC, RBC, and TPO-mediated platelet counts. Increasing the hemoglobin, protein, and antioxidant capability of blood papaya inhibits dengue infection. DENV2—dengue virus type 2; RBC—red blood cell; TPO—thrombopoietin; WBC—white blood cell.
Figure 2. Protective effects of papaya against dengue pathophysiology. Papaya inhibits the release of chemokines, cytokines, viral assembly protease, DENV2, and IgM-induced platelet destruction. In order to inhibit thrombocytopenia, papaya upregulates WBC, RBC, and TPO-mediated platelet counts. Increasing the hemoglobin, protein, and antioxidant capability of blood papaya inhibits dengue infection. DENV2—dengue virus type 2; RBC—red blood cell; TPO—thrombopoietin; WBC—white blood cell.
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Table 1. Summary of the protective effects of papaya extract against dengue pathogenesis in animal models.
Table 1. Summary of the protective effects of papaya extract against dengue pathogenesis in animal models.
Experimental
Models		Dose, Time, and Route of Papaya Extract TreatmentMajor Research
Outcomes		Alterations in Molecular MarkersRef.
DENV-2 induced AG129 MiceFCPLJ
500 and 1000 mg/kg BW for 3 days
Orally		Modulating the release of certain cytokines↑ MCP-1, G-CSF, IL-6, and TNF-α,
CCL2/ MCP-1,
↓ CCL6/MRP-1, CCL8/MCP-2, CCL12/MCP-5, CCL17/TARC, IL1R1, IL1RN/IL1Ra, NAMPT/PBEF1, PF4/CXCL4, CCL12/MCP-5, IL1R1		[6]
ATCC VR-induced AG129 MiceFCPLJ
1000 mg/kg BW for 3 days
Orally		Affected the regulation of genes endothelial permeability regulation↑ CCL2,
↓ ITGB3, ICAM1, FN1		[6]
MouseCPLE,
0.2 mL/2 g BW/day for 7 days
Orally		Increase platelet count and RBC↑ Platelet, RBC,[57]
DENV-2 induced AG129 MiceFCPLJ
500 and 1000 mg/kg BW for 3 days
Orally		Augmentation of WBC, neutrophil, and anti-inflammatory activity↑ WBC, neutrophil
↓ GM-CSF, GRO-alpha, IL-6, MCP-1, MIP-1 beta, IL-1 beta, IFN-γ, TNF-α		[58]
Hydroxyurea-induced thrombocytopenic miceMLCC
0.72 mL/100 g for 3 days
Orally		Increase platelet, RBC, and WBC↑ Platelet, WBC, RBC
↓ Carrageenan induced edema, vascular permeability		[59]
Cyclophosphamide-induced thrombocytopenic ratCPLAE
400 and 800 mg/kg p.o.
15 days		Increase platelet levels and reduce clotting duration.↑ Platelet[60]
Cyclophosphamide-induced thrombocytopenic ratsSCPLE
50 and 150 mg/kg BW, p.o.
14 days		Reduce bleeding time and clotting time↑ PC, TLC, DLC, DTH
↓ TNF-α		[61]
Wistar ratsMLCC
0.18, 0.36 and 0.72 mL/100g BW for 3 days
Orally		Stimulate immunological cell proliferation, enhancement of phagocytic activity, and modulation of cytokine responses.↑ Platelet, WBC, BMC, PM, SC
↓ TNF-α, IL-6, IFNγ,		[62]
Anagrelide-induced Sprague Dawley ratsCPLE
0.2 mg/mL,1 mg/mL, for 10 days
Orally		Augmentation of platelet↑ Platelet[63]
Non-mouse-adapted NGC strain DEN-2-induced AG129 miceFCPLJ
500 and 100 mg/kg BW for 3 days
Orally		Morbidity decreasedDid not influence the levels of plasma NS1 and viral RNA.[64]
Carboplatin-induced thrombocytopenia in miceCPLJ
5 and 10 mL/kg for 21 days
Orally		Prevents fall in platelet count↑ Platelet[65]
Cyp-induced thrombocytopenic ratsCPLJ
200 and 400 mg/kg BW for 14 days
Orally		Boost platelet count and normalize clotting time.↑ Platelet, cMpl[66]
Hydroxyurea-induced thrombocytopenic Wistar ratsMLJCP
0.18, 0.36 and 0.72 mL/100 gm BW
For 3 days
Orally		Augmentation of platelet↓ TPO, PAF
↑ Platelet, IL-6		[67]
ATCC VR—non-adapted serotype 2 dengue virus New Guinea C strain; BMC—bone marrow cell; CCL2—chemokine (C–C motif) ligand 2; MCP-1—monocyte chemoattractant protein-1; CCL6/MRP-1: chemokine (C-C motif) ligand 6/multidrug resistance-associated protein 1; CCL8/MCP-2—chemokine (C-C motif) ligand 8/monocyte chemoattractant protein-2; CCL12/MCP-5—chemokine (C-C motif) ligand 12/monocyte chemoattractant protein-5; CCL17/TARC—chemokine (C-C motif) ligand 17/thymus and activation-regulated chemokine; cMpl—a member of the hematopoietin family; CPLE—Carica papaya leaf extract; CPLAE—Carica papaya leaf aqueous extract; Cyp—cyclophosphamide; DENV-2—dengue virus type 2; DLC—differential leucocyte count; DTH—delayed-type hypersensitivity; FCPLJ—freeze-dried Carica papaya leaf juice; FN1—fibronectin 1; GM-CSF—granulocyte–macrophage colony-stimulating factor; GRO-alpha—growth-regulated protein alpha; ICAM1—intercellular adhesion molecule 1; IFN-γ—interferon gamma; IL-1 beta—interleukin-1 beta; IL1RN/IL1Ra—Interleukin-1 receptor antagonist; IL1R1—Interleukin-1 receptor type; IL-6—interleukin-6; ITGB3—integrin beta 3; MCP-1—monocyte chemoattractant protein-1; MIP-1 beta—macrophage inflammatory protein-1 beta; MLCC—mature leaf concentrate of Carica papaya; MLJCP—mature leaf juice of Carica papaya; NAMPT/PBEF1—Nicotinamide phosphoribosyl transferase/pre-b-cell colony-enhancing factor 1; NGC strain DEN-2—New Guinea C strain dengue virus; p.o—per os—by mouth; PC—platelet count; PAF—platelet-activating factor; PF4/CXCL4—platelet factor 4/chemokine (c-x-c motif) ligand 4; PM—peritoneal macrophages; RBC—red blood cell; SC—splenocytes; SCPLE—standardized CPL aqueous extract; TPO—thrombopoietin; TLC—total leucocyte count; TNF-α—tumor necrosis factor alpha; WBC—white blood cell. ↑ indicates the upregulation and ↓ indicates the downregulation.
Table 2. Summary on the protective effects of papaya extract against dengue pathogenesis in cell models.
Table 2. Summary on the protective effects of papaya extract against dengue pathogenesis in cell models.
Experimental ModelsDose and Time of Papaya ExtractMajor Research OutcomesAlterations in Molecular Markers/Active IngredientsRef.
Vero CCL-81 cell(12.5, 25, 50 and 100 μg/mL) for 5 days at 37 °CCytotoxic effect, immunomodulatorDENV2 viral titer ↓, viral foci ↓[18]
PRP and PPP treated with CPLE10 µM ADP-induced 10 mL blood incubated with CPLE for 30 minReduction in platelet aggregation↓ Platelet aggregation[68]
CPLE-treated blood cells9.375, 18.75, 37.5, 75, 150 and 300 µg/mL for 20 min at 55 °CErythrocyte membrane-stabilizing potential; inhibition of hemolysis, antibiotics, antiviral, and
antitumor agents.		Hemolysis of erythrocytes ↓[69]
CPLE-treated ES cell2.5 g in 2.5 mL waterPlatelet propagation from ES cellPAR4 thrombin receptor-activating peptide AYPGFK, ↑ TPO.[70]
CPLE-treated LLC-MK2 cell line2 g in 100 mL DMSO for 5 daysCytotoxic effect; anti-DENV2 activityProtocatechuic acids, erythrocyte glutathione peroxidase, Th1 ↑[71]
ADP—adenosine diphosphate; AYPGFK—PAR4 thrombin receptor activating peptide; CPLE—Carica papaya leaf extract; DMSO—dimethyl sulfoxide; ES—embryonic stem; IL-3—interleukin-3; IL-6—interleukin-6; LLC-MK2—rhesus monkey kidney epithelial cells; PAR4—protease-activated receptor 4; PBMCs—peripheral blood leukocytes PPP—dengue-infected plasma; PRP—platelet-rich plasma; SCF—stem cell factor; SHED—human deciduous dental pulp stem cells; Th1—type 1 helper T cell; TPO—thrombopoietin; UPJ—unripe Carica papaya pulp juice. ↑ indicates the upregulation and ↓ indicates the downregulation.
Table 3. Summary of clinical trials of Carica papaya leaf extract in dengue patients.
Table 3. Summary of clinical trials of Carica papaya leaf extract in dengue patients.
Sl. NoNo. of
Subjects		Daily DoseFollow Up
Time		Alterations in Various ParametersRef.
1285275–550 mg syrup3 times; 5 days↑ Platelet, WBC, and RBC[7]
2511100 mg (1 tablet), leaf extract3 times; 5 days↑ Platelet[16]
31 male25 mL, aqueous leaf extractTwice daily; 5 days↑ PLT, WBC, and NEUT[82]
48013.2 gm of CPC12 capsules twice daily; 2–7 days↑ Platelet, ↓ Hematocrit[116]
522850 g, leaves juiceOnce daily; 3 days↑ Platelet[117]
PLT—platelets count; WBC—white blood cells; NEUT—neutrophils; CPC—Carica papaya leaf extract capsules; RBC—red blood cells. ↑ indicates the upregulation and ↓ indicates the downregulation.
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Shoyshob, T.Z.; Heya, I.A.; Afrin, N.; Enni, M.A.; Asha, I.J.; Moni, A.; Hannan, M.A.; Uddin, M.J. Protective Mechanisms of Carica papaya Leaf Extract and Its Bioactive Compounds Against Dengue: Insights and Prospects. Immuno 2024, 4, 629-645. https://doi.org/10.3390/immuno4040037

AMA Style

Shoyshob TZ, Heya IA, Afrin N, Enni MA, Asha IJ, Moni A, Hannan MA, Uddin MJ. Protective Mechanisms of Carica papaya Leaf Extract and Its Bioactive Compounds Against Dengue: Insights and Prospects. Immuno. 2024; 4(4):629-645. https://doi.org/10.3390/immuno4040037

Chicago/Turabian Style

Shoyshob, Tanvir Zaman, Irin Amin Heya, Nusrat Afrin, Mansura Akter Enni, Israt Jahan Asha, Akhi Moni, Md. Abdul Hannan, and Md. Jamal Uddin. 2024. "Protective Mechanisms of Carica papaya Leaf Extract and Its Bioactive Compounds Against Dengue: Insights and Prospects" Immuno 4, no. 4: 629-645. https://doi.org/10.3390/immuno4040037

APA Style

Shoyshob, T. Z., Heya, I. A., Afrin, N., Enni, M. A., Asha, I. J., Moni, A., Hannan, M. A., & Uddin, M. J. (2024). Protective Mechanisms of Carica papaya Leaf Extract and Its Bioactive Compounds Against Dengue: Insights and Prospects. Immuno, 4(4), 629-645. https://doi.org/10.3390/immuno4040037

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