BackgroundCarica papaya leaves have been used for traditional treatment of dengue fever and have been reported to exhibit an immunomodulatory activity by affecting the level of cytokine production in vitro and in vivo. Due to the lack of adequate in vivo evidence in dengue disease model, the present study was initiated to screen and identify the cytokines affected by freeze-dried C. papaya leaf juice (FCPLJ) treatment in AG129 mice infected with DEN-2 dengue virus.MethodsThe AG129 mice were fed orally with FCPLJ for 3 consecutive days after 24 h of dengue virus inoculation. Plasma cytokines were screened by using ProcartaPlex immunoassay. The gene expression in the liver was analyzed by using RT2 Profiler PCR Array.ResultsThe results showed that FCPLJ treatment has increased the plasma CCL2/MCP-1 level during peak of viremia. Gene expression study has identified 8 inflammatory cytokine genes which were downregulated in the liver of infected AG129 mice treated with FCPLJ. The downregulated inflammatory cytokine genes were CCL6/MRP-1, CCL8/MCP-2, CCL12/MCP-5, CCL17/TARC, IL1R1, IL1RN/IL1Ra, NAMPT/PBEF1 and PF4/CXCL4.ConclusionThe findings indicated the possible immunomodulatory role of FCPLJ during dengue virus infection in AG129 mice.Electronic supplementary materialThe online version of this article (10.1186/s12906-019-2438-3) contains supplementary material, which is available to authorized users.

Eurycoma longifolia is one of the commonly consumed herbal preparations and its major chemical compound, eurycomanone, has been described to have antimalarial, antipyretic, aphrodisiac, and cytotoxic activities. Today, the consumption of E. longifolia is popular through the incorporation of its extract in food items, most frequently in drinks such as tea and coffee. In the current study, the characterisation of the physicochemical and pharmacokinetic (PK) attributes of eurycomanone were conducted via a series of in vitro and in vivo studies in rats and mice. The solubility and chemical stability of eurycomanone under the conditions of the gastrointestinal tract environment were determined. The permeability of eurycomanone was investigated by determining its distribution coefficient in aqueous and organic environments and its permeability using the parallel artificial membrane permeability assay system and Caco-2 cultured cells. Eurycomanone’s stability in plasma and its protein-binding ability were measured by using an equilibrium dialysis method. Its stability in liver microsomes across species (mice, rat, dog, monkey, and human) and rat liver hepatocytes was also investigated. Along with the PK evaluations of eurycomanone in mice and rats, the PK parameters for the Malaysian Standard (MS: 2409:201) standardised water extract of E. longifolia were also evaluated in rats. Both rodent models showed that eurycomanone in both the compound form and extract form had a half-life of 0.30 h. The differences in the bioavailability of eurycomanone in the compound form between the rats (11.8%) and mice (54.9%) suggests that the PK parameters cannot be directly extrapolated to humans. The results also suggest that eurycomanone is not readily absorbed across biological membranes. However, once absorbed, the compound is not easily metabolised (is stable), hence retaining its bioactive properties, which may be responsible for the various reported biological activities.

Coffee infused with the additive Eurycomalongifolia, also known as Tongkat ali (TA), has become widely available in the Malaysian market. Safety evaluations for consumption of the products have been called for due to the herbal addition. This study investigates the acute, subacute and chronic effects of a commercial TA coffee in Sprague Dawley rats when given in a single, repeated and prolonged dosage. The dosages of 0.005, 0.05, 0.30 and 2 g/kg body weight (BW) were used in the acute study and 0.14, 0.29 and 1 g/kg BW were used in the repeated dose studies. The in-life parameters measured were food and water intake, body weight and clinical observations. Blood were collected for hematology and clinical biochemistry analyses. All animals were subjected to full necropsies. Non-toxicity-related changes were observed in the food and water consumption parameters. Body weight showed normal increments and none of the animals had any clinical signs of toxicity. Microscopically assessed organ tissues did not reveal any abnormalities. There was significant decrease of platelet count in all the chronic study male treated groups. Significant elevation of renal profile parameters in both gender groups given 0.29 g/kg BW, along with liver and lipid profile elevation in some female groups of the chronic study were noted. No dose-dependent relationship was apparent in the dosage range tested, though these changes may suggest an initial safety indication to the TA coffee. The study concludes that the no observed adverse effect level (NOAEL) for this commercial TA coffee was 1 g/kg BW.

A combined polyherbal formulation containing tongkat ali (Eurycoma longifolia) and kacip fatimah (Labisia pumila) aqueous extracts was evaluated for its safety aspect. A repeated dose 28-day toxicity study using Wistar rats was conducted where the polyherbal formulation was administered at doses 125, 500 and 2000 mg/kg body weight to male and female treatment groups daily via oral gavage, with rats receiving only water as the control group. In-life parameters measured include monitoring of food and water consumption and clinical and functional observations. On day 29, blood was collected for haematological and biochemical analysis. The rats were necropsied and the organs were collected for histopathological examination. This study showed that the combined formulation did not induce any significant toxicity effect at any dose level in terms of morbidity, mortality, behaviour, functional observation, body weight, food and water consumption, whole blood haematology and serum biochemistry. However, there were some microscopic changes in the histopathological examinations of some organs given 2000 mg/kg body weight, which may suggest an early response to the polyherbal formulation. From this study, the no observed adverse effect level is estimated to be more than 500 mg/kg body weight but not exceeding 2000 mg/kg body weight. The observed effects at the highest dose indicate the need for further study of longer dosing duration.

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