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Fulltext Immunosuppressive effects of the standardized extract of Phyllanthus amarus on cellular immune responses in Wistar-Kyoto rats

Ilangkovan M, Jantan I, Mesaik MA, Bukhari SN

Drug Des Devel Ther, 2015;9:4917-30.
PMID: 26347462 DOI: 10.2147/DDDT.S88189

Phyllanthus amarus (family: Euphorbiaceae) is of immense interest due to its wide spectrum of biological activities. In the present study, the standardized 80% ethanol extract of P. amarus was investigated for its modulatory activity on various cellular immune parameters, including chemotaxis of neutrophils, engulfment of Escherichia coli by neutrophils, and Mac-1 expression, in leukocytes isolated from treated/nontreated Wistar-Kyoto rats. The detailed cell-mediated activity of P. amarus was also investigated, including analysis of the effects on T- and B-cell proliferation and CD4(+) and CD8(+) T-cell subsets in splenic mononuclear cells, and estimation of serum cytokine production by activated T-cells. The main components of the extract, phyllanthin, hypophyllanthin, corilagin, geraniin, ellagic acid, and gallic acid were identified and quantitatively analyzed in the extracts, using validated reversed-phase high-performance liquid chromatography (HPLC) methods. N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophils isolated from rats administered with the extract of P. amarus, at doses ranging from 100 to 400 mg/kg for 14 days, revealed a significant dose-dependent reduction in neutrophil migration (P<0.05). Similar patterns of inhibition were also observed in phagocytic activity and in fMLP-induced changes in expression of β2 integrin polymorphonuclear neutrophils. The results in P. amarus-treated rats also demonstrated a dose-dependent inhibition of both lipopolysaccharide-stimulated B-cell proliferation and concanavalin A-stimulated T-cell proliferation as compared with sensitized control. At a dose of 400 mg/kg (P<0.01), there was a significant decrease in the (%) expression of CD4(+) and CD8(+) in splenocytes and in serum cytokines of T helper (Th1) (IL-2 and IFN-γ) and Th2 (IL-4). In conclusion, P. amarus showed effective immunosuppressive activities in cellular immune response, by various immune regulatory mechanisms, and may be useful for improvement of immune-related disorders.
Inhibitory Effects of the Standardized Extract of Phyllanthus amarus on Cellular and Humoral Immune Responses in Balb/C Mice

Ilangkovan M, Jantan I, Mesaik MA, Bukhari SN

Phytother Res, 2016 Aug;30(8):1330-8.
PMID: 27137750 DOI: 10.1002/ptr.5633

Phyllanthus amarus has been shown to have strong inhibitory effects on phagocytic activity of human neutrophils and on cellular immune responses in Wistar-Kyoto rats. In this study, we investigated the effects of daily treatment of standardized extract of P. amarus at 50, 100 and 200 mg/kg for 14 days in Balb/C mice by measuring the myeloperoxidase activity (MPO), nitric oxide (NO) release, macrophage phagocytosis, swelling of footpad in delayed type hypersensitivity (DTH), and serum immunoglobulins, ceruloplasmin and lysozyme levels. Qualitative and quantitative analyses of the extract using validated reversed-phase HPLC methods identified phyllanthin, hypophyllanthin, corilagin and geraniin as the biomarkers. Significant dose-dependent inhibitions of MPO activity and NO release were observed in treated mice. The extract also inhibited E. coli phagocytic capacity of peritoneal macrophages of treated mice and inhibited the sheep red blood cells (sRBC)-induced swelling rate of mice paw in the DTH. There was also a significant decrease in non-specific humoral immunity including ceruloplasmin and lysozyme levels in the extract-fed groups as well as the release of serum level immunoglobulins. The strong inhibitory effects of the extract on the cellular and humoral immune responses suggest the potential of the plant to be developed as an effective immunosuppressive agent. Copyright © 2016 John Wiley & Sons, Ltd.
Suppressive Effects of the Standardized Extract of Phyllanthus amarus on Type II Collagen-induced Rheumatoid Arthritis in Sprague Dawley Rats

Alam J, Jantan I, Kumolosasi E, Nafiah MA, Mesaik MA

Curr Pharm Biotechnol, 2018;19(14):1156-1169.
PMID: 30539691 DOI: 10.2174/1389201020666181211124954

BACKGROUND: Standardized extract of Phyllanthus amarus has been shown to possess inhibitory effects on cellular and humoral immune responses in Wistar-Kyoto rats and Balb/c mice.
OBJECTIVE: In the present study, the standardized extract of P. amarus was investigated for its suppressive effects on type II collagen-induced rheumatoid arthritis (TCIA) in Sprague Dawley rats.
METHOD: The major components of the extracts, lignans and phenolic compounds were analysed by using a validated reversed phase HPLC and LC-MS/MS. A rheumatoid arthritis rat model was induced by administering a bovine type II collagen emulsion subcutaneously at the base of tail, on day 0 and 7 of the experiment. Effects of the extract on severity assessment, changes in the hind paw volume, bone mineral density, body weight and body temperature were measured. Concentrations of cytokines (TNF-α, IL-1β, IL-1α, IL-6) released, matrix metalloproteinases (MMP-1, MMP-3 MMP-9) and their inhibitor (TIMP-1), haematological and biochemical changes were also measured. ELISA was used to measure the cytokines and proteinases in the rat serum and synovial fluid according to manufacturer's instructions.
RESULTS: The extract dose-dependently modulated the progression in physical parameters (i.e. decrease in body weight, increase in body temperature, reduced hind paw volume, reduced the severity of arthritis), bone mineral density, haematological and biochemical perturbations, serum cytokines production and levels of matrix metalloproteinases and their inhibitor in the synovial fluid. Histopathological examination of the knee joint also revealed that the extract effectively reduced synovitis, pannus formation, bone resorption and cartilage destruction.
CONCLUSION: The results suggest that the oral administration of a standardized extract of P. amarus was able to suppress the humoral and cellular immune responses to type II collagen, resulting in the reduction of the development of TCIA in the rats.
Fulltext Immunosuppressive phenolic compounds from Hydnora abyssinica A. Braun

Koko WS, Mesaik MA, Ranjitt R, Galal M, Choudhary MI

BMC Complement Altern Med, 2015;15:400.
PMID: 26553149 DOI: 10.1186/s12906-015-0931-x

Hydnora abyssinica (HA) A. Braun is an endemic Sudanese medicinal plant traditionally used as anti-inflammatory and against many infectious diseases. However, it proved to be very rich in phenols and tannins, so the present study was undertaken to investigate the immunomodulatory potential of the whole plant ethanolic extract and its isolated compounds.
Synthetic indole Mannich bases: Their ability to modulate in vitro cellular immunity

Mesaik MA, Khan KM, Rahim F, Taha M, Haider SM, Perveen S, et al.

Bioorg Chem, 2015 Jun;60:118-22.
PMID: 26000491 DOI: 10.1016/j.bioorg.2015.05.003

The synthetic indole Mannich bases 1-13 have been investigated for their ability to modulate immune responses measured in vitro. These activities were based on monitoring their affects on T-lymphocyte proliferation, reactive oxygen species (ROS), IL (interleukin)-2, IL-4, and nitric oxide production. Compound 5 was found to be the most potent immunomodulator in this context. Four of the synthesized compounds, 5, 11, 12, and 13, have significant potent inhibitory effects on T-cell proliferation, IL-4, and nitric oxide production. However, none of the thirteen indole compounds exerted any activity against ROS production.
The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies

Khan KM, Mesaik MA, Abdalla OM, Rahim F, Soomro S, Halim SA, et al.

Bioorg Chem, 2016 Feb;64:21-8.
PMID: 26637945 DOI: 10.1016/j.bioorg.2015.11.004

Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti-bacterial, and anti-allergic activities. The objective of the present study was to evaluate effects of benzothiazole analogs (compounds 1-26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8-10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC50 ranging from 3.7 to 11.9 μM compared to that of the standard drug, prednisolone <1.5 μM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC50 values ranging between <4.0 and 12.8 μM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC50 values between <4.0 and 15.2 μM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 μg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P<0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC50 range of <4.0 to 40.3 μM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naïve T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases.