Background Neuroinflammation has been identified to be the key player in most neurodegenerative diseases. If neuroinflammation is left to be unresolved, chronic neuroinflammation will be establish. Such situation is due to the overly-activated microglia which have the tendency to secrete an abundance amount of pro-inflammatory cytokines into the neuron microenvironment. The abundance of pro-inflammatory cytokines will later cause toxic and death to neurons. Toll-like receptor 4 (TLR4)/MD-2 complex found on the cell surface of microglia is responsible for the attachment of LPS and activation of nuclear factor-κB (NF-κB) downstream signalling pathway. Albeit vitexin has been shown to possess anti-inflammatory property, however, little is known on its ability to bind at the binding site of TLR4/MD-2 complex of microglia as well as to be an antagonist for LPS. Results The present study reveals that both vitexin and donepezil are able to bind at the close proximity of LPS binding site located at the TLR4/MD-2 complex with the binding energy of − 4.35 and − 9.14 kcal/mol, respectively. During molecular dynamic simulations, both vitexin and donepezil formed stable complex with TLR4/MD-2 throughout the 100 ns time length with the root mean square deviation (RMSD) values of 2.5 Å and 4.0 Å, respectively. The root mean square fluctuation (RMSF) reveals that both compounds are stable. Interestingly, the radius of gyration (rGyr) for donepezil shows notable fluctuations when compare with vitexin. The MM-GBSA results showed that vitexin has higher binding energy in comparison with donepezil. Conclusions Taken together, the findings suggest that vitexin is able to bind at the binding site of TLR4/MD-2 complex with more stability than donepezil throughout the course of 100 ns simulation. Hence, vitexin has the potential to be an antagonist candidate for LPS.

BACKGROUND: Eventhough 6-Mercaptopurine act as a major drug for rheumatoid arthritis (RA) treatment, however, its toxicity become a limitation. Therefore, this current study investigated whether 6-hydroxy-2-mercaptopurine (6H2MP) and 6-thioguanine (6TG) compounds are purine nucleoside analogues as a potential treatment of RA. The objective was to evaluate the therapeutics effects, especially the anti-inflammatory potential of 6H2MP and 6TG in the lipopolysaccharides (LPS)-induced RAW264.7 cells and phorbol myristate acetate (PMA)-induced HIG-82 cells.METHODS: Macrophage cells (RAW264.7) and rabbit synoviocytes (HIG-82) cells were induced using LPS and PMA to evaluate the anti-inflammatory potential of 6H2MP and 6TG. The cytotoxicity assessment was done by using MTT assay, while enzyme-linked immunosorbent assay (ELISA) was used to determine the anti‑inflammatory potential, including tumour necrosis factor (TNF-α), interleukins (IL-1β, and IL-6).RESULTS: Upon LPS-induced, RAW 264.7 macrophages demonstrated that 6H2MP and 6TG could suppress the production of nitric oxide (NO) in vitro. The half-maximal inhibitory concentration (IC50) value of 6TG and 6H2MP were 10.73 and 13.31, respectively. Further studied in PMA-induced HIG-82 synovial fibroblast cells showed that 6H2MP and 6TG also suppressed the release of NO, Prostaglandin E2 (PGE2), and inflammatory cytokines such as TNF-α, IL-1β and IL-6. The 6TG is more effective to reduce inflammatory reactions compared to 6H2MP, by the lower dose needed compared to 6H2MP in all experiments except in PGE2.CONCLUSION: The inhibition of inflammatory mediators is an important mechanism by which 6TG and 6H2MP may alleviate pain and articular inflammation. These results indicated that 6H2MP and 6TG are effective candidates for ameliorating inflammatory-associated complications.KEYWORDS: anti-inflammatory, HIG-82 cells, RAW264.7 cells, 6-Thioguanine, 6-Hydroxy-2-Mercaptopurine

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