A new acyl derivative of sulfadimethoxine inhibits phagocyte oxidative burst and ameliorates inflammation in a mice model of zymosan-induced generalised inflammation.

Chronic inflammation and oxidative stress play a pivotal role in the pathophysiology of most challenging illnesses, including cancer, Alzheimer's, cardiovascular and autoimmune diseases. The present study aimed to investigate the anti-inflammatory potential of a new sulfadimethoxine derivative N-(4-(N-(2,6-dimethoxypyrimidin-4-yl) sulfamoyl) phenyl) dodecanamide (MHH-II-32). The compound was characterised by applying 1H-, 13C-NMR, EI-MS and HRFAB-MS spectroscopic techniques. The compound inhibited zymosan-induced oxidative bursts from whole blood phagocytes and isolated polymorphonuclear cells with an IC50 value of (2.5 ± 0.4 and 3.4 ± 0.3 µg/mL), respectively. Furthermore, the inhibition of nitric oxide with an IC50 (3.6 ± 2.2 µg/mL) from lipopolysaccharide-induced J774.2 macrophages indicates its in vitro anti-inflammatory efficacy. The compound did not show toxicity towards normal fibroblast cells. The observational findings, gross anatomical analysis of visceral organs and serological tests revealed the non-toxicity of the compound at the highest tested intraperitoneal (IP) dose of 100 mg/kg in acute toxicological studies in Balb/c mice. The compound treatment (100 mg/kg) (SC) significantly (P < 0.001) downregulated the mRNA expression of inflammatory markers TNF-α, IL-1ß, IL-2, IL-13, and NF-κB, which were elevated in zymosan-induced generalised inflammation (IP) in Balb/c mice while upregulated the expression of anti-inflammatory cytokine IL-10, which was reduced in zymosan-treated mice. No suppressive effect was observed at the dose of 25 mg/kg. Ibuprofen was taken as a standard drug. The results revealed that the new acyl derivative of sulfadimethoxine has an immunomodulatory effect against generalised inflammatory response with non-toxicity both in vitro and in vivo, and has therapeutic potential for various chronic inflammatory illnesses.

In-vitro inhibition of NLRP3 inflammasome by 3,6-dihydroxyflavone (3,6-DHF): a therapeutic strategy for the treatment of chronic inflammatory and autoimmune diseases.

Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex has an important role in immune system and its abnormal activation is associated with the pathogenesis of various inflammatory and auto-immune diseases. The study reveals the anti-inflammatory effects of 3,6-dihydroxyflavone (3,6-DHF). Here, we aimed to determine the inhibitory effects of 3,6-DHF on NLRP3 inflammasome and its associated components, thereby determining the signaling pathways involved in the inhibition. Reactive oxygen species (ROS) and nitric oxide (NO) were quantified by chemiluminescence and Griess methods, respectively. Inflammatory cell model was induced in human leukemic monocytes (THP-1). mRNA levels were estimated through real-time RT-PCR, protein expressions were evaluated by protein slot blot and immunocytochemistry, MTT and alamar blue assays were employed for toxicity studies. The compound 3,6-DHF was found to be the potent inhibitor of NLRP3 inflammasome by targeting the molecules involve in its activation pathway. Anti-inflammatory effects were revealed by inhibition of ROS and NO, reduction in the transcription of caspase-1, ASC, IL-1ß and TLR-4 was observed along with the marked inhibition of NLRP3, IL-18, NF-κB and pNF-κB at translational level. 3,6-DHF was non-toxic on normal human fibroblast (BJ) and THP-1 cells and, could be a potential therapeutic agent in NLRP3 inflammasome driven diseases.