RESUMEN
Dengue virus (DENV) infections are straining public health systems worldwide. Vitamin D, a secosteroid hormone, is currently being investigated for its immunomodulatory effects in DENV infections. The objectives of the present study was to study the effect of 1, 25 dihydroxy vitamin D3 (1,25(OH)2D3) on the expression of genes coding for RNA sensing pattern recognition receptors, downstream signaling components including oligoadenylate synthetases (OAS) and interferon stimulated gene 15 (ISG15) and T helper (Th)1, Th2 and Th17 cytokine response in DENV infected U937-DC-SIGN cells and THP-1 macrophages. U937-DC-SIGN RNA was investigated for the expression of TLR3, DDX58, IFIH1, OAS1, OAS2, OAS3, CAMP and ISG15 genes using gene expression assays. Interleukin (IL)-12p70, IL-10, IL-4 and IL-17A levels were assessed in the THP-1 macrophage culture supernatants. The results revealed that 1,25(OH)2D3 increased the expression of DDX58, OAS1, OAS2 and OAS3 at 0.1⯵M while higher concentration had diminishing effect. 1,25(OH)2D3 enhanced the expression of ISG15 and CAMP genes. 1,25(OH)2D3 suppressed the levels of IL-4 and IL-17A. Lower concentration of 1,25(OH)2D3 suppressed IL-12p70 and IL-10 levels while a higher concentration enhanced the levels. The results suggest that 1,25(OH)2D3 may have concentration dependent immunomodulatory effects. Higher dose of 1,25(OH)2D3 might have an immunoregulatory role in ameliorating inflammation during dengue infections. Further studies are needed to evaluate the efficacy of different doses of 1,25(OH)2D3 in preventing severe dengue.
Asunto(s)
Calcitriol/farmacología , Moléculas de Adhesión Celular/genética , Citocinas/inmunología , Virus del Dengue/efectos de los fármacos , Lectinas Tipo C/genética , Macrófagos/efectos de los fármacos , Receptores de Superficie Celular/genética , Receptores de Reconocimiento de Patrones/genética , Dengue/inmunología , Dengue/virología , Virus del Dengue/fisiología , Expresión Génica/efectos de los fármacos , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , Macrófagos/inmunología , Macrófagos/virología , ARN/genética , Células U937 , Replicación Viral/efectos de los fármacosRESUMEN
We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H37Rv and Dormant stage H37Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb was evaluated by testing against other bacterial strains. Some derivatives showed promising activity along with low cytotoxicity. The most potent compound in the whole cell assay (MIC 0.325 µM against H37Rv) showed selectivity in the enzyme assay and exhibited synergy with second line anti-TB agent p-amino salicylic acid. This study therefore provides promising molecules for further development as antituberculosis DHFR inhibitors.