RESUMO
Indole- and hydantoin-based derivatives both exhibit anti-inflammatory activity, suggesting that the structures of indole and hydantoin are functional for this activity. In the present study, we synthesized two types of indole-hydantoin derivatives, IH-1 (5-(1H-indole-3-ylmethylene) imidazolidine-2,4-dione) and IH-2 (5-(1H-indole-3-ylmethyl) imidazolidine-2,4-dione) and examined their effects on LPS-induced inflammatory responses in murine macrophage-like RAW264.7 cells. LPS-induced inflammatory responses were not affected by indole, hydantoin, or IH-2. In contrast, IH-1 significantly inhibited the LPS-induced production of nitric oxide (NO) and secretion of CCL2 and CXCL1 by suppressing the mRNA expression of inducible NO synthase (iNOS), CCL2, and CXCL1. IH-1 markedly inhibited the LPS-induced activation of NF-κB without affecting the degradation of IκBα or nuclear translocation of NF-κB. IH-1 markedly attenuated the transcriptional activity of NF-κB by suppressing the LPS-induced phosphorylation of the NF-κB p65 subunit at Ser276. Furthermore, IH-1 prevented the LPS-induced interaction of NF-κB p65 subunit with a transcriptional coactivator, cAMP response element-binding protein (CBP). Collectively, these results revealed the potential of the novel indole-hydantoin derivative, IH-1 as an anti-inflammatory drug.
Assuntos
Anti-Inflamatórios/farmacologia , Hidantoínas/farmacologia , Indóis/farmacologia , Inflamação/prevenção & controle , Macrófagos/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Ativação Transcricional/efeitos dos fármacos , Animais , Anti-Inflamatórios/síntese química , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Humanos , Hidantoínas/síntese química , Indóis/síntese química , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Células RAW 264.7 , Transdução de Sinais , Células THP-1 , Fator de Transcrição RelA/genética , Células U937RESUMO
Myxococcus xanthus PdeA and PdeB, enzymes homologous to class III 3',5'-cyclic nucleotide phosphodiesterases, hydrolyzed 3',5'- and 2',3'-cyclic AMP (cAMP) to adenosine, and also demonstrated phosphatase activity toward nucleoside 5'-tri-, 5'-di-, 5'- and 3'-monophosphates with highest activities for nucleoside 5'-monophosphates. The substrate specificities of PdeA and PdeB show no similarity to that of any known cNMP phosphodiesterase, nucleotidase, or phosphatase. The enzyme activities of PdeA and PdeB were stimulated by 50 microM Mn(2+) or Co(2+). The K(m) values of PdeA and PdeB for 3',5'-cAMP, 2',3'-cAMP, 5'-ATP, and 5'-AMP were in the low micromolar range (1.4-12.5 microM).