Treatment of Sepsis Pathogenesis with High Mobility Group Box Protein 1Regulating Anti-inflammatory Agents
- Treatment of Sepsis Pathogenesis with High Mobility Group Box Protein 1Regulating Anti-inflammatory Agents
- 이상희; 조완상; 구자영; 박연주; 오근희; 송진숙; 배명애; 임동현; 이동섭; 박승범
- Issue Date
- Journal of medicinal chemistry
- VOL 60, NO 1-179
- Sepsis is one of the major causes of death worldwide when associated with multiple organ failure. However, there is a critical lack of adequate sepsis therapies because of its diverse patterns of pathogenesis. The pro-inflammatory cytokine cascade mediates sepsis pathogenesis, and high mobility group box proteins (HMGBs) play an important role as late-stage cytokines. We previously reported the small-molecule modulator, inflachromene (1d), which inhibits the release of HMGBs and, thereby, reduces the production of pro-inflammatory cytokines. In this context, we intraperitoneally administered Id to a cecal ligation and puncture (CLP)-induced mouse model of sepsis and confirmed that it successfully ameliorated sepsis pathogenesis. On the basis of a structure activity relationship study, we discovered new candidate compounds, 2j and 21, with improved therapeutic efficacy in vivo. Therefore, our study clearly demonstrates that the regulation of HMGB1 release using small molecules is a promising strategy for the treatment of sepsis.
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