The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, 210023, China.
Sci Rep. 2020 Nov 6;10(1):19272. doi: 10.1038/s41598-020-76285-x.
Clinical reports have found that with the improvement of treatment, most septic patients are able to survive the severe systemic inflammatory response and to enter the immunoparalysis stage. Considering that immunoparalysis leads to numerous deaths of clinical sepsis patients, alleviation of the occurrence and development of immunoparalysis has become a top priority in the treatment of sepsis. In our study, we investigate the effects of oroxylin A on sepsis in cecal ligation and puncture (CLP) mice. We find that the 60 h + 84 h (30 mg/kg) injection scheme of oroxylin A induce the production of pro-inflammatory factors, and further significantly improves the survival of CLP mice during the middle or late stages of sepsis. Mechanistically, C/EBP-homologous protein (CHOP) is upregulated and plays anti-inflammatory roles to facilitate the development of immunoparalysis in CLP mice. Oroxylin A induces the transcription of E3 ligase F-box only protein 15 gene (fbxo15), and activated FBXO15 protein binds to CHOP and further mediates the degradation of CHOP through the proteasome pathway, which eventually relieves the immunoparalysis of CLP mice. Taken together, these findings suggest oroxylin A relieves the immunoparalysis of CLP mice by degrading CHOP through interacting with FBXO15.
临床报告发现，随着治疗的改善，大多数脓毒症患者能够从严重的全身炎症反应中存活下来，并进入免疫麻痹阶段。鉴于免疫麻痹导致大量临床脓毒症患者死亡，缓解免疫麻痹的发生和发展已成为脓毒症治疗的重中之重。在我们的研究中，我们研究了白杨素 A 对盲肠结扎和穿刺（CLP）小鼠脓毒症的影响。我们发现，白杨素 A 的 60 h + 84 h（30 mg/kg）注射方案诱导促炎因子的产生，并在脓毒症的中晚期进一步显著提高 CLP 小鼠的存活率。在机制上，C/EBP 同源蛋白（CHOP）上调并发挥抗炎作用，促进 CLP 小鼠免疫麻痹的发展。白杨素 A 诱导 E3 连接酶 F-box 仅蛋白 15 基因（fbxo15）的转录，激活的 FBXO15 蛋白与 CHOP 结合，并通过蛋白酶体途径进一步介导 CHOP 的降解，最终缓解 CLP 小鼠的免疫麻痹。总之，这些发现表明，白杨素 A 通过与 FBXO15 相互作用降解 CHOP 来缓解 CLP 小鼠的免疫麻痹。
