Sepsis is a life-threatening clinical condition caused by infection and transposition of pathogens and pathogen-associated molecular patterns (PAMPs) into the host bloodstream. During sepsis, activation of toll-like receptors (TLRs) on immune cells triggers the release of pro-inflammatory cytokines and overstimulates the production of vasodilatory mediators such as nitric oxide (NO). These vascular changes lead to widespread inflammation, tissue damage, multiple organ failure, and often death. New therapeutic options are urgently needed. To this end, thiostrepton (TST) has emerged as a candidate for sepsis treatment due to its action as an antibiotic and anti-inflammatory molecule (TLR7-9 inhibitor). Reports in the literature suggest that TLR9 inhibition substantially suppresses the excessive host inflammatory response and attenuates sepsis-induced mortality in the cecal ligation and puncture (CLP) murine model of sepsis. However, to the best of our knowledge, TST has never been directly tested as a therapeutic option for the management of sepsis, possibly due to its low water solubility and drug delivery issues. These facts prompted us to test the central hypothesis that TST encapsulated in phospholipid sterically stabilized micelles (TST-SSM) could be developed into a novel treatment for sepsis. Thus, using our published method of encapsulating the hydrophobic antibiotic TST-SSM, we evaluated the in vivo efficacy of TST-SSM nanomedicine in the murine model of polymicrobial sepsis. We found that TST-SSM increased the median survival of CLP-induced septic mice from 31 to 44 hr by reducing the bacterial burden in the blood and peritoneal lavage. Moreover, plasma levels of pro-inflammatory cytokines (interleukin 6 and tumor necrosis factor-alpha) and NO derivatives were also reduced, whereas renal and hepatic function biomarkers creatinine and aspartate transferase were significantly improved. In conclusion, we identified that TST-SSM nanomedicine has significant potential as a therapeutic agent for sepsis management, primarily due to its anti-inflammatory and antibiotic properties.

中文翻译：

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硫链丝菌肽纳米药物是一种 TLR9 抑制剂，可减轻小鼠脓毒症引起的炎症

脓毒症是一种危及生命的临床病症，由病原体和病原体相关分子模式 (PAMP) 感染和转座到宿主血流中引起。在脓毒症期间，免疫细胞上 Toll 样受体 (TLR) 的激活会触发促炎细胞因子的释放，并过度刺激一氧化氮 (NO) 等血管舒张介质的产生。这些血管变化会导致广泛的炎症、组织损伤、多器官衰竭，甚至常常导致死亡。迫切需要新的治疗选择。为此，硫链丝菌素 (TST) 由于其作为抗生素和抗炎分子（TLR7-9 抑制剂）的作用而成为脓毒症治疗的候选药物。文献报道表明，在脓毒症盲肠结扎穿刺 (CLP) 小鼠模型中，TLR9 抑制可显着抑制过度的宿主炎症反应，并降低脓毒症引起的死亡率。然而，据我们所知，TST 从未作为败血症治疗的治疗选择进行过直接测试，这可能是由于其水溶性低和药物输送问题。这些事实促使我们检验一个中心假设，即封装在磷脂空间稳定胶束中的 TST (TST-SSM) 可以开发为脓毒症的新型治疗方法。因此，利用我们发表的封装疏水性抗生素 TST-SSM 的方法，我们评估了TST-SSM 纳米药物在多种微生物脓毒症小鼠模型中的体内功效。我们发现，TST-SSM 通过减少血液和腹腔灌洗液中的细菌负荷，将 CLP 诱导的脓毒症小鼠的中位生存期从 31 小时延长至 44 小时。此外，促炎细胞因子（白细胞介素6和肿瘤坏死因子-α）和NO衍生物的血浆水平也降低，而肾功能和肝功能生物标志物肌酐和天冬氨酸转移酶显着改善。总之，我们发现 TST-SSM 纳米药物作为脓毒症治疗药物具有巨大的潜力，这主要是由于其抗炎和抗生素特性。