Department of Bioscience and Biotechnology, Research Institute for Bioactive-Metabolome Network, Konkuk University, Seoul 05029, Korea.
Molecules. 2019 Nov 4;24(21):3984. doi: 10.3390/molecules24213984.
Isorhamnetin is a flavonoid that is abundant in the fruit of L. It is widely studied for its ability to modulate inflammatory responses. In this study, we evaluated the potential of isorhamnetin to prevent gram-negative sepsis. We investigated its efficacy using an -induced sepsis model. Our study reveals that isorhamnetin treatment significantly enhances survival and reduces proinflammatory cytokine levels in the serum and lung tissue of -infected mice. Further, isorhamnetin treatment also significantly reduces the levels of aspartate aminotransferase, alanine amino transferase and blood urea nitrogen, suggesting that it can improve liver and kidney function in infected mice. Docking studies reveal that isorhamnetin binds deep in the hydrophobic binding pocket of MD-2 via extensive hydrophobic interactions and hydrogen bonding with Tyr102, preventing TLR4/MD-2 dimerization. Notably, binding and secreted alkaline phosphatase reporter gene assays show that isorhamnetin can interact directly with the TLR4/MD-2 complex, thus inhibiting the TLR4 cascade, which eventually causes systemic inflammation, resulting in death due to cytokine storms. We therefore presume that isorhamnetin could be a suitable therapeutic candidate to treat bacterial sepsis.
山奈酚是一种黄酮类化合物，在李属果实中含量丰富。它因其调节炎症反应的能力而被广泛研究。在这项研究中，我们评估了山奈酚预防革兰氏阴性菌败血症的潜力。我们使用脂多糖诱导的败血症模型来评估其疗效。我们的研究表明，山奈酚治疗可显著提高感染脂多糖的小鼠的存活率，并降低血清和肺组织中促炎细胞因子的水平。此外，山奈酚治疗还可显著降低天冬氨酸氨基转移酶、丙氨酸氨基转移酶和血尿素氮的水平，表明它可改善感染小鼠的肝肾功能。对接研究表明，山奈酚通过与 Tyr102 的广泛疏水相互作用和氢键，在 MD-2 的疏水结合口袋深处结合，从而阻止 TLR4/MD-2 二聚化。值得注意的是，结合和分泌碱性磷酸酶报告基因检测表明，山奈酚可以与 TLR4/MD-2 复合物直接相互作用，从而抑制 TLR4 级联反应，最终导致全身炎症，因细胞因子风暴而导致死亡。因此，我们推测山奈酚可能是治疗细菌败血症的合适治疗候选药物。
