College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, China.
Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China.
Int Immunopharmacol. 2020 Dec;89(Pt A):107014. doi: 10.1016/j.intimp.2020.107014. Epub 2020 Oct 8.
Acute lung injury (ALI) is a life-threatening disorder with high rates of morbidity and mortality. Up to now, there are still no effective drugs for its therapies due to the complexity of its etiology and pathogenesis. In this present study, we investigated the protective effect of Nervilifordin F (NF) on ALI induced by intestinal ischemia/reperfusion (II/R) and its related mechanism. Firstly, the ALI model rats were induced through II/R, and treated with NF. Then, the pathological and cytokine level changes in the lung tissue of ALI rats were evaluated by hematoxylin and eosin and enzyme-linked immunosorbent assay (ELISA). The related genes expression level of mammalian target of rapamycin (mTOR) pathway and inflammasome were measured by real-time quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemistry. Finally, the NF-protein complexes were predicted by SYBYL-X 2.0. The results indicated that NF can significant reduces the levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-1β, and inhibits the expression of inflammasome related genes (such as toll-like receptor 4 (TLR4), p65, NOD-like receptor protein 3 (NLRP3) and Caspase 1), thereby reduce inflammation in II/R-induced ALI rats. Moreover, NF can activate the expression of FK506 binding protein 25 (FKBP25) and down-regulate the expression of mTOR and p70 ribosomal protein S6 kinase 1 (p70S6K). In addition, molecular docking results showed that NF can be combined well with p70S6K, TLR4, mTOR and NLRP3, which further verified the inhibitory effect of NF on ALI inflammation. Therefore, the findings indicate that NF can alleviates II/R-induced inflammation of ALI rats by inhibiting inflammasome related genes and mTOR pathway, which expected to use as a potential drug for the treatment of ALI.
急性肺损伤（ALI）是一种危及生命的疾病，发病率和死亡率都很高。到目前为止，由于其病因和发病机制的复杂性，仍然没有有效的治疗药物。在本研究中，我们研究了 Nervilifordin F（NF）对肠缺血/再灌注（II/R）诱导的 ALI 的保护作用及其相关机制。首先，通过 II/R 诱导 ALI 大鼠模型，并给予 NF 治疗。然后，通过苏木精和伊红和酶联免疫吸附测定（ELISA）评估 ALI 大鼠肺组织的病理和细胞因子水平变化。通过实时定量聚合酶链反应（RT-qPCR）、western blot 和免疫组化测定哺乳动物雷帕霉素靶蛋白（mTOR）途径和炎性体相关基因的表达水平。最后，通过 SYBYL-X 2.0 预测 NF-蛋白复合物。结果表明，NF 可显著降低肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6 和 IL-1β 的水平，并抑制炎性体相关基因（如 toll 样受体 4（TLR4）、p65、NOD 样受体蛋白 3（NLRP3）和 Caspase 1）的表达，从而减轻 II/R 诱导的 ALI 大鼠的炎症。此外，NF 可激活 FK506 结合蛋白 25（FKBP25）的表达，并下调 mTOR 和 p70 核糖体蛋白 S6 激酶 1（p70S6K）的表达。此外，分子对接结果表明，NF 可与 p70S6K、TLR4、mTOR 和 NLRP3 结合良好，进一步验证了 NF 对 ALI 炎症的抑制作用。因此，研究结果表明，NF 通过抑制炎性体相关基因和 mTOR 通路减轻 II/R 诱导的 ALI 大鼠炎症，有望作为 ALI 的潜在治疗药物。
