Xin Jianzeng, Sun Yupei, Huang Shuai, Yang Pufan, Mou Xiaofeng, Dai Shengjun, Du Yuan, Liu Sheng
Yantai Key Laboratory of Characteristic Agricultural Bioresource Conservation & Germplasm Innovative Utilization, School of Life Sciences, Yantai University, Yantai 264005, PR China.
School of Pharmacy, Yantai University, Yantai 264005, PR China.
Bioorg Chem. 2025 Aug;163:108779. doi: 10.1016/j.bioorg.2025.108779. Epub 2025 Jul 19.
Sepsis-induced acute lung injury (ALI) is a critical health concern with high morbidity and mortality, while its effective treatment options are limited. Our previous study, identified forsyqinlingine C (FC), a novel C9-monoterpenoid alkaloid from the ripe fruit of Forsythia suspensa (Thunb.) Vahl, exhibits notable anti-inflammatory activity. In this study, we reported the total synthesis of FC and its therapeutic potential against sepsis-induced ALI for the first time. The target compound was achieved in four steps, including barbier reaction, heck reaction, hydroxyl reduction and hydroboration oxidation, with impressive combined yields of 45 % and high purity of 95 %. In biological study, an inflammatory cell model and a murine model of sepsis-induced ALI were established to explore the potential protective effect of FC and its underlying mechanisms. Our findings indicated that FC could inhibit the expression levels of TLR4, TRIF, p-NF-κB p65, and p-IκB-α and reduce the production of downstream inflammatory cytokine (IL-6 and TNF-α) in MLE-12 cells. In vivo, FC significantly alleviates LPS-induced lung injury by reducing MPO levels, and lung W/D ratios, and ameliorating histopathological alterations. FC also decreased TNF-α and IL-6 production induced by LPS in the murine serum, BALF, and lung tissue in a dose-dependent manner. Meanwhile, FC inhibited the expression levels of TLR4, TRIF, p-NF-κB p65, and p-IκB-α, which are activated by LPS administration. Furthermore, molecular docking studies results speculated that FC could disturb the TLR4/TRIF signaling pathway. In conclusion, FC demonstrated potential in alleviating sepsis-induced ALI, primarily by inhibiting LPS-stimulated inflammatory response through the TLR4/TRIF/NF-κB signaling pathway. This research offers an alternative treatment for sepsis-induced ALI.
脓毒症诱导的急性肺损伤（ALI）是一个严重的健康问题，发病率和死亡率都很高，而其有效的治疗选择却很有限。我们之前的研究从连翘（Forsythia suspensa (Thunb.) Vahl）成熟果实中鉴定出一种新型C9-单萜生物碱连翘秦灵碱C（FC），它具有显著的抗炎活性。在本研究中，我们首次报道了FC的全合成及其对脓毒症诱导的ALI的治疗潜力。目标化合物通过四步反应实现，包括巴比耶反应、赫克反应、羟基还原和硼氢化氧化，总产率令人印象深刻地达到45%，纯度高达95%。在生物学研究中，建立了炎症细胞模型和脓毒症诱导的ALI小鼠模型，以探索FC的潜在保护作用及其潜在机制。我们的研究结果表明，FC可以抑制MLE-12细胞中TLR4、TRIF、p-NF-κB p65和p-IκB-α的表达水平，并减少下游炎症细胞因子（IL-6和TNF-α）的产生。在体内，FC通过降低MPO水平、肺湿干重比以及改善组织病理学改变，显著减轻LPS诱导的肺损伤。FC还以剂量依赖性方式降低LPS在小鼠血清、支气管肺泡灌洗液（BALF）和肺组织中诱导的TNF-α和IL-6的产生。同时，FC抑制了LPS给药激活的TLR4、TRIF、p-NF-κB p65和p-IκB-α的表达水平。此外，分子对接研究结果推测FC可能会干扰TLR4/TRIF信号通路。总之，FC在减轻脓毒症诱导的ALI方面显示出潜力，主要是通过TLR4/TRIF/NF-κB信号通路抑制LPS刺激的炎症反应。这项研究为脓毒症诱导的ALI提供了一种替代治疗方法。
