Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun 130021, China.
Department of General Practice, The First Hospital of Jilin University, Changchun, 130021, China.
Biomed Pharmacother. 2024 Oct;179:117359. doi: 10.1016/j.biopha.2024.117359. Epub 2024 Sep 4.
Sepsis, a frequently fatal condition, emerges from an exaggerated inflammatory response to infection, resulting in multi-organ dysfunction and alarmingly high mortality rates. Despite the urgent need for effective treatments, current therapeutic options remain limited to antibiotics, with no other efficacious alternatives available. Echinatin (Ecn), a potent bioactive compound extracted from the roots and rhizomes of licorice, has gained significant attention for its broad pharmacological properties, particularly its ability to combat oxidative stress. Recent research highlights the crucial role that oxidative stress plays in the onset and progression of sepsis further emphasizing the potential therapeutic value of Ecn in this context. In this study, we explored the protective effects of Ecn in a murine model of sepsis induced by cecal ligation and puncture (CLP). Ecn demonstrated a significant reduction in the levels of inflammatory cytokines and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Network pharmacology analysis identified 41 targets and top 15 pathways involved in the Ecn-mediated signaling network, revealing that Ecn might exert its effects through key targets including the NF-κB and MAPK signaling pathways. Molecular docking studies suggested a strong affinity between Ecn and MEK, with kinetic simulations and binding energy calculations confirming a stable interaction. Mechanistically, Ecn treatment inhibited NF-κB and the MEK/ERK signaling pathway, as evidenced by decreased phosphorylation of IκBα and nuclear p65, along with reduced phosphorylation of MEK and ERK in both LPS-stimulated RAW 264.7 macrophages and septic mice. Furthermore, the administration of MEK signaling agonists reversed the anti-inflammatory effects of Ecn, indicating the involvement of this signaling pathway in Ecn's protective mechanism. Notably, our investigation revealed that Ecn did not affect bacterial proliferation either in vivo or in vitro, underscoring its specific immunomodulatory effects rather than direct antimicrobial activity. In summation, our findings underscored the potential of Ecn as an innovative therapeutic remedy for sepsis-induced injury, particularly through the regulation of the NF-κB and MEK/ERK signaling pathway. This exploration unveiled a promising therapeutic approach for treating sepsis, supplementing existing interventions and addressing their constraints.
脓毒症是一种常见的致命病症，源于对感染的过度炎症反应，导致多器官功能障碍和惊人的高死亡率。尽管迫切需要有效的治疗方法，但目前的治疗选择仍然限于抗生素，没有其他有效的替代方法。从甘草的根和根茎中提取的有效生物化合物——獐牙菜苦苷（Ecn），因其广泛的药理学特性，特别是其抵抗氧化应激的能力，受到了广泛关注。最近的研究强调了氧化应激在脓毒症发病和进展中的关键作用，进一步强调了 Ecn 在这方面的潜在治疗价值。在这项研究中，我们探讨了 Ecn 在盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠模型中的保护作用。Ecn 显著降低了脂多糖（LPS）刺激的 RAW 264.7 巨噬细胞中炎症细胞因子和活性氧（ROS）的水平。网络药理学分析鉴定了 41 个 Ecn 介导的信号网络涉及的靶点和前 15 个途径，表明 Ecn 可能通过包括 NF-κB 和 MAPK 信号通路在内的关键靶点发挥作用。分子对接研究表明 Ecn 与 MEK 之间具有很强的亲和力，动力学模拟和结合能计算证实了稳定的相互作用。从机制上讲，Ecn 处理抑制了 NF-κB 和 MEK/ERK 信号通路，表现为 LPS 刺激的 RAW 264.7 巨噬细胞和脓毒症小鼠中 IκBα和核 p65 的磷酸化减少，以及 MEK 和 ERK 的磷酸化减少。此外，MEK 信号激动剂的给药逆转了 Ecn 的抗炎作用，表明该信号通路参与了 Ecn 的保护机制。值得注意的是，我们的研究表明，Ecn 无论是在体内还是体外都不会影响细菌的增殖，这强调了它的特异性免疫调节作用，而不是直接的抗菌活性。总之，我们的研究结果强调了 Ecn 作为一种创新的脓毒症诱导损伤治疗方法的潜力，特别是通过调节 NF-κB 和 MEK/ERK 信号通路。这项研究揭示了一种有前途的治疗脓毒症的方法，补充了现有的干预措施，并解决了它们的局限性。
