Chronic inflammation induces autoimmune disorders and chronic diseases. Several natural products activate nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, attenuating inflammatory responses. Ergosta-7,9(11),22-trien-3β-ol (EK100) isolated from Cordyceps militaris showed anti-inflammatory and antioxidative activity, but those mechanisms are still unclear. This study is the first to investigate EK100 on antioxidant Nrf2 relative genes expression in LPS-stimulated macrophage-like cell lines. The results showed that EK100 reduced IL-6 (interleukin-6) and tumor necrosis factor-α production. EK100 also attenuated a mitogen-activated protein kinase/activator protein-1 (MAPK/AP-1) pathway and interleukin-6/Janus kinase/signal transducer and activator of transcription (IL-6/JAK/STAT) pathway in LPS-stimulated cells. Toll-like receptor 4 (TLR4) inhibitor CLI-095 and MAPK inhibitors can synergize the anti-inflammatory response of EK100 in LPS-stimulated cells. Moreover, EK100 activated Nrf2/HO-1 (heme oxygenase-1) signaling in LPS-stimulated murine macrophage-like RAW 264.7 cells, murine microglial BV2 cells, and human monocytic leukemia THP-1 cells. However, Nrf2 small interfering RNA (Nrf2 siRNA) reversed EK100-induced antioxidative proteins expressions. In conclusion, EK100 showed anti-inflammatory responses via activating the antioxidative Nrf2/HO-1 signaling and inhibiting TLR4 related MAPK/AP-1 induced IL-6/JAK/STAT pathways in the LPS-stimulated cells in vitro. The results suggest EK100 acts as a novel antioxidant with multiple therapeutic targets that can potentially be developed to treat chronic inflammation-related diseases.

中文翻译：

---

Ergosta-7,9(11),22-trien-3β-ol 通过抑制 MAPK/AP-1 诱导的 IL-6/JAK/STAT 通路和激活 LPS 刺激的巨噬细胞样中的 Nrf2/HO-1 信号传导来减弱炎症反应细胞

慢性炎症会诱发自身免疫性疾病和慢性疾病。几种天然产物激活核因子红细胞 2 相关因子 2 (Nrf2) 信号，减弱炎症反应。Ergosta-7,9(11),22-trien-3β-ol (EK100) 从蛹虫草中分离显示出抗炎和抗氧化活性，但这些机制仍不清楚。本研究首次研究了 EK100 对 LPS 刺激的巨噬细胞样细胞系中抗氧化剂 Nrf2 相关基因表达的影响。结果表明，EK100 减少了 IL-6（白细胞介素-6）和肿瘤坏死因子-α 的产生。EK100 还减弱了 LPS 刺激中的丝裂原活化蛋白激酶/激活蛋白 1 (MAPK/AP-1) 通路和白细胞介素 6/Janus 激酶/信号转导和转录激活剂 (IL-6/JAK/STAT) 通路细胞。Toll 样受体 4 (TLR4) 抑制剂 CLI-095 和 MAPK 抑制剂可以在 LPS 刺激的细胞中协同 EK100 的抗炎反应。此外，EK100 在 LPS 刺激的小鼠巨噬细胞样 RAW 264.7 细胞、小鼠小胶质细胞 BV2 细胞、和人单核细胞白血病 THP-1 细胞。然而，Nrf2 小干扰 RNA (Nrf2 siRNA) 逆转了 EK100 诱导的抗氧化蛋白表达。总之，EK100 显示出抗炎反应通过在体外LPS 刺激的细胞中激活抗氧化 Nrf2/HO-1 信号并抑制 TLR4 相关的 MAPK/AP-1 诱导的 IL-6/JAK/STAT 通路。结果表明，EK100 作为一种新型抗氧化剂，具有多种治疗靶点，可用于治疗慢性炎症相关疾病。