Targeting TLR4 and regulating the Keap1/Nrf2 pathway with andrographolide to suppress inflammation and ferroptosis in LPS-induced acute lung injury

IF 4 2区 医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Chinese Journal of Natural Medicines Pub Date : 2024-10-01 DOI:10.1016/S1875-5364(24)60727-2
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Abstract

Acute lung injury (ALI) is a severe inflammatory condition with a high mortality rate, often precipitated by sepsis. The pathophysiology of ALI involves complex mechanisms, including inflammation, oxidative stress, and ferroptosis, a novel form of regulated cell death. This study explores the therapeutic potential of andrographolide (AG), a bioactive compound derived from Andrographis, in mitigating Lipopolysaccharide (LPS)-induced inflammation and ferroptosis. Our research employed in vitro experiments with RAW264.7 macrophage cells and in vivo studies using a murine model of LPS-induced ALI. The results indicate that AG significantly suppresses the production of pro-inflammatory cytokines and inhibits ferroptosis in LPS-stimulated RAW264.7 cells. In vivo, AG treatment markedly reduces lung edema, decreases inflammatory cell infiltration, and mitigates ferroptosis in lung tissues of LPS-induced ALI mice. These protective effects are mediated via the modulation of the Toll-like receptor 4 (TLR4)/Kelch-like ECH-associated protein 1(Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Molecular docking simulations identified the binding sites of AG on the TLR4 protein (Kd value: −33.5 kcal·mol−1), and these interactions were further corroborated by Cellular Thermal Shift Assay (CETSA) and SPR assays. Collectively, our findings demonstrate that AG exerts potent anti-inflammatory and anti-ferroptosis effects in LPS-induced ALI by targeting TLR4 and modulating the Keap1/Nrf2 pathway. This study underscores AG’s potential as a therapeutic agent for ALI and provides new insights into its underlying mechanisms of action.
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用穿心莲内酯靶向TLR4并调节Keap1/Nrf2通路,以抑制LPS诱导的急性肺损伤中的炎症和铁变态反应。
急性肺损伤(ALI)是一种严重的炎症,死亡率很高,通常由败血症诱发。急性肺损伤的病理生理学涉及复杂的机制,包括炎症、氧化应激和铁变态反应(一种新的细胞死亡调节形式)。本研究探讨了穿心莲内酯(AG)(一种从穿心莲中提取的生物活性化合物)在减轻脂多糖(LPS)诱导的炎症和铁细胞凋亡方面的治疗潜力。我们的研究采用了 RAW264.7 巨噬细胞体外实验和 LPS 诱导 ALI 的小鼠模型体内研究。结果表明,AG 能明显抑制促炎细胞因子的产生,并能抑制 LPS 刺激的 RAW264.7 细胞中的铁蛋白沉积。在体内,AG 治疗可明显减轻 LPS 诱导的 ALI 小鼠肺组织的肺水肿、减少炎性细胞浸润并减轻铁细胞沉着。这些保护作用是通过调节 Toll 样受体 4 (TLR4)/Kelch-like ECH-associated protein 1(Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) 信号通路介导的。分子对接模拟确定了 AG 在 TLR4 蛋白上的结合位点(Kd 值:-33.5 kcal-mol-1),细胞热移试验(CETSA)和 SPR 试验进一步证实了这些相互作用。总之,我们的研究结果表明,AG 通过靶向 TLR4 和调节 Keap1/Nrf2 通路,在 LPS 诱导的 ALI 中发挥了强有力的抗炎和抗铁细胞生成作用。这项研究强调了 AG 作为 ALI 治疗药物的潜力,并对其潜在的作用机制提供了新的见解。
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来源期刊
Chinese Journal of Natural Medicines
Chinese Journal of Natural Medicines INTEGRATIVE & COMPLEMENTARY MEDICINE-PHARMACOLOGY & PHARMACY
CiteScore
7.50
自引率
4.30%
发文量
2235
期刊介绍: The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM). Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.
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