β-carboline alkaloids attenuate bleomycin induced pulmonary fibrosis in mice through inhibiting NF-kb/p65 phosphorylation and epithelial-mesenchymal transition
β-carboline alkaloids attenuate bleomycin induced pulmonary fibrosis in mice through inhibiting NF-kb/p65 phosphorylation and epithelial-mesenchymal transition
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DOI：
10.1016/j.jep.2019.112096
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发表时间：
2019-10-28
影响因子：
5.4
通讯作者：
Tao, Yanduo
中科院分区：
文献类型：
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作者：
Cui, Yulei;Jiang, Lei;Tao, Yanduo
民族药理学相关性：植物甘肃雪灵芝在传统医学中长期用于治疗肺部炎症。然而，该植物的抗肺纤维化作用及其相应的活性成分尚未得到广泛的研究。本研究的目的：本研究的目的是探讨黄芪的抗肺纤维化作用及其相应的活性成分。材料与方法：采用体内实验方法，研究甘肃黄芪乙酸乙酯提取物富集部位（第一部分）的抗肺纤维化作用。通过博莱霉素（BLM）诱导的肺纤维化小鼠（5组，n = 10），每天以50、100和150 mg/kg的剂量给药15天，以评价甘肃黄芪的作用。体外实验采用脂多糖（LPS）诱导的RAW264.7炎症细胞模型和TGF-β 1诱导的A549细胞模型，评价第一部分分离的12种β-咔啉生物碱的抗炎和逆转上皮-间质转化（EMT）作用。本研究中，从甘肃雪灵芝中提取的一个名为Part1的组分在150 mg/kg剂量下表现出较强的抗肺纤维化作用。体内实验表明，经Partl处理后，小鼠的存活率和体重显著增加。Part1能显著抑制炎症的发生、胶原的沉积、TGF-β 1和α-SMA的表达，并能显著提高E-cadherin的表达。第一部分的疗效均呈剂量依赖性。第一部分共鉴定了12个β-咔啉生物碱类化合物，它们均通过抑制NF-κ B/p65磷酸化而对炎症细胞因子MCP-1、TNF-α、IL-6和IL-1 β具有抑制作用，不同化合物在不同水平上逆转上皮-间质转化（EMT）过程。结论：β-咔啉生物碱的抗纤维化作用可能是通过抑制NF-κ B/p65通路的炎症反应，逆转EMT的进程。
Ethnopharmacological relevance: The plant Arenaria kansuensis is used in traditional medicine to treat lung inflammation for a long time. However, the anti-pulmonary fibrosis effect and its corresponding bioactive constituents of this plant have not been studied extensively.Aim of the study: The purpose of this study was to investigate the anti-pulmonary fibrosis effect and its corresponding bioactive constituents of A. kansuensis and its possible mechanism.Materials and methods: In vivo experiment, the anti-pulmonary fibrosis effects of the fraction (Part1) enriched from ethyl acetate extracts of the whole plant A. kansuensis were evaluated through bleomycin (BLM)-induced pulmonary fibrosis mice (five groups, n = 10) daily at doses of 50, 100 and 150 mg/kg for 15 days. In vitro experiment, the anti-inflammation and reversed epithelial-mesenchymal transition (EMT) effect of 12 beta-carboline alkaloids isolated from Part1 were evaluated through lipopolysaccharide (LPS)-induced RAW264.7 inflammatory cell model and TGF-beta 1 induced A549 cell model.Results: In this study, a fraction named Part1 extracted from Arenaria kansuensis presented strong anti-pulmonary fibrosis effect at the dose of 150 mg/kg. Vivo experiments showed that the survival rate and body weight of mice significantly increased after Partl treatment. Part1 could significantly inhibit the initial of inflammation, deposition of collagen and expression of TGF-beta 1 and alpha-SMA, moreover, the expression of E-cadherin was significantly elevated after administration of Part1. All the cure effects of Part1 were in dose dependent manner. A total of 12 beta-carboline alkaloids were identified in Part1 and they all showed suppressive effect on inflammatory cytokines including MCP-1, TNF-alpha, IL-6 and IL-1 beta through inhibition of NF-kb/p65 phosphorylation, and that epithelial-mesenchymal transition (EMT) process was reversed by different compounds in different levels. The expression of indicators of EMT including alpha-SMA, vimentin and E-cadherin was significantly improved after given different beta-carboline alkaloids.Conclusions: This study showed that antifibrogenic effect of beta-carboline alkaloids was due to inhibiting the initial of inflammation through NF-kb/p65 pathway and reversing the process of EMT.