Systems pharmacology approach uncovers Ligustilide attenuates experimental colitis in mice by inhibiting PPARγ-mediated inflammation pathways
Systems pharmacology approach uncovers Ligustilide attenuates experimental colitis in mice by inhibiting PPARγ-mediated inflammation pathways
复制标题
系统药理学方法揭示藁本内酯通过抑制 PPARγ 介导的炎症途径来减轻小鼠实验性结肠炎。
DOI：
10.1007/s10565-020-09563-z
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发表时间：
2020-10-31
影响因子：
6.1
通讯作者：
Fang, Jiansong
中科院分区：
文献类型：
--
作者：
Huang, Yujie;Zhang, Yifan;Fang, Jiansong
炎症性肠病（Inflammatory bowel disease，IBD）是一种引起胃肠道炎症的慢性特发性疾病，目前缺乏有效的药物靶点和治疗方法。为了识别针对一致靶点的新型治疗剂，我们利用了一个系统药理学驱动的框架，该框架结合了天然产物和IBD疾病基因的药物靶点网络。我们的计算机模拟方法发现，白芷和蛇床子的主要活性成分之一阿替利特（LIG）有效地减弱IBD。以下体内外实验结果表明LIG通过抑制炎症细胞浸润、MPO和iNOS活性以及IL-1β、IL-6和TNF-α的表达和产生来预防葡聚糖硫酸钠（DSS）诱导的实验性小鼠结肠炎。随后，网络分析有助于验证LIG通过激活PPARγ抑制NF-κB和MAPK/AP-1通路来减轻结肠炎，这在体外RAW 264.7细胞和骨髓源性巨噬细胞中得到进一步证实。总之，本研究揭示了LIG激活PPARγ以抑制NF-κB和AP-1信号传导的激活，从而最终减轻DSS诱导的结肠炎，其具有有希望的活性并且可能作为IBD治疗的候选物。我们证明LIG可以通过抑制NF-κB和AP-1通路来减轻IBD中的炎症，所述NF-κB和AP-1通路通过激活PPARγ来减少巨噬细胞中促炎细胞因子的表达。这些发现提供了全面的临床前证据，表明LIG可能成为未来IBD治疗的有希望的候选药物。图形化大灯：1.系统药理学发现阿替利特减轻小鼠实验性结肠炎。2.基于网络的分析预测了阿昔利特抗IBD的机制，并通过抑制PPARγ介导的炎症通路进行了验证。3.阿昔利特通过激活PPARγ抑制NF-κB和AP-1的活化，从而减轻DSS诱导的结肠炎.阿替利特具有很好的活性，可作为治疗IBD的候选药物。
Inflammatory bowel disease (IBD) is a chronic idiopathic disorder causing inflammation in the gastro-intestinal tract, which is lack of effective drug targets and medications. To identify novel therapeutic agents against consistent targets, we exploited a systems pharmacology–driven framework that incorporates drug-target networks of natural product and IBD disease genes. Our in silico approach found that Ligustilide (LIG), one of the major active components ofAngelica acutilobaandCnidium Officinale, potently attenuated IBD. The following in vivo and in vitro results demonstrated that LIG prevented experimental mice colitis induced by dextran sulfate sodium (DSS) via suppressing inflammatory cell infiltration, the activity of MPO and iNOS, and the expression and production of IL-1β, IL-6, and TNF-α. Subsequently, the network analysis helped to validate that LIG alleviated colitis by inhibiting NF-κB and MAPK/AP-1 pathway through activating PPARγ, which were further confirmed in RAW 264.7 cells and bone marrow–derived macrophages in vitro. In summary, this study reveals that LIG activated PPARγ to inhibit the activation of NF-κB and AP-1 signaling thus eventually alleviated DSS-induced colitis, which has promising activities and may serve as a candidate for the treatment of IBD.Graphical abstractThis study suggested novel computational and experimental pharmacology approaches to identify potential IBD therapeutic agents by exploiting polypharmacology of natural products. We demonstrated that LIG could attenuate inflammation in IBD by inhibiting NF-κB and AP-1 pathways via PPARγ activation to reduce the expression of pro-inflammatory cytokines in macrophages. These findings offer comprehensive pre-clinical evidence that LIG may serve as a promising candidate for IBD therapy in the future. Graphical headlights: 1. Systems pharmacology uncovered Ligustilide attenuates experimental colitis in mice. 2. Network-based analysis predicted the mechanism of Ligustilide against IBD, which was validated by inhibiting PPARγ-mediated inflammation pathways. 3. Ligustilide activated PPARγ to inhibit NF-κB and AP-1 activation thus eventually alleviated DSS-induced colitis.4. Ligustilide has promising activities and may serve as a candidate for the treatment of IBD.