Abstract
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 of Angelica acutiloba and Cnidium 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 abstract
This 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.
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Abbreviations
- IBD:
-
Inflammatory bowel disease
- DSS:
-
Dextran sulfate sodium
- MPO:
-
Myeloperoxidase
- iNOS:
-
Inducible nitric oxide synthase
- PPARγ:
-
Peroxisome proliferator-activated receptor-γ
- 5-ASA:
-
5-Aminosalicylic acid
- GWAS:
-
Genome-wide association studies
- DAI:
-
Disease activity index
- LPS:
-
Lipopolysaccharide
- BMDMs:
-
Bone marrow–derived macrophages
- IL-1β:
-
Interleukin-1β
- IL-6:
-
Interleukin-6
- TNF-α:
-
Tumor necrosis factor-α
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Funding
This work was supported by the National Natural Science Foundation of China (No.82074278, No81673627 and No.81903890); the Guangzhou Science Technology and Innovation Commission Technology Research Projects (No.201805010005); the youth scientific research training project of GZUCM (2019QNPY05); and the start-up support for scientific research of Xinglin Yong Scholar in Guangzhou University of Chinese Medicine (A1-AFD018181Z3926).
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Y.H. and J.F. designed and wrote the manuscript; Y.Z., T.W., and Y.M. performed in vivo experiments; Y.Z., J.X., and M.L. performed in vitro experiments; Z.W. and Y.L. analyzed the data; J.F. performed the computational analyses, S.F. and H.P. assisted with the manuscript modification; J.F. and W.Q. supervised the study.
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Animal experimental protocols were approved by the Institutional Animal Care and Use Committee and strictly followed the National Institutes of Health regulations.
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Huang, Y., Zhang, Y., Wan, T. et al. Systems pharmacology approach uncovers Ligustilide attenuates experimental colitis in mice by inhibiting PPARγ-mediated inflammation pathways. Cell Biol Toxicol 37, 113–128 (2021). https://doi.org/10.1007/s10565-020-09563-z
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DOI: https://doi.org/10.1007/s10565-020-09563-z