Network analysis and experimental pharmacology study explore the protective effects of Isoliquiritigenin on 5-fluorouracil-Induced intestinal mucositis

5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for malignant tumors. However, intestinal mucositis caused by 5-FU is a severe dose-limiting toxic effect and even leads to treatment interruption. Isoliquiritigenin (ISL) is one of the main active compounds of licorice, which is a traditional Chinese herbal medicine commonly used in inflammation and gastrointestinal diseases. It is speculated that ISL have protective effects on intestinal mucositis. However, no such studies have been reported. Therefore, to investigate the impact of ISL on 5-Fu-induced intestinal mucositis, a strategy based on network prediction and pharmacological experimental validation was proposed in this study. Firstly, the targets and mechanism of ISL in alleviating 5-Fu-induced gastrointestinal toxicity were predicted by network analysis. And the results were further confirmed by molecular docking. Then, a mouse model of intestinal mucositis was established by intraperitoneal injection of 5-FU (384 μmol/kg) to verify the prediction of network analysis. The network analysis results suggested that PTGS2 (Prostaglandin G/H synthase 2) and NOS2 (Nitric oxide synthase, inducible) might be the critical targets of ISL for reducing the intestinal toxicity of 5-FU. In addition, KEGG and GO enrichment analysis revealed that the HIF-1, TNF, MAPK, IL-17, PI3K-Akt, Ras, NF-kappa B signaling pathway, and biological processes of the inflammatory response, apoptosis regulation, NO production and NF-kappa B transcription factor activity might be involved in the mechanism of ISL against intestinal mucositis. Subsequent animal experiments showed that ISL could reduce the weight loss, leukopenia and mucosal damage caused by 5-FU. Compared with the intestinal mucositis model, the protein expressions of PTGS2, NOS2, TNFα (Tumor necrosis factor-alpha) and NF-κB p65 (nuclear factor kappa-B P65) were decreased after ISL treatment. In conclusion, this study is the fist time to find that ISL can attenuate 5-FU-induced intestinal mucositis in mice. Its anti-mucositis effect may be through regulating TNF/NF-κB pathway and inhibiting inflammatory mediators PTGS2 and NOS2. It will provide a potential candidate for the prevention and treatment of chemotherapy-induced intestinal mucositis.

[1]  J. Ko,et al.  Isoliquiritigenin inhibits pancreatic cancer progression through blockade of p38 MAPK-regulated autophagy. , 2022, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[2]  Min Chen,et al.  Renal Expression of Annexin A1 Is Associated With the Severity of Renal Injury in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis , 2022, Frontiers in Medicine.

[3]  Ziren Su,et al.  Protective Effects of Oxyberberine in 5-Fluorouracil-Induced Intestinal Mucositis in the Mice Model , 2022, Evidence-based complementary and alternative medicine : eCAM.

[4]  Jingjing Chen,et al.  Network Pharmacology and Experimental Validation to Reveal the Pharmacological Mechanisms of Chongcaoyishen Decoction Against Chronic Kidney Disease , 2022, Frontiers in Molecular Biosciences.

[5]  Peng Wang,et al.  Protective effect of homogeneous polysaccharides of Wuguchong (HPW) on intestinal mucositis induced by 5-fluorouracil in mice , 2022, Nutrition & Metabolism.

[6]  J. Figueiredo,et al.  Losartan improves intestinal mucositis induced by 5-fluorouracil in mice , 2021, Scientific Reports.

[7]  P. Xu,et al.  Therapeutic Effects of Naringin in Rheumatoid Arthritis: Network Pharmacology and Experimental Validation , 2021, Frontiers in Pharmacology.

[8]  Y. S. Alqahtani.  Bioactive stigmastadienone from Isodon rugosus as potential anticholinesterase, α-glucosidase and COX/LOX inhibitor: In-vitro and molecular docking studies , 2021, Steroids.

[9]  A. Wu,et al.  mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2′,4′-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications , 2021, Frontiers in Oncology.

[10]  Yingyan Yu,et al.  Perspectives on the Role of Isoliquiritigenin in Cancer , 2021, Cancers.

[11]  Shao Li.  Network Pharmacology Evaluation Method Guidance - Draft , 2021 .

[12]  Hongbo Hu,et al.  Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study , 2020, Signal Transduction and Targeted Therapy.

[13]  G. Suddek,et al.  Empagliflozin ameliorates ethanol-induced liver injury by modulating NF-κB/Nrf-2/PPAR-γ interplay in mice. , 2020, Life sciences.

[14]  R. Tan,et al.  Isoliquiritigenin Attenuates UUO-Induced Renal Inflammation and Fibrosis by Inhibiting Mincle/Syk/NF-Kappa B Signaling Pathway , 2020, Drug design, development and therapy.

[15]  Yeong Shik Kim,et al.  Mucoprotective effects of Saikosaponin-A in 5-fluorouracil-induced intestinal mucositis in mice model. , 2019, Life sciences.

[16]  Jiumao Lin,et al.  Qingjie Fuzheng Granule attenuates 5-fluorouracil-induced intestinal mucosal damage. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[17]  Li-kun Gong,et al.  A new recombinant MS-superoxide dismutase alleviates 5-fluorouracil-induced intestinal mucositis in mice , 2019, Acta Pharmacologica Sinica.

[18]  V. M. P. Pereira,et al.  Amifostine reduces inflammation and protects against 5-fluorouracil-induced oral mucositis and hyposalivation , 2019, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[19]  Yeong Shik Kim,et al.  Diadzein ameliorates 5‐fluorouracil‐induced intestinal mucositis by suppressing oxidative stress and inflammatory mediators in rodents , 2019, European journal of pharmacology.

[20]  D. Czerucka,et al.  Modulation of 5-fluorouracil activation of toll-like/MyD88/NF-κB/MAPK pathway by Saccharomyces boulardii CNCM I-745 probiotic. , 2019, Cytokine.

[21]  G. Seo,et al.  Isoliquiritigenin‐mediated p62/SQSTM1 induction regulates apoptotic potential through attenuation of caspase‐8 activation in colorectal cancer cells , 2018, European Journal of Pharmacology.

[22]  Rui Gao,et al.  Network pharmacology-based identification of protective mechanism of Panax Notoginseng Saponins on aspirin induced gastrointestinal injury. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[23]  G. S. Kireeva,et al.  Effect of the polyphenol composition BP-C3 on haematological and intestinal indicators of 5-fluorouracil toxicity in mice. , 2018, Experimental and therapeutic medicine.

[24]  Guisen Li,et al.  Isoliquiritigenin attenuates LPS-induced AKI by suppression of inflammation involving NF-κB pathway. , 2018, American journal of translational research.

[25]  Hai‐Liang Zhu,et al.  Isoliquiritigenin (ISL) and its formulations: potential antitumor agents. , 2018, Current medicinal chemistry.

[26]  A. C. Medeiros,et al.  Protective effect of dexamethasone on 5-FU-induced oral mucositis in hamsters , 2017, PloS one.

[27]  R. Aebersold,et al.  Contribution of Mass Spectrometry-Based Proteomics to the Understanding of TNF-α Signaling. , 2017, Journal of proteome research.

[28]  Núria Queralt-Rosinach,et al.  DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants , 2016, Nucleic Acids Res..

[29]  Ying Liu,et al.  The anti-inflammatory activity of licorice, a widely used Chinese herb , 2016, Pharmaceutical biology.

[30]  J. Bornstein,et al.  Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5‐fluorouracil , 2016, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[31]  B. Deng,et al.  Isoliquiritigenin decreases the incidence of colitis-associated colorectal cancer by modulating the intestinal microbiota , 2016, Oncotarget.

[32]  Fen Du,et al.  Isoliquiritigenin Attenuates Atherogenesis in Apolipoprotein E-Deficient Mice , 2016, International journal of molecular sciences.

[33]  Tzong-Ming Shieh,et al.  Isoliquiritigenin induces apoptosis and autophagy and inhibits endometrial cancer growth in mice , 2016, Oncotarget.

[34]  C. Yeung,et al.  Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model , 2015, PloS one.

[35]  Jianping Chen,et al.  A Review: The Pharmacology of Isoliquiritigenin , 2015, Phytotherapy research : PTR.

[36]  G. Che,et al.  Cross-talk between endothelial and tumor cells via basic fibroblast growth factor and vascular endothelial growth factor signaling promotes lung cancer growth and angiogenesis , 2015, Oncology letters.

[37]  Junichiro Shibata,et al.  Saireito (TJ-114), a Japanese Traditional Herbal Medicine, Reduces 5-Fluorouracil-Induced Intestinal Mucositis in Mice by Inhibiting Cytokine-Mediated Apoptosis in Intestinal Crypt Cells , 2015, PloS one.

[38]  François Schiettecatte,et al.  OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders , 2014, Nucleic Acids Res..

[39]  A. F. Scott,et al.  OMIM.org: Online Mendelian Inheritance in Man , 2015 .

[40]  Houyin Shi,et al.  Bifidobacterium infantis has a beneficial effect on 5-fluorouracil-induced intestinal mucositis in rats. , 2015, Beneficial microbes.

[41]  Y. Li,et al.  Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6. , 2014, Toxicology and applied pharmacology.

[42]  W. Chu.  Tumor necrosis factor. , 2013, Cancer letters.

[43]  F. Cunha,et al.  Inflammatory intestinal damage induced by 5-fluorouracil requires IL-4. , 2013, Cytokine.

[44]  Yi-Fang Huang,et al.  5-Fluorouracil Induced Intestinal Mucositis via Nuclear Factor-κB Activation by Transcriptomic Analysis and In Vivo Bioluminescence Imaging , 2012, PloS one.

[45]  李佳橙,et al.  5-Fluorouracil induced intestinal mucositis via nuclear factor-κB activation by transcriptomic analysis and in vivo bioluminescence imaging , 2012 .

[46]  T. Gilmore,et al.  NF‐κB: where did it come from and why? , 2012, Immunological reviews.

[47]  S. Ghosh,et al.  Crosstalk in NF-κB signaling pathways , 2011, Nature Immunology.

[48]  S. Ghosh,et al.  NF-κB in immunobiology , 2011, Cell Research.

[49]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[50]  Alexander Martin,et al.  BisoGenet: a new tool for gene network building, visualization and analysis , 2010, BMC Bioinformatics.

[51]  T. Lawrence.  The nuclear factor NF-kappaB pathway in inflammation. , 2009, Cold Spring Harbor perspectives in biology.

[52]  S. Ghosh,et al.  The NF-kappaB family of transcription factors and its regulation. , 2009, Cold Spring Harbor perspectives in biology.

[53]  Hyun-kyung Shin,et al.  The anti-inflammatory effects of methylsulfonylmethane on lipopolysaccharide-induced inflammatory responses in murine macrophages. , 2009, Biological & pharmaceutical bulletin.

[54]  Ji-Yeon Kim,et al.  Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-kappaB in RAW 264.7 macrophages. , 2008, European journal of pharmacology.

[55]  Y. Surh,et al.  Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. , 2001, Mutation research.