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image of Forsythiaside A Ameliorates Inflammation by Regulating the Autophagy in Methotrexate-induced Intestinal Mucositis

Abstract

Background

Methotrexate (MTX) effectively eliminates cancerous cells but can also cause inflammation intestinal, known as mucositis. Forsythiaside A (FTA) from Forsythia suspensa has shown promise in relieving mucositis by targeting the NLRP3 pathways. Since NLRP3 inflammasome activation is negatively regulated by autophagy, this study explores how FTA-mediated autophagy affects NLRP3 inflammasome in treating MTX-induced intestinal inflammation.

Methods

Intestinal mucositis was induced in rats with MTX. FTA's impact was assessed using HE staining and ELISA. The mechanism was studied using immunofluorescence, western blot, and ELISA.

Results

FTA treatment resulted in reduced levels of D-lactic acid and diamine oxidase (DAO) in MTX-treated rats. Western blot and immunofluorescence analyses revealed up-regulation of Beclin-1 and LC3II/I, accumulation of LC3, and down-regulation of p62 expression levels in MTX-treated rats following 40 or 80 mg/kg FTA intervention. However, when the autophagy inhibitor 3-MA was used, the intestinal pathology was exacerbated, the inflammatory scores increased, and serum levels of TNF-α, IL-1β, and IL-18 were elevated. Western blotting indicated decreased LC3II/I expression, while NLRP3, cleaved caspase 1, and cleaved IL-1β expressions were upregulated.

Conclusion

These findings suggested that FTA alleviated MTX-treated intestinal mucositis by activating autophagy, which in turn inhibits the NLRP3 inflammasome.

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2025-01-29
2025-04-14

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References

  1. Farhadi A. Banan A. Fields J. Keshavarzian A. Intestinal barrier: An interface between health and disease. J. Gastroenterol. Hepatol. 2003 18 5 479 497 10.1046/j.1440‑1746.2003.03032.x 12702039
    [Google Scholar]
  2. Tao S. Duanmu Y. Dong H. Tian J. Ni Y. Zhao R. A high-concentrate diet induced colonic epithelial barrier disruption is associated with the activating of cell apoptosis in lactating goats. BMC Vet. Res. 2014 10 1 235 10.1186/s12917‑014‑0235‑2 25256013
    [Google Scholar]
  3. Johansson M.E.V. Hansson G.C. Immunological aspects of intestinal mucus and mucins. Nat. Rev. Immunol. 2016 16 10 639 649 10.1038/nri.2016.88 27498766
    [Google Scholar]
  4. Majumdar A.S. Karbelkar S.A. Altered systemic bioavailability and organ distribution of azathioprine in methotrexate-induced intestinal mucositis in rats. Indian J. Pharmacol. 2016 48 3 241 247 10.4103/0253‑7613.182895 27298491
    [Google Scholar]
  5. Nagakubo J. Tomimatsu T. Kitajima M. Takayama H. Aimi N. Horie T. Characteristics of transport of fluoresceinated methotrexate in rat small intestine. Life Sci. 2001 69 7 739 747 10.1016/S0024‑3205(01)01162‑6 11487087
    [Google Scholar]
  6. Boukhettala N. Leblond J. Claeyssens S. Faure M. Le Pessot F. Bôle-Feysot C. Hassan A. Mettraux C. Vuichoud J. Lavoinne A. Breuillé D. Déchelotte P. Coëffier M. Methotrexate induces intestinal mucositis and alters gut protein metabolism independently of reduced food intake. Am. J. Physiol. Endocrinol. Metab. 2009 296 1 E182 E190 10.1152/ajpendo.90459.2008 18984853
    [Google Scholar]
  7. Shibutani S.T. Saitoh T. Nowag H. Münz C. Yoshimori T. Autophagy and autophagy-related proteins in the immune system. Nat. Immunol. 2015 16 10 1014 1024 10.1038/ni.3273 26382870
    [Google Scholar]
  8. Klionsky D.J. Emr S.D. Autophagy as a regulated pathway of cellular degradation. Science 2000 290 5497 1717 1721 10.1126/science.290.5497.1717 11099404
    [Google Scholar]
  9. Levine B. Mizushima N. Virgin H.W. Autophagy in immunity and inflammation. Nature 2011 469 7330 323 335 10.1038/nature09782 21248839
    [Google Scholar]
  10. Zhou R. Yazdi A.S. Menu P. Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011 469 7329 221 225 10.1038/nature09663 21124315
    [Google Scholar]
  11. Dikic I. Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 2018 19 6 349 364 10.1038/s41580‑018‑0003‑4 29618831
    [Google Scholar]
  12. Aparicio I.M. Martin Muñoz P. Salido G.M. Peña F.J. Tapia J.A. The autophagy-related protein LC3 is processed in stallion spermatozoa during short-and long-term storage and the related stressful conditions. Animal 2016 10 7 1182 1191 10.1017/S1751731116000240 26932581
    [Google Scholar]
  13. Chang Y.P. Ka S.M. Hsu W.H. Chen A. Chao L.K. Lin C.C. Hsieh C.C. Chen M.C. Chiu H.W. Ho C.L. Chiu Y.C. Liu M.L. Hua K.F. Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy. J. Cell. Physiol. 2015 230 7 1567 1579 10.1002/jcp.24903 25535911
    [Google Scholar]
  14. Li B. Shao S. Yuan L. Jia R. Sun J. Ji Q. Sui H. Zhou L. Zhang Y. Liu H. Li Q. Wang Y. Zhang B. Effects of mild moxibustion on intestinal microbiome and NLRP3 inflammasome in rats with 5-fluorouracil-induced intestinal mucositis. J. Integr. Med. 2021 19 2 144 157 10.1016/j.joim.2020.12.004 33353843
    [Google Scholar]
  15. Kimura T. Jain A. Choi S.W. Mandell M.A. Schroder K. Johansen T. Deretic V. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J. Cell Biol. 2015 210 6 973 989 10.1083/jcb.201503023 26347139
    [Google Scholar]
  16. Todd I. Negm O.H. Reps J. Radford P. Figueredo G. McDermott E.M. Drewe E. Powell R.J. Bainbridge S. Hamed M. A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing. Pharmacol. Res. 2017 125 Pt B 188 200
    [Google Scholar]
  17. Law A.H.Y. Yang C.L.H. Lau A.S.Y. Chan G.C.F. Antiviral effect of forsythoside A from Forsythia suspensa (Thunb.) Vahl fruit against influenza A virus through reduction of viral M1 protein. J. Ethnopharmacol. 2017 209 236 247 10.1016/j.jep.2017.07.015 28716571
    [Google Scholar]
  18. Tong C. Chen T. Chen Z. Wang H. Wang X. Liu F. Dai H. Wang X. Li X. Forsythiaside a plays an anti-inflammatory role in LPS-induced mastitis in a mouse model by modulating the MAPK and NF-κB signaling pathways. Res. Vet. Sci. 2021 136 390 395 10.1016/j.rvsc.2021.03.020 33799169
    [Google Scholar]
  19. Zheng X. Fu Y. Shi S.S. Wu S. Yan Y. Xu L. Wang Y. Jiang Z. Effect of Forsythiaside A on the RLRs Signaling Pathway in the Lungs of Mice Infected with the Influenza A Virus FM1 Strain. Molecules 2019 24 23 4219 10.3390/molecules24234219 31757053
    [Google Scholar]
  20. Lu Z. Yang H. Cao H. Huo C. Chen Y. Liu D. Xie P. Zhou H. Liu J. Yu L. Forsythoside A protects against lipopolysaccharide-induced acute lung injury through up-regulating microRNA-124. Clin. Sci. 2020 134 19 2549 2563 10.1042/CS20200598 32975280
    [Google Scholar]
  21. Lang W. Cheng M. Zheng X. Zhao Y. Qu Y. Jia Z. Gong H. Ali I. Tang J. Zhang H. Forsythiaside A alleviates methotrexate-induced intestinal mucositis in rats by modulating the NLRP3 signaling pathways. Int. Immunopharmacol. 2022 103 108466 10.1016/j.intimp.2021.108466 34933162
    [Google Scholar]
  22. Lang W. Wen X. Zhang S. Liang X. Chen L. Zhang D. Zhou R. Ali I. Hu X. Zhang H. Cheng M. Cynaroside ameliorates methotrexate-induced enteritis in rats through inhibiting NLRP3 inflammasome activation. Front. Immunol. 2024 15 1405084 10.3389/fimmu.2024.1405084 38835771
    [Google Scholar]
  23. Murray M.J. Barbose J.J. Cobb C.F. Serum D(-)-lactate levels as a predictor of acute intestinal ischemia in a rat model. J. Surg. Res. 1993 54 5 507 509 10.1006/jsre.1993.1078 8361176
    [Google Scholar]
  24. Fukudome I. Kobayashi M. Dabanaka K. Maeda H. Okamoto K. Okabayashi T. Baba R. Kumagai N. Oba K. Fujita M. Hanazaki K. Diamine oxidase as a marker of intestinal mucosal injury and the effect of soluble dietary fiber on gastrointestinal tract toxicity after intravenous 5-fluorouracil treatment in rats. Med. Mol. Morphol. 2014 47 2 100 107 10.1007/s00795‑013‑0055‑7 24005798
    [Google Scholar]
  25. Su S.H. Wu Y.F. Lin Q. Wang D.P. Hai J. URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion. J. Neuroinflammation 2019 16 1 260 10.1186/s12974‑019‑1668‑0 31815636
    [Google Scholar]
  26. Gong L. Yu L. Gong X. Wang C. Hu N. Dai X. Peng C. Li Y. Exploration of anti-inflammatory mechanism of forsythiaside A and forsythiaside B in CuSO4-induced inflammation in zebrafish by metabolomic and proteomic analyses. J. Neuroinflammation 2020 17 1 173 10.1186/s12974‑020‑01855‑9 32493433
    [Google Scholar]
  27. Zhou F. Peng J. Zhao Y. Huang W. Jiang Y. Li M. Wu X. Lu B. Varietal classification and antioxidant activity prediction of Osmanthus fragrans Lour. flowers using UPLC–PDA/QTOF–MS and multivariable analysis. Food Chem. 2017 217 490 497 10.1016/j.foodchem.2016.08.125 27664663
    [Google Scholar]
  28. de Koning B.A.E. van Dieren J.M. Lindenbergh-Kortleve D.J. van der Sluis M. Matsumoto T. Yamaguchi K. Einerhand A.W. Samsom J.N. Pieters R. Nieuwenhuis E.E.S. Contributions of mucosal immune cells to methotrexate-induced mucositis. Int. Immunol. 2006 18 6 941 949 10.1093/intimm/dxl030 16636014
    [Google Scholar]
  29. Lin H.C. Visek W.J. Colon mucosal cell damage by ammonia in rats. J. Nutr. 1991 121 6 887 893 10.1093/jn/121.6.887 2033472
    [Google Scholar]
  30. Izquierdo-Casas J. Comas-Basté O. Latorre-Moratalla M.L. Lorente-Gascón M. Duelo A. Vidal-Carou M.C. Soler-Singla L. Low serum diamine oxidase (DAO) activity levels in patients with migraine. J. Physiol. Biochem. 2018 74 1 93 99 10.1007/s13105‑017‑0571‑3 28624934
    [Google Scholar]
  31. Nielsen C. Lindholt J.S. Erlandsen E.J. Mortensen F.V. d-lactate as a marker of venous-induced intestinal ischemia: An experimental study in pigs. Int. J. Surg. 2011 9 5 428 432 10.1016/j.ijsu.2011.04.004 21530695
    [Google Scholar]
  32. Parzych K.R. Klionsky D.J. An overview of autophagy: morphology, mechanism, and regulation. Antioxid. Redox Signal. 2014 20 3 460 473 10.1089/ars.2013.5371 23725295
    [Google Scholar]
  33. Cao Z. Wang Y. Long Z. He G. Interaction between autophagy and the NLRP3 inflammasome. Acta Biochim. Biophys. Sin. 2019 51 11 1087 1095 10.1093/abbs/gmz098 31609412
    [Google Scholar]
  34. Deretic V. Saitoh T. Akira S. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 2013 13 10 722 737 10.1038/nri3532 24064518
    [Google Scholar]
  35. Zhang H. Lang W. Liu X. Bai J. Jia Q. Shi Q. Procyanidin A1 alleviates DSS-induced ulcerative colitis via regulating AMPK/mTOR/p70S6K-mediated autophagy. J. Physiol. Biochem. 2022 78 1 213 227 10.1007/s13105‑021‑00854‑5 35001346
    [Google Scholar]
  36. Dupont N. Jiang S. Pilli M. Ornatowski W. Bhattacharya D. Deretic V. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β. EMBO J. 2011 30 23 4701 4711 10.1038/emboj.2011.398 22068051
    [Google Scholar]
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Forsythiaside A Ameliorates Inflammation by Regulating the Autophagy in Methotrexate-induced Intestinal Mucositis
Bentham Science Publishers ; https://doi.org/10.2174/0113862073324564241211064620
/content/journals/cchts/10.2174/0113862073324564241211064620
/content/journals/cchts/10.2174/0113862073324564241211064620
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  • Article Type:     Research Article
Keywords: autophagy ; LC3II/I ; methotrexate ; Forsythiaside A ; NLRP3 inflammasome ; intestinal mucositis

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