Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Letters in Drug Design & Discovery
  4. Volume 21, Issue 17
  5. Article
Volume 21, Issue 17
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

AHR and its signaling pathways are promising therapeutic targets for psoriasis. Recent studies in traditional Chinese medicine have confirmed that Indirubin acts as an efficient ligand of AHR, inhibiting the inflammatory response. Clarifying its mechanism of action remains essential.

Objective

This study uses bioinformatics to predict Indirubin’s potential molecular mechanism in treating psoriasis and validate the results in animal models.

Methods

Indirubin and psoriasis-related targets were screened using the TCMPSP, GeneCards, and OMIM databases. Using the STRING database, a network was constructed and enriched for target protein function. Imiquimod was used to validate the core targets in a psoriasis-like mouse model.

Results

Network pharmacology suggested that indirubin targets pathways mainly involved in cancer, inflammation, apoptosis, and other disease mechanisms, including PI3K-Akt, IL-17, and TNF pathways related to psoriasis pathogenesis. Indirubin significantly affected the severity of imiquimod-induced skin lesions in psoriasis-like mice. It also inhibited the expression of IL-6 and il-1β inflammatory factors and rescued p65 and p-p65 expressions in psoriasis-like mice.

Conclusion

Network pharmacology, combined with cellular experiments, tentatively confirmed that Indirubin reduces the inflammatory response in psoriasis-like mice through the AHR/NF-κB signaling pathway.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/lddd/10.2174/0115701808316043240718070156
2024-08-20
2025-06-18

  • From This Site

    /content/journals/lddd/10.2174/0115701808316043240718070156
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. GriffithsC.E.M. ArmstrongA.W. GudjonssonJ.E. BarkerJ.N.W.N. Psoriasis.Lancet2021397102811301131510.1016/S0140‑6736(20)32549‑6 33812489
     [Google Scholar]
  2. Guttman-YasskyE. DhingraN. LeungD.Y.M. New era of biologic therapeutics in atopic dermatitis.Expert Opin. Biol. Ther.201313454956110.1517/14712598.2013.758708 23323893
     [Google Scholar]
  3. FragaN.A.A. OliveiraM.F.P. FolladorI. RochaB.O. RêgoV.R. Psoriasis and uveitis: a literature review.An. Bras. Dermatol.201287687788310.1590/S0365‑05962012000600009 23197207
     [Google Scholar]
  4. BeutnerK.R. TyringS. Human papillomavirus and human disease.Am. J. Med.19971025A91510.1016/S0002‑9343(97)00178‑2 9217657
     [Google Scholar]
  5. YangX.J. MengX.H. Advances in the treatment of psoriasis.Journal of Mudanjiang Medical College2020416120124
     [Google Scholar]
  6. DongL.J. YeR.X. ZhangX.B. XuX. Research progress on the efficacy and side effects of cyclosporine in the treatment of psoriasis.J. Dermatol. Vener. Dis. Diagnosis Treat.2020273207213
     [Google Scholar]
  7. ZhaoC.H. ZhenL. Research progress on the effects of biologic agents for psoriasis on cardiovascular disease.J. Integr. Med. & Cardio. Dis.2021192262265
     [Google Scholar]
  8. WangB. GuoS.J. LiY.X. ZhangG.Q. Progress in the mechanism and application of photodynamic therapy for the treatment of psoriasis.Shandong Medicine20216148891
     [Google Scholar]
  9. LiC.D. LiL.E. MengJ.Y. LiuQ.Y. LvZ.Y. ZhangQ. Progress of research on blood-heat evidence in the treatment of common psoriasis in Chinese medicine.Liaoning Zhongyiyao Daxue Xuebao2021234117121
     [Google Scholar]
  10. LaiJ. LiuY. PengY. GeP. HeC. LiuC. ChenY. GuoA. HuC. Indirubin Treatment of Lipopolysaccharide-Induced Mastitis in a Mouse Model and Activity in Mouse Mammary Epithelial Cells.Mediators Inflamm.2017201711310.1155/2017/3082805 28255203
     [Google Scholar]
  11. LinY.K. SeeL.C. HuangY.H. ChiC.C. HuiR.C.Y. Comparison of indirubin concentrations in indigo naturalis ointment for psoriasis treatment: a randomized, double‐blind, dosage‐controlled trial.Br. J. Dermatol.2018178112413110.1111/bjd.15894 28815560
     [Google Scholar]
  12. GaitanisG. MagiatisP. VelegrakiA. BassukasI.D. A traditional Chinese remedy points to a natural skin habitat: indirubin (indigo naturalis) for psoriasis and the Malassezia metabolome.Br. J. Dermatol.2018179380010.1111/bjd.16807 29791716
     [Google Scholar]
  13. GuangliR. Comparison of the effects and mechanisms of AZT, paeoniflorin, and Indirubin on mouse psoriasis models.2019
     [Google Scholar]
  14. BockK.W. Aryl hydrocarbon receptor (AHR)-mediated inflammation and resolution: Non-genomic and genomic signaling.Biochem. Pharmacol.202018211422010.1016/j.bcp.2020.114220 32941865
     [Google Scholar]
  15. FurueM. TakaharaM. NakaharaT. UchiH. Role of AhR/ARNT system in skin homeostasis.Arch. Dermatol. Res.2014306976977910.1007/s00403‑014‑1481‑7 24966027
     [Google Scholar]
  16. XueX. WuJ. LiJ. XuJ. DaiH. TaoC. LiC. HuJ. Indirubin attenuates mouse psoriasis-like skin lesion in a CD274-dependent manner: an achievement of RNA sequencing.Biosci. Rep.2018386BSR2018095810.1042/BSR20180958 30341238
     [Google Scholar]
  17. FurueM. Hashimoto-HachiyaA. TsujiG. Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis.Int. J. Mol. Sci.20192021542410.3390/ijms20215424 31683543
     [Google Scholar]
  18. HuY.Q. LiuP. MuZ.L. ZhangJ.Z. Aryl hydrocarbon receptor expression in serum, peripheral blood mononuclear cells, and skin lesions of patients with atopic dermatitis and its correlation with disease severity.Chin. Med. J. (Engl.)2020133214815310.1097/CM9.0000000000000591 31868801
     [Google Scholar]
  19. XiongH. XuY. TanG. HanY. TangZ. XuW. ZengF. GuoQ. Glycyrrhizin ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice and inhibits TNF-α-induced ICAM-1 expression via NF-κB/MAPK in HaCaT cells.Cell. Physiol. Biochem.20153541335134610.1159/000373955 25720416
     [Google Scholar]
  20. RajanN. LangtryJ.A.A. Generalized exacerbation of psoriasis associated with imiquimod cream treatment of superficial basal cell carcinomas.Clin. Exp. Dermatol.200631114014110.1111/j.1365‑2230.2005.01938.x 16309513
     [Google Scholar]
  21. QuivyV. Van LintC. Regulation at multiple levels of NF-κB-mediated transactivation by protein acetylation.Biochem. Pharmacol.20046861221122910.1016/j.bcp.2004.05.039 15313420
     [Google Scholar]
  22. GottliebA.B. ChamianF. MasudS. CardinaleI. AbelloM.V. LowesM.A. ChenF. MaglioccoM. KruegerJ.G. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques.J. Immunol.200517542721272910.4049/jimmunol.175.4.2721 16081850
     [Google Scholar]
  23. ZhangA. NingB. SunN. WeiJ. JuX. Indirubin Increases CD4+CD25+Foxp3+ Regulatory T Cells to Prevent Immune Thrombocytopenia in Mice.PLoS One20151011e014263410.1371/journal.pone.0142634 26571298
     [Google Scholar]
  24. WeiJ. LiuM. XiaoT. QuL. ChenH.D. HeC.D. Analysis of predisposing factors of common psoriasis.Chin. Gen. Med.2011142427832785
     [Google Scholar]
  25. LvY.T. WangW.L. Advances in the study of regulatory T lymphocytes and Th17 cells and psoriasis.International Journal of Dermatologic. Venereology2012385313315
     [Google Scholar]
  26. van der FitsL. MouritsS. VoermanJ.S.A. KantM. BoonL. LamanJ.D. CornelissenF. MusA.M. FlorenciaE. PrensE.P. LubbertsE. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.J. Immunol.200918295836584510.4049/jimmunol.0802999 19380832
     [Google Scholar]
  27. ShibataS. TadaY. AsanoY. YanabaK. SugayaM. KadonoT. KandaN. WatanabeS. SatoS. IL-27 activates Th1-mediated responses in imiquimod-induced psoriasis-like skin lesions.J. Invest. Dermatol.2013133247948810.1038/jid.2012.313 22951728
     [Google Scholar]
  28. WangG. LiuY. Traditional Chinese medicine is effective and safe in the treatment of psoriasis.Int. J. Dermatol.200443755210.1111/j.1365‑4632.2004.02181.x 15230903
     [Google Scholar]
  29. TruninaT.I. The lipid peroxidation status of psoriasis patients]. Lik. Sprava, 1998, (3), 105-107. [The lipid peroxidation status of psoriasis patients]. 9695582
     [Google Scholar]
  30. KupetskyE.A. MathersA.R. FerrisL.K. Anti-cytokine therapy in the treatment of psoriasis.Cytokine201361370471210.1016/j.cyto.2012.12.027 23410503
     [Google Scholar]
  31. MicaliG. LacarrubbaF. MusumeciM.L. MassiminoD. NascaM.R. Cutaneous vascular patterns in psoriasis.Int. J. Dermatol.201049324925610.1111/j.1365‑4632.2009.04287.x 20465659
     [Google Scholar]
  32. ZabaL.C. KruegerJ.G. LowesM.A. Resident and “inflammatory” dendritic cells in human skin.J. Invest. Dermatol.2009129230230810.1038/jid.2008.225 18685620
     [Google Scholar]
  33. MahlerV. DiepgenT. SkudlikC. BeckerD. DickelH. FartaschM. GeierJ. HäberleM. HillenU. KrohnS. JohnS.M. WeisshaarE. WerfelT. ZagrodnikF. Psoriasis predisposition and occupational triggering factors in the appraisal of occupational medical expertises.J. Dtsch. Dermatol. Ges.2014126519529 24889306
     [Google Scholar]
  34. FryL. BakerB.S. Triggering psoriasis: the role of infections and medications.Clin. Dermatol.200725660661510.1016/j.clindermatol.2007.08.015 18021899
     [Google Scholar]
  35. GabayC. LamacchiaC. PalmerG. IL-1 pathways in inflammation and human diseases.Nat. Rev. Rheumatol.20106423224110.1038/nrrheum.2010.4 20177398
     [Google Scholar]
  36. GruazD. DidierjeanL. GrassiJ. FrobertY. DayerJ.M. SauratJ.H. Interleukin 1 alpha and beta in psoriatic skin: enzymoimmunoassay, immunoblot studies and effect of systemic retinoids.Dermatology1989179420220610.1159/000248361 2695356
     [Google Scholar]
  37. ShepherdJ. LittleM.C. NicklinM.J.H. Psoriasis-like cutaneous inflammation in mice lacking interleukin-1 receptor antagonist.J. Invest. Dermatol.2004122366566910.1111/j.0022‑202X.2004.22305.x 15086551
     [Google Scholar]
  38. NakajimaA. MatsukiT. KomineM. AsahinaA. HoraiR. NakaeS. IshigameH. KakutaS. SaijoS. IwakuraY. TNF, but not IL-6 and IL-17, is crucial for the development of T cell-independent psoriasis-like dermatitis in Il1rn-/- mice.J. Immunol.201018531887189310.4049/jimmunol.1001227 20610641
     [Google Scholar]
  39. MengG. ZhangF. FussI. KitaniA. StroberW. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses.Immunity200930686087410.1016/j.immuni.2009.04.012 19501001
     [Google Scholar]
  40. NebertD.W. KarpC.L. Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)-metabolized eicosanoids and AHR biology.J. Biol. Chem.200828352360613606510.1074/jbc.R800053200 18713746
     [Google Scholar]
  41. PlotnikovE.Y. SilachevD.N. PopkovV.A. ZorovaL.D. PevznerI.B. ZorovS.D. JankauskasS.S. BabenkoV.A. SukhikhG.T. ZorovD.B. Intercellular Signalling Cross-Talk: To Kill, To Heal and To Rejuvenate.Heart Lung Circ.201726764865910.1016/j.hlc.2016.12.002 28190758
     [Google Scholar]
  42. Di MeglioP. DuarteJ.H. AhlforsH. OwensN.D.L. LiY. VillanovaF. TosiI. HirotaK. NestleF.O. MrowietzU. GilchristM.J. StockingerB. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.Immunity2014406989100110.1016/j.immuni.2014.04.019 24909886
     [Google Scholar]
  43. AdachiJ. MoriY. MatsuiS. TakigamiH. FujinoJ. KitagawaH. MillerC.A.III KatoT. SaekiK. MatsudaT. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine.J. Biol. Chem.200127634314753147810.1074/jbc.C100238200 11425848
     [Google Scholar]
  44. WangC. PetrielloM.C. ZhuB. HennigB. PCB 126 induces monocyte/macrophage polarization and inflammation through AhR and NF-κB pathways.Toxicol. Appl. Pharmacol.2019367718110.1016/j.taap.2019.02.006 30768972
     [Google Scholar]
/content/journals/lddd/10.2174/0115701808316043240718070156
Loading
Indirubin as an AHR Ligand: A Combined Network Pharmacology and Experimental Approach to Psoriasis Therapy
Letters in Drug Design & Discovery 21, 3946 (2024); https://doi.org/10.2174/0115701808316043240718070156
/content/journals/lddd/10.2174/0115701808316043240718070156
/content/journals/lddd/10.2174/0115701808316043240718070156
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): AHR/NF-κB pathway; imiquimod; Indirubin; network pharmacology; NF-κB; psoriasis

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test