Skip to content
2000
Volume 32, Issue 14
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Introduction

Nepetin is a type of O-methylated flavone (6-hydroxy luteolin) and has been found in many herbal medicines that exhibit various pharmacological properties, including anti-inflammatory responses. Here, we aimed to investigate the efficacy of nepetin in attenuating inflammatory responses in cultured keratinocytes and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in BALB/c mice.

Methods

Various assay methods including cell viability, flow cytometry, fluorometry, confocal microscopy, western blot, ELISA techniques, staining methods, score and scratch frequency assessment, were employed to explore the mechanisms.

Results

LPS-treated keratinocytes showed a significant increase in inflammatory mediators (iNOS, COX-2, PGES2, and NO) and cytokines (IL-1β, IL-6, and TNF-α) in a dose-dependent manner. Treatment with nepetin prevented LPS-induced cell death and inhibited inflammatory mediators and the production of cytokines in cultured keratinocytes. This inhibition was achieved by nepetin, which inhibited LPS-induced ROS production and the translocation of NF-κB in the cultures, thereby inhibiting the generation of inflammatory mediators and/or cytokines. In a mouse model of AD, treatment with nepetin reduced skin inflammation symptoms in a dose-dependent manner, as evidenced by the significant reduction of inflammation-related cytokines, skin lesions, and behavior scores.

Conclusion

Based on the present and study, nepetin is the safest bioactive compound with potential therapeutic applications for AD-related skin lesions and adverse skin reactions.

Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673244967231101114033
2024-01-09
2025-10-08
Loading full text...

Full text loading...

References

  1. SinghN. BabyD. RajguruJ. PatilP. ThakkannavarS. PujariV. Inflammation and cancer.Ann. Afr. Med.201918312112610.4103/aam.aam_56_1831417011
    [Google Scholar]
  2. WaldmanA.R. AhluwaliaJ. UdkoffJ. BorokJ.F. EichenfieldL.F. Atopic dermatitis.Pediatr. Rev.201839418019310.1542/pir.2016‑016929610426
    [Google Scholar]
  3. ShenD. FengY. ZhangX. LiuJ. GongL. LiaoH. LiR. In vitro immunomodulatory effects of Inonotus obliquus extracts on resting m0 macrophages and LPS-induced M1 macrophages.Evid. Based Complement. Alternat. Med.2022202211210.1155/2022/825134435497923
    [Google Scholar]
  4. HussainZ. ThuH.E. ShuidA.N. KesharwaniP. KhanS. HussainF. Phytotherapeutic potential of natural herbal medicines for the treatment of mild-to-severe atopic dermatitis: A review of human clinical studies.Biomed. Pharmacother.20179359660810.1016/j.biopha.2017.06.08728686974
    [Google Scholar]
  5. HonK.L. LeungA.K.C. LeungT.N.H. LeeV.W.Y. Investigational drugs for atopic dermatitis.Expert Opin. Investig. Drugs201827863764710.1080/13543784.2018.149472330058384
    [Google Scholar]
  6. LiH. ZhangZ. ZhangH. GuoY. YaoZ. Update on the pathogenesis and therapy of atopic dermatitis.Clin. Rev. Allergy Immunol.202161332433810.1007/s12016‑021‑08880‑334338977
    [Google Scholar]
  7. NygaardU. VestergaardC. DeleuranM. Emerging treatment options in atopic dermatitis: Systemic therapies.Dermatology2017233534435710.1159/00048440629320765
    [Google Scholar]
  8. SalvatiL. CosmiL. AnnunziatoF. From emollients to biologicals: Targeting atopic dermatitis.Int. J. Mol. Sci.202122191038110.3390/ijms22191038134638722
    [Google Scholar]
  9. BieberT. Atopic dermatitis: An expanding therapeutic pipeline for a complex disease.Nat. Rev. Drug Discov.2022211214010.1038/s41573‑021‑00266‑634417579
    [Google Scholar]
  10. SivaranjaniN. Role of reactive oxygen species and antioxidants in atopic dermatitis.J. Clin. Diagn. Res.2013712268310.7860/JCDR/2013/6635.3732
    [Google Scholar]
  11. GongA.G.W. ZhangL.M.L. LamC.T.W. XuM.L. WangH.Y. LinH.Q. DongT.T.X. TsimK.W.K. Polysaccharide of danggui buxue tang, an ancient chinese herbal decoction, induces expression of pro-inflammatory cytokines possibly via activation of nfκb signaling in cultured RAW 264.7 cells.Phytother. Res.201731227428310.1002/ptr.574527807897
    [Google Scholar]
  12. GongG. WangH. KongX. DuanR. DongT.T.X. TsimK.W.K. Flavonoids are identified from the extract of Scutellariae radix to suppress inflammatory-induced angiogenic responses in cultured RAW 264.7 macrophages.Sci. Rep.2018811741210.1038/s41598‑018‑35817‑230479366
    [Google Scholar]
  13. PerkinsM.A. OsterhuesM.A. FarageM.A. RobinsonM.K. A noninvasive method to assess skin irritation and compromised skin conditions using simple tape adsorption of molecular markers of inflammation.Skin Res. Technol.20017422723710.1034/j.1600‑0846.2001.70405.x11737818
    [Google Scholar]
  14. HobbsR.M. Silva-VargasV. GrovesR. WattF.M. Expression of activated MEK1 in differentiating epidermal cells is sufficient to generate hyperproliferative and inflammatory skin lesions.J. Invest. Dermatol.2004123350351510.1111/j.0022‑202X.2004.23225.x15304090
    [Google Scholar]
  15. LeeJ.H. JoE.H. LeeB. NohH.M. ParkS. LeeY.M. KimD.K. ParkM.C. Soshiho-tang, a traditional herbal medicine, alleviates atopic dermatitis symptoms via regulation of inflammatory mediators.Front. Pharmacol.20191074210.3389/fphar.2019.0074231338033
    [Google Scholar]
  16. KangS.J. JoE.H. YangG.J. ShimY.H. HongJ.E. ParkM.C. Efficacy and safety of Soshiho-tang in patients with atopic dermatitis and gastrointestinal disorders.Medicine (Baltimore)20199818e1547910.1097/MD.000000000001547931045830
    [Google Scholar]
  17. ChenX. HanR. HaoP. WangL. LiuM. JinM. KongD. LiX. Nepetin inhibits IL-1β induced inflammation via NF-κB and MAPKs signaling pathways in ARPE-19 cells.Biomed. Pharmacother.2018101879310.1016/j.biopha.2018.02.05429477475
    [Google Scholar]
  18. JiN. KimS.G. ParkH.H. LeeE. LeeY.J. JinM. LeeE. Nepetin, a natural compound from Inulae flos, suppresses degranulation and eicosanoid generation through PLCγ1 and Akt signaling pathways in mast cells.Arch. Pharm. Res.202043222423210.1007/s12272‑020‑01212‑732016828
    [Google Scholar]
  19. ThitilertdechaP. TantithavornV. PoungpairojP. OnlamoonN. Determination of suppressive effect on human T-cell activation by hispidulin, nepetin, and vanillic acid.Immunopharmacol. Immunotoxicol.201941659159810.1080/08923973.2019.167516531595796
    [Google Scholar]
  20. JiaJ.M. WuC.F. LiuW. YuH. HaoY. ZhengJ.H. JiY.R. Antiinflammatory and analgesic activities of the tissue culture of Saussurea involucrata.Biol. Pharm. Bull.20052891612161410.1248/bpb.28.161216141525
    [Google Scholar]
  21. GongG. HuangJ. YangY. QiB. HanG. ZhengY. HeH. ChanK. TsimK.W.K. DongT.T.X. Saussureae involucratae herba (Snow Lotus): Review of chemical compositions and pharmacological properties.Front. Pharmacol.202010154910.3389/fphar.2019.0154932009958
    [Google Scholar]
  22. GongG. XieF. ZhengY. HuW. QiB. HeH. DongT.T.X. TsimK.W.K. The effect of methanol extract from Saussurea involucrata in the lipopolysaccharide-stimulated inflammation in cultured RAW 264.7 cells.J. Ethnopharmacol.202025111253210.1016/j.jep.2019.11253231884036
    [Google Scholar]
  23. ClavinM. GorzalczanyS. MachoA. MuñozE. FerraroG. AcevedoC. MartinoV. Anti-inflammatory activity of flavonoids from Eupatorium arnottianum.J. Ethnopharmacol.2007112358558910.1016/j.jep.2007.04.00717570627
    [Google Scholar]
  24. GarayevE. Di GiorgioC. HerbetteG. MabroukiF. ChiffolleauP. RouxD. SallanonH. OllivierE. EliasR. BaghdikianB. Bioassay-guided isolation and UHPLC-DAD-ESI-MS/MS quantification of potential anti-inflammatory phenolic compounds from flowers of Inula montana L.J. Ethnopharmacol.201822617618410.1016/j.jep.2018.08.00530102993
    [Google Scholar]
  25. SabaE. LeeY. YangW.K. LeeY.Y. KimM. WooS.M. KimK. KwonY.S. KimT.H. KwakD. ParkY.C. ShinH.J. HanC.K. OhJ.W. LeeY.C. KangH.S. RheeM.H. KimS.H. Effects of a herbal formulation, KGC3P, and its individual component, nepetin, on coal fly dust-induced airway inflammation.Sci. Rep.20201011403610.1038/s41598‑020‑68965‑532820197
    [Google Scholar]
  26. AutissierP. SoulasC. BurdoT.H. WilliamsK.C. Evaluation of a 12-color flow cytometry panel to study lymphocyte, monocyte, and dendritic cell subsets in humans.Cytometry A201077A541041910.1002/cyto.a.2085920099249
    [Google Scholar]
  27. GassmannM. GrenacherB. RohdeB. VogelJ. Quantifying Western blots: Pitfalls of densitometry.Electrophoresis200930111845185510.1002/elps.20080072019517440
    [Google Scholar]
  28. NiwaY. SumiH. KawahiraK. TerashimaT. NakamuraT. AkamatsuH. Protein oxidative damage in the stratum corneum: Evidence for a link between environmental oxidants and the changing prevalence and nature of atopic dermatitis in Japan.Br. J. Dermatol.2003149224825410.1046/j.1365‑2133.2003.05417.x12932228
    [Google Scholar]
  29. GongG. ZhengY. The anti-UV properties of saussurea involucrate matsum. & Koidz. via regulating PI3K/Akt pathway in B16F10 cells.J. Ethnopharmacol.202126911369410.1016/j.jep.2020.11369433321189
    [Google Scholar]
  30. ChoiD. KangW. ParkT. Anti-allergic and anti-inflammatory effects of undecane on mast cells and keratinocytes.Molecules2020257155410.3390/molecules2507155432231089
    [Google Scholar]
  31. DeguineJ. BartonG.M. MyD88: A central player in innate immune signaling.F1000Prime Rep.201469710.12703/P6‑9725580251
    [Google Scholar]
  32. TakedaK. AkiraS. TLR signaling pathways.Semin. Immunol.20041613910.1016/j.smim.2003.10.00314751757
    [Google Scholar]
  33. HouD.D. ZhangW. GaoY.L. SunY. WangH.X. QiR.Q. ChenH.D. GaoX.H. Anti-inflammatory effects of quercetin in a mouse model of MC903-induced atopic dermatitis.Int. Immunopharmacol.20197410567610.1016/j.intimp.2019.10567631181406
    [Google Scholar]
  34. StänderS. Atopic dermatitis.N. Engl. J. Med.2021384121136114310.1056/NEJMra202391133761208
    [Google Scholar]
  35. WilliamsH. ChalmersJ. Prevention of atopic dermatitis.Acta Derm. Venereol.202010012adv0016610.2340/00015555‑351632419030
    [Google Scholar]
  36. AliF. VyasJ. FinlayA. Counting the burden: Atopic dermatitis and health-related quality of life.Acta Derm. Venereol.202010012adv0016110.2340/00015555‑351132412644
    [Google Scholar]
  37. GanesanK. XuB. A critical review on polyphenols and health benefits of black soybeans.Nutrients20179545510.3390/nu905045528471393
    [Google Scholar]
  38. GanesanK. XuB. Polyphenol-rich lentils and their health promoting effects.Int. J. Mol. Sci.20171811239010.3390/ijms1811239029125587
    [Google Scholar]
  39. GanesanK. XuB. Polyphenol-rich dry common beans (Phaseolus vulgaris L.) and their health benefits.Int. J. Mol. Sci.20171811233110.3390/ijms1811233129113066
    [Google Scholar]
  40. GanesanK. XuB. Molecular targets of vitexin and isovitexin in cancer therapy: A critical review.Ann. N. Y. Acad. Sci.20171401110211310.1111/nyas.1344628891090
    [Google Scholar]
  41. ColomboI. SangiovanniE. MaggioR. MattozziC. ZavaS. CorbettY. FumagalliM. CarlinoC. CorsettoP.A. ScaccabarozziD. CalvieriS. GismondiA. TaramelliD. Dell’AgliM. HaCaT cells as a reliable in vitro differentiation model to dissect the inflammatory/repair response of human keratinocytes.Mediators Inflamm.2017201711210.1155/2017/743562129391667
    [Google Scholar]
  42. YangC.C. HungY.L. KoW.C. TsaiY.J. ChangJ.F. LiangC.W. ChangD.C. HungC.F. Effect of neferine on DNCB-induced atopic dermatitis in HaCaT cells and BALB/c mice.Int. J. Mol. Sci.20212215823710.3390/ijms2215823734361003
    [Google Scholar]
  43. KangJ.K. KangH.K. HyunC.G. Anti-inflammatory effects of spiramycin in LPS-activated RAW 264.7 macrophages.Molecules20222710320210.3390/molecules2710320235630676
    [Google Scholar]
  44. LiuY. ChenW. ZhengF. YuH. WeiK. Xanthatin alleviates LPS-induced inflammatory response in RAW264.7 macrophages by inhibiting NF-κB, MAPK and STATs activation.Molecules20222714460310.3390/molecules27144603
    [Google Scholar]
  45. XuZ. ShenZ. WuB. GongS. ChenB. Small molecule natural compound targets the NF-κB signaling and ameliorates the development of osteoarthritis.J. Cell. Physiol.2021236117298730710.1002/jcp.3039233870507
    [Google Scholar]
  46. LeeY. YangW.K. YeeS.M. KimS.M. ParkY.C. ShinH.J. HanC.K. LeeY.C. KangH.S. KimS.H. KGC3P attenuates ovalbumin-induced airway inflammation through downregulation of p-PTEN in asthmatic mice.Phytomedicine20196215294210.1016/j.phymed.2019.15294231102886
    [Google Scholar]
  47. ThitilertdechaP. TantithavornV. PoungpairojP. OnlamoonN. Synergistic immunosuppressive effect of hispidulin and nepetin mixtures on human T lymphocytes.Immunopharmacol. Immunotoxicol.202244569370310.1080/08923973.2022.207721635549795
    [Google Scholar]
  48. AkramM. SyedA.S. KimK.A. LeeJ.S. ChangS.Y. KimC.Y. BaeO.N. Heme oxygenase 1-mediated novel anti-inflammatory activities of Salvia plebeia and its active components.J. Ethnopharmacol.201517432233010.1016/j.jep.2015.08.02826319962
    [Google Scholar]
  49. LajterI. PanS.P. NiklesS. OrtmannS. VasasA. Csupor-LöfflerB. ForgóP. HohmannJ. BauerR. Inhibition of COX-2 and NF-κB1 gene expression, NO production, 5-LOX, and COX-1 and COX-2 enzymes by extracts and constituents of onopordum acanthium.Planta Med.201581141270127610.1055/s‑0035‑154624226383017
    [Google Scholar]
  50. KoH.H. ChiangY.C. TsaiM.H. LiangC.J. HsuL.F. LiS.Y. WangM.C. YenF.L. LeeC.W. Eupafolin, a skin whitening flavonoid isolated from Phyla nodiflora, downregulated melanogenesis: Role of MAPK and Akt pathways.J. Ethnopharmacol.2014151138639310.1016/j.jep.2013.10.05424212072
    [Google Scholar]
  51. YenF-L. LinZ-C. LeeC-W. TsaiM-H. KoH-H. FangJ-Y. ChiangY-C. LiangC-J. HsuL-F.H. HuS.C-S. Eupafolin nanoparticles protect HaCaT keratinocytes from particulate matter-induced inflammation and oxidative stress.Int. J. Nanomedicine2016113907392610.2147/IJN.S10906227570454
    [Google Scholar]
  52. TsaiM.H. LinZ.C. LiangC.J. YenF.L. ChiangY.C. LeeC.W. Eupafolin inhibits PGE2 production and COX2 expression in LPS-stimulated human dermal fibroblasts by blocking JNK/AP-1 and Nox2/p47phox pathway.Toxicol. Appl. Pharmacol.2014279224025110.1016/j.taap.2014.06.01224967690
    [Google Scholar]
  53. LeeC.W. LinZ.C. HsuL.F. FangJ.Y. ChiangY.C. TsaiM.H. LeeM.H. LiS.Y. HuS.C.S. LeeI.T. YenF.L. Eupafolin ameliorates COX-2 expression and PGE2 production in particulate pollutants-exposed human keratinocytes through ROS/MAPKs pathways.J. Ethnopharmacol.201618930030910.1016/j.jep.2016.05.00227180879
    [Google Scholar]
  54. CiesielskaA. MatyjekM. KwiatkowskaK. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling.Cell. Mol. Life Sci.20217841233126110.1007/s00018‑020‑03656‑y33057840
    [Google Scholar]
  55. BaekW.Y. ChoiY.S. LeeS.W. SonI.O. JeonK.W. ChoiS.D. SuhC.H. Toll-like receptor signaling inhibitory peptide improves inflammation in animal model and human systemic lupus erythematosus.Int. J. Mol. Sci.202122231276410.3390/ijms22231276434884569
    [Google Scholar]
  56. HaqueM.A. JantanI. HarikrishnanH. Zerumbone suppresses the activation of inflammatory mediators in LPS-stimulated U937 macrophages through MyD88-dependent NF-κB/MAPK/PI3K-Akt signaling pathways.Int. Immunopharmacol.20185531232210.1016/j.intimp.2018.01.00129310107
    [Google Scholar]
  57. LanganS.M. IrvineA.D. WeidingerS. Atopic dermatitis.Lancet20203961024734536010.1016/S0140‑6736(20)31286‑132738956
    [Google Scholar]
  58. KimJ. KimB.E. LeungD.Y.M. Pathophysiology of atopic dermatitis: Clinical implications.Allergy Asthma Proc.2019402849210.2500/aap.2019.40.420230819278
    [Google Scholar]
  59. LeeY. ChoiH.K. N’dehK.P.U. ChoiY-J. FanM. KimE. ChungK-H. AnJ.H. Inhibitory effect of centella asiatica extract on DNCB-induced atopic dermatitis in HaCaT cells and BALB/c mice.Nutrients202012241110.3390/nu12020411
    [Google Scholar]
  60. GongG. ZhengY. XiaoJ. DongT. TsimK. Nepetin, a flavonoid derived from saussureae involucratae, suppresses the LPS-induced inflammatory response in cultured human keratinocytes.Research Square10.21203/rs.3.rs‑139746/v1
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673244967231101114033
Loading
/content/journals/cmc/10.2174/0109298673244967231101114033
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

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