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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2018

Open Access 01-12-2018 | Research article

Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-κB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT)

Authors: Nurul Atika Razali, Nur Amiza Nazarudin, Kok Song Lai, Faridah Abas, Syahida Ahmad

Published in: BMC Complementary Medicine and Therapies | Issue 1/2018

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Abstract

Background

Histamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited in efficacy and associated with several common side effects. Therefore, alternative therapeutic preferences are derived from natural products in an effort to provide safe yet reliable anti-inflammatory agents. Curcumin and their derivatives are among compounds of interest in natural product research due to numerous pharmacological benefits including anti-inflammatory activities. Here, we investigate the effects of chemically synthesized curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65), in reducing cytokine production in histamine-induced HaCaT cells.

Methods

Interleukin (IL)-6 cytokine production in histamine-induced HaCaT cells were measured using enzyme-linked immunosorbent assay (ELISA) and cytotoxicity effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the inhibitory effects of MS65 on nuclear factor-kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways.

Results

Histamine enhanced IL-6 production in HaCaT cells, with the highest production of IL-6 at 97.41 ± 2.33 pg/mL after 24 h of exposure. MS65 demonstrated a promising anti-inflammatory activity by inhibiting IL-6 production with half maximal inhibitory concentration (IC50) value of 4.91 ± 2.50 μM and median lethal concentration (LC50) value of 28.82 ± 7.56 μM. In gene expression level, we found that MS65 inhibits NF-κB and MAPK pathways through suppression of IKK/IκB/NFκB and c-Raf/MEK/ERK inflammatory cascades.

Conclusion

Taken together, our results suggest that MS65 could be used as a lead compound on developing new medicinal agent for the treatment of allergic skin diseases.
Literature
1.
Warner JO, Kaliner MA, Crisci CD, Del Giacco S, Frew AJ, Liu GH, et al. Allergy practice worldwide: a report by the world allergy organization specialty and training council. Int Arch Allergy Immunol. 2006;139(2):166–74.CrossRefPubMed
2.
Canonica GW, Blaiss M. Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence. World Allergy Organ J. 2011;4(2):47–53.CrossRefPubMedPubMedCentral
3.
Bäumer W, Glatzer F, Roßbach K, Ohtsu H, Seike M, Mommert S, et al. Histamine in atopic disorders: atopic dermatitis and pruritus. In: Stark H, editor. Histamine H4 receptor: a novel drug target in immunoregulatory and inflammatory diseases. London: Man; 2013. p. 173–200.
4.
Fitzsimons R, van der Poel LA, Thornhill W, du Toit G, Shah N, Brough HA. Antihistamine use in children. Arch Dis Child Educ Pract Ed. 2015;100:122–31.CrossRefPubMed
5.
Thurmond RL, Gelfand EW, Dunford PJ. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov. 2008;7:41–53.CrossRefPubMed
6.
Gschwandtner M, Mildner M, Mlitz V, Gruber F, Eckhart L, Werfel T, et al. Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model. Allergy. 2013;68:37–47.CrossRefPubMed
7.
Albanesi C. Keratinocytes in allergic skin diseases. Curr Opin Allergy Clin Immunol. 2010;10(5):452–6.CrossRefPubMed
8.
Marone G, Granata F, Spadaro G. The histamine-cytokine network in allergic inflammation. J Allergy Clin Immunol. 2003;112(4):83–8.CrossRef
9.
Dávila I, Sastre J, Bartra J, Cuvillo A, Jáuregui I, Montoro J, et al. Effect of H1 antihistamines upon the cardiovascular system. J Investig Allergol Clin Immunol. 2006;16(1):13–23.PubMed
10.
Matsubara M, Tamura T, Ohmori K, Hasegawa K. Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2 +-dependent protein kinase C, Raf/MEK/ERK and IKK/IκB/NF-κB signal cascades. Biochem Pharmacol. 2005;69:433–49.CrossRefPubMed
11.
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–88.CrossRefPubMed
12.
Sugawara T, Gallucci RM, Simeonova PP, Luster MI. Regulation and role of interleukin 6 in wounded human epithelial keratinocytes. Cytokine. 2001;15(6):328–36.CrossRefPubMed
13.
Stannard J, Myers E, Reed TJ, Lowe L, Kahlenberg JM. Keratinocyte-associated IL-6 is elevated in cutaneous lupus rashes and production of IL-6 by keratinocytes is enhanced in non-involved lupus skin [abstract]. Arthritis Rheumatol. 2015;67(10):1072–3.
14.
Zappia CD, Granja-galeano G, Fernández N, Shayo C, Davio C, Fitzsimons CP, et al. Effects of histamine H1 receptor signalling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Sci Rep. 2015;5:17476.CrossRefPubMedPubMedCentral
15.
Motala C. H1 antihistamines in allergic disease. Curr Allergy Clin Im. 2009;22(2):71–4.
16.
Leurs R, Church MK, Taglialatela M. Review article H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy. 2002;32:489–98.CrossRefPubMed
17.
Gutzmer R, Gschwandtner M, Rossbach K, Mommert S, Werfel T, Kietzmann M, et al. Pathogenetic and therapeutic implications of the histamine H4 receptor in inflammatory skin diseases and pruritus. Front Biosci (Schol Ed). 2011;3:985–94.CrossRef
18.
Kumar D, Kumar M, Kumar A, Singh SK. Chalcone and curcumin derivatives: a way ahead for malarial treatment. Mini Rev Med Chem. 2013;13(14):2116–33.CrossRefPubMed
19.
Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41(1):40–59.CrossRefPubMed
20.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25(4):402–8.CrossRefPubMed
21.
Grossman RM, Krueger J, Yourish D, Granelli-piperno A, Murphy DP, May LT, et al. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci U S A. 1989;86:6367–71.CrossRefPubMedPubMedCentral
22.
Navarini AA, French LE, Hofbauer GFL. Interrupting IL-6-receptor signalling improves atopic dermatitis but associates with bacterial superinfection. J Allergy Clin Immunol. 2011;128(5):1128–30.CrossRefPubMed
23.
Kasperska-Zajac A, Grzanka A, Damasiewicz-Bodzek A. IL-6 transsignalling in patients with chronic spontaneous urticaria. PLoS One. 2015;10(12):e0145751.CrossRefPubMedPubMedCentral
24.
Triggiani M, Gentile M, Secondo A, Granata F, Oriente A, Taglialatela M, et al. Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J Immunol. 2014;166(6):4083–91.CrossRef
25.
Park I, Um J, Cho J, Lee SH, Lee SH, Lee H. Histamine promotes the release of interleukin-6 via the H1R/p38 and NF-κB pathways in nasal fibroblasts. Allergy Asthma Immunol Res. 2014;6(6):567–72.CrossRefPubMedPubMedCentral
26.
Liu W, Li Y, Yue Y, Zhang K, Chen Q, Wang H, et al. Bioorganic & medicinal chemistry letters synthesis and biological evaluation of curcumin derivatives containing NSAIDs for their anti-inflammatory activity. Bioorg Med Chem Lett. 2015;25(15):3044–51.CrossRefPubMed
27.
Song MY, Yim JY, Yim JM, Kang IJ, Rho HW, Kim HS, et al. Use of curcumin to decrease nitric oxide production during the induction of antitumor responses by IL-2. J Immunother. 2011;34(2):149–64.CrossRefPubMed
28.
Priyadarsini KI. Chemical and structural features influencing the biological activity of curcumin. Curr Pharm Des. 2013;19(11):2093–100.PubMed
29.
Malik P, Mukherjee TK. Review article: structure-function elucidation of antioxidative and prooxidative activities of the polyphenolic compound curcumin. Chin J Biol. 2014;396708:1–8.
30.
Vairappan CS, Kamada T, Lee WW, Jeon YJ. Anti-inflammatory activity of halogenated secondary metabolites of Laurencia snackeyi (weber-van Bosse) Masuda in LPS-stimulated RAW264.7 macrophages. J Appl Phycol. 2013;25:1805–13.CrossRef
31.
Rani P, Pal D, Hegde RR, Hashim SR. Anticancer, anti-inflammatory, and analgesic activities of synthesized 2-(substituted phenoxy) acetamide derivatives. Biomed Res Int. 2014;386473:1–9.CrossRef
32.
Joshi H, Singh BK, Saxena G, Singh V, Singh RP, Arya E. Novel halogens substituted coumarin-aldehyde as an anti-inflammatory agent. World J Pharm Sci. 2013;2(3):1–15.
33.
Somchit N, Kimseng R, Dhar R, Hiransai P, Changtam C, Suksamrarn A, et al. Curcumin pyrazole blocks lipopolysaccharide-induced inflammation via suppression of JNK activation in RAW 264.7 macrophages. Asian Pac J of Allergy Immunol. 2017; https://​doi.​org/​10.​12932/​AP-130417-0073.
34.
Herrera-Rodriguez LN, Khan F, Robins KT, Meyer HP. Perspectives on biotechnological halogenation. Part I: halogenated products and enzymatic halogenation. Chim Oggi-Chem Today. 2011;29:31–3.
35.
Hernandes MZ, Cavalcanti SMT, Moreira DRM, de Azevedo Jr WF, Leite ACL. Halogen atoms in the modern medicinal chemistry: hints for the drug design. Curr Drug Targets. 2010;11:1–12.CrossRef
36.
Strunecká A, Patočka J, Connett P. Fluorine in medicine. J Appl Biomed. 2004;2:141–50.
37.
Wang B-C, Wang L-J, Jiang B, Wang S-Y, Wu N, Li X-Q, et al. Application of fluorine in drug design during 2010-2015 years: a mini-review. Mini-Rev Med Chem. 2017;17:683–92.CrossRefPubMed
38.
Shah P, Westwell AD. The role of fluorine in medicinal chemistry. J Enzyme Inhib Med Chem. 2007;22(5):527–40.CrossRefPubMed
39.
Goindi S, Kumar G, Kaur A. Novel flexible vesicles based topical formulation of levocetirizine: in vivo evaluation using oxazolone-induced atopic dermatitis in murine model. J Liposome Res. 2014;24(3):249–57.CrossRefPubMed
40.
Ekiz F, Yuksel I, Ekiz O, Coban S, Basar O, Yuksel O. Levocetirizine induced hepatotoxicity in a patient with chronic urticarial. Ann Hepatol. 2011;10(2):237–8.PubMed
41.
Kataria G, Saxena A, Sharma S. Levocetirizine induced fixed drug eruption: a rare case report. Int J Sci Stud. 2014;2(7):228–9.
42.
43.
Megson AC, Walker EM, Hill SJ. Role of protein kinase Cα in signalling from the histamine H1 receptor to the nucleus. Mol Pharmacol. 2001;69:1012–21.CrossRef
44.
Das AK, Yoshimura S, Mishima R, Fujimoto K, Mizuguchi H, Fukui H. Full paper stimulation of histamine H1 receptor up-regulates histamine H1 receptor itself through activation of receptor gene transcription. J Pharm Sci. 2007;103(4):374–82.CrossRef
45.
Mizuguchi H, Terao T, Kitai M, Ikeda M, Yoshimura Y, Das AK, et al. Involvement of protein kinase cδ/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 (PARP-1) signalling pathway in histamine-induced up-regulation of histamine H1 receptor gene expression in Hela cells. J Biol Chem. 2011;286(35):30542–51.CrossRefPubMedPubMedCentral
Metadata
Title
Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-κB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT)
Authors
Nurul Atika Razali
Nur Amiza Nazarudin
Kok Song Lai
Faridah Abas
Syahida Ahmad
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2018
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-018-2223-8

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