Gamma-terpinene counteracts in vivo dinitrochlorobenzene-induced atopic dermatitis in mice
DOI:
https://doi.org/10.1590/s2175-97902026e24410Keywords:
Cytokines, Dermatological, Dinitrochlorobenzene, Monoterpenes, Skin pharmacologyAbstract
Atopic dermatitis is a chronic skin condition characterized by impaired barrier function and underlying inflammation. Monoterpenes, a diverse class of secondary metabolites commonly found in essential oils, have been extensively documented for their potent anti-inflammatory properties. Therefore, this study evaluated the effects of gamma-terpinene (GT) on dinitrochlorobenzene (DNCB)-induced atopic dermatitis in a murine model. Macroscopic and histopathological analyses were conducted to assess skin lesions and ear edema, along with the assessment of serum immunoglobulin E (IgE), lactate dehydrogenase (LDH), and inflammatory cytokines (IL-4, IL-6, IL-1β, and TNF-α) in skin tissues. Histopathological analysis revealed a reduction in skin thickness, spongiosis, inflammatory cell infiltration, along with the presence of blisters and vesicles in both the epidermis and dermis. Additionally, cellular disarrangement and dermal fibrosis were observed. GT significantly decreased ear edema, serum IgE, and LDH levels, along with the expression of tissue IL-4, IL-6, IL-1β, and TNF-α. Therefore, the potential anti-inflammatory response induced by GT in atopic dermatitis suggests its potential for the development of GT-based therapies for chronic inflammatory skin disorders.
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Alvarenga JFR, Genaro B, Costa BL, Purgatto E, Manach C, Fiamoncini J. Monoterpenes: current knowledge on food source, metabolism, and health effect. Crit Rev Food Sci Nutr. 2023;63(10):1352-1389.
Ashrafizadeh M, Ahmadi Z, Mohammadinejad R, Kaviyani N, Tavakol S. Monoterpenes modulating autophagy: A review study. Basic Clin Pharmacol Toxicol. 2020;126:9–20.
Braddock M, Hanania NA, Sharafkhaneh A, Colice G., Carlsson M. Potential risks related to modulating interleukin-13 and interleukin-4 signalling: a systematic review. Drug Saf. 2018;45:489-509.
Broeders JA, Ahmed Ali U, Fischer G. Systematic review and meta-analysis of randomized clinical trials (RCTs) comparing topical calcineurin inhibitors with topical corticosteroids for atopic dermatitis: a 15-year experience. J Am Acad Dermatol. 2016;75:410-419.e3.
Chen E. Psychological stress and its relationship to cytokines and inflammatory diseases. In: Cytokines: Stress and Immunity, 2nd ed., Boca Raton, FL, Taylor & Francis Group, 2007;29-49.
Choi JH, Jin SW, Park BH, Kim HG, Khanal T, Han HJ, et al. Cultivated ginseng inhibits 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice and TNF-α/IFN-γ-induced TARC activation in HaCaT cells. Food Chem Toxicol. 2013;56:195-203.
Choi JK, Jang YH, Lee S, Lee, SR, Choi YA, Jin M, et al. Chrysin attenuates atopic dermatitis by suppressing inflammation of keratinocytes. Food Chem Toxicol. 2017;110:142-150.
Choi YA, Yu JH, Jung HD, Lee S, Park PH, Lee, HS, Kim, SH. Inhibitory effect of ethanol extract of Ampelopsis brevipedunculata rhizomes on atopic dermatitis-like skin inflammation. J Ethnopharmacol. 2019;238,111850.
Choi YY, Kim MH, Lee H, Jo SY, Yang WM. (R)-(+)-pulegone suppresses allergic and inflammation responses on 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice model. J Dermatol Sci. 2018;91:292-300.
Coondoo A, Phiske M, Verma S, Lahiri K. Side-effects of topical steroids: A long overdue revisit. Indian Dermatol Online J. 2014;5(4):416-25.
Dajee M, Muchamuel T, Schryver B, Oo A, Alleman-Sposeto J, De Vry CG, et al. Blockade of experimental atopic dermatitis via topical nf-κb decoy oligonucleotide. J Invest Dermatol. 2006;126(8):1792-1803.
Damiani G, Eggenhöffner R, Pigatto PDM, Bragazzi NL. Nanotechnology meets atopic dermatitis: Current solutions, challenges and future prospects. Insights and implications from a systematic review of the literature. Bioac Mater. 2019;4:380-86.
Das J, Chen CH, Yang L, Cohn l, Ray P, Ray A. A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nat Immunol. 2001;2:45–50.
Dehsheikh AB, Sourestani MM, Dehsheikh PB, Mottaghipisheh J, Vitalini S, Iriti M. Monoterpenes: Essential Oil Components with Valuable Features. Mini-rev Med Chem. 2020;20(11):958–74.
Farhana A, Lappin SL. Biochemistry, Lactate Dehydrogenase. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557536/.
Fujii Y, Takeuchi H, Sakuma S, Sengoku T, Takakura S. Characterization of a 2,4-dinitrochlorobenzene-induced chronic dermatitis model in rats. Skin Pharmacol Physiol. 2009;22:240–47.
Galozzi P, Bindoli S, Doria A, Sfriso P. The revisited role of interleukin-1 alpha and beta in autoimmune and inflammatory disorders and in comorbidities. Autoimmun Rev. 2021;20:102785.
Gochnauer H, Valdes-Rodriguez R, Cardwell L, Anolik RB. The Psychosocial Impact of Atopic Dermatitis. Adv Exp Med Biol. 2017;1027:57-69.
Gong X, Ren Y. Larvicidal and ovicidal activity of carvacrol, p-cymene, and γ-terpinene from Origanum vulgare essential oil against the cotton bollworm, Helicoverpa armigera (Hübner). Environ Sci Pollut Res Int. 2020;27(15):18708-18716.
Guo Y, Baschieri A, Amorati R, Valgimigli L. Synergic antioxidant activity of γ-terpinene with phenols and polyphenols enabled by hydroperoxyl radicals. Food Chem. 2021;345:128468.
Hajhashemi V, Sajjadi SE, Zomorodkia M. Antinociceptive and anti-inflammatory activities of Bunium persicum essential oil, hydroalcoholic and polyphenolic extracts in animal models. Pharm Biol. 2011;49(2):146–51.
Hanifin JM, Tofte, SJ. Update on therapy of atopic dermatitis. JACI: In Practice. 1999;104(3):S123-S125.
Hernandez TD, Aleman SJ, Bao-Loc-Trung M, Forte MV, Brandt W, Armstrong C, et al. Advancing treatment in atopic dermatitis: a comprehensive review of clinical efficacy, safety, and comparative insights into corticosteroids, calcineurin inhibitors, and phosphodiesterase-4 inhibitors as topical therapies. Cureus. 2024;2;16(3):e55393.
Homey B, Steinhoff M, Ruzicka T, Leung DYM. Cytokines and chemokines orchestrate atopic skin inflammation. JACI: In Practice. 2006;118:178e189.
Hosokawa C, Takeuchi S, Furue M. Severity scores, itch scores, and plasma substance p levels in atopic dermatitis treated with standard topical therapy with oral olopatadine hydrochloride. J Dermatol. 2009;36:185–90.
Islam MT, Quispe C, Islam MA, Ali ES, Saha S, Asha UH, et al. Effects of nerol on paracetamol-induced liver damage in Wistar albino rats. Biomed & Pharmacother. 2021;140:111732.
Joo SS, Yoo YM, Ko SH, Choi W, Park MJ, Kang HY, et al. Effects of essential oil from Chamaecypris obtusa on the development of atopic dermatitis-like skin lesions and the suppression of Th cytokines. J Dermatol Sci. 2010;60(2):122-5.
Jung M, Lee TH, Oh HJ, Kim H, Son YS, Lee EH, Kim J. Inhibitory effect of 5,6-dihydroergosteol-glucoside on atopic dermatitis-like skin lesions via suppression of NF-κB and STAT activation. J Dermatol Sci. 2015;79:252-61.
Kaminishi K, Soma Y, Kawa Y, Mizoguchi M. Flow cytometric analysis of IL-4, IL-13 and IFN-γ expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease. J Dermatol Sci. 2020;29(1):19-25.
Kang J, Lee S, Kim N, Dhakal H, Choi YA, Kwon TK, et al. Hispidulin alleviates 2,4-dinitrochlorobenzene and house dust mite extract-induced atopic dermatitis-like skin inflammation. Biomed Phamacother. 2021;137:111359.
Kato A, Kamata M, Ito M, Uchida H, Nagata M, Fukaya S, et al. Higher baseline serum lactate dehydrogenase level is associated with poor effectiveness of dupilumab in the long term in patients with atopic dermatitis. J Dermatol. 2020;47:1013-1019.
Kogawa K, Minakawa S, Matsuzaki Y, Okamoto A, Ogasawara S, Saito N, Sawamura D. Correlation between lactate dehydrogenase and other laboratory data in patients with Atopic dermatitis. J Cutan Immunol Alergy. 2022;5:133–35.
Kwon HI, Jeong NH, Jun SH, Son JH, Kim S, Jeon H, et al. Thymol attenuates the worsening of atopic dermatitis induced by Staphylococcus aureus membrane vesicles. Int Immunopharmacol. 2018;59:301-309.
Ku JM, Hong SH, Kim HI, Seo HS, Shin YC, Ko SG. Effects of Angelicae dahuricae radix on 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice model. BMC Complement Altern Med. 2017;17:98.
Lee D-H, Park J-K, Choi J, Jang H, Seol JW. Anti-inflammatory effects of natural Flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis model. Int Immunopharmacol. 2020;89:107046.
Legat FJ. Itch in Atopic Dermatitis – What is new? Front Med. 2021;(8):644760.
Liu T, Zhang L, Joo D. NF-κB signaling in inflammation. Sig. Transduct. Target Ther. 2017;2:17023.
Lugović-Mihić L, Meštrović-Štefekov J, Potočnjak I, Cindrić T, Ilić I, Lovrić I, et al. Atopic dermatitis: disease features, therapeutic options, and a multidisciplinary approach. Life (Basel). 2023;13(6):1419.
Manjelievskaia J, Boytsov N, Brouillette MA, Onyekwere U, Pierce E, Goldblum O, Bonafede M. The direct and indirect costs of adult atopic dermatitis. J Manag Care Spec Pharm. 2021;(10):1416-1425.
Matsumoto K, Mizukoshi K, Oyobikawa M, Ohshima H, Tagami H. Establishment of an atopic dermatitis-like skin model in a hairless mouse by repeated elicitation of contact hypersensitivity that enables to conduct functional analyses of the stratum corneum with various non-invasive biophysical instruments. Skin Res Technol. 2004;10:122-29.
Monteiro TM. Study of the anxiolytic and immunomodulatory activity of Gamma-terpinene. [Doctoral dissertation]. João Pessoa: Federal University of Paraiba: Postgraduate Program in Natural and Synthetic Bioactive Products, 2018. https://repositorio.ufpb.br/jspui/handle/123456789/13706.
Morishima Y, Kawashima H, Takekuma K, Hoshika A. Changes in serum lactate dehydrogenase activity in children with atopic dermatites. Pediatr Int. 2010;52:171-74.
Mukai H, Noguchi T, Kamimura K, Nishioka K, Nishiyama S. Significance of elevated serum LDH (lactate dehydrogenase) activity in atopic dermatitis. J Dermatol. 1990;17(8):477-81.
Ozcan MM, Chalchat JC. Chemical composition and antifungal activity of rosemary (Rosmarinus officinalis L.) oil from Turkey. Int J Food Sci Nutr. 2008;59(7-8):691-8.
Park G, Oh SM. Inhibitory effects of Juglans mandshurica leaf on allergic dermatitis-like skin lesions-induced by 2,4-dinitrochlorobenzene in mice. Exp Toxicol Pathol. 2014:66:97–101.
Park S, Lee JB, Kang S. Topical application of Chrysanthemum Indicum L. attenuates the development of atopic dermatitis-like skin lesions by suppressing serum IgE levels, IFN-γ, and IL-4 in Nc/Nga mice. eCAM. 2021;2012:821967.
Passos FF, Lopes EM, de Araújo JM, de Sousa DP, Veras LM, Leite JR, Almeida FR. Involvement of Cholinergic and Opioid System in γ-Terpinene-Mediated Antinociception. Evid Based Complement Alternat Med. 2015;829414.
Qu R, Chen X, Hu J, Fu Y, Peng J, Li Y, et al. Ghrelin protects against contact dermatitis and psoriasiform skin inflammation by antagonizing TNF-α/NF-κB signaling pathways. Sci Rep. 2019;9:1348.
Ramalho TR, Filgueiras LR, de Oliveira MTP, de Araujo Lima AL, Bezerra-Santos CR, Jancar S, Piuvezam MR. Gamma-terpinene modulation of LPS-stimulated macrophages is dependent on the PGE2/IL-10 axis. Planta Med. 2016;82:1341–45.
Ramalho TR, Oliveira MTP, Lima ALA, Santos CRB, Piuvezam, MR. Gamma-terpinene modulates acute inflammatory response in mice. Planta Med. 2015;81:1248-54.
Rick JW, Lio P, Swetha A, Hsiao JL, Shi, VY. Atopic Dermatitis: A Guide to Transitioning to Janus Kinase Inhibitors. Dermatitis. 2023;34(4):297-300.
Silverberg NB. Atopic Dermatitis Prevention and Treatment. Cutis. 2017;100:173-77.
Saeki H, Furue M, Furukawa F, Hide M, Ohtsuki M, Katayama I, et al. Guidelines for management of atopic dermatitis. J. Dermatol. 2009;36:563-577.
Salakhutdinov NF, Volcho KP, Yarovaya OI. Monoterpenes as a renewable source of biologically active compounds. Pure Appl. Chem. 2017;89(8):1105-1117.
Shipman AR, Bahrani, S, Shipman KE. Investigative algorithms for disorders affecting plasma lactate dehydrogenase: a narrative review. J Lab Precis Med. 2024;9.
Spergel JM, Mizoguchi E, Oettgen H, Bhan AK, Geha RS. Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. J Clin Invest. 1999;103(8):1103-11.
Souza RP, Pimentel VD, Sousa RWR, Sena EP, Silva ACA, Dittz D, et al. Non-clinical investigations about cytotoxic and anti-platelet activities of gamma-terpinene. Naunyn-Schmiedeberg's Arch Pharmacol. 2024;397:8145–8160.
Suzuki Y, Sakai H, Shimada T, Omura M, Kumazawa S, Nakayama T. Characterization of gamma-terpinene synthase from Citrus unshiu (Satsuma mandarin). Biofactors. 2004;21(1-4):79-82. doi: 10.1002/biof.552210115. PMID: 15630174.
Tanaka A, Muto S, Jung K, Itai A, Matsuda H. Topical application with a new NF-κB inhibitor improves atopic dermatitis in NC/NgaTnd mice. J Invest Dermatol. 2007;127(4):855-863.
Tanaka T, Narazari M, Kishimoto T. IL-6 in Inflammation, Immunity, and Disease. Cold Spring Harb Perspect Biol. 2014;6:a016295.
Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Primers. 2018;(4):1.
Wu S, Pang Y, He Y, Zhang X, Peng L, Guo J, Zeng, J. A comprehensive review of natural products against atopic dermatitis: Flavonoids, alkaloids, terpenes, glycosides and other compounds. Biomed Pharmacother. 2021;140:111741.
Zheng YQ, Wei W. Total glucosides of paeony suppresses adjuvant arthritis in rats and intervenes cytokine-signaling between different types of synoviocytes. Int Immunopharmacol. 2005;5(10):1560–73.
Zhou P, Yang X, Jia X, Yu J, Asenso J, Xiao F, et al. Effect of 6'-acetylpaeoniflorin on dinitrochlorobenzene-induced allergic contact dermatitis in BALB/c mice. Immunol Res. 2016;64(4):857-68.
Zielińska-Błajet M, Feder-Kubis J. Monoterpenes and their derivatives-recent development in biological and medical applications. Int J Mol Sci. 2020;21(19):7078.
Zochedh A, Priya M, Shunmuganarayanan A, Thandavarayan K, Sultan AB. Investigation on structural, spectroscopic, DFT, biological activity and molecular docking simulation of essential oil Gamma-Terpinene. J Mol Struct. 2022;2:133651.
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