Ginger‑derived compounds exert <em>in vivo</em> and <em>in vitro</em> anti‑asthmatic effects by inhibiting the T‑helper 2 cell‑mediated allergic response

Kim,Eungyung; Jang,Soyoung; Yi,Jun Koo; Kim,Hyeonjin; Kwon,Hong Ju; Im,Hobin; Huang,Hai; Zhang,Haibo; Cho,Na Eun; Sung,Yonghun; Kim,Sung-Hyun; Choi,Yeon Shik; Li,Shengqing; Ryoo,Zae Young; Kim,Myoung Ok

doi:10.3892/etm.2021.10971

Ginger‑derived compounds exert in vivo and in vitro anti‑asthmatic effects by inhibiting the T‑helper 2 cell‑mediated allergic response

Authors:
- Eungyung Kim
- Soyoung Jang
- Jun Koo Yi
- Hyeonjin Kim
- Hong Ju Kwon
- Hobin Im
- Hai Huang
- Haibo Zhang
- Na Eun Cho
- Yonghun Sung
- Sung-Hyun Kim
- Yeon Shik Choi
- Shengqing Li
- Zae Young Ryoo
- Myoung Ok Kim
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Affiliations: Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk 37224, Republic of Korea, School of Life Science, BK21 Plus KNU Creative Bioresearch Group, Kyungpook National University, Daegu 41566, Republic of Korea, Gyeongsangbukdo Livestock Research Institute, Yeongju, Gyeongsang 36052, Republic of Korea, Laboratory Animal Center, Daegu‑Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea, Department of Bio‑Medical Analysis, Korea Polytechnic College, Nonsan, Chungcheongnam 32943, Republic of Korea, Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
Published online on: November 15, 2021 https://doi.org/10.3892/etm.2021.10971
Article Number: 49
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

6‑Shogaol (SHO) and 6‑gingerol (GIN), naturally derived compounds of ginger (Zingiber officinale Roscoe), have been found to have anti‑allergic effects on dermatitis‑like skin lesions and rhinitis. Although SHO and GIN have demonstrated a potential in various inflammatory diseases, their efficacy and mechanism in asthma have not been largely examined. Therefore, the present study demonstrated the anti‑asthmatic effects of SHO and GIN on the T‑helper (Th) 2 cell‑mediated allergic response pathway in an ovalbumin (OVA)‑induced asthma mouse model. The asthma mouse model was established with an intraperitoneal (i.p.) injection of 50 µg OVA and 1 mg aluminum hydroxide with or without an i.p. injection of SHO and GIN (10 mg/kg) before treatment with OVA. In addition, the current study assessed mast cell degranulation in antigen‑stimulated RBL‑2H3 cells under different treatment conditions (SHO or GIN at 0, 10, 25, 50 and 100 nM) and determined the mRNA and protein levels of anti‑oxidative enzymes [superoxide dismutase (SOD)1, SOD2, glutathione peroxidase‑1/2, catalase] in lung tissues. SHO and GIN inhibited eosinophilia in the bronchoalveolar lavage fluids and H&E‑stained lung tissues. Both factors also decreased mucus production in periodic acid‑Schiff‑stained lung tissues and the levels of Th2 cytokines in these tissues. GIN attenuated oxidative stress by upregulating the expression levels of anti‑oxidative proteins. In an in vitro experiment, the degranulation of RBL‑2H3 rat mast cells was significantly decreased. It was found that SHO and GIN effectively suppressed the allergic response in the mouse model by inhibiting eosinophilia and Th2 cytokine production. Collectively, it was suggested that SHO can inhibit lung inflammation by attenuating the Th2 cell‑mediated allergic response signals, and that GIN can inhibit lung inflammation and epithelial cell remodeling by repressing oxidative stress. Therefore, SHO and GIN could be used therapeutically for allergic and eosinophilic asthma.

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1	Okuyama K, Ohwada K, Sakurada S, Sato N, Sora I, Tamura G, Takayanagi M and Ohno I: The distinctive effects of acute and chronic psychological stress on airway inflammation in a murine model of allergic asthma. Allergol Int. 56:29–35. 2007.PubMed/NCBI View Article : Google Scholar
2	Meyer EH, DeKruyff RH and Umetsu DT: T cells and NKT cells in the pathogenesis of asthma. Annu Rev Med. 59:281–292. 2008.PubMed/NCBI View Article : Google Scholar
3	Zhang J, Li C and Guo S: Effects of inhaled inactivated Mycobacterium phlei on airway inflammation in mouse asthmatic models. J Aerosol Med Pulm Drug Deliv. 25:96–103. 2012.PubMed/NCBI View Article : Google Scholar
4	O'Garra A: Commitment factors for T helper cells. Curr Biol. 10:R492–R494. 2000.PubMed/NCBI View Article : Google Scholar
5	Williams AS, Eynott PR, Leung SY, Nath P, Jupp R, De Sanctis GT, Resnick R, Adcock IM and Chung KF: Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation. Pulm Pharmacol Ther. 22:27–32. 2009.PubMed/NCBI View Article : Google Scholar
6	Walker JA and McKenzie AN: TH2 cell development and function. Nat Rev Immunol. 18:121–133. 2018.PubMed/NCBI View Article : Google Scholar
7	Asano T, Kume H, Taki F, Ito S and Hasegawa Y: Thalidomide attenuates airway hyperresponsiveness and eosinophilic inflammation in a murine model of allergic asthma. Biol Pharm Bull. 33:1028–1032. 2010.PubMed/NCBI View Article : Google Scholar
8	Heo JY and Im DS: Anti-allergic effects of salvianolic acid A and tanshinone IIA from Salvia miltiorrhiza determined using in vivo and in vitro experiments. Int Immunopharmacol. 67:69–77. 2019.PubMed/NCBI View Article : Google Scholar
9	Ishii T, Niikura Y, Kurata K, Muroi M, Tanamoto K, Nagase T, Sakaguchi M and Yamashita N: Time-dependent distinct roles of Toll-like receptor 4 in a house dust mite-induced asthma mouse model. Scand J Immunol. 87(e12641)2018.PubMed/NCBI View Article : Google Scholar
10	White MC, Etzel RA, Wilcox WD and Lloyd C: Exacerbations of childhood asthma and ozone pollution in Atlanta. Environ Res. 65:56–68. 1994.PubMed/NCBI View Article : Google Scholar
11	Perez L, Declercq C, Iñiguez C, Aguilera I, Badaloni C, Ballester F, Bouland C, Chanel O, Cirarda FB, Forastiere F, et al: Chronic burden of near-roadway traffic pollution in 10 European cities (APHEKOM network). Eur Respir J. 42:594–605. 2013.PubMed/NCBI View Article : Google Scholar
12	Norris G, YoungPong SN, Koenig JQ, Larson TV, Sheppard L and Stout JW: An association between fine particles and asthma emergency department visits for children in Seattle. Environ Health Perspect. 107:489–493. 1999.PubMed/NCBI View Article : Google Scholar
13	Barnett AG, Williams GM, Schwartz J, Neller AH, Best TL, Petroeschevsky AL and Simpson RW: Air pollution and child respiratory health: A case-crossover study in Australia and New Zealand. Am J Respir Crit Care Med. 171:1272–1278. 2005.PubMed/NCBI View Article : Google Scholar
14	Lipworth BJ: Clinical pharmacology of corticosteroids in bronchial asthma. Pharmacol Ther. 58:173–209. 1993.PubMed/NCBI View Article : Google Scholar
15	Bjermer L and Diamant Z: Current and emerging nonsteroidal anti-inflammatory therapies targeting specific mechanisms in asthma and allergy. Treat Respir Med. 3:235–246. 2004.PubMed/NCBI View Article : Google Scholar
16	Oray M, Abu Samra K, Ebrahimiadib N, Meese H and Foster CS: Long-term side effects of glucocorticoids. Expert Opin Drug Saf. 15:457–465. 2016.PubMed/NCBI View Article : Google Scholar
17	Lee BK, Park SJ, Nam SY, Kang S, Hwang J, Lee SJ and Im DS: Anti-allergic effects of sesquiterpene lactones from Saussurea costus (Falc.) Lipsch. determined using in vivo and in vitro experiments. J Ethnopharmacol. 213:256–261. 2018.PubMed/NCBI View Article : Google Scholar
18	Liu YN, Zha WJ, Ma Y, Chen FF, Zhu W, Ge A, Zeng XN and Huang M: Galangin attenuates airway remodelling by inhibiting TGF-β1-mediated ROS generation and MAPK/Akt phosphorylation in asthma. Sci Rep. 5(11758)2015.PubMed/NCBI View Article : Google Scholar
19	Grzanna R, Lindmark L and Frondoza CG: Ginger - an herbal medicinal product with broad anti-inflammatory actions. J Med Food. 8:125–132. 2005.PubMed/NCBI View Article : Google Scholar
20	Prasad S and Tyagi AK: Ginger and its constituents: Role in prevention and treatment of gastrointestinal cancer. Gastroenterol Res Pract. 2015(142979)2015.PubMed/NCBI View Article : Google Scholar
21	Kawamoto Y, Ueno Y, Nakahashi E, Obayashi M, Sugihara K, Qiao S, Iida M, Kumasaka MY, Yajima I, Goto Y, et al: Prevention of allergic rhinitis by ginger and the molecular basis of immunosuppression by 6-gingerol through T cell inactivation. J Nutr Biochem. 27:112–122. 2016.PubMed/NCBI View Article : Google Scholar
22	Yocum GT, Hwang JJ, Mikami M, Danielsson J, Kuforiji AS and Emala CW: Ginger and its bioactive component 6-shogaol mitigate lung inflammation in a murine asthma model. Am J Physiol Lung Cell Mol Physiol. 318:L296–L303. 2020.PubMed/NCBI View Article : Google Scholar
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
24	Shi H, Qin S, Huang G, Chen Y, Xiao C, Xu H, Liang G, Xie Z, Qin X, Wu J, et al: Infiltration of eosinophils into the asthmatic airways caused by interleukin 5. Am J Respir Cell Mol Biol. 16:220–224. 1997.PubMed/NCBI View Article : Google Scholar
25	Deo SS, Mistry KJ, Kakade AM and Niphadkar PV: Role played by Th2 type cytokines in IgE mediated allergy and asthma. Lung India. 27:66–71. 2010.PubMed/NCBI View Article : Google Scholar
26	Barnes PJ: Th2 cytokines and asthma: An introduction. Respir Res. 2:64–65. 2001.PubMed/NCBI View Article : Google Scholar
27	Sahiner UM, Birben E, Erzurum S, Sackesen C and Kalayci Ö: Oxidative stress in asthma: Part of the puzzle. Pediatr Allergy Immunol. 29:789–800. 2018.PubMed/NCBI View Article : Google Scholar
28	Powell CV, Nash AA, Powers HJ and Primhak RA: Antioxidant status in asthma. Pediatr Pulmono. 18:34–38. 1994.PubMed/NCBI View Article : Google Scholar
29	Ahmad A, Shameem M and Husain Q: Relation of oxidant-antioxidant imbalance with disease progression in patients with asthma. Ann Thorac Med. 7:226–232. 2012.PubMed/NCBI View Article : Google Scholar
30	Kumar RK, Herbert C and Foster PS: The ‘classical’ ovalbumin challenge model of asthma in mice. Curr Drug Targets. 9:485–494. 2008.PubMed/NCBI View Article : Google Scholar
31	Park G, Kim HG, Ju MS, Ha SK, Park Y, Kim SY and Oh MS: 6-Shogaol, an active compound of ginger, protects dopaminergic neurons in Parkinson's disease models via anti-neuroinflammation. Acta Pharmacol Sin. 34:1131–1139. 2013.PubMed/NCBI View Article : Google Scholar
32	Kim MO, Lee MH, Oi N, Kim SH, Bae KB, Huang Z, Kim DJ, Reddy K, Lee SY, Park SJ, et al: [6]-shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2. Carcinogenesis. 35:683–691. 2014.PubMed/NCBI View Article : Google Scholar
33	Bogaert P, Tournoy KG, Naessens T and Grooten J: Where asthma and hypersensitivity pneumonitis meet and differ: Noneosinophilic severe asthma. Am J Pathol. 174:3–13. 2009.PubMed/NCBI View Article : Google Scholar
34	Brussino L, Heffler E, Bucca C, Nicola S and Rolla G: Eosinophils target therapy for severe asthma: Critical points. Biomed Res Int: Oct 25, 2018 (Epub ahead of print). doi: 10.1155/2018/7582057.
35	Patadia MO, Murrill LL and Corey J: Asthma: Symptoms and presentation. Otolaryngol Clin North Am. 47:23–32. 2014.PubMed/NCBI View Article : Google Scholar
36	Silveira JS, Antunes GL, Kaiber DB, da Costa MS, Marques EP, Ferreira FS, Gassen RB, Breda RV, Wyse ATS, Pitrez P, et al: Reactive oxygen species are involved in eosinophil extracellular traps release and in airway inflammation in asthma. J Cell Physiol. 234:23633–23646. 2019.PubMed/NCBI View Article : Google Scholar
37	Fahy JV and Dickey BF: Airway mucus function and dysfunction. N Engl J Med. 363:2233–2247. 2010.PubMed/NCBI View Article : Google Scholar
38	Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR and Fahy JV: T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 180:388–395. 2009.PubMed/NCBI View Article : Google Scholar
39	Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL and Donaldson DD: Interleukin-13: Central mediator of allergic asthma. Science. 282:2258–2261. 1998.PubMed/NCBI View Article : Google Scholar
40	Lambrecht BN, Hammad H and Fahy JV: The cytokines of asthma. Immunity. 50:975–991. 2019.PubMed/NCBI View Article : Google Scholar
41	Tavernier J, Plaetinck G, Guisez Y, van der Heyden J, Kips J, Peleman R and Devos R: The role of interleukin 5 in the production and function of eosinophils. In: Hematopoietic cell Growth Factors and their Receptors. Whetton AD and Gordon J (eds). Plenum Press, New York, NY, pp321-361, 1996.
42	Kips JC: Cytokines in asthma. Eur Respir J Suppl. 34:24s–33s. 2001.PubMed/NCBI View Article : Google Scholar
43	Debeuf N, Haspeslagh E, van Helden M, Hammad H and Lambrecht BN: Mouse models of asthma. Curr Protoc Mouse Biol. 6:169–184. 2016.PubMed/NCBI View Article : Google Scholar
44	Dabbagh K, Takeyama K, Lee HM, Ueki IF, Lausier JA and Nadel JA: IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J Immunol. 162:6233–6237. 1999.PubMed/NCBI
45	Trautmann A, Krohne G, Bröcker EB and Klein CE: Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4. J Immunol. 160:5053–5057. 1998.PubMed/NCBI
46	Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL and Donaldson DD: Interleukin-13: Central mediator of allergic asthma. Science. 282:2258–2261. 1998.PubMed/NCBI View Article : Google Scholar
47	Gour N and Wills-Karp M: IL-4 and IL-13 signaling in allergic airway disease. Cytokine. 75:68–78. 2015.PubMed/NCBI View Article : Google Scholar
48	Matucci A, Maggi E and Vultaggio A: Eosinophils, the IL-5/IL-5Rα axis, and the biologic effects of benralizumab in severe asthma. Respir Med. 160(105819)2019.PubMed/NCBI View Article : Google Scholar
49	Bradding P, Walls AF and Holgate ST: The role of the mast cell in the pathophysiology of asthma. J Allergy Clin Immunol. 117:1277–1284. 2006.PubMed/NCBI View Article : Google Scholar
50	Tomasiak MM, Tomasiak M, Zietkowski Z, Skiepko R and Bodzenta-Lukaszyk A: N-acetyl-beta-hexosaminidase activity in asthma. Int Arch Allergy Immunol. 146:133–137. 2008.PubMed/NCBI View Article : Google Scholar
51	Mishra V, Banga J and Silveyra P: Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacological targets. Pharmacol Ther. 181:169–182. 2018.PubMed/NCBI View Article : Google Scholar
52	Erzurum SC: New insights in oxidant biology in asthma. Ann Am Thorac Soc. (Suppl 1): 13:S35–S9. 2016.PubMed/NCBI View Article : Google Scholar
53	Comhair SA and Erzurum SC: Redox control of asthma: Molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 12:93–124. 2010.PubMed/NCBI View Article : Google Scholar
54	Dugasani S, Pichika MR, Nadarajah VD, Balijepalli MK, Tandra S and Korlakunta JN: Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J Ethnopharmacol. 127:515–520. 2010.PubMed/NCBI View Article : Google Scholar
55	Chen F, Tang Y, Sun Y, Veeraraghavan VP, Mohan SK and Cui C: 6-shogaol, a active constiuents of ginger prevents UVB radiation mediated inflammation and oxidative stress through modulating NrF2 signaling in human epidermal keratinocytes (HaCaT cells). J Photochem Photobiol B. 197(111518)2019.PubMed/NCBI View Article : Google Scholar
56	Na JY, Song K, Lee JW, Kim S and Kwon J: Pretreatment of 6-shogaol attenuates oxidative stress and inflammation in middle cerebral artery occlusion-induced mice. Eur J Pharmacol. 788:241–247. 2016.PubMed/NCBI View Article : Google Scholar
57	Chakraborty D, Mukherjee A, Sikdar S, Paul A, Ghosh S and Khuda-Bukhsh AR: [6]-Gingerol isolated from ginger attenuates sodium arsenite induced oxidative stress and plays a corrective role in improving insulin signaling in mice. Toxicol Lett. 210:34–43. 2012.PubMed/NCBI View Article : Google Scholar
58	Koussounadis A, Langdon SP, Um IH, Harrison DJ and Smith VA: Relationship between differentially expressed mRNA and mRNA-protein correlations in a xenograft model system. Sci Rep. 5(10775)2015.PubMed/NCBI View Article : Google Scholar
59	Fortelny N, Overall CM, Pavlidis P and Freue GV: Can we predict protein from mRNA levels? Nature. 547:E19–E20. 2017.PubMed/NCBI View Article : Google Scholar