Crocin from saffron ameliorates allergic airway inflammation through NF-κB, IL-17, and Nrf2/HO-1 signaling pathways in mice

Articles in Press

Document Type : Original Article

Authors

1 Department of Genetics and Pathology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran

2 Lung Diseases Research Center, Faculty of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

3 Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran

4 Lung Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran

5 Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

10.22038/ijbms.2024.80614.17447

Abstract

Objective(s): Asthma is a complex inflammatory disorder with the infiltration of inflammatory cells in the lung airways. Saffron’s active component, crocin, has been proven to possess anti-inflammatory and anti-oxidant effects. The objective of this current study was to explore the impact of crocin on NF-kB and nuclear erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathways in ovalbumin (OVA)-sensitized mice, aiming to understand its mechanism.
Materials and Methods: Four different groups were formed by dividing forty male BALB/C mice: control group, OVA-sensitized group (OVA), OVA combined with crocin 30 mg/kg (OVA-Cr30), and the OVA combined with crocin 60 mg/kg (OVA-Cr60). In order to determine the total number of WBC and inflammatory cells infiltrating the lung, we utilized the bronchoalveolar lavage fluid for counting purposes. The mRNA and protein levels of Nrf2, HO-1, IL-17, and NF-κB in lung tissue were assessed through real-time PCR and western blot techniques. 
Results: Crocin significantly prevented the increase of total WBC and inflammatory cells in the lung tissue (P<0.001 for all) and histopathological changes in OVA-sensitized mice. Furthermore, crocin displayed suppressive effects on the enhancement of NF-kB (P<0.01) and IL-17 (P<0.05) mRNA and protein levels in OVA-sensitized mice while preserving Nrf2 (P<0.01) and HO-1 (P<0.05) expression levels. Crocin effects became increasingly apparent when utilized at high concentrations.
Conclusion: Crocin decreased airway inflammation, partially by inhibiting NF-κB and IL-17 and up-regulating Nrf2/HO-1 mRNA and protein expression levels. 

Keywords

Main Subjects

References

1. Han X, Krempski JW, Nadeau K. Advances and novel developments in mechanisms of allergic inflammation. Allergy 2020; 75:3100-3111.
2. Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature 2008; 454:445-454.
3. Bryant N, Muehling LM. T-cell responses in asthma exacerbations. Ann Allergy Asthma Immunol 2022; 129:709-718.
4. Aslani MR, Sharghi A, Boskabady MH, Ghobadi H, Keyhanmanesh R, Alipour MR, et al. Altered gene expression levels of IL-17/TRAF6/MAPK/USP25 axis and pro-inflammatory cytokine levels in lung tissue of obese ovalbumin-sensitized rats. Life Sci 2022; 296:120425.
5. Aslani MR, Keyhanmanesh R, Khamaneh AM, Abbasi MM, Fallahi M, Alipour MR. Tracheal overexpression of IL-1β, IRAK-1 and TRAF-6 mRNA in obese-asthmatic male Wistar rats. Iran J Basic Med Sci 2016; 19:350-357.
6. Aslani MR, Keyhanmanesh R, Khamaneh AM, Ebrahimi Saadatlou MA, Mesgari Abbasi M, Alipour MR. Lung altered expression of IL-1β mRNA and its signaling pathway molecules in obese-asthmatic male Wistar rats. Iran J Allergy Asthma Immunol 2016; 15:183-197.
7. Akhavanakbari G, Babapour B, Alipour MR, Keyhanmanesh R, Ahmadi M, Aslani MR. Effect of high fat diet on NF-кB microRNA146a negative feedback loop in ovalbumin-sensitized rats. Biofactors 2019; 45:75-84.
8. Shaban NZ, Sleem AA, Abu-Serie MM, Maher AM, Habashy NH. Regulation of the NF-κB signaling pathway and IL-13 in asthmatic rats by aerosol inhalation of the combined active constituents of Punica granatum juice and peel. Biomed Pharmacother 2022; 155:113721.
9. Gu X, Zhang Q, Du Q, Shen H, Zhu Z. Pinocembrin attenuates allergic airway inflammation via inhibition of NF-κB pathway in mice. Int Immunopharmacol 2017; 53:90-95.
10. Wang C, Choi YH, Xian Z, Zheng M, Piao H, Yan G. Aloperine suppresses allergic airway inflammation through NF-κB, MAPK, and Nrf2/HO-1 signaling pathways in mice. Int Immunopharmacol 2018; 65:571-579.
11. Sussan TE, Gajghate S, Chatterjee S, Mandke P, McCormick S, Sudini K, et al. Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function. Am J Physiol Lung Cell Mol Physiol 2015; 309:L27-L36.
12. Saadat S, Aslani MR, Ghorani V, Keyhanmanesh R, Boskabady MH. The effects of Nigella sativa on respiratory, allergic and immunologic disorders, evidence from experimental and clinical studies, a comprehensive and updated review. Phytother Res 2021; 35:2968-2996.
13. Khazdair MR, Saadat S, Aslani MR, Shakeri F, Boskabady MH. Experimental and clinical studies on the effects of Portulaca oleracea L. and its constituents on respiratory, allergic, and immunologic disorders, a review. Phytother Res 2021; 35:6813-6842.
14. Ghasemi Z, Rezaee R, Aslani MR, Boskabady MH. Anti-inflammatory, anti-oxidant, and immunomodulatory activities of the genus Ferula and their constituents: A review. Iran J Basic Med Sci 2021; 24:1613-1623.
15. Ghobadi H, Abdollahi N, Madani H, Aslani MR. Effect of crocin from saffron (Crocus sativus L.) supplementation on oxidant/antioxidant markers, exercise capacity, and pulmonary function tests in COPD patients: A randomized, double-blind, placebo-controlled trial. Front Pharmacol 2022; 13:884710.
16. Aslani MR, Abdollahi N, Matin S, Zakeri A, Ghobadi H. Effect of crocin of Crocus sativus L. on serum inflammatory markers (IL-6 and TNF-α) in chronic obstructive pulmonary disease patients: a randomised, double-blind, placebo-controlled trial. Br J Nutr 2023; 130:446-453.
17. Abedi A, Ghobadi H, Sharghi A, Iranpour S, Fazlzadeh M, Aslani MR. Effect of saffron supplementation on oxidative stress markers (MDA, TAC, TOS, GPx, SOD, and pro-oxidant/antioxidant balance): An updated systematic review and meta-analysis of randomized placebo-controlled trials. Front Med (Lausanne) 2023; 10:1071514.
18. Boskabady MH, Aslani MR. Relaxant effect of Crocus sativus (saffron) on guinea-pig tracheal chains and its possible mechanisms. J Pharm Pharmacol 2006; 58:1385-1390.
19. Rahimi G, Shams S, Aslani MR. Effects of crocin supplementation on inflammatory markers, lipid profiles, insulin and cardioprotective indices in women with PCOS: A randomized, double-blind, placebo-controlled trial. Phytother Res 2022; 36:2605-2615.
20. Salem M, Shaheen M, Borjac J. Crocin suppresses inflammation-induced apoptosis in rmTBI mouse model via modulation of Nrf2 transcriptional activity. PharmaNutrition 2022; 21:100308.
21. Dianat M, Radan M, Badavi M, Mard SA, Bayati V, Ahmadizadeh M. Crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: The role of Nrf2 antioxidant system in preventing oxidative stress. Respir Res 2018; 19:58.
22. Zhang D, Qi BY, Zhu WW, Huang X, Wang XZ. Crocin alleviates lipopolysaccharide-induced acute respiratory distress syndrome by protecting against glycocalyx damage and suppressing inflammatory signaling pathways. Inflamm Res 2020; 69:267-278.
23. Xiong Y, Wang J, Yu H, Zhang X, Miao C. Anti-asthma potential of crocin and its effect on MAPK signaling pathway in a murine model of allergic airway disease. Immunopharmacol Immunotoxicol 2015; 37:236-243.
24. Majid K, Vahideh G, Mohammad Hosein B. Animal model of asthma, various methods and measured parameters: A methodological review. Iran J Allergy Asthma Immunol 2017; 15:445-465.
25. Hassan G, Mohammad Reza A, Rana K, Mohammad Hossein B, Mohammad Reza A. Effect of high-fat diet on tracheal responsiveness to methacholine and insulin resistance index in ovalbumin-sensitized male and female rats. Iran J Allergy Asthma Immunol 2019; 18:48-61.
26. Aslani MR, Keyhanmanesh R, Alipour MR. Increased visfatin expression is associated with nuclear factor-κB in obese ovalbumin-sensitized male Wistar rat tracheae. Med Princ Pract 2017; 26:351-358.
27. Moradi A, Aslani MR, Mirshekari Jahangiri H, Naderi N, Aboutaleb N. Protective effects of 4-methylumbelliferone on myocardial ischemia/reperfusion injury in rats through inhibition of oxidative stress and downregulation of TLR4/NF-κB/NLRP3 signaling pathway. Naunyn Schmiedebergs Arch Pharmacol 2024; 397:5015-5027.
28. Eftekhar N, Moghimi A, Mohammadian Roshan N, Saadat S, Boskabady MH. Immunomodulatory and anti-inflammatory effects of hydro-ethanolic extract of Ocimum basilicum leaves and its effect on lung pathological changes in an ovalbumin-induced rat model of asthma. BMC Complement Altern Med 2019; 19:349.
29. Zhang Q, Wang L, Chen B, Zhuo Q, Bao C, Lin L. Propofol inhibits NF-κB activation to ameliorate airway inflammation in ovalbumin (OVA)-induced allergic asthma mice. Int Immunopharmacol 2017; 51:158-164.
30. Aslani MR, Jafari Z, Rahbarghazi R, Rezaie J, Delkhosh A, Ahmadi M. Effects of crocin on T-bet/GATA-3 ratio, and miR-146a and miR-106a expression levels in lung tissue of ovalbumin-sensitized mice. Iran J Basic Med Sci 2022; 25:1267-1274.
31. Samitas K, Delimpoura V, Zervas E, Gaga M. Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives. Eur Respir Rev 2015; 24:594-601.
32. Bai D, Sun T, Lu F, Shen Y, Zhang Y, Zhang B, et al. Eupatilin suppresses OVA-induced asthma by inhibiting NF-κB and MAPK and activating Nrf2 signaling pathways in mice. Int J Mol Sci 2022; 23:1582.
33. Ma C, Ma Z, Fu Q, Ma S. Curcumin attenuates allergic airway inflammation by regulation of CD4+CD25+ regulatory T cells (Tregs)/Th17 balance in ovalbumin-sensitized mice. Fitoterapia 2013; 87:57-64.
34. Saadat S, Mohamadian Roshan N, Aslani MR, Boskabady MH. Rosuvastatin suppresses cytokine production and lung inflammation in asthmatic, hyperlipidemic and asthmatic-hyperlipidemic rat models. Cytokine 2020; 128:154993.
35. Zhang JH, Yang X, Chen YP, Zhang JF, Li CQ. Nrf2 activator RTA-408 protects against ozone-induced acute asthma exacerbation by suppressing ROS and γδT17 cells. Inflammation 2019; 42:1843-1856.
36. Che L, Jin Y, Zhang C, Lai T, Zhou H, Xia L, et al. Ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade. Sci Rep 2016; 6:18680.
37. Sur S, Crotty TB, Kephart GM, Hyma BA, Colby TV, Reed CE, et al. Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis 1993; 148:713-719.
38. Serra MF, Cotias AC, Pimentel AS, Arantes ACS, Pires ALA, Lanzetti M, et al. Gold nanoparticles inhibit steroid-insensitive asthma in mice preserving histone deacetylase 2 and NRF2 pathways. Antioxidants (Basel) 2022; 11:1659.
39. Michaeloudes C, Abubakar-Waziri H, Lakhdar R, Raby K, Dixey P, Adcock IM, et al. Molecular mechanisms of oxidative stress in asthma. Mol Aspects Med 2022; 85:101026.
40. Boutten A, Goven D, Artaud-Macari E, Boczkowski J, Bonay M. NRF2 targeting: A promising therapeutic strategy in chronic obstructive pulmonary disease. Trends Mol Med 2011; 17:363-371.
41. Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, et al. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med 2005; 202:47-59.
42. Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 2006; 26:221-229.
43. Liu L, Shang Y, Li M, Han X, Wang J, Wang J. Curcumin ameliorates asthmatic airway inflammation by activating nuclear factor-E2-related factor 2/haem oxygenase (HO)-1 signalling pathway. Clin Exp Pharmacol Physiol 2015; 42:520-529.
44. Lai IR, Chang KJ, Tsai HW, Chen CF. Pharmacological preconditioning with simvastatin protects liver from ischemia-reperfusion injury by heme oxygenase-1 induction. Transplantation 2008; 85:732-738.
45. Ryter SW, Choi AM. Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation. Transl Res 2016; 167:7-34.
46. Aslani MR, Amani M, Masrori N, Boskabady MH, Ebrahimi HA, Chodari L. Crocin attenuates inflammation of lung tissue in ovalbumin-sensitized mice by altering the expression of endoplasmic reticulum stress markers. Biofactors 2022; 48:204-215.
47. Aslani MR, Armin F, Abedi A, Keramati E, Ghobadi H. Potential role of saffron and its components on miRNA levels in various disorders, a comprehensive review. Iran J Basic Med Sci 2023; 26:1120-1130.
48. Saeideh S, Yasavoli M, Gholamnezhad Z, Aslani MR, Boskabady MH. The relaxant effect of crocin on rat tracheal smooth muscle and its possible mechanisms. Iran J Pharm Res 2019; 18:1358-1370.
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 16 September 2024

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