Interaction of saffron and its constituents with Nrf2 signaling pathway: A review

Document Type : Review Article

Authors

1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Saffron (Crocus sativus) is a natural compound and its constituents such as crocin, crocetin, and safranal have many pharmacological properties such as anti-oxidant, anti-inflammatory, antitumor, antigenotoxic, anti-depressant, hepatoprotective, cardioprotective, and neuroprotective. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays an important role against inflammation, oxidative stress, and carcinogenesis. In the regulation of the Nrf2 signaling pathway, kelch-like ECH-associated protein 1 (keap1) is the most studied pathway. In this review, we gathered various studies and describe the pharmacological effects of saffron and its constituents with their related mechanisms of action, particularly the Nrf2 signaling pathway. In this review, we used search engines or electronic databases including Scopus, Web of Science, and Pubmed, without time limitation. The search keywords contained saffron, “Crocus sativus”, crocetin, crocin, safranal, picrocrocin, “nuclear factor erythroid 2-related factor 2“, and Nrf2. Saffron and its constituents could have protective properties through various mechanisms particularly the Nrf2/HO-1/Keap1 signaling pathway in different tissues such as the liver, heart, brain, pancreas, lung, joints, colon, etc. The vast majority of studies discussed in this review indicate that saffron and its constituents could induce the Nrf2 signaling pathway leading to its anti-oxidant and therapeutic effects.

Keywords


1. Suchareau M, Bordes A, Lemée L. Improved quantification method of crocins in saffron extract using HPLC-DAD after qualification by HPLC-DAD-MS. Food Chem 2021;362: 130199. 
2. Godugu C, Pasari LP, Khurana A, Anchi P, Saifi MA, Bansod SP, et al. Crocin, an active constituent of Crocus sativus ameliorates cerulein induced pancreatic inflammation and oxidative stress. Phyther Res 2020;34:825–835. 
3. Bhooma V, Nagasathiya K, Vairamani M, Parani M. Identification of synthetic dyes magenta III (new fuchsin) and rhodamine B as common adulterants in commercial saffron. Food Chem 2020;309:125793. 
4. Farag MA, Hegazi N, Dokhalahy E, Khattab AR. Chemometrics based GC-MS aroma profiling for revealing freshness, origin and roasting indices in saffron spice and its adulteration. Food Chem 2020;331:127358. 
5. Sun C, Nile SH, Zhang Y, Qin L, El-Seedi HR, Daglia M, et al. Novel insight into utilization of flavonoid glycosides and biological properties of saffron (Crocus sativus L.) flower byproducts. J Agric Food Chem 2020;68:10685–10696. 
6. Pour FK, Aryaeian N, Mokhtare M, Mirnasrollahi Parsa RS, Jannani L, Agah S, et al. The effect of saffron supplementation on some inflammatory and oxidative markers, leptin, adiponectin, and body composition in patients with nonalcoholic fatty liver disease: A double-blind randomized clinical trial. Phyther Res 2020;34:3367–3378. 
7. Forouzanfar F, Asadpour E, Hosseinzadeh H, Boroushaki MT, Adab A, Dastpeiman SH, et al. Safranal protects against ischemia-induced PC12 cell injury through inhibiting oxidative stress and apoptosis. Naunyn Schmiedebergs Arch Pharmacol 2021;394:707–716. 
8. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: A comprehensive review. Food Chem Toxicol 2014;64:65–80. 
9. Li N, Fan M, Li Y, Qian H, Zhang H, Qi X, et al. Stability assessment of crocetin and crocetin derivatives in Gardenia yellow pigment and Gardenia fruit pomace in presence of different cooking methods. Food Chem 2020;312:126031. 
10. Puglia C, Santonocito D, Musumeci T, Cardile V, Graziano ACE, Salerno L, et al. Nanotechnological approach to increase the anti-oxidant and cytotoxic efficacy of crocin and crocetin. Planta Med 2019;85:258–265. 
11. Rao SV, Hemalatha P, Yetish S, Muralidhara M, Rajini PS. Prophylactic neuroprotective propensity of crocin, a carotenoid against rotenone induced neurotoxicity in mice: behavioural and biochemical evidence. Metab Brain Dis 2019;34:1341–1353. 
12. Veisi A, Akbari G, Mard SA, Badfar G, Zarezade V, Mirshekar MA. Role of crocin in several cancer cell lines: An updated review. Iran J Basic Med Sci 2020;23:3–12. 
13.  Singla RK, Bhat GV. Crocin : An overview. Indo Glob J Pharm Sci 2011;1:281–286.
14. Rameshrad M, Razavi BM, Hosseinzadeh H. Saffron and its derivatives, crocin, crocetin and safranal: a patent review. Expert Opin Ther Pat 2018;28:147–165. 
15. Gedik S, Erdemli ME, Gul M, Yigitcan B, Gozukara Bag H, Aksungur Z, et al. Hepatoprotective effects of crocin on biochemical and histopathological alterations following acrylamide-induced liver injury in Wistar rats. Biomed Pharmacother 2017;95:764–770. 
16. Ghorbanzadeh V, Mohammadi M, Dariushnejad H, Abhari A, Chodari L, Mohaddes G. Efeito cardioprotetor de crocina combinado com exercício voluntário em ratos: Papel do mir-126 e mir-210 na angiogênese cardíaca. Arq Bras Cardiol 2017;109:54–62. 
17.  Hassani FV, Masjedi E, Hosseinzadeh H, Bedrood Z, Abnous K, Mehri S. Protective effect of crocin on bisphenol A - induced spatial learning and memory impairment in adult male rats: Role of oxidative stress and AMPA receptor. Iran J Basic Med Sci 2020;23:1146–1154. 
18. Giaccio M. Crocetin from saffron: An active component of an ancient spice. Crit Rev Food Sci Nutr 2004;44:155–172..
19. Colapietro A, Mancini A, D’Alessandro AM, Festuccia C. Crocetin and crocin from saffron in cancer chemotherapy and chemoprevention. Anticancer Agents Med Chem 2019;19:38–47. 
20. Razavi BM, Hosseinzadeh H, Movassaghi AR, Imenshahidi M, Abnous K. Protective effect of crocin on diazinon induced cardiotoxicity in rats in subchronic exposure. Chem Biol Interact 2013;203:547–555. 
21. Mehdizadeh R, Parizadeh MR, Khooei AR, Mehri S, Hosseinzadeh H. Cardioprotective effect of saffron extract and safranal in isoproterenol-induced myocardial infarction in Wistar rats. Iran J Basic Med Sci 2013;16:56–63. 
22. Riahi-Zanjani B, Balali-Mood M, Mohammadi E, Badie-Bostan H, Memar B, Karimi G. Safranal as a safe compound to mice immune system. Avicenna J Phytomedicine 2015;5:441–449. 
23. Amin B, Nakhsaz A, Hosseinzadeh H. Evaluation of the antidepressant-like effects of acute and sub-acute administration of crocin and crocetin in mice. Avicenna J Phytomedicine 2015;5:458–468. 
24. Hosseinzadeh H, Ziaee T, Sadeghi A. The effect of saffron, Crocus sativus stigma, extract and its constituents, safranal and crocin on sexual behaviors in normal male rats. Phytomedicine 2008;15:491–495. 
25. Bostan HB, Mehri S, Hosseinzadeh H. Toxicology effects of saffron and its constituents: A review. Iran J Basic Med Sci 2017;20:110–121. 
26. Vahdati Hassani F, Mehri S, Abnous K, Birner-Gruenberger R, Hosseinzadeh H. Protective effect of crocin on BPA-induced liver toxicity in rats through inhibition of oxidative stress and downregulation of MAPK and MAPKAP signaling pathway and miRNA-122 expression. Food Chem Toxicol 2017;107: 395-405. 
27. Yousefsani BS, Pourahmad J, Hosseinzadeh H. The mechanism of protective effect of crocin against liver mitochondrial toxicity caused by arsenic III. Taylor & Francis 2018;28:105-114. 
28. Razavi BM, Hosseinzadeh H. Saffron as an antidote or a protective agent against natural or chemical toxicities. DARU, J Pharm Sci 2015;23:1–9. 
29. Khorasany AR, Hosseinzadeh H. Therapeutic effects of saffron (Crocus sativus L.) in digestive disorders: A review. Iran J Basic Med Sci 2016;19:455–469. 
30. Mutneja E, Verma VK, Malik S, Sahu AK, Ray R, Bhatia J, et al. Erdosteine salvages cardiac necrosis: Novel effect through modulation of MAPK and Nrf-2/HO-1 pathway. J Biochem Mol Toxicol. 2020;34:1–12. 
31. Ahmadi Z, Ashrafizadeh M. Melatonin as a potential modulator of Nrf2. Fundam Clin Pharmacol 2020;34:11–19. 
32. Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the β-globin locus control region. Proc Natl Acad Sci USA. 1994;91:9926–9930. 
33. Baird L, Tsujita T, Kobayashi EH, Funayama R, Nagashima T, Nakayama K, et al. A homeostatic shift facilitates endoplasmic reticulum proteostasis through transcriptional integration of proteostatic stress response pathways. Mol Cell Biol 2017;37: e00439-16. 
34. Steffen J, Seeger M, Koch A, Krüger E. Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol Cell 2010;40:147–158. 
35. Chevillard G, Blank V. NFE2L3 (NRF3): The Cinderella of the Cap’n’Collar transcription factors. Cell Mol Life Sci 2011;68:3337–3348. 
36. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 2014;39:199–218. 
37. Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: A thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev 2018;98:1169–1203. 
38. Davies KJA, Forman HJ. Does Bach1 & c-Myc dependent redox dysregulation of Nrf2 & adaptive homeostasis decrease cancer risk in ageing? Free Radic Biol Med 2019;134:708–714. 
39. Liu L, Locascio LM, Doré S. Critical role of Nrf2 in experimental ischemic stroke. Front Pharmacol 2019;10:153. 
40. Schmidlin CJ, Dodson MB, Madhavan L, Zhang DD. Redox regulation by NRF2 in aging and disease. Free Radic Biol Med 2019;134:702–707. 
41. Shen Y, Liu X, Shi J, Wu X. Involvement of Nrf2 in myocardial ischemia and reperfusion injury. Int J Biol Macromol 2019;125:496–502. 
42. Vasconcelos AR, Dos Santos NB, Scavone C, Munhoz CD. Nrf2/ARE pathway modulation by dietary energy regulation in neurological disorders. Front Pharmacol 2019;10:1–18. 
43. Wu B, Luo H, Zhou X, Cheng C yi, Lin L, Liu B lin, et al. Succinate-induced neuronal mitochondrial fission and hexokinase II malfunction in ischemic stroke: Therapeutical effects of kaempferol. Biochim Biophys Acta - Mol Basis Dis 2017;1863:2307–2318. 
44. Yen CH, Hsiao HH. NRF2 is one of the players involved in bone marrow mediated drug resistance in multiple Myeloma. Int J Mol Sci 2018;19:3503. 
45. Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, et al. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol Cell Biol1996;16:6083–6095. 
46. Zhou S, Jin J, Bai T, Sachleben LR, Cai L, Zheng Y. Potential drugs which activate nuclear factor E2-related factor 2 signaling to prevent diabetic cardiovascular complications: A focus on fumaric acid esters. Life Sci 2015;134:56–62. 
47. Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov 2019;18:295–317. 
48. Martín-Montalvo A, Villalba JM, Navas P, De Cabo R. NRF2, cancer and calorie restriction. Oncogene 2011;30:505–520. 
49. Sporn MB, Liby KT. NRF2 and cancer: The Good, the bad and the importance of context. Nat Rev Cancer 2012;12:564–571. 
50. Akbari G, Mard SA, Dianat M, Mansouri E. The hepatoprotective and microRNAs ownregulatory effects of crocin following hepatic ischemia-reperfusion injury in rats. Oxid Med Cell Longev 2017;2017:1702967. 
51. Liang Y, Zheng B, Chu L, Ma D, Wang H, Chu X, et al. Protective effects of crocetin on arsenic trioxide-induced hepatic injury : involvement of suppression in oxidative stress and inflammation through activation of Nrf2 signaling pathway in rats. Drug Des Devel Ther 2020;14:1921-1931. 
52. Liu Y, Yao C, Wang Y, Liu X, Xu S, Liang L. Protective effect of crocin on liver function and survival in rats with traumatic hemorrhagic shock. J Surg Res 2021;261:301–309. 
53. Ye H, Luo J, Hu D, Yang S, Zhang A, Qiu Y, et al. otal flavonoids of crocus sativus petals release tert -butyl hydroperoxide-induced oxidative stress in BRL-3A cells. Oxid Med Cell Longev 2021;2021: 5453047. 
54. Liang Y, Zheng B, Li J, Shi J, Chu L, Han X, et al. Crocin ameliorates arsenic trioxide‑induced cardiotoxicity via Keap1-Nrf2/HO-1 pathway: Reducing oxidative stress, inflammation, and apoptosis. Biomed Pharmacother 2020;131: 110713. 
55. Efentakis P, Rizakou A, Christodoulou E, Chatzianastasiou A, López MG, León R, et al. Saffron (Crocus sativus) intake provides nutritional preconditioning against myocardial ischemia–reperfusion injury in Wild Type and ApoE(−/−) mice: Involvement of Nrf2 activation. Nutr Metab Cardiovasc Dis 2017;27:919–929. 
56. Yang M, Mao G, Ouyang L, Shi C, Hu P, Huang S. Crocetin alleviates myocardial ischemia/reperfusion injury by regulating inflammation and the unfolded protein response. Mol Med Rep 2020;21:641–648. 
57. Wang X, Yuan B, Cheng B, Liu Y, Zhang B, Wang X, et al. Crocin alleviates myocardial ischemia/reperfusion-induced endoplasmic reticulum stress via regulation of miR-34a/Sirt1/Nrf2 pathway. Shock 2019;51:123–130. 
58. Zhang W, Li Y, Ge Z. Cardiaprotective effect of crocetin by attenuating apoptosis in isoproterenol induced myocardial infarction rat model. Biomed Pharmacother 2017;93:376–382. 
59. Elsherbiny NM, Eisa NH, El-Sherbiny M, Said E. Chemo-preventive effect of crocin against experimentally-induced hepatocarcinogenesis via regulation of apoptotic and Nrf2 signaling pathways. Environ Toxicol Pharmacol. 2020;80:103494. 
60. Kawabata K, Tung NH, Shoyama Y, Sugie S, Mori T, Tanaka T. Dietary crocin inhibits colitis and colitis-associated colorectal carcinogenesis in male ICR mice. Evidence-Based Complement Altern Med 2012;2012: 820415. 
61. Wu Z, Hui J. Crocin reverses 1-methyl-3-nitroso-1-nitroguanidine (MNNG)- induced malignant transformation in GES-1 cells through the Nrf2/ Hippo signaling pathway. J Gastrointest Oncol 2020;11:1242–1252. 
62.  Kim SH, Lee JM, Kim SC, Park CB, Lee PC. Proposed cytotoxic mechanisms of the saffron carotenoids crocin and crocetin on cancer cell lines. Biochem Cell Biol 2014;92:105–111. 
63. Dianat M, Radan M, Mard SA, Sohrabi F, Saryazdi SSN. Contribution of reactive oxygen species via the OXR1 signaling pathway in the pathogenesis of monocrotaline-induced pulmonary arterial hypertension: The protective role of crocin. Life Sci 2020;256:117848. 
64. 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 anti-oxidant system in preventing oxidative stress. Respir Res 2018;19:1–20. 
65. Zaghloul MS, Said E, Suddek GM, Salem HA. Crocin attenuates lung inflammation and pulmonary vascular dysfunction in a rat model of bleomycin-induced pulmonary fibrosis. Life Sci 2019;235:116794..
66. Radan M, Dianat M, Badavi M, Mard SA, Bayati V, Ahmadizadeh M. The association of cigarette smoke exposure with lung cellular toxicity and oxidative stress: The protective role of crocin. Inflammation 2020;43:135–145. 
67.  Sharma B, Kumar H, Kaushik P, Mirza R, Awasthi R, Kulkarni GT. Therapeutic benefits of saffron in brain diseases: New lights on possible pharmacological mechanisms. In Sarwat M, Sumaiya S., editors.Saffron: The Age-Old Panacea in a New Light. 1st ed. Academic Press; 2020; p. 117-130.
68. Wen X. Safranal prevents rotenone-induced oxidative stress and apoptosis in an in vitro model of Parkinson’s disease through regulating Keap1/Nrf2 signaling pathway. Cell Mol Biol 2016;62:11–17. 
69. Lei M, Guo C, Hua L, Xue S, Yu D, Zhang C, et al. Crocin attenuates joint pain and muscle dysfunction in osteoarthritis rat. Inflammation. 2017;40:2086–2093. 
70. Li Y, Kakkar R, Wang J. in vivo  and in vitro approach to anti-arthritic and anti-inflammatory effect of crocetin by alteration of nuclear factor-e2-related factor 2/hem oxygenase (HO)-1 and NF-κB expression. Front Pharmacol 2018;9:1–12. 
71.  Khodir AE, Said E, Atif H, ElKashef HA, Salem HA. Targeting Nrf2/HO-1 signaling by crocin: Role in attenuation of AA-induced ulcerative colitis in rats. Biomed Pharmacother 2019;110:389–399. 
72. Singh G, Haileselassie Y, Brim H, Ashktorab H, Habtezion A. Protective effect of saffron in mouse colitis models through immune modulation. Gastroenterology 2020;158:S-1043. 
73. Qiu Y, Jiang X, Liu D, Deng Z, Hu W, Li Z, et al. The hypoglycemic and renal protection properties of crocin via oxidative stress-regulated NF-κB signaling in db/db mice. Front Pharmacol. 2020;11:1–11. 
74. Kim JH, Park GY, Bang SY, Park SY, Bae SK, Kim Y. Crocin suppresses LPS-stimulated expression of inducible nitric oxide synthase by upregulation of heme oxygenase-1 via calcium/calmodulin-dependent protein kinase 4. Mediators Inflamm 2014;2014:728709. 
75. Chen X, Huang J, Lv Y, Chen Y, Rao J. Crocin exhibits an antihypertensive effect in a rat model of gestational hypertension and activates the Nrf-2/HO-1 signaling pathway. Hypertens Res 2021;44:642–650. 
76. Gupta M, Wani A, Ahsan AU, Ali M, Chibber P, Singh S, et al. Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization. Toxicol Appl Pharmacol 2021;423:115582. 
77. Mard SA, Akbari G, Dianat M, Mansouri E. Protective effects of crocin and zinc sulfate on hepatic ischemia-reperfusion injury in rats: a comparative experimental model study. Biomed Pharmacother 2017;96:48–55. 
78. Pradhan J, Mohanty C, Sahoo SK. Protective efficacy of crocetin and its nanoformulation against cyclosporine A-mediated toxicity in human embryonic kidney cells. Life Sci 2019;216:39–48.