Crocus Sativus (Saffron): An Immunoregulatory Factor in the Autoimmune and Non-autoimmune Diseases
-
Javad Poursamimi
,
Zhaleh Shariati-Sarabi
,
Jalil Tavakkol-Afshari
,
Seyed Ahmad Mohajeri
,
Mojgan Mohammadi
Abstract
It has been reported that patients with arthritis, osteoarthritis, atherosclerosis, coronary artery disease, brain ischemia, diabetes, and inflammatory bowel disease (IBD) suffer from pro-inflammatory and oxidant related responses. Therefore, anti-inflammatory and anti-oxidant therapies are used to improve the quality of life of the patients. Saffron is a herbal drug that has immunomodulatory and antioxidant properties. Hence, Saffron and its components have been proposed as therapeutic agents for the treatment of the diseases. Therefore, this review article was designed to collect recent information regarding the effects of saffron and its components on the amelioration of the inflammatory symptoms in the autoimmune and non-autoimmune diseases and anti-cancerous effects from 1999 up to now via searching the Pubmed, Google Scholar, and Scopus databases. Due to fact that several investigations have reviewed the roles played by Saffron on autoimmune and non-autoimmune diseases such as multiple sclerosis, mood disorders, and Alzheimer's disease, this review article focuses on other diseases to keep the novelty of the present review for readers.
1. Job KM, Kiang TKL, Constance JE, Sherwin CMT, Enioutina EY. Herbal medicines: challenges in the modern world. Part 4. Canada and United States. Expert Rev Clin Pharmacol. 2016;9(12):1597-609.
2. Ege B, Yumrutas O, Ege M, Pehlivan M, Bozgeyik I. Pharmacological properties and therapeutic potential of saffron (Crocus sativus L.) in osteosarcoma. J Pharm Pharmacol. 2019;72(1):56-67.
3. Srivastava R, Ahmed H, Dixit RK. Crocus sativus L.: a comprehensive review. Pharmacogn Rev. 2010;4(8):200-8.
4. Bhat JV, Broker R. Riboflavine and thiamine contents of saffron, Crocus sativus linn. Nature. 1953;172(4377):544.
5. Christodoulou E, Kadoglou NPE, Stasinopoulou M, Konstandi OA, Kenoutis C, Kakazanis ZI, et al. Crocus sativus L. aqueous extract reduces atherogenesis, increases atherosclerotic plaque stability and improves glucose control in diabetic atherosclerotic animals. Atherosclerosis. 2018;268:207-14.
6. Zengin G, Aumeeruddy MZ, Diuzheva A, Jekő J, Cziáky Z, Yıldıztugay A, et al. A comprehensive appraisal on Crocus chrysanthus (Herb.) Herb. flower extracts with HPLC–MS/MS profiles, antioxidant and enzyme inhibitory properties. J Pharm Biomed Anal. 2019;164:581-9.
7. Karimi-Nazari E, Nadjarzadeh A, Masoumi R, Marzban A, Mohajeri SA, et al. Effect of saffron (Crocus sativus L.) on lipid profile, glycemic indices and antioxidant status among overweight/obese prediabetic individuals: A double-blinded, randomized controlled trial. Clinical nutrition ESPEN. 2019;34:130-6.
8. Nikbakht-Jam I, Khademi M, Nosrati M, Eslami S, Foroutan-Tanha M, Sahebkar A, et al. Effect of crocin extracted from saffron on pro-oxidant–anti-oxidant balance in subjects with metabolic syndrome: a randomized, placebo-controlled clinical trial. European Journal of Integrative Medicine. 2016;8:307-12.
9. Safarinejad MR, Shafiei N, Safarinejad S. A prospective double‐blind randomized placebo‐controlled study of the effect of saffron (Crocus sativus Linn.) on semen parameters and seminal plasma antioxidant capacity in infertile men with idiopathic oligoasthenoteratozoospermia. Phytother Res. 2011;25(4):508-16.
10. Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Human Psychopharmacology: Clinical and Experimental. 2014;29(6):517-27.
11. Tabeshpour J, Sobhani F, Sadjadi SA, Hosseinzadeh H, Mohajeri SA, Rajabi O, et al. A double-blind, randomized, placebo-controlled trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate postpartum depression. Phytomedicine. 2017;36:145-52.
12. Khorasanchi Z, Shafiee M, Kermanshahi F, Khazaei M, Ryzhikov M, Parizadeh MR, et al. Crocus sativus a natural food coloring and flavoring has potent anti-tumor properties. Phytomedicine. 2018;43:21-7.
13. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol. 2014;64:65-80.
14. Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, Tsatsakis AM. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna journal of phytomedicine. 2015;5(5):376-391.
15. Sadeghnia HR, Shaterzadeh H, Forouzanfar F, Hosseinzadeh H. Neuroprotective effect of safranal, an active ingredient of Crocus sativus, in a rat model of transient cerebral ischemia. Folia Neuropathol. 2017;55(3):206-13.
16. Dehestani V, SHARIATI SZ, Mohiti S, Akhlaghi S. Liver toxicity in rheumatoid arthritis patients treated with methotrexate. 2015;4(3):102-105.
17. Sarabi ZS, Saeidi MG, Khodashahi M, Rezaie AE, Hashemzadeh K, Khodashahi R, et al. Evaluation of the anti-inflammatory effects of atorvastatin on patients with rheumatoid arthritis: a randomized clinical trial. Electronic physician. 2016;8(8):2700.
18. Ghoryani M, Shariati-Sarabi Z, Tavakkol-Afshari J, Ghasemi A, Poursamimi J, Mohammadi M. Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow-derived mesenchymal stem cells: A successful clinical trial in Iran. Biomed Pharmacother. 2019;109:1834-40.
19. 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;9:1341.
20. Li L, Zhang H, Jin S, Liu C. Effects of crocin on inflammatory activities in human fibroblast-like synoviocytes and collagen-induced arthritis in mice. Immunologic research. 2018;66(3):406-13.
21. 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(6):2086-93.
22. Hemshekhar M, Sebastin Santhosh M, Sunitha K, Thushara RM, Kemparaju K, Rangappa KS, et al. A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status. Biochimie. 2012;94(12):2723-33.
23. Ding Q, Zhong H, Qi Y, Cheng Y, Li W, Yan S, et al. Anti-arthritic effects of crocin in interleukin-1β-treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflamm Res. 2013;62(1):17-25.
24. Poursamimi J, Shariati-Sarabi Z, Tavakkol-Afshari J, Mohajeri SA, Ghoryani M, Mohammadi M. Immunoregulatory effects of KrocinaTM, an herbal medicine made of crocin, on osteoarthritis patients: a successful clinical trial in Iran. Iranian Journal of Allergy, Asthma and Immunology. 2019; article in press.
25. Li J, Lei H-t, Cao L, Mi Y-N, Li S, Cao Y-X. Crocin alleviates coronary atherosclerosis via inhibiting lipid synthesis and inducing M2 macrophage polarization. Int Immunopharmacol. 2018;55:120-7.
26. Pan JX. LncRNA H19 promotes atherosclerosis by regulating MAPK and NF-kB signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(2):322-8.
27. Christodoulou E, Kadoglou NPE, Stasinopoulou M, Konstandi OA, Kenoutis C, Kakazanis ZI, et al. Crocus sativus L. aqueous extract reduces atherogenesis, increases atherosclerotic plaque stability and improves glucose control in diabetic atherosclerotic animals. Atherosclerosis. 2018;268:207-14.
28. Mahdavifard S, Bathaie SZ, Nakhjavani M, Taghikhani M. The synergistic effect of antiglycating agents (MB-92) on inhibition of protein glycation, misfolding and diabetic complications in diabetic-atherosclerotic rat. Eur J Med Chem. 2016;121:892-902.
29. Hemmati M, Zohoori E, Mehrpour O, Karamian M, Asghari S, Zarban A, et al. Anti-atherogenic potential of jujube, saffron and barberry: anti-diabetic and antioxidant actions. EXCLI journal. 2015;14:908.
30. Xu G-L, Yu S-Q, Gong Z-N, Zhang S-Q. Study of the effect of crocin on rat experimental hyperlipemia and the underlying mechanisms. Zhongguo Zhongyao Zazhi. 2005;30(5):369-72.
31. Abedimanesh N, Bathaie SZ, Abedimanesh S, Motlagh B, et al. Saffron and crocin improved appetite, dietary intakes and body composition in patients with coronary artery disease. Journal of cardiovascular and thoracic research. 2017;9(4):200.
32. Wang Y, Sun J, Liu C, Fang C. Protective effects of crocetin pretreatment on myocardial injury in an ischemia/reperfusion rat model. Eur J Pharmacol. 2014;741:290-6.
33. Joukar S, Ghasemipour-Afshar E, Sheibani M, Naghsh N, Bashiri A. Protective effects of saffron (Crocus sativus) against lethal ventricular arrhythmias induced by heart reperfusion in rat: a potential anti-arrhythmic agent. Pharm Biol. 2013;51(7):836-43.
34. Jahanbakhsh Z, Rasoulian B, Jafari M, Shekarforoush S, Esmailidehaj M, taghi Mohammadi M, et al. Protective effect of crocin against reperfusion-induced cardiac arrhythmias in anaesthetized rats. EXCLI journal. 2012;11:20-9.
35. Llorens S, Mancini A, Serrano-Díaz J, D’Alessandro A, Nava E, Alonso G, et al. Effects of crocetin esters and crocetin from Crocus sativus L. on aortic contractility in rat genetic hypertension. Molecules. 2015;20(9):17570-84.
36. Wang Y, Wang Q, Yu W, Du H. Crocin Attenuates Oxidative Stress and Myocardial Infarction Injury in Rats. Int Heart J. 2018;59(2):387-393.
37. 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. Nutrition, Metabolism and Cardiovascular Diseases. 2017;27(10):919-29.
38. Nader M, Chahine N, Salem C, Chahine R. Saffron (Crocus sativus) pretreatment confers cardioprotection against ischemia-reperfusion injuries in isolated rabbit heart. J Physiol Biochem. 2016;72(4):711-9.
39. Bharti S, Golechha M, Kumari S, Siddiqui KM, Arya DS. Akt/GSK-3β/eNOS phosphorylation arbitrates safranal-induced myocardial protection against ischemia–reperfusion injury in rats. Eur J Nutr. 2012;51(6):719-27.
40. Zeng C, Li H, Fan Z, Zhong L, Guo Z, Guo Y, et al. Crocin-elicited autophagy rescues myocardial ischemia/reperfusion injury via paradoxical mechanisms. The American journal of Chinese medicine. 2016;44(3):515-30.
41. Chahine N, Nader M, Duca L, Martiny L, Chahine R. Saffron extracts alleviate cardiomyocytes injury induced by doxorubicin and ischemia-reperfusion in vitro. Drug Chem Toxicol. 2016;39(1):87-96.
42. Chahine N, Makhlouf H, Duca L, Martiny L, Chahine R. Cardioprotective effect of saffron extracts against acute doxorubicin toxicity in isolated rabbit hearts submitted to ischemia-reperfusion injury. Zeitschrift für Naturforschung C. 2014;69(11-12):459-70.
43. Huang Z, Nan C, Wang H, Su Q, Xue W, Chen Y, et al. Crocetin ester improves myocardial ischemia via Rho/ROCK/NF-κB pathway. Int Immunopharmacol. 2016;38:186-93.
44. Ochiai T, Shimeno H, Mishima K-i, Iwasaki K, Fujiwara M, Tanaka H, et al. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochimica et Biophysica Acta (BBA)-General Subjects. 2007;1770(4):578-84.
45. Huang A, Jia L. Crocin enhances hypothermia therapy in hypoxic ischemia-induced brain injury in mice. Acta Neurol Belg. 2019:1-8.
46. Farjah GH, Salehi S, Ansari MH, Pourheidar B. Protective effect of Crocus sativus L.(Saffron) extract on spinal cord ischemia-reperfusion injury in rats. Iranian journal of basic medical sciences. 2017;20(3):334-37.
47. Chen L, Qi Y, Yang X. Neuroprotective effects of crocin against oxidative stress induced by ischemia/reperfusion injury in rat retina. Ophthalmic Res. 2015;54(3):157-68.
48. Vakili A, Einali MR, Bandegi AR. Protective effect of crocin against cerebral ischemia in a dose-dependent manner in a rat model of ischemic stroke. J Stroke Cerebrovasc Dis. 2014;23(1):106-13.
49. Zheng Y-Q, Liu J-X, Wang J-N, Xu L. Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. Brain Res. 2007;1138:86-94.
50. Saleem S, Ahmad M, Ahmad AS, Yousuf S, Ansari MA, et al. Effect of saffron (Crocus sativus) on neurobehavioral and neurochemical changes in cerebral ischemia in rats. J Med Food. 2006;9(2):246-53.
51. Hosseinzadeh H, Sadeghnia HR, Ghaeni FA, Motamedshariaty VS, Mohajeri SA. Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytother Res. 2012;26(3):381-6.
52. Hosseinzadeh H, Sadeghnia HR. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J Pharm Pharm Sci. 2005;8(3):394-9.
53. Asadollahi M, Nikdokht P, Hatef B, Sadr SS, Sahraei H, Assarzadegan F, et al. Protective properties of the aqueous extract of saffron (Crocus sativus L.) in ischemic stroke, randomized clinical trial. J Ethnopharmacol. 2019;238:111833.
54. Greene S. Perspectives of quality control in diabetes treatment at the end of the century: facts and visions. Horm Res Paediatr. 1998;50(1):103-5.
55. Arababadi MK, Naghavi N, Hassanshahi G, Mahmoodi M. Is CCR5-Δ32 mutation associated with diabetic nephropathy in type 2 diabetes? Ann Saudi Med. 2009;29(5):413.
56. Mohammadi M, Gozashti MH, Aghadavood M, Mehdizadeh MR, Hayatbakhsh MM. Clinical significance of serum IL-6 and TNF-α levels in patients with metabolic syndrome. Reports of biochemistry & molecular biology. 2017;6(1):74-79.
57. Samaha MM, Said E, Salem HA. A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets. Environ Toxicol Pharmacol. 2019;72:103238.
58. Motamedrad M, Shokouhifar A, Hemmati M, Moossavi M. The regulatory effect of saffron stigma on the gene expression of the glucose metabolism key enzymes and stress proteins in streptozotocin-induced diabetic rats. Res Pharm Sci. 2019;14(3):255-262.
59. Faridi S, Delirezh N, Froushani SMA. Beneficial effects of hydroalcoholic extract of saffron in alleviating experimental autoimmune diabetes in C57bl/6 mice. Iranian Journal of Allergy, Asthma and Immunology. 2019;18(1).
60. Jiang SP, Shen Q, Lu Y, Yan YQ, Tong YP, Wang P. Effect of saffron aqueous extract on the level of blood glucose in experimental diabetes mice. Zhongguo ying yong sheng li xue za zhi= Zhongguo yingyong shenglixue zazhi= Chinese journal of applied physiology. 2018;34(2):173-76.
61. Roshankhah S, Jalili C, Salahshoor MR. Effects of Crocin on Sperm Parameters and Seminiferous Tubules in Diabetic Rats. Advanced biomedical research. 2019;8(4).
62. Delkhosh-Kasmaie F, Farshid AA, Tamaddonfard E, Imani M. The effects of safranal, a constitute of saffron, and metformin on spatial learning and memory impairments in type-1 diabetic rats: behavioral and hippocampal histopathological and biochemical evaluations. Biomed Pharmacother. 2018;107:203-11.
63. Abou-Hany HO, Atef H, Said E, Elkashef HA, Salem HA. Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats. Chem Biol Interact. 2018;284:90-100.
64. Asri-Rezaei S, Tamaddonfard E, Ghasemsoltani-Momtaz B, Erfanparast A, Gholamalipour S. Effects of crocin and zinc chloride on blood levels of zinc and metabolic and oxidative parameters in streptozotocin-induced diabetic rats. Avicenna journal of phytomedicine. 2015;5(5):403.
65. Altinoz E, Oner Z, Elbe H, Cigremis Y, Turkoz Y. Protective effects of saffron (its active constituent, crocin) on nephropathy in streptozotocin-induced diabetic rats. Hum Exp Toxicol. 2015;34(2):127-34.
66. Ishizuka F, Shimazawa M, Umigai N, Ogishima H, Nakamura S, Tsuruma K, et al. Crocetin, a carotenoid derivative, inhibits retinal ischemic damage in mice. Eur J Pharmacol. 2013;703(1-3):1-10.
67. Xuan B, ZHOU Y-H, Li NA, MIN Z-D, CHIOU GCY. Effects of crocin analogs on ocular blood flow and retinal function. J Ocul Pharmacol Ther. 1999;15(2):143-52.
68. Mohammadzadeh-Moghadam H, Nazari SM, Shamsa A, Kamalinejad M, Esmaeeli H, Asadpour AA, et al. Effects of a topical saffron (Crocus sativus L) gel on erectile dysfunction in diabetics: A randomized, parallel-group, double-blind, placebo-controlled trial. J Evid Based Complementary Altern Med. 2015;20(4):283-6.
69. Abou-Hany HO, Atef H, Said E, Elkashef HA, Salem HA. Crocin reverses unilateral renal ischemia reperfusion injury-induced augmentation of oxidative stress and toll like receptor-4 activity. Environ Toxicol Pharmacol. 2018;59:182-9.
70. Qi Y, Chen L, Zhang L, Liu W-B, Chen X-Y, Yang X-G. Crocin prevents retinal ischaemia/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K/AKT signalling pathway. Exp Eye Res. 2013;107:44-51.
71. Yang X, Huo F, Liu B, Liu J, Chen T, Li J, et al. Crocin inhibits oxidative stress and pro-inflammatory response of microglial cells associated with diabetic retinopathy through the activation of PI3K/Akt signaling pathway. J Mol Neurosci. 2017;61(4):581-9.
72. Dehghan F, Hajiaghaalipour F, Yusof A, Muniandy S, Hosseini SA, Heydari S, et al. Saffron with resistance exercise improves diabetic parameters through the GLUT4/AMPK pathway in-vitro and in-vivo. Sci Rep. 2016;6:25139.
73. Maeda A, Kai K, Ishii M, Ishii T, Akagawa M. Safranal, a novel protein tyrosine phosphatase 1 B inhibitor, activates insulin signaling in C 2 C 12 myotubes and improves glucose tolerance in diabetic KK‐Ay mice. Mol Nutr Food Res. 2014;58(6):1177-89.
74. Kang C, Lee H, Jung E-S, Seyedian R, Jo M, Kim J, et al. Saffron (Crocus sativus L.) increases glucose uptake and insulin sensitivity in muscle cells via multipathway mechanisms. Food Chem. 2012;135(4):2350-8.
75. Moravej Aleali A, Amani R, Shahbazian H, Namjooyan F, Latifi SM, Cheraghian B. The effect of hydroalcoholic Saffron (Crocus sativus L.) extract on fasting plasma glucose, HbA1c, lipid profile, liver, and renal function tests in patients with type 2 diabetes mellitus: A randomized double‐blind clinical trial. Phytother Res. 2019;33(6):1648-1657.
76. Suh KS, Chon S, Jung W-W, Choi EM. Crocin attenuates methylglyoxal-induced osteoclast dysfunction by regulating glyoxalase, oxidative stress, and mitochondrial function. Food Chem Toxicol. 2019;124:367-73.
77. Milajerdi A, Jazayeri S, Shirzadi E, Hashemzadeh N, Azizgol A, Djazayery A, et al. The effects of alcoholic extract of saffron (Crocus satious L.) on mild to moderate comorbid depression-anxiety, sleep quality, and life satisfaction in type 2 diabetes mellitus: A double-blind, randomized and placebo-controlled clinical trial. Complement Ther Med. 2018;41:196-202.
78. Sepahi S, Mohajeri SA, Hosseini SM, Khodaverdi E, Shoeibi N, Namdari M, et al. Effects of Crocin on diabetic maculopathy: a placebo-controlled randomized clinical trial. Am J Ophthalmol. 2018;190:89-98.
79. Milajerdi A, Jazayeri S, Hashemzadeh N, Shirzadi E, Derakhshan Z, Djazayeri A, et al. The effect of saffron (Crocus sativus L.) hydroalcoholic extract on metabolic control in type 2 diabetes mellitus: A triple-blinded randomized clinical trial. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2018;23(16):1-25.
80. Azimi P, Ghiasvand R, Feizi A, Hosseinzadeh J, Bahreynian M, et al. Effect of cinnamon, cardamom, saffron and ginger consumption on blood pressure and a marker of endothelial function in patients with type 2 diabetes mellitus: A randomized controlled clinical trial. Blood Press. 2016;25(3):133-40.
81. Azimi P, Ghiasvand R, Feizi A, Hariri M, Abbasi B. Effects of cinnamon, cardamom, saffron, and ginger consumption on markers of glycemic control, lipid profile, oxidative stress, and inflammation in type 2 diabetes patients. The review of diabetic studies: RDS. 2014;11(3-4):258-66.
82. Weitgasser R, Lechleitner M, Koch T, Galvan G, Mühlmann J, Steiner K, et al. Antibodies to heat-shock protein 65 and neopterin levels in patients with type 1 diabetes mellitus. Experimental and clinical endocrinology & diabetes. 2003;111(3):127-31.
83. Shemshian M, Mousavi SH, Norouzy A, Kermani T, Moghiman T, Sadeghi A, et al. Saffron in metabolic syndrome: its effects on antibody titers to heat-shock proteins 27, 60, 65 and 70. Journal of Complementary and Integrative Medicine. 2014;11(1):43-9.
84. Shahbazian H, Aleali AM, Amani R, Namjooyan F, Cheraghian B, Latifi SM, et al. Effects of saffron on homocysteine, and antioxidant and inflammatory biomarkers levels in patients with type 2 diabetes mellitus: a randomized double-blind clinical trial. Avicenna journal of phytomedicine. 2019;9(5):436-45.
85. Ebrahimi F, Aryaeian N, Pahlavani N, Abbasi D, Hosseini AF, Fallah S, et al. The effect of saffron (Crocus sativus L.) supplementation on blood pressure, and renal and liver function in patients with type 2 diabetes mellitus: A double-blinded, randomized clinical trial. Avicenna journal of phytomedicine. 2019;9(4):322-33.
86. Sairenji T, Collins KL, Evans DV. An Update on Inflammatory Bowel Disease. Primary care. 2017;44(4):673-92.
87. Rezaei N, Avan A, Pashirzad M, Rahmani F, Moradi Marjaneh R, Behnam-Rassouli R, et al. Crocin as a novel therapeutic agent against colitis. Drug Chem Toxicol. 2019;24:1-8.
88. Mohammadi M, Zahedi MJ, Nikpoor AR, Nazem M, et al. Determination of Vitamin D Serum Levels and Status of the C3435T Polymorphism of Multidrug Resistance 1 Gene in Southeastern Iranian Patients with Ulcerative Colitis. Middle East journal of digestive diseases. 2015;7(4):245-52.
89. 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;110:389-99.
90. 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. 2012;2012.
91. Gezici S. Comparative anticancer activity analysis of saffron extracts and a principle component, crocetin for prevention and treatment of human malignancies. J Food Sci Technol. 2019;56(12):5435-43.
92. 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(2):105-11.
93. Ege B, Yumrutas O, Ege M, Pehlivan M, Bozgeyik I. Pharmacological properties and therapeutic potential of saffron (Crocus sativus L.) in osteosarcoma. J Pharm Pharmacol. 2019;72(1):56-67.
94. Zhou Y, Xu Q, Shang J, Lu L, Chen G. Crocin inhibits the migration, invasion, and epithelial‐mesenchymal transition of gastric cancer cells via miR‐320/KLF5/HIF‐1α signaling. Journal of cellular physiology. 2019;234(10):17876-885.
95. Li S, Qu Y, Shen X-Y, Ouyang T, Fu W-B, Luo T, et al. Multiple Signal Pathways Involved in Crocetin-Induced Apoptosis in KYSE-150 Cells. Pharmacology. 2019;103(5-6):263-72.
96. Deng L, Li J, Lu S, Su Y. Crocin inhibits proliferation and induces apoptosis through suppressing MYCN expression in retinoblastoma. J Biochem Mol Toxicol. 2019;33(5):e22292.
97. Liu T, Tian L, Fu X, Wei L, Li J, Wang T. Saffron inhibits the proliferation of hepatocellular carcinoma via inducing cell apoptosis. Panminerva Med. 2019.
98. Neyshaburinezhad N, Hashemi M, Ramezani M, Arabzadeh S, Behravan J, Kalalinia F. The effects of crocetin, extracted from saffron, in chemotherapy against the incidence of multiple drug resistance phenotype. Iranian journal of basic medical sciences. 2018;21(11):1192.
99. Giakoumettis D, Pourzitaki C, Vavilis T, Tsingotjidou A, Kyriakoudi A, Tsimidou M, et al. Crocus sativus L. Causes a Non Apoptotic Calpain Dependent Death in C6 Rat Glioma Cells, Exhibiting a Synergistic Effect with Temozolomide. Nutr Cancer. 2019;71(3):491-507.
100. Arzi L, Riazi G, Sadeghizadeh M, Hoshyar R, Jafarzadeh N. A Comparative Study on Anti-Invasion, Antimigration, and Antiadhesion Effects of the Bioactive Carotenoids of Saffron on 4T1 Breast Cancer Cells Through Their Effects on Wnt/β-Catenin Pathway Genes. DNA Cell Biol. 2018;37(8):697-707.
101. Menghini L, Leporini L, Vecchiotti G, Locatelli M, Carradori S, Ferrante C, et al. Crocus sativus L. stigmas and byproducts: qualitative fingerprint, antioxidant potentials and enzyme inhibitory activities. Food research international. 2018;109:91-8.
102. Kim B, Park B. Saffron carotenoids inhibit STAT3 activation and promote apoptotic progression in IL-6-stimulated liver cancer cells. Oncol Rep. 2018;39(4):1883-91.
103. Arzi L, Farahi A, Jafarzadeh N, Riazi G, Sadeghizadeh M, Hoshyar R. Inhibitory Effect of Crocin on Metastasis of Triple-Negative Breast Cancer by Interfering with Wnt/β-Catenin Pathway in Murine Model. DNA Cell Biol. 2018;37(12):1068-75.
104. Li S, Shen X-Y, Ouyang T, Qu Y, Luo T, Wang H-Q. Synergistic anticancer effect of combined crocetin and cisplatin on KYSE-150 cells via p53/p21 pathway. Cancer Cell Int. 2017;17(1):98.
105. Lu P, Lin H, Gu Y, Li L, Guo H, Wang F, et al. Antitumor effects of crocin on human breast cancer cells. Int J Clin Exp Med. 2015;8(11):20316.
106. Sawant AV, Srivastava S, Prassanawar SS, Bhattacharyya B, Panda D. Crocin, a carotenoid, suppresses spindle microtubule dynamics and activates the mitotic checkpoint by binding to tubulin. Biochem Pharmacol. 2019;163:32-45.
107. Zhang A, Li J. Crocetin shifts autophagic cell survival to death of breast cancer cells in chemotherapy. Tumor Biology. 2017;39(3):1010428317694536.
108. Geromichalos GD, Papadopoulos T, Sahpazidou D, Sinakos Z. Safranal, a Crocus sativus L constituent suppresses the growth of K-562 cells of chronic myelogenous leukemia. In silico and in vitro study. Food Chem Toxicol. 2014;74:45-50.
109. Rezaee R, Mahmoudi M, Abnous K, Rabe SZT, Tabasi N, Hashemzaei M, et al. Cytotoxic effects of crocin on MOLT-4 human leukemia cells. Journal of Complementary and Integrative Medicine. 2013;10(1):105-12.
110. Sun Y, Xu H-J, Zhao Y-X, Wang L-Z, Sun L-R, Wang Z, et al. Crocin exhibits antitumor effects on human leukemia HL-60 cells in vitro and in vivo. Evid Based Complement Alternat Med. 2013;2013.
111. Bhandari PR. Crocus sativus L.(saffron) for cancer chemoprevention: a mini review. Journal of traditional and complementary medicine. 2015;5(2):81-7.
112. Babaei A, Arshami J, Haghparast A, Mesgaran MD. Effects of saffron (Crocus sativus) petal ethanolic extract on hematology, antibody response, and spleen histology in rats. Avicenna journal of phytomedicine. 2014;4(2):103.
113. Moradzadeh M, Ghorbani A, Erfanian S, Mohaddes ST, Rahimi H, Karimiani EG, et al. Study of the mechanisms of crocetin‐induced differentiation and apoptosis in human acute promyelocytic leukemia cells. J Cell Biochem. 2019;120(2):1943-57.
2. Ege B, Yumrutas O, Ege M, Pehlivan M, Bozgeyik I. Pharmacological properties and therapeutic potential of saffron (Crocus sativus L.) in osteosarcoma. J Pharm Pharmacol. 2019;72(1):56-67.
3. Srivastava R, Ahmed H, Dixit RK. Crocus sativus L.: a comprehensive review. Pharmacogn Rev. 2010;4(8):200-8.
4. Bhat JV, Broker R. Riboflavine and thiamine contents of saffron, Crocus sativus linn. Nature. 1953;172(4377):544.
5. Christodoulou E, Kadoglou NPE, Stasinopoulou M, Konstandi OA, Kenoutis C, Kakazanis ZI, et al. Crocus sativus L. aqueous extract reduces atherogenesis, increases atherosclerotic plaque stability and improves glucose control in diabetic atherosclerotic animals. Atherosclerosis. 2018;268:207-14.
6. Zengin G, Aumeeruddy MZ, Diuzheva A, Jekő J, Cziáky Z, Yıldıztugay A, et al. A comprehensive appraisal on Crocus chrysanthus (Herb.) Herb. flower extracts with HPLC–MS/MS profiles, antioxidant and enzyme inhibitory properties. J Pharm Biomed Anal. 2019;164:581-9.
7. Karimi-Nazari E, Nadjarzadeh A, Masoumi R, Marzban A, Mohajeri SA, et al. Effect of saffron (Crocus sativus L.) on lipid profile, glycemic indices and antioxidant status among overweight/obese prediabetic individuals: A double-blinded, randomized controlled trial. Clinical nutrition ESPEN. 2019;34:130-6.
8. Nikbakht-Jam I, Khademi M, Nosrati M, Eslami S, Foroutan-Tanha M, Sahebkar A, et al. Effect of crocin extracted from saffron on pro-oxidant–anti-oxidant balance in subjects with metabolic syndrome: a randomized, placebo-controlled clinical trial. European Journal of Integrative Medicine. 2016;8:307-12.
9. Safarinejad MR, Shafiei N, Safarinejad S. A prospective double‐blind randomized placebo‐controlled study of the effect of saffron (Crocus sativus Linn.) on semen parameters and seminal plasma antioxidant capacity in infertile men with idiopathic oligoasthenoteratozoospermia. Phytother Res. 2011;25(4):508-16.
10. Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Human Psychopharmacology: Clinical and Experimental. 2014;29(6):517-27.
11. Tabeshpour J, Sobhani F, Sadjadi SA, Hosseinzadeh H, Mohajeri SA, Rajabi O, et al. A double-blind, randomized, placebo-controlled trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate postpartum depression. Phytomedicine. 2017;36:145-52.
12. Khorasanchi Z, Shafiee M, Kermanshahi F, Khazaei M, Ryzhikov M, Parizadeh MR, et al. Crocus sativus a natural food coloring and flavoring has potent anti-tumor properties. Phytomedicine. 2018;43:21-7.
13. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol. 2014;64:65-80.
14. Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, Tsatsakis AM. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna journal of phytomedicine. 2015;5(5):376-391.
15. Sadeghnia HR, Shaterzadeh H, Forouzanfar F, Hosseinzadeh H. Neuroprotective effect of safranal, an active ingredient of Crocus sativus, in a rat model of transient cerebral ischemia. Folia Neuropathol. 2017;55(3):206-13.
16. Dehestani V, SHARIATI SZ, Mohiti S, Akhlaghi S. Liver toxicity in rheumatoid arthritis patients treated with methotrexate. 2015;4(3):102-105.
17. Sarabi ZS, Saeidi MG, Khodashahi M, Rezaie AE, Hashemzadeh K, Khodashahi R, et al. Evaluation of the anti-inflammatory effects of atorvastatin on patients with rheumatoid arthritis: a randomized clinical trial. Electronic physician. 2016;8(8):2700.
18. Ghoryani M, Shariati-Sarabi Z, Tavakkol-Afshari J, Ghasemi A, Poursamimi J, Mohammadi M. Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow-derived mesenchymal stem cells: A successful clinical trial in Iran. Biomed Pharmacother. 2019;109:1834-40.
19. 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;9:1341.
20. Li L, Zhang H, Jin S, Liu C. Effects of crocin on inflammatory activities in human fibroblast-like synoviocytes and collagen-induced arthritis in mice. Immunologic research. 2018;66(3):406-13.
21. 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(6):2086-93.
22. Hemshekhar M, Sebastin Santhosh M, Sunitha K, Thushara RM, Kemparaju K, Rangappa KS, et al. A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status. Biochimie. 2012;94(12):2723-33.
23. Ding Q, Zhong H, Qi Y, Cheng Y, Li W, Yan S, et al. Anti-arthritic effects of crocin in interleukin-1β-treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflamm Res. 2013;62(1):17-25.
24. Poursamimi J, Shariati-Sarabi Z, Tavakkol-Afshari J, Mohajeri SA, Ghoryani M, Mohammadi M. Immunoregulatory effects of KrocinaTM, an herbal medicine made of crocin, on osteoarthritis patients: a successful clinical trial in Iran. Iranian Journal of Allergy, Asthma and Immunology. 2019; article in press.
25. Li J, Lei H-t, Cao L, Mi Y-N, Li S, Cao Y-X. Crocin alleviates coronary atherosclerosis via inhibiting lipid synthesis and inducing M2 macrophage polarization. Int Immunopharmacol. 2018;55:120-7.
26. Pan JX. LncRNA H19 promotes atherosclerosis by regulating MAPK and NF-kB signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(2):322-8.
27. Christodoulou E, Kadoglou NPE, Stasinopoulou M, Konstandi OA, Kenoutis C, Kakazanis ZI, et al. Crocus sativus L. aqueous extract reduces atherogenesis, increases atherosclerotic plaque stability and improves glucose control in diabetic atherosclerotic animals. Atherosclerosis. 2018;268:207-14.
28. Mahdavifard S, Bathaie SZ, Nakhjavani M, Taghikhani M. The synergistic effect of antiglycating agents (MB-92) on inhibition of protein glycation, misfolding and diabetic complications in diabetic-atherosclerotic rat. Eur J Med Chem. 2016;121:892-902.
29. Hemmati M, Zohoori E, Mehrpour O, Karamian M, Asghari S, Zarban A, et al. Anti-atherogenic potential of jujube, saffron and barberry: anti-diabetic and antioxidant actions. EXCLI journal. 2015;14:908.
30. Xu G-L, Yu S-Q, Gong Z-N, Zhang S-Q. Study of the effect of crocin on rat experimental hyperlipemia and the underlying mechanisms. Zhongguo Zhongyao Zazhi. 2005;30(5):369-72.
31. Abedimanesh N, Bathaie SZ, Abedimanesh S, Motlagh B, et al. Saffron and crocin improved appetite, dietary intakes and body composition in patients with coronary artery disease. Journal of cardiovascular and thoracic research. 2017;9(4):200.
32. Wang Y, Sun J, Liu C, Fang C. Protective effects of crocetin pretreatment on myocardial injury in an ischemia/reperfusion rat model. Eur J Pharmacol. 2014;741:290-6.
33. Joukar S, Ghasemipour-Afshar E, Sheibani M, Naghsh N, Bashiri A. Protective effects of saffron (Crocus sativus) against lethal ventricular arrhythmias induced by heart reperfusion in rat: a potential anti-arrhythmic agent. Pharm Biol. 2013;51(7):836-43.
34. Jahanbakhsh Z, Rasoulian B, Jafari M, Shekarforoush S, Esmailidehaj M, taghi Mohammadi M, et al. Protective effect of crocin against reperfusion-induced cardiac arrhythmias in anaesthetized rats. EXCLI journal. 2012;11:20-9.
35. Llorens S, Mancini A, Serrano-Díaz J, D’Alessandro A, Nava E, Alonso G, et al. Effects of crocetin esters and crocetin from Crocus sativus L. on aortic contractility in rat genetic hypertension. Molecules. 2015;20(9):17570-84.
36. Wang Y, Wang Q, Yu W, Du H. Crocin Attenuates Oxidative Stress and Myocardial Infarction Injury in Rats. Int Heart J. 2018;59(2):387-393.
37. 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. Nutrition, Metabolism and Cardiovascular Diseases. 2017;27(10):919-29.
38. Nader M, Chahine N, Salem C, Chahine R. Saffron (Crocus sativus) pretreatment confers cardioprotection against ischemia-reperfusion injuries in isolated rabbit heart. J Physiol Biochem. 2016;72(4):711-9.
39. Bharti S, Golechha M, Kumari S, Siddiqui KM, Arya DS. Akt/GSK-3β/eNOS phosphorylation arbitrates safranal-induced myocardial protection against ischemia–reperfusion injury in rats. Eur J Nutr. 2012;51(6):719-27.
40. Zeng C, Li H, Fan Z, Zhong L, Guo Z, Guo Y, et al. Crocin-elicited autophagy rescues myocardial ischemia/reperfusion injury via paradoxical mechanisms. The American journal of Chinese medicine. 2016;44(3):515-30.
41. Chahine N, Nader M, Duca L, Martiny L, Chahine R. Saffron extracts alleviate cardiomyocytes injury induced by doxorubicin and ischemia-reperfusion in vitro. Drug Chem Toxicol. 2016;39(1):87-96.
42. Chahine N, Makhlouf H, Duca L, Martiny L, Chahine R. Cardioprotective effect of saffron extracts against acute doxorubicin toxicity in isolated rabbit hearts submitted to ischemia-reperfusion injury. Zeitschrift für Naturforschung C. 2014;69(11-12):459-70.
43. Huang Z, Nan C, Wang H, Su Q, Xue W, Chen Y, et al. Crocetin ester improves myocardial ischemia via Rho/ROCK/NF-κB pathway. Int Immunopharmacol. 2016;38:186-93.
44. Ochiai T, Shimeno H, Mishima K-i, Iwasaki K, Fujiwara M, Tanaka H, et al. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochimica et Biophysica Acta (BBA)-General Subjects. 2007;1770(4):578-84.
45. Huang A, Jia L. Crocin enhances hypothermia therapy in hypoxic ischemia-induced brain injury in mice. Acta Neurol Belg. 2019:1-8.
46. Farjah GH, Salehi S, Ansari MH, Pourheidar B. Protective effect of Crocus sativus L.(Saffron) extract on spinal cord ischemia-reperfusion injury in rats. Iranian journal of basic medical sciences. 2017;20(3):334-37.
47. Chen L, Qi Y, Yang X. Neuroprotective effects of crocin against oxidative stress induced by ischemia/reperfusion injury in rat retina. Ophthalmic Res. 2015;54(3):157-68.
48. Vakili A, Einali MR, Bandegi AR. Protective effect of crocin against cerebral ischemia in a dose-dependent manner in a rat model of ischemic stroke. J Stroke Cerebrovasc Dis. 2014;23(1):106-13.
49. Zheng Y-Q, Liu J-X, Wang J-N, Xu L. Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. Brain Res. 2007;1138:86-94.
50. Saleem S, Ahmad M, Ahmad AS, Yousuf S, Ansari MA, et al. Effect of saffron (Crocus sativus) on neurobehavioral and neurochemical changes in cerebral ischemia in rats. J Med Food. 2006;9(2):246-53.
51. Hosseinzadeh H, Sadeghnia HR, Ghaeni FA, Motamedshariaty VS, Mohajeri SA. Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytother Res. 2012;26(3):381-6.
52. Hosseinzadeh H, Sadeghnia HR. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J Pharm Pharm Sci. 2005;8(3):394-9.
53. Asadollahi M, Nikdokht P, Hatef B, Sadr SS, Sahraei H, Assarzadegan F, et al. Protective properties of the aqueous extract of saffron (Crocus sativus L.) in ischemic stroke, randomized clinical trial. J Ethnopharmacol. 2019;238:111833.
54. Greene S. Perspectives of quality control in diabetes treatment at the end of the century: facts and visions. Horm Res Paediatr. 1998;50(1):103-5.
55. Arababadi MK, Naghavi N, Hassanshahi G, Mahmoodi M. Is CCR5-Δ32 mutation associated with diabetic nephropathy in type 2 diabetes? Ann Saudi Med. 2009;29(5):413.
56. Mohammadi M, Gozashti MH, Aghadavood M, Mehdizadeh MR, Hayatbakhsh MM. Clinical significance of serum IL-6 and TNF-α levels in patients with metabolic syndrome. Reports of biochemistry & molecular biology. 2017;6(1):74-79.
57. Samaha MM, Said E, Salem HA. A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets. Environ Toxicol Pharmacol. 2019;72:103238.
58. Motamedrad M, Shokouhifar A, Hemmati M, Moossavi M. The regulatory effect of saffron stigma on the gene expression of the glucose metabolism key enzymes and stress proteins in streptozotocin-induced diabetic rats. Res Pharm Sci. 2019;14(3):255-262.
59. Faridi S, Delirezh N, Froushani SMA. Beneficial effects of hydroalcoholic extract of saffron in alleviating experimental autoimmune diabetes in C57bl/6 mice. Iranian Journal of Allergy, Asthma and Immunology. 2019;18(1).
60. Jiang SP, Shen Q, Lu Y, Yan YQ, Tong YP, Wang P. Effect of saffron aqueous extract on the level of blood glucose in experimental diabetes mice. Zhongguo ying yong sheng li xue za zhi= Zhongguo yingyong shenglixue zazhi= Chinese journal of applied physiology. 2018;34(2):173-76.
61. Roshankhah S, Jalili C, Salahshoor MR. Effects of Crocin on Sperm Parameters and Seminiferous Tubules in Diabetic Rats. Advanced biomedical research. 2019;8(4).
62. Delkhosh-Kasmaie F, Farshid AA, Tamaddonfard E, Imani M. The effects of safranal, a constitute of saffron, and metformin on spatial learning and memory impairments in type-1 diabetic rats: behavioral and hippocampal histopathological and biochemical evaluations. Biomed Pharmacother. 2018;107:203-11.
63. Abou-Hany HO, Atef H, Said E, Elkashef HA, Salem HA. Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats. Chem Biol Interact. 2018;284:90-100.
64. Asri-Rezaei S, Tamaddonfard E, Ghasemsoltani-Momtaz B, Erfanparast A, Gholamalipour S. Effects of crocin and zinc chloride on blood levels of zinc and metabolic and oxidative parameters in streptozotocin-induced diabetic rats. Avicenna journal of phytomedicine. 2015;5(5):403.
65. Altinoz E, Oner Z, Elbe H, Cigremis Y, Turkoz Y. Protective effects of saffron (its active constituent, crocin) on nephropathy in streptozotocin-induced diabetic rats. Hum Exp Toxicol. 2015;34(2):127-34.
66. Ishizuka F, Shimazawa M, Umigai N, Ogishima H, Nakamura S, Tsuruma K, et al. Crocetin, a carotenoid derivative, inhibits retinal ischemic damage in mice. Eur J Pharmacol. 2013;703(1-3):1-10.
67. Xuan B, ZHOU Y-H, Li NA, MIN Z-D, CHIOU GCY. Effects of crocin analogs on ocular blood flow and retinal function. J Ocul Pharmacol Ther. 1999;15(2):143-52.
68. Mohammadzadeh-Moghadam H, Nazari SM, Shamsa A, Kamalinejad M, Esmaeeli H, Asadpour AA, et al. Effects of a topical saffron (Crocus sativus L) gel on erectile dysfunction in diabetics: A randomized, parallel-group, double-blind, placebo-controlled trial. J Evid Based Complementary Altern Med. 2015;20(4):283-6.
69. Abou-Hany HO, Atef H, Said E, Elkashef HA, Salem HA. Crocin reverses unilateral renal ischemia reperfusion injury-induced augmentation of oxidative stress and toll like receptor-4 activity. Environ Toxicol Pharmacol. 2018;59:182-9.
70. Qi Y, Chen L, Zhang L, Liu W-B, Chen X-Y, Yang X-G. Crocin prevents retinal ischaemia/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K/AKT signalling pathway. Exp Eye Res. 2013;107:44-51.
71. Yang X, Huo F, Liu B, Liu J, Chen T, Li J, et al. Crocin inhibits oxidative stress and pro-inflammatory response of microglial cells associated with diabetic retinopathy through the activation of PI3K/Akt signaling pathway. J Mol Neurosci. 2017;61(4):581-9.
72. Dehghan F, Hajiaghaalipour F, Yusof A, Muniandy S, Hosseini SA, Heydari S, et al. Saffron with resistance exercise improves diabetic parameters through the GLUT4/AMPK pathway in-vitro and in-vivo. Sci Rep. 2016;6:25139.
73. Maeda A, Kai K, Ishii M, Ishii T, Akagawa M. Safranal, a novel protein tyrosine phosphatase 1 B inhibitor, activates insulin signaling in C 2 C 12 myotubes and improves glucose tolerance in diabetic KK‐Ay mice. Mol Nutr Food Res. 2014;58(6):1177-89.
74. Kang C, Lee H, Jung E-S, Seyedian R, Jo M, Kim J, et al. Saffron (Crocus sativus L.) increases glucose uptake and insulin sensitivity in muscle cells via multipathway mechanisms. Food Chem. 2012;135(4):2350-8.
75. Moravej Aleali A, Amani R, Shahbazian H, Namjooyan F, Latifi SM, Cheraghian B. The effect of hydroalcoholic Saffron (Crocus sativus L.) extract on fasting plasma glucose, HbA1c, lipid profile, liver, and renal function tests in patients with type 2 diabetes mellitus: A randomized double‐blind clinical trial. Phytother Res. 2019;33(6):1648-1657.
76. Suh KS, Chon S, Jung W-W, Choi EM. Crocin attenuates methylglyoxal-induced osteoclast dysfunction by regulating glyoxalase, oxidative stress, and mitochondrial function. Food Chem Toxicol. 2019;124:367-73.
77. Milajerdi A, Jazayeri S, Shirzadi E, Hashemzadeh N, Azizgol A, Djazayery A, et al. The effects of alcoholic extract of saffron (Crocus satious L.) on mild to moderate comorbid depression-anxiety, sleep quality, and life satisfaction in type 2 diabetes mellitus: A double-blind, randomized and placebo-controlled clinical trial. Complement Ther Med. 2018;41:196-202.
78. Sepahi S, Mohajeri SA, Hosseini SM, Khodaverdi E, Shoeibi N, Namdari M, et al. Effects of Crocin on diabetic maculopathy: a placebo-controlled randomized clinical trial. Am J Ophthalmol. 2018;190:89-98.
79. Milajerdi A, Jazayeri S, Hashemzadeh N, Shirzadi E, Derakhshan Z, Djazayeri A, et al. The effect of saffron (Crocus sativus L.) hydroalcoholic extract on metabolic control in type 2 diabetes mellitus: A triple-blinded randomized clinical trial. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2018;23(16):1-25.
80. Azimi P, Ghiasvand R, Feizi A, Hosseinzadeh J, Bahreynian M, et al. Effect of cinnamon, cardamom, saffron and ginger consumption on blood pressure and a marker of endothelial function in patients with type 2 diabetes mellitus: A randomized controlled clinical trial. Blood Press. 2016;25(3):133-40.
81. Azimi P, Ghiasvand R, Feizi A, Hariri M, Abbasi B. Effects of cinnamon, cardamom, saffron, and ginger consumption on markers of glycemic control, lipid profile, oxidative stress, and inflammation in type 2 diabetes patients. The review of diabetic studies: RDS. 2014;11(3-4):258-66.
82. Weitgasser R, Lechleitner M, Koch T, Galvan G, Mühlmann J, Steiner K, et al. Antibodies to heat-shock protein 65 and neopterin levels in patients with type 1 diabetes mellitus. Experimental and clinical endocrinology & diabetes. 2003;111(3):127-31.
83. Shemshian M, Mousavi SH, Norouzy A, Kermani T, Moghiman T, Sadeghi A, et al. Saffron in metabolic syndrome: its effects on antibody titers to heat-shock proteins 27, 60, 65 and 70. Journal of Complementary and Integrative Medicine. 2014;11(1):43-9.
84. Shahbazian H, Aleali AM, Amani R, Namjooyan F, Cheraghian B, Latifi SM, et al. Effects of saffron on homocysteine, and antioxidant and inflammatory biomarkers levels in patients with type 2 diabetes mellitus: a randomized double-blind clinical trial. Avicenna journal of phytomedicine. 2019;9(5):436-45.
85. Ebrahimi F, Aryaeian N, Pahlavani N, Abbasi D, Hosseini AF, Fallah S, et al. The effect of saffron (Crocus sativus L.) supplementation on blood pressure, and renal and liver function in patients with type 2 diabetes mellitus: A double-blinded, randomized clinical trial. Avicenna journal of phytomedicine. 2019;9(4):322-33.
86. Sairenji T, Collins KL, Evans DV. An Update on Inflammatory Bowel Disease. Primary care. 2017;44(4):673-92.
87. Rezaei N, Avan A, Pashirzad M, Rahmani F, Moradi Marjaneh R, Behnam-Rassouli R, et al. Crocin as a novel therapeutic agent against colitis. Drug Chem Toxicol. 2019;24:1-8.
88. Mohammadi M, Zahedi MJ, Nikpoor AR, Nazem M, et al. Determination of Vitamin D Serum Levels and Status of the C3435T Polymorphism of Multidrug Resistance 1 Gene in Southeastern Iranian Patients with Ulcerative Colitis. Middle East journal of digestive diseases. 2015;7(4):245-52.
89. 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;110:389-99.
90. 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. 2012;2012.
91. Gezici S. Comparative anticancer activity analysis of saffron extracts and a principle component, crocetin for prevention and treatment of human malignancies. J Food Sci Technol. 2019;56(12):5435-43.
92. 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(2):105-11.
93. Ege B, Yumrutas O, Ege M, Pehlivan M, Bozgeyik I. Pharmacological properties and therapeutic potential of saffron (Crocus sativus L.) in osteosarcoma. J Pharm Pharmacol. 2019;72(1):56-67.
94. Zhou Y, Xu Q, Shang J, Lu L, Chen G. Crocin inhibits the migration, invasion, and epithelial‐mesenchymal transition of gastric cancer cells via miR‐320/KLF5/HIF‐1α signaling. Journal of cellular physiology. 2019;234(10):17876-885.
95. Li S, Qu Y, Shen X-Y, Ouyang T, Fu W-B, Luo T, et al. Multiple Signal Pathways Involved in Crocetin-Induced Apoptosis in KYSE-150 Cells. Pharmacology. 2019;103(5-6):263-72.
96. Deng L, Li J, Lu S, Su Y. Crocin inhibits proliferation and induces apoptosis through suppressing MYCN expression in retinoblastoma. J Biochem Mol Toxicol. 2019;33(5):e22292.
97. Liu T, Tian L, Fu X, Wei L, Li J, Wang T. Saffron inhibits the proliferation of hepatocellular carcinoma via inducing cell apoptosis. Panminerva Med. 2019.
98. Neyshaburinezhad N, Hashemi M, Ramezani M, Arabzadeh S, Behravan J, Kalalinia F. The effects of crocetin, extracted from saffron, in chemotherapy against the incidence of multiple drug resistance phenotype. Iranian journal of basic medical sciences. 2018;21(11):1192.
99. Giakoumettis D, Pourzitaki C, Vavilis T, Tsingotjidou A, Kyriakoudi A, Tsimidou M, et al. Crocus sativus L. Causes a Non Apoptotic Calpain Dependent Death in C6 Rat Glioma Cells, Exhibiting a Synergistic Effect with Temozolomide. Nutr Cancer. 2019;71(3):491-507.
100. Arzi L, Riazi G, Sadeghizadeh M, Hoshyar R, Jafarzadeh N. A Comparative Study on Anti-Invasion, Antimigration, and Antiadhesion Effects of the Bioactive Carotenoids of Saffron on 4T1 Breast Cancer Cells Through Their Effects on Wnt/β-Catenin Pathway Genes. DNA Cell Biol. 2018;37(8):697-707.
101. Menghini L, Leporini L, Vecchiotti G, Locatelli M, Carradori S, Ferrante C, et al. Crocus sativus L. stigmas and byproducts: qualitative fingerprint, antioxidant potentials and enzyme inhibitory activities. Food research international. 2018;109:91-8.
102. Kim B, Park B. Saffron carotenoids inhibit STAT3 activation and promote apoptotic progression in IL-6-stimulated liver cancer cells. Oncol Rep. 2018;39(4):1883-91.
103. Arzi L, Farahi A, Jafarzadeh N, Riazi G, Sadeghizadeh M, Hoshyar R. Inhibitory Effect of Crocin on Metastasis of Triple-Negative Breast Cancer by Interfering with Wnt/β-Catenin Pathway in Murine Model. DNA Cell Biol. 2018;37(12):1068-75.
104. Li S, Shen X-Y, Ouyang T, Qu Y, Luo T, Wang H-Q. Synergistic anticancer effect of combined crocetin and cisplatin on KYSE-150 cells via p53/p21 pathway. Cancer Cell Int. 2017;17(1):98.
105. Lu P, Lin H, Gu Y, Li L, Guo H, Wang F, et al. Antitumor effects of crocin on human breast cancer cells. Int J Clin Exp Med. 2015;8(11):20316.
106. Sawant AV, Srivastava S, Prassanawar SS, Bhattacharyya B, Panda D. Crocin, a carotenoid, suppresses spindle microtubule dynamics and activates the mitotic checkpoint by binding to tubulin. Biochem Pharmacol. 2019;163:32-45.
107. Zhang A, Li J. Crocetin shifts autophagic cell survival to death of breast cancer cells in chemotherapy. Tumor Biology. 2017;39(3):1010428317694536.
108. Geromichalos GD, Papadopoulos T, Sahpazidou D, Sinakos Z. Safranal, a Crocus sativus L constituent suppresses the growth of K-562 cells of chronic myelogenous leukemia. In silico and in vitro study. Food Chem Toxicol. 2014;74:45-50.
109. Rezaee R, Mahmoudi M, Abnous K, Rabe SZT, Tabasi N, Hashemzaei M, et al. Cytotoxic effects of crocin on MOLT-4 human leukemia cells. Journal of Complementary and Integrative Medicine. 2013;10(1):105-12.
110. Sun Y, Xu H-J, Zhao Y-X, Wang L-Z, Sun L-R, Wang Z, et al. Crocin exhibits antitumor effects on human leukemia HL-60 cells in vitro and in vivo. Evid Based Complement Alternat Med. 2013;2013.
111. Bhandari PR. Crocus sativus L.(saffron) for cancer chemoprevention: a mini review. Journal of traditional and complementary medicine. 2015;5(2):81-7.
112. Babaei A, Arshami J, Haghparast A, Mesgaran MD. Effects of saffron (Crocus sativus) petal ethanolic extract on hematology, antibody response, and spleen histology in rats. Avicenna journal of phytomedicine. 2014;4(2):103.
113. Moradzadeh M, Ghorbani A, Erfanian S, Mohaddes ST, Rahimi H, Karimiani EG, et al. Study of the mechanisms of crocetin‐induced differentiation and apoptosis in human acute promyelocytic leukemia cells. J Cell Biochem. 2019;120(2):1943-57.
| Files | ||
| Issue | Vol 19, No S1 (2020) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v19i(s1.r1).2852 | |
| PMID | 32534508 | |
| Keywords | ||
| Arthritis Atherosclerosis Brain ischemia Cancer Coronary artery disease Diabetes Inflammatory bowel disease Leukemia Osteoarthritis Saffron | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Poursamimi J, Shariati-Sarabi Z, Tavakkol-Afshari J, Mohajeri SA, Mohammadi M. Crocus Sativus (Saffron): An Immunoregulatory Factor in the Autoimmune and Non-autoimmune Diseases. Iran J Allergy Asthma Immunol. 2020;19(S1):27-42.
