Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: A review

Document Type: Review Article


1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran

2 Social Security Organization, Mashhad, Islamic Republic of Iran

3 Inflammation and Inflammatory Diseases Research Center, Mashhad University of Medical Science, Mashhad, Islamic Republic of Iran

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


The medicinal uses of saffron, the dried stigmas of Crocus sativus L., have very long history in food coloring agent, and flavoring agent as well as traditional medicine for the treatment of several diseases. Crocus sativus is rich in carotenoids that affect immunity. This review summarizes the putative immunoregulatory effects of saffron and its active its derivatives including crocin, crocetin and safranal. In modern studies, its active constituents including protective effects, anti-inflammatory activities and molecular mechanisms of saffron on the immune system have been demonstrated. Furthermore, the beneficial effects of saffron on inhibition of serum levels nuclear transcription factor κB (NF-κB) p65 unit, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) and some interleukin (IL) such as IL-1β, IL-6, IL-12, IL-17A were reported. Furthermore, saffron has been known as the antagonist of NF-κB and the agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). In addition, saffron down-regulates the key pro-inflammatory enzymes such as myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phospholipase A2, and prostanoids.
This review summarizes the protective roles of C. sativus and its constituents against the pathogenesis of immune diseases and understanding a better management of these problems. Taken together, the main bioactive constituents of saffron may have health-promoting with important benefits in immune-related disorders. Finally, our study indicates that these bioactive constituents can affect both cellular and humoral immunity functions.


Main Subjects

1. Hosseinzadeh H, Nassiri-Asl M. Avicenna’s (Ibn Sina) the Canon of Medicine and saffron (Crocus sativus): a review. Phytother Res 2013; 27:475-483.
2. Mollazadeh H, Emami SA, Hosseinzadeh H. Razi’s Al-Hawi and saffron (Crocus sativus): a review. Iran J Basic Med Sci 2015; 18:1153-1166.
3. Hoshyar R, Mollaei H. A comprehensive review on anticancer mechanisms of the main carotenoid of saffron, crocin. J Pharm Pharmacol 2017; 69:1419-1427.
4. Amin B, Hosseinzadeh H. Chapter 33 - Analgesic and anti-inflammatory effects of Crocus sativus L. (Saffron). In: Watson RR, Preedy VR, editors. Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease. San Diego: Academic Press; 2015. p. 319-324.
5. Rezaee R, Hosseinzadeh H. Safranal: from an aromatic natural product to a rewarding pharmacological agent. Iran J Basic Med Sci 2013; 16:12-26.
6. 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.
7. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol 2014; 64:65-80.
8. Tarantilis PA, Tsoupras G, Polissiou M. Determination of saffron (Crocus sativus L.) components in crude plant extract using high-performance liquid chromatography-UV-visible photodiode-array detection-mass spectrometry. J Chromatogr A 1995; 699:107-118.
9. Kubo I, Kinst-Hori I. Flavonols from saffron flower: tyrosinase inhibitory activity and inhibition mechanism. J Agric Food Chem 1999; 47:4121-4125.
10. Hosseini A, Razavi BM, Hosseinzadeh H. Saffron (Crocus sativus) petal as a new pharmacological target: a review. Iran J Basic Med Sci 2018; 21:1091-1099.
11. Poma A, Fontecchio G, Carlucci G, Chichiricco G. Anti-inflammatory properties of drugs from saffron crocus. Antiinflamm Antiallergy Agents Med Chem 2012; 11:37-51.
12. Hosseini A, Razavi BM, Hosseinzadeh H. Pharmacokinetic properties of saffron and its active components. Eur J Drug Metab Pharmacokinet 2018; 43:383-390.
13. Amin A, Hamza AA, Daoud S, Khazanehdari K, Hrout AA, Baig B, et al. Saffron-based crocin prevents early lesions of liver cancer: in vivo, in vitro and network analyses. Recent Pat Anticancer Drug Discov 2016; 11:121-133.
14. Patel S, Sarwat M, Khan TH. Mechanism behind the anti-tumour potential of saffron (Crocus sativus L.): The molecular perspective. Crit Rev Oncol Hematol 2017; 115:27-35.
15. Bolhassani A, Khavari A, Bathaie SZ. Saffron and natural carotenoids: biochemical activities and anti-tumor effects. Biochim Biophys Acta 2014; 1845:20-30.
16. Li K, Li YAN, Ma Z, Zhao JIE. Crocin exerts anti-inflammatory and anti-catabolic effects on rat intervertebral discs by suppressing the activation of JNK. Int J Mol Med 2015; 36:1291-1299.
17. Moallem SA, Hosseinzadeh H, Farahi S. A study of acute and chronic anti-nociceptive and anti-inflammatory effects of thiamine in mice. Iran Biomed J 2008; 12:173-178.
18. Assimopoulou AN, Sinakos Z, Papageorgiou VP. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res 2005; 19:997-1000.
19. Hosseinzadeh H, Younesi HM. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC Pharmacol 2002; 2:7.
20. Boskabady MH, Tabatabaee A, Byrami G. The effect of the extract of Crocus sativus and its constituent safranal, on lung pathology and lung inflammation of ovalbumin sensitized guinea-pigs. Phytomedicine 2012; 19:904-911.
21. Razavi M, Hosseinzadeh H, Abnous K, Motamedshariaty VS, Imenshahidi M. Crocin restores hypotensive effect of subchronic administration of diazinon in rats. Iran J Basic Med Sci 2013; 16:64-72.
22. Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol 2014; 29:517-527.
23. Ghasemi T, Abnous K, Vahdati F, Mehri S, Razavi BM, Hosseinzadeh H. Antidepressant effect of Crocus sativus aqueous extract and its effect on CREB, BDNF, and VGF transcript and protein levels in rat hippocampus. Drug Res (Stuttg) 2015; 65:337-343.
24. 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.
25. Zamani Taghizadeh Rabe S, Sahebari M, Mahmoudi Z, Hosseinzadeh H, Haghmorad D, Tabasi N, et al. Inhibitory effect of Crocus sativus L. ethanol extract on adjuvant-induced arthritis. Food Agric Immunol 2015; 26:170-180.
26. Higashino S, Sasaki Y, Giddings JC, Hyodo K, Sakata SF, Matsuda K, et al. Crocetin, a carotenoid from Gardenia jasminoides Ellis, protects against hypertension and cerebral thrombogenesis in stroke-prone spontaneously hypertensive rats. Phytother Res 2014; 28:1315-1319.
27. Imenshahidi M, Hosseinzadeh H, Javadpour Y. Hypotensive effect of aqueous saffron extract (Crocus sativus L.) and its constituents, safranal and crocin, in normotensive and hypertensive rats. Phytother Res 2010; 24:990-994.
28. Mousavi M, Baharara J, Shahrokhabadi K. The synergic effects of Crocus sativus L. and low frequency electromagnetic field on VEGFR2 gene expression in human breast cancer cells. Avicenna J Med Biotechnol 2014; 6:123-127.
29. Umigai N, Tanaka J, Tsuruma K, Shimazawa M, Hara H. Crocetin, a carotenoid derivative, inhibits VEGF-induced angiogenesis via suppression of p38 phosphorylation. Curr Neurovasc Res 2012; 9:102-109.
30. Bie X, Chen Y, Zheng X, Dai H. The role of crocetin in protection following cerebral contusion and in the enhancement of angiogenesis in rats. Fitoterapia 2011; 82:997-1002.
31. 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 j 2015; 14:908-915.
32. Liu M, Amini A, Ahmad Z. Safranal and its analogs inhibit Escherichia coli ATP synthase and cell growth. Int J Biol Macromol 2017; 95:145-152.
33. Eslami M, Bayat M, Mozaffari Nejad AS, Sabokbar A, Anvar AA. Effect of polymer/nanosilver composite packaging on long-term microbiological status of Iranian saffron (Crocus sativus L.). Saudi J Biol Sci 2016; 23:341-347.
34. De Monte C, Bizzarri B, Gidaro MC, Carradori S, Mollica A, Luisi G, et al. Bioactive compounds of Crocus sativus L. and their semi-synthetic derivatives as promising anti-Helicobacter pylori, anti-malarial and anti-leishmanial agents. J Enzyme Inhib Med Chem 2015; 30:1027-1033.
35. 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 2017; 268:207-214.
36. Farshid AA, Tamaddonfard E, Moradi-Arzeloo M, Mirzakhani N. The effects of crocin, insulin and their co-administration on the heart function and pathology in streptozotocin-induced diabetic rats. Avicenna J Phytomed 2016; 6:658-670.
37. Mashmoul M, Azlan A, Khaza’ai H, Yusof BN, Noor SM. Saffron: a natural potent antioxidant as a promising anti-obesity drug. Antioxidants (Basel) 2013; 2:293-308.
38. 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; 55:206-213.
39. Samarghandian S, Samini F, Azimi-Nezhad M, Farkhondeh T. Anti-oxidative effects of safranal on immobilization-induced oxidative damage in rat brain. Neurosci Lett 2017; 659:26-32.
40. Hosseinzadeh H, Sadeghnia HR, Rahimi A. Effect of safranal on extracellular hippocampal levels of glutamate and aspartate during kainic Acid treatment in anesthetized rats. Planta Med 2008; 74:1441-1445.
41. Konstantopoulos P, Doulamis IP, Tzani A, Korou ML, Agapitos E, Vlachos IS, et al. Metabolic effects of Crocus sativus and protective action against non-alcoholic fatty liver disease in diabetic rats. Biomed Rep 2017; 6:513-518.
42. Mashmoul M, Azlan A, Mohtarrudin N, Mohd Yusof BN, Khaza’ai H, Khoo HE, et al. Protective effects of saffron extract and crocin supplementation on fatty liver tissue of high-fat diet-induced obese rats. BMC Complement Altern Med 2016; 16:401.
43. Omidi A, Riahinia N, Montazer Torbati MB, Behdani MA. Hepatoprotective effect of Crocus sativus (saffron) petals extract against acetaminophen toxicity in male Wistar rats. Avicenna J Phytomed 2014; 4:330-336.
44. Lari P, Abnous K, Imenshahidi M, Rashedinia M, Razavi M, Hosseinzadeh H. Evaluation of diazinon-induced hepatotoxicity and protective effects of crocin. Toxicol Ind Health 2015; 31:367-376.
45. Razavi BM, Hosseinzadeh H. Saffron as an antidote or a protective agent against natural or chemical toxicities. Daru 2015; 23:31.
46. 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; 72:711-719.
47. Goyal SN, Arora S, Sharma AK, Joshi S, Ray R, Bhatia J, et al. Preventive effect of crocin of Crocus sativus on hemodynamic, biochemical, histopathological and ultrastuctural alterations in isoproterenol-induced cardiotoxicity in rats. Phytomedicine 2010; 17:227-232.
48. Nahid K, Fariborz M, Ataolah G, Solokian S. The effect of an Iranian herbal drug on primary dysmenorrhea: a clinical controlled trial. J Midwifery Womens Health 2009; 54:401-404.
49. Bagatini MD, Cardoso AM, dos Santos AA, Carvalho FB. Immune system and chronic diseases. J Immunol Res 2017; 2017:4284327.
50. Labzin LI, Heneka MT, Latz E. Innate immunity and neurodegeneration. Annu Rev Med 2018; 69:437-449.
51. 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 Phytomed 2015; 5: 441-449.
52. Babaei A, Arshami J, Haghparast A, Danesh Mesgaran M. Effects of saffron (Crocus sativus) petal ethanolic extract on hematology, antibody response, and spleen histology in rats. Avicenna J Phytomed 2014; 4: 103-109.
53. Bayrami G, Boskabady MH. The potential effect of the extract of Crocus sativus and safranal on the total and differential white blood cells of ovalbumin-sensitized guinea pigs. Res Pharm Sci 2012; 7: 249-255.
54. Kianbakht S, Ghazavi A. Immunomodulatory effects of saffron: a randomized double-blind placebo-controlled clinical trial. Phytother Res 2011; 25: 1801-5.
55. Bakshi HA, Hakkim FL, Sam S. Molecular mechanism of crocin induced caspase mediated MCF-7 cell death: in vivo toxicity profiling and ex vivo macrophage activation. Asian Pac J Cancer Prev 2016; 17: 1499-506.
56. Li J, Lei HT, Cao L, Mi YN, Li S, Cao YX. Crocin alleviates coronary atherosclerosis via inhibiting lipid synthesis and inducing M2 macrophage polarization. Int Immunopharmacol 2018; 55: 120-127.
57. Yosri H, Elkashef WF, Said E, Gameil NM. Crocin modulates IL-4/IL-13 signaling and ameliorates experimentally induced allergic airway asthma in a murine model. Int Immunopharmacol 2017; 50: 305-312.
58. Bukhari SI, Pattnaik B, Rayees S, Kaul S, Dhar MK. Safranal of Crocus sativus L. inhibits inducible nitric oxide synthase and attenuates asthma in a mouse model of asthma. Phytother Res 2015; 29: 617-27.
59. Boskabady MH, Seyedhosseini Tamijani SM, Rafatpanah H, Rezaei A, Alavinejad A. The effect of Crocus sativus extract on human lymphocytes’ cytokines and T helper 2/T helper 1 balance. J Med Food 2011; 14: 1538-45.
60. Feyzi R, Boskabady MH, Seyedhosseini Tamijani SM, Rafatpanah H, Rezaei SA. The effect of safranal on Th1/Th2 cytokine balance. Iran J Immunol 2016; 13: 263-273.
61. Soeda S, Ochiai T, Paopong L, Tanaka H, Shoyama Y, Shimeno H. Crocin suppresses tumor necrosis factor-alpha-induced cell death of neuronally differentiated PC-12 cells. Life Sci 2001; 69: 2887-98.
62. Mohammadi E, Mehri S, Badie Bostan H, Hosseinzadeh H. Protective effect of crocin against d-galactose-induced aging in mice. Avicenna J Phytomed 2018; 8: 14-23.
63. Kermani T, Zebarjadi M, Mehrad-Majd H, Mirhafez SR, Shemshian M, Ghasemi F, et al. Anti-inflammatory effect of Crocus sativus on serum cytokine levels in subjects with metabolic syndrome: a randomized, double-blind, placebo- controlled trial. Curr Clin Pharmacol 2017; 12: 122-126.
64. Samarghandian S, Azimi-Nezhad M, Farkhondeh T. Immunomodulatory and antioxidant effects of saffron aqueous extract (Crocus sativus L.) on streptozotocin-induced diabetes in rats. Indian Heart J 2017; 69: 151-159.
65. 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: 2723-2733.
66. Ding Q, Zhong H, Qi Y, Cheng Y, Li W, Yan S, et al. Anti-arthritic effects of crocin in interleukin-1beta-treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflamm Res 2013; 62: 17-25.
67. Wang X, Zhang G, Qiao Y, Feng C, Zhao X. Crocetin attenuates spared nerve injury-induced neuropathic pain in mice. J Pharmacol Sci 2017; 135: 141-147.
68. Tamaddonfard E, Farshid AA, Maroufi S, Kazemi-Shojaei S, Erfanparast A, Asri-Rezaei S, et al. Effects of safranal, a constituent of saffron, and vitamin E on nerve functions and histopathology following crush injury of sciatic nerve in rats. Phytomedicine 2014; 21: 717-723.
69. Farokhnia M, Shafiee Sabet M, Iranpour N, Gougol A, Yekehtaz H, Alimardani R, et al. Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer’s disease: a double-blind randomized clinical trial. Hum Psychopharmacol 2014; 29: 351-359.
70. Kashani L, Raisi F, Saroukhani S, Sohrabi H, Modabbernia A, Nasehi A-A, et al. Saffron for treatment of fluoxetine-induced sexual dysfunction in women: randomized double-blind placebo-controlled study. Hum Psychopharmacol 2013; 28: 54-60.
71. Modabbernia A, Sohrabi H, Nasehi A-A, Raisi F, Saroukhani S, Jamshidi A, et al. Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology (Berl) 2012; 223: 381-388.
72. Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, et al. Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16-week, randomized and placebo-controlled trial. J Clin Pharm Ther 2010; 35: 581-588.
73. Kell G, Rao A, Beccaria G, Clayton P, Inarejos-García AM, Prodanov M. affron® a novel saffron extract (Crocus sativus L.) improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo-controlled clinical trial. Complement Ther Med 2017; 33: 58-64.
74. Azimi P, Ghiasvand R, Feizi A, Hosseinzadeh J, Bahreynian M, Hariri 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: 133-140.
75. Mazidi M, Shemshian M, Mousavi SH, Norouzy A, Kermani T, Moghiman T, et al. A double-blind, randomized and placebo-controlled trial of Saffron (Crocus sativus L.) in the treatment of anxiety and depression. J Complement Integr Med 2016; 13: 195-199.
76. Fadai F, Mousavi B, Ashtari Z, Ali beigi N, Farhang S, Hashempour S, et al. Saffron aqueous extract prevents metabolic syndrome in patients with schizophrenia on olanzapine treatment: a randomized triple blind placebo controlled study. Pharmacopsychiatry 2014; 47: 156-161.
77. Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: A randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord 2015; 174: 51-56.
78. 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. Evid Based Complement Alternat Med 2012; 2012:820415.
79. Ayatollahi H, Javan AO, Khajedaluee M, Shahroodian M, Hosseinzadeh H. Effect of Crocus sativus L. (Saffron) on coagulation and anticoagulation systems in healthy volunteers. Phytother Res 2014; 28: 539-543.
80. Melnyk JP, Wang S, Marcone MF. Chemical and biological properties of the world’s most expensive spice: Saffron. Food Res Int 2010; 43: 1981-1989.
81. Schmidt M, Betti G, Hensel A. Saffron in phytotherapy: pharmacology and clinical uses. Wien Med Wochenschr 2007; 157: 315.
82. Zeinali M, Rezaee SA, Hosseinzadeh H. An overview on immunoregulatory and anti-inflammatory properties of chrysin and flavonoids substances. Biomed Pharmacother 2017; 92: 998-1009.
83. Lawrence T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol 2009; 1: a001651.
84. Pradere JP, Hernandez C, Koppe C, Friedman RA, Luedde T, Schwabe RF. Negative regulation of NF-kappaB p65 activity by serine 536 phosphorylation. Sci Signal 2016; 9: ra85.
85. Wright HL, Moots RJ, Bucknall RC, Edwards SW. Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 2010; 49: 1618-1631.
86. 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. Z Naturforsch C 2014; 69:459-470.
87. 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; 703:1-10.
88. 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; 135:2350-2358.
89. Cai J, Yi FF, Bian ZY, Shen DF, Yang L, Yan L, et al. Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway. J Cell Mol Med 2009; 13:909-925.
90. Patel NK, Bhutani KK. Suppressive effects of Mimosa pudica (L.) constituents on the production of LPS-induced pro-inflammatory mediators. Excli j 2014; 13:1011-1021.
91. Zhang C, Ma J, Fan L, Zou Y, Dang X, Wang K, et al. Neuroprotective effects of safranal in a rat model of traumatic injury to the spinal cord by anti-apoptotic, anti-inflammatory and edema-attenuating. Tissue Cell 2015; 47: 291-300.
92. Baghishani F, Mohammadipour A, Hosseinzadeh H, Hosseini M, Ebrahimzadeh-Bideskan A. The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin. Metab Brain Dis 2018; 33: 907-916.
93. 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. Evid Based Complement Alternat Med 2012; 2012: 820415.
94. Zhou C, Bai W, Chen Q, Xu Z, Zhu X, Wen A, et al. Protective effect of crocetin against burn-induced intestinal injury. J Surg Res 2015; 198: 99-107.
95. Mahmoudzadeh L, Najafi H, Ashtiyani SC, Yarijani ZM. Anti-inflammatory and protective effects of saffron extract in ischaemia/reperfusion-induced acute kidney injury. Nephrology (Carlton) 2017; 22: 748-754.
96. Hariri AT, Moallem SA, Mahmoudi M, Memar B, Hosseinzadeh H. Sub-acute effects of diazinon on biochemical indices and specific biomarkers in rats: protective effects of crocin and safranal. Food Chem Toxicol 2010; 48: 2803-2808.
97. Boskabady MH, Byrami G, Feizpour A. The effect of safranal, a constituent of Crocus sativus (saffron), on tracheal responsiveness, serum levels of cytokines, total NO and nitrite in sensitized guinea pigs. Pharmacol Rep 2014; 66: 56-61.
98. Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta 2005; 1754: 253-262.
99. 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.
100. 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. Z Naturforsch C 2014; 69: 459-470.
101. 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: 1-10.
102. 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: 2350-2358.
103. Cai J, Yi FF, Bian ZY, Shen DF, Yang L, Yan L, et al. Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway. J Cell Mol Med 2009; 13: 909-925.
104. Patel NK, Bhutani KK. Suppressive effects of Mimosa pudica (L.) constituents on the production of LPS-induced pro-inflammatory mediators. Excli j 2014; 13: 1011-1021.
105. Xu GL, Li G, Ma HP, Zhong H, Liu F, Ao GZ. Preventive effect of crocin in inflamed animals and in LPS-challenged RAW 264.7 cells. J Agric Food Chem 2009; 57: 8325-8330.
106. 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.
107. Song L, Kang C, Sun Y, Huang W, Liu W, Qian Z. Crocetin inhibits lipopolysaccharide-induced inflammatory response in human umbilical vein endothelial cells. Cell Physiol Biochem 2016; 40: 443-452.
108. Kazi HA, Qian Z. Crocetin reduces TNBS-induced experimental colitis in mice by downregulation of NFkB. Saudi J Gastroenterol 2009; 15: 181-187.
109. Conti A, Miscusi M, Cardali S, Germano A, Suzuki H, Cuzzocrea S, et al. Nitric oxide in the injured spinal cord: synthases cross-talk, oxidative stress and inflammation. Brain Res Rev 2007; 54: 205-218.
110. Masri F. Role of nitric oxide and its metabolites as potential markers in lung cancer. Ann Thorac Med 2010; 5: 123-127.
111. Zhu Y, Zhu M, Lance P. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Exp Cell Res 2012; 318: 2116-2127.
112. Samarghandian S, Azimi-Nezhad M, Samini F. Ameliorative effect of saffron aqueous extract on hyperglycemia, hyperlipidemia, and oxidative stress on diabetic encephalopathy in streptozotocin induced experimental diabetes mellitus. Biomed Res Int 2014; 2014: 920857.
113. Esmaeilizadeh M, Dianat M, Badavi M, Samarbaf-zadeh A, Naghizadeh B. Effect of crocin on nitric oxide synthase expression in post-ischemic isolated rat heart. Avicenna J Phytomed 2015; 5: 420-426.
114. Chen B, Hou Z-H, Dong Z, Li C-D. Crocetin downregulates the proinflammatory cytokines in methylcholanthrene-induced rodent tumor model and inhibits COX-2 expression in cervical cancer cells. BioMed Research International 2015; 2015: 829513.
115. Qiu Y-Y, Zhang Y-W, Qian X-F, Bian T. miR-371, miR-138, miR-544, miR-145, and miR-214 could modulate Th1/Th2 balance in asthma through the combinatorial regulation of Runx3. Am J Transl Res 2017; 9: 3184-3199.
116. Diao M, Min J, Guo F, Zhang CL. Effects of salbutamol aerosol combined with magnesium sulfate on T-lymphocyte subgroup and Th1/Th2 cytokines of pediatric asthma. Exp Ther Med 2017; 13: 117-120.
117. Hansbro PM, Scott GV, Essilfie AT, Kim RY, Starkey MR, Nguyen DH, et al. Th2 cytokine antagonists: potential treatments for severe asthma. Expert Opin Investig Drugs 2013; 22: 49-69.