Antiinflammatory, Antioxidant, and Immunomodulatory Effects of Crocus sativus L. and its Main Constituents

Phytotherapy Research

Volumn 30, Issue 7, 2016, Pages 1072-1094

  Boskabady, Mohammad Hossein ^a   Farkhondeh, Tahereh ^a  

^a MASHHAD UNIVERSITY OF MEDICAL SCIENCES   (Iran)

Author keywords

antiinflammatory; antioxidant; crocetin; crocins; Crocus sativus; immunomodulation; safranal

Indexed keywords

AQUAPORIN 4; CASPASE 3; CROCETIN; CROCIN; CROCUS SATIVUS EXTRACT; FIBRINOGEN; GAMMA INTERFERON; GLIAL FIBRILLARY ACIDIC PROTEIN; HEAT SHOCK PROTEIN 70; HISTAMINE H1 RECEPTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 10; INTERLEUKIN 13; INTERLEUKIN 1BETA; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 6; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE P38; MONOCYTE CHEMOTACTIC PROTEIN 1; MYELOPEROXIDASE; PROSTAGLANDIN E2; PROTEIN BCL XL; PROTEIN C; PROTEIN S100B; SAFRANAL; TRYPTASE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; CELL VIABILITY; CROCUS SATIVUS; CYTOKINE RESPONSE; DRUG MECHANISM; HUMAN; IMMUNOMODULATION; INFLAMMATION; NEUROPATHIC PAIN; NONHUMAN; OXIDATIVE STRESS; PAW EDEMA; PROTEIN EXPRESSION; RENAL PROTECTION; REVIEW; SIGNAL TRANSDUCTION;

EID: 84964385437     PISSN: 0951418X     EISSN: 10991573     Source Type: Journal    
DOI: 10.1002/ptr.5622     Document Type: Review

References (141)

1. Abdullaev F, Ortega CH, Miranda PR. 2007. HPLC quantification of major active components from 11 different saffron (Crocus sativus L.) sources. Food Chem 100: 1126–1131.
2. Abdullaev FI, Espinosa-Aguirre JJ. 2004. Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials. Cancer Detect Prev 28: 426–432.
3. Abdullaev FI. 1993. Biological effects of saffron. Biofactors 4: 83–86.
4. Abdullaev FI. 2002. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.) Exp Biol Med 227: 20–25.
5. Aggarwal BB, Harikumar KB. 2009. Potential therapeutic effects of Curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Bio 41: 40–59.
6. Agha-Hosseini M1, Kashani L, Aleyaseen A, et al. 2008. Crocus sativus L. (saffron) in the treatment of premenstrual syndrome: a double-blind, randomised and placebo-controlled trial. BJOG 115: 515–519.
7. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. 2005. Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo-controlled trial. Phytother Res 19: 148–51.
8. Alavizadeh SH, Hosseinzadeh H. 2014. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol 64: 65–80.
9. Altinoz E, Oner Z, Elbe H, Cigremis Y, Turkoz Y. 2015. Protective effects of saffron (its active constituent, crocin) on nephropathy in streptozotocin-induced diabetic rats. Hum Exp Toxicol 34: 127–134.
10. Altinoz E, Ozmen T, Oner Z, Elbe H, Erdemli ME, Bag HG. 2015. Effect of crocin on oxidative stress in recovery from single bout of swimming exercise in rats. Gen Physiol Biophys. DOI:10.4149/gpb_2015018.
11. Amin B, Abnous K, Motamedshariaty V, Hosseinzadeh H. 2014. Attenuation of oxidative stress, inflammation and apoptosis by ethanolic and aqueous extracts of Crocus sativus L. stigma after chronic constriction injury of rats. An Acad Bras Cienc 86: 1821–1832.
12. Asadi MH, Zafari F, Sarveazad A, et al. 2014. Saffron improves epididymal sperm parameters in rats exposed to cadmium. Nephrourol Mon 6: e12125. DOI:10.5812/numonthly.1215.
13. Assimopoulou AN, Sinakos Z, Papageorgiou VP. 2005. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res 19: 997–1000.
14. Averill FJ, Hubbard WC, Proud D, Gleich GJ, Liu MC. 1992. Platelet activation in the lung after antigen challenge in a model of allergic asthma. Am Rev Respir Dis 145: 571–576.
15. Azimi P, Ghiasvand R, Feizi A, Hariri M, Abbasi B. 2014. Effects of cinnamon, cardamom, saffron, and ginger consumption on markers of glycemic control, lipid profile, oxidative stress, and inflammation in type 2 diabetes patients. Rev Diabet Stud 11: 258–266.
16. Babaei A, Arshami J, Haghparas A, Danesh MM. 2014. Effects of saffron (Crocus sativus) petal ethanolic extract on hematology, antibody response, and spleen histology in rats. Avicenna J Phytomed 4: 103–109.
17. Balkissoon R, Lommatzsch S, Carolan B, Make B. 2011. Chronic obstructive pulmonary disease: a concise review. Med Clin North Am 95: 1125–1141.
18. Bandegi AR, Rashidypour A, Vafaei AA, Ghadrdoost A. 2014. Protective effects of Crocus Sativus L. extract and crocin against chronic-stress induced oxidative damage of brain, liver and kidneys in rats. Pharm Bull 4: 493–499.
19. Bani S, Pandey A, Agnihotri KV, Pathania V, Singh B. 2011. Selective Th2 upregulation by Crocus sativus: a neutraceutical Spice. Evid Based Complement Altern Med 2011: 639862. DOI:10.1155/2011/639862.
20. Bathaie SZ. 27 October 2008. Isolation, purification and identification of crocins (carotenoids) from saffron (in particular Iranian saffron). Iran Patent 54958.
21. Bayrami G, Boskabady MH, Jalali S, Farkhondeh T. 2013. The effect of the extract of Crocus sativus on tracheal responsiveness and plasma levels of IL-4, IFN-γ, total NO and nitrite in ovalbumin sensitized guinea-pigs. J Ethno Pharmacol 147: 530–535.
22. Bayrami G, Boskabady MH. 2012. The potential effect of the extract of Crocus sativus and safranal on total and differential white blood cells in blood of ovalbumin-sensitized guinea-pigs. Res Pharmac Sci 7: 249–255.
23. Bhandari PR. 2015. Crocus sativus L. (saffron) for cancer chemoprevention: a mini review. J Tradit Complement Med 5: 81–87.
24. Bharti S, Golechha M, Kumari S, Siddiqui KM, Arya DS. 2012. Akt/GSK-3β/eNOS phosphorylation arbitrates safranal-induced myocardial protection against ischemia-reperfusion injury in rats. Eur J Nutr 51: 719–27.
25. Bloemen K, Verstraelen S, Van Den Heuvel R, Witters H, Nelissen I, Schoeters G. 2007. The allergic cascade: review of the most important molecules in the asthmatic lung. Immunol Lett 113: 6–18.
26. Boskabady MH, Aslani MR. 2006. Relaxant effect of Crocus sativus on guinea pig tracheal chains and its possible mechanisms. J Pharm Pharmacol 58: 1385–1390.
27. Boskabady MH, Bayrami G, Faizpour A. 2014. 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 66: 56–61.
28. Boskabady MH, Bayrami G, Tabatabaee A. 2012. The effect of the extract of Crocus sativus and its constituent safranal, on lung pathology and lung inflammation of ovalbumin sensitized guinea-pigs. Phytomed 19: 904–911.
29. Boskabady MH, Ghasemzadeh M, Nemati H, Esmaeilzadeh M. 2010. Inhibitory effect of Crocus sativus (saffron) on histamine (H1) receptors of guinea pig tracheal chains. Pharmezie 65: 300–305.
30. 1 balance. J Med Food 14: 1538–1545.
31. Boskabady MH, Shafei MN, Shakiba A, Sang SH. 2008. Effect of aqueous-ethanol extract from Crocus sativus (saffron) on guinea-pig isolated heart. Phytother Res 22: 330–334.
32. Boussabbeh M, Ben Salem I, Neffati F, Najjar MF, Bacha H, Abid-Essefi S. 2015. Crocin prevents patulin-induced acute toxicity in cardiac tissues via the regulation of oxidative damage and apoptosis. J Biochem Mo Toxicol DOI:10.1002/jbt.21718.
33. Boussabbeh M, Prola A, Ben Salem I, et al. 2015. Crocin and quercetin prevent PAT-induced apoptosis in mammalian cells: Involvement of ROS-mediated ER stress pathway. Environ Toxicol. DOI:10.1002/tox.22185.
34. Bukhari SI, Pattnaik B, Rayees S, Kaul S, Dhar MK. 2015. Safranal of Crocus sativus L. inhibits inducible nitric oxide synthase and attenuates asthma in a mouse model of asthma. Phytother Res 29: 617–627.
35. Cai J, Yi FF, Bian ZY, et al. 2009. Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway. J Cell Mol Med 13: 909–925.
36. Cao PC, Xiao WX, Yan YB, et al. 2014. Preventive effect of crocin on osteoporosis in an ovariectomized rat model. Evid Based Complement Altern Med 2014: 825181.
37. Chahine N, Nader M, Duca L, Martiny L, Chahine R. 2015. Saffron extracts alleviate cardiomyocytes injury induced by doxorubicin and ischemia-reperfusion in vitro. Drug Chem Toxicol 17: 1–10.
38. Cohn L, Elias JA, Chupp GL. 2004. Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol 22: 789–815.
39. Das I, Chakrabart RN, Das S. 2004. Saffron can prevent chemically induced skin carcionogenesis in Swiss albino mice. Asian Pac J Cancer Prev 5: 70–76.
40. Dhar MH, Shah KU, Ghongane BB, Rane SR. 2013. Nephroprotective activity of Crocus sativus extract against gentamicin and/or ceftazidime-induced nephrotoxicity in rats. Int J Pharm Bio Sci 4: 864–870.
41. Dianat M, Esmaeilizadeh M, Badavi M, Samarbaf-Zadeh AR, Naghizadeh B. 2014. Protective effects of crocin on ischemia-reperfusion induced oxidative stress in comparison with vitamin E in isolated rat hearts. Jundishapur J Nat Pharm Prod 9: e17187. DOI:10.17795/jjnpp-17187.
42. Domej W, Oettl K, Renner W. 2014. Oxidative stress and free radicals in COPD-implications and relevance for treatment. Int J Chron Obstruct Pulmon Dis 9: 1207–1224.
43. El-Beshbishy HA, Hassan MH, Aly HAA, Doghish AS, Alghaithy AAA. 2012. Crocin “saffron” protects against beryllium chloride toxicity in rats through diminution of oxidative stress and enhancing gene expression of antioxidant enzymes. Ecotoxicol Environ Saf 83: 47–54.
44. El-Maraghy SA, Rizk SM, Shahin NN. 2015. Gastroprotective effect of crocin in ethanol-induced gastric injury in rats. Chem Biol Interact 229: 26–35.
45. Fernández JA. 2004. Biology, biotechnology and biomedicine of saffron. Recent Res Devel Plant Sci 2: 127–159.
46. Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F. 2011. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol 667: 222–229.
47. Ghaeni FA, Amin B, Hariri AT, Meybodi NT, Hosseinzadeh H. 2014. Antilithiatic effects of crocin on ethylene glycol-induced lithiasis in rats. Urolithiasis 42: 549–558.
48. Ghazavi A, Mosayebi G, Salehi H, Abtahi H. 2009. Effect of ethanol extract of saffron (Crocus sativus L.) on the inhibition of experimental autoimmune encephalomyelitis in C57bl/6 mice. Pak J Biol Sci 12: 690–695.
49. Gholamnezhad Z, Keyhanmanesh R, Boskabady MH. 2015. Anti-inflammatory, antioxidant, and immunomodulatory aspects of Nigella sativa for its preventive and bronchodilatory effects on obstructive respiratory diseases: a review of basic and clinical evidence. J Funct Foods 17: 910–927.
50. Gholamnezhad Z, Koushyar H, Byrami G, Boskabady MH. 2013. The extract of Crocus sativus and its constituent safranal, affect serum levels of endothelin and total protein in sensitized guinea-pigs. Iran J Basic Med Sci 16: 1022–1026.
51. Goli SAM, Mokhtari F, Rahimmalek M. 2012. Phenolic compounds and antioxidant activity from saffron (Crocus sativus L.) petal. J Agr Sci 4: 175–181.
52. Goyal SN, Arora S, Sharma AK, Joshi S, Ray R, Bhatia J. 2010. Preventive effect of crocin of Crocus sativus on hemodynamic, biochemical, histopathological and ultrastuctural alterations in isoproterenol-induced cardiotoxicity in rats. Phytomedicin 17: 227–32.
53. Gubory KH. 2014. Environmental pollutants and lifestyle factors induce oxidative stress and poor prenatal development. Reprod Biomed Online 29: 17–31.
54. Halataei BA, Khosravi M, Arbabian S, et al. 2011. Saffron (Crocus sativus) aqueous extract and its constituent crocin reduce stress-induced anorexia in mice. Phytother Resv 25: 1833–1838.
55. Hariri AT, Moallem SA, Mahmoudi M, Memar B, Hosseinzadeh H. 2010. Sub-acute effects of diazinon on biochemical indices and specific biomarkers in rats: protective effects of crocin and safranal. Food Chem Toxicol 48: 2803–2808.
56. Hassan MH, Bahashawan SA, Abdelghany TM, Abd-Allah GM, Ghobara MM. 2015. Crocin abrogates carbon tetrachloride-induced renal toxicity in rats via modulation of metabolizing enzymes and diminution of oxidative stress, apoptosis, and inflammatory cytokines. J Biochem Mol Toxico 29: 330–339.
57. Hazman Ö, Bozkurt MF. 2015. Anti-inflammatory and antioxidative activities of safranal in the reduction of renal dysfunction and damage that occur in diabetic nephropathy. Inflammation 38: 1537–1545.
58. Hazman O, Ovalı S. 2014. Investigation of the anti-inflammatory effects of safranal on high-fat diet and multiple low dose streptozotocin induced type 2 diabetes rat model. Inflammation 38: 1012–1019.
59. Hemshekhar M, Sebastin Santhosh M, Sunitha K, et al. 2012. A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status. Biochimie 94: 2723–2733.
60. Higashino S, Sasaki Y, Giddings JC, et al. 2014. Crocetin, a carotenoid from Gardenia jasminoides Ellis, protects against hypertension and cerebral thrombogenesis in stroke-prone spontaneously hypertensive rats. Phytother Res 28: 1315–1319.
61. Hosseinzadeh H, Ghenaati J. 2006. Evaluation of the antitussive effect of stigma and petals of saffron (Crocus sativus) and its components, safranal and crocin in guinea pigs. Fitoterapia 77: 446–448.
62. Hosseinzadeh H, Modaghegh MH, Saffari Z. 2009. Crocus sativus L. (Saffron) extract and its active constituents (crocin and safranal) on ischemia-reperfusion in rat skeletal muscle. Evid Based Complement Altern Med 6: 343–350.
63. Hosseinzadeh H, Sadeghi Shaki S, Khadem Samenic A, Taghiabadi E. 2013. Acute and subacute toxicity of safranal, a constituent of saffron, in mice and rats. Inter J Prod Res 12: 93–99.
64. Hosseinzadeh H, Sadeghnia HR, Ghaeni FA, Motamedshariaty VS, Mohajeri SA. 2012. Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytother Res 26: 381–386.
65. Hosseinzadeh H, Sadeghnia HR, Ziaee T, Danaee A. 2005. Protective effect of aqueous saffron extract (Crocus sativus L.) and crocin, its active constituent, on renal ischemia-reperfusion-induced oxidative damage in rats. J Pharm Pharmaceut Sci 8: 387–393.
66. Hosseinzadeh H, Sadeghnia HR. 2005. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J Pharm Pharm Sci 22: 394–399.
67. Hosseinzadeh H, Shamsaie F, Mehri S. 2009. Antioxidant activity of aqueous and ethanolic extracts of Crocus sativus L. stigma and its bioactive constituents, crocin and safranal. Phcog Mag 5: 419–424.
68. Hosseinzadeh H, Shariaty V. 2007. Antinociceptive effects of safranal, a constituent of Crocus sativus (saffron), in mice. Pharmacol Online 2: 498–503.
69. Hosseinzadeh H, Shariaty VM, Sameni AK, Vahabzadeh M. 2010. Acute and sub-acute toxicity of crocin, a constituent of Crocus sativus L. (saffron), in mice and rats. Pharmacol Online 2: 943–951.
70. Hosseinzadeh H, Younesi HM. 2002. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC Pharmacol 15: 7.
71. Hosseinzadeh H, Nassiri-Asl M. 2013. Avicenna's (Ibn Sina) the Canon of Medicine and saffron (Crocus sativus): a review. Phytother Res 27: 475–83.
72. Ishizuka F, Shimazawa M, Umigai N, et al. 2013. Crocetin, a carotenoid derivative, inhibits retinal ischemic damage in mice. Eur J Pharmacol 703: 1–10.
73. Karami M, Bathaie SZ, Tiraihi T, Habibi-Rezaei M, Arabkheradmand J, Faghihzadeh S. 2013. Crocin improved locomotor function and mechanical behavior in the rat model of contused spinal cord injury through decreasing calcitonin gene related peptide (CGRP). Phytomedicine 21: 62–67.
74. Kawabata K, Tung NH, Shoyama Y, Sugie S, Mori T, Tanaka T. 2012. Dietary crocin inhibits colitis and colitis-associated colorectal carcinogenesis in male ICR mice. Evid Based Complement Altern Med 2012:. DOI:10.1155/1012/820415.
75. Kazi HA, Qian Z. 2009. Crocetin reduces TNBS-induced experimental colitis in mice by downregulation of NFkB. Saudi J Gastroenterol 15: 181–187.
76. Khan MB, Hoda MN, Ishrat T, et al. 2012. Neuroprotective efficacy of Nardostachys jatamansi and crocetin in conjunction with selenium in cognitive impairment. Neurol Sci 33: 1011–1020.
77. Kianbakht S, Ghazavi A. 2011. Immunomodulatory effects of saffron: a randomized double-blind placebo-controlled clinical trial. Phytother Res 25: 1801–1805.
78. Kianbakht S, Mozaffari K. 2009. Effects of saffron and its active constituents, crocin and safranal, on prevention of indomethacin induced gastric ulcers in diabetic and nondiabetic rats. J Med Plants 8: 30–38.
79. Kim JH, Park GY, Bang SY, Park SY, Bae SK, Kim Y. 2014. 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: 728709.
80. Kowal K, Pampuc A, Kowal-Bielecka O, DuBuske LM, Bodzenta-Lukaszyk A. 2006. Platelet activation in allergic asthma patients during allergen challenge with Dermatophagoides pteronyssinus. Clin Exp Allergy 36: 426–432.
81. Lage M, Cantrell C. 2009. Quantification of saffron (Crocus sativus L.) metabolites crocins, picrocrocin and safranal for quality determination of the spice grown under different environmental Moroccan conditions. Sci Hortic 121: 366–373.
82. Lari P, Abnous K, Imenshahidi M, Rashedinia M, Razavi M, Hosseinzadeh H. 2015. Evaluation of diazinon-induced hepatotoxicity and protective effects of crocin. Toxicol Ind Health 31: 367–376.
83. Linardaki ZI, Orkoula MG, Kokkosis AG, Lamari FN, Margarity M. 2013. Investigation of the neuroprotective action of saffron (Crocus sativus L.) in aluminum-exposed adult mice through behavioral and neurobiochemical assessment. Food Chem Toxicol 52: 163–70.
84. Mahmoudabady M, Neamati A, Vosooghi S, Aghababa H. 2013. Hydroalcoholic extract of Crocus sativus effects on bronchial inflammatory cells in ovalbumin sensitized rats. Avicenna J Phytomed 3: 356–363.
85. Mehdizadeh R, Parizadeh MR, Khooei AR, Mehri S, Hosseinzadeh H. 2013. Cardioprotective effect of saffron extract and safranal in isoproterenol-induced myocardial infarction in Wistar rats. Iran J Basic Med Sci 16: 56–63.
86. Mehri S, Abnous K, Mousavi S, Motamed Shariaty V, Hosseinzadeh H. 2012. Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 32: 227–235.
87. Moshiri E1, Basti AA, Noorbala AA, Jamshidi AH, Hesameddin Abbasi S, Akhondzadeh S. 2006. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: a double-blind, randomized and placebo-controlled trial. Phytomedicine 13: 607–611.
88. Mousavi SH, Tayarani NZ, Parsaee H. 2010. Protective effect of saffron extract and crocin on reactive oxygen species-mediated high glucose-induced toxicity in PC12 Cells. Cell Mol Neurobiol 30: 185–191.
89. Naghizadeh B, Boroushaki MT, Mashhadian NV, Mansouri SMT. 2008. Protective effects of crocin against cisplatin-induced acute renal failure and oxidative stress in rats. Iran Biomed J 12: 93–100.
90. Nair SC, Kurumboor SK, Hasegawa JH. 1995. Saffron chemoprevention in biology and medicine: a review. Cancer Biother 10: 257–264.
91. Nair SC, Panikkar KR, Parthod RK. 1993. Protective effects of crocetin on the bladder toxicity induced by cyclophosphamide. Cancer Biother 8: 339–343.
92. Nam KN, Park YM, Jung HJ, et al. 2010. Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells. Eur J Pharmacol 648: 110–116.
93. Nemati H, Boskabady MH, Ahmadzadef VH. 2008. Stimulatory effect of Crocus sativus (saffron) on beta 2-adrenoceptors of guinea pig tracheal chains. Phytomedicine 15: 1038–1045.
94. Ochiai T, Ohno S, Soeda S, Tanaka H, Shoyama Y, Shimeno H. 2004. Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of a-tocopherol. Neurosci Lett 362: 61–64.
95. Papandreou MA, Tsachaki M, Efthimiopoulos S, Cordopatis P, Lamari FN, Margarity M. 2011. Memory enhancing effects of saffron in aged mice are correlated with antioxidant protection. Behav Brain Res 219: 197–204.
96. Park HS, Kim SR, Lee YC. 2009. Impact of oxidative stress on lung diseases. Respirology 14: 27–38.
97. Premkumar K, Thirunavukkarasu C, Abraham SK, Santhiya ST, Ramesh A. 2006. Protective effect of saffron (Crocus sativus L.) aqueous extract against genetic damage induced by anti-tumor agents in mice. Hum Exp Toxicol 25: 79–84.
98. Rashedinia M, Lari P, Abnous K, Hosseinzadeh H. 2015. Protective effect of crocin on acrolein-induced tau phosphorylation in the rat brain. Acta Neurobiol Exp (Wars) 75: 208–219.
99. Razavi B, Hosseinzadeh H, Abnous K, Imenshahidi M. 2014. Protective effect of crocin on diazinon induced vascular toxicity in subchronic exposure in rat aorta ex vivo. Drug Chem Toxicol 37: 378–830.
100. Rezaee R, Hosseinzadeh H. 2013. Safranal: from an aromatic natural product to a rewarding pharmacological agent. Iran J Basic Med Sci 16: 12–26.
101. Rios JL, Recio MC, Giner RM, Manz S. 1996. An update review of saffron and its active constituents. Phytother Res 10: 189–193.
102. Sadeghnia HR, Kamkar M, Assadpour E, Boroushaki MT, Ghorbani A. 2013. Protective effect of safranal, a constituent of Crocus sativus, on quinolinic acid-induced oxidative damage in rat hippocampus. Iran J Basic Med Sci 16: 73–82.
103. Saleh D, Ernst P, Lim S, Barnes PJ, Giaid A. 1998. Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid. FASEB J 12: 929–937.
104. Salem IB, Boussabbeh M, Neffati F, Najjar MF, Abid-Essefi S, Bacha H. 2015. Zearalenone-induced changes in biochemical parameters, oxidative stress and apoptosis in cardiac tissue: protective role of crocin. Hum Exp Toxicol. DOI:10.1177/0960327115597467.
105. Santhosh MS, Sundaram MS, Sunitha K, Jnaneshwari S, Devaraja S, Kemparaju K. 2016. Propensity of crocin to offset Vipera russelli venom induced oxidative stress mediated neutrophil apoptosis: a biochemical insight. Cytotechnology DOI:10.1007/s10616-014-9752-x.
106. Santhosh SM, Hemshekhar M, Thushara RM, Devaraja S, Kemparaju K, Girish KS. 2013. Vipera russelli venom-induced oxidative stress and hematological alterations: amelioration by crocin a dietary colorant. Cell Biochem Function 31: 41–50.
107. Sapanidou V, Taitzoglou I, Tsakmakidis Ι, et al. 2015. The antioxidant effect of crocin on bovine sperm quality and fertilization outcome. Theriogenology 84: 1273–1282.
108. Schmidt M, Betti G, Hensel A. 2007. Saffron in phytotherapy: pharmacology and clinical uses. Wien Med Wochenschr 157: 315–319.
109. Shati A, Alamri S. 2010. Role of saffron (Crocus sativus L.) and honey syrup on aluminium induced hepatotoxicity. Saudi Med J 31: 1106–1113.
110. Soeda S, Ochiai T, Tanaka H, Shoyama Y, Shimeno H. 2005. Prevention of ischemic neuron death by a saffron's carotenoid pigment crocin and its mechanism of action. Focus Neurochem Res 139–156.
111. Sun Y, Yang J, Wang LZ, Sun LR, Dong Q. 2014. Crocin attenuates cisplatin-induced liver injury in the mice. Hum Exp Toxicol 33: 855–862.
112. Tamaddonfard E, Farshid AA, Hosseini L. 2012. Crocin alleviates the local paw edema induced by histamine in rats. Avicenna J Phytomed 2: 97–104.
113. Tamaddonfard E, Farshid AA, Maroufi S, et al. 2014. Effects of safranal, a constituent of saffron, and vitamin E on nerve functions and histopathology following crush injury of sciatic nerve in rats. Phytomedicine 21: 717–723.
114. Tamaddonfard E, Karim Eghdami F, Samadi F, Erfanparast A. 2013. Comparison of the effects of crocin, safranal and diclofenac on local inflammation and inflammatory pain responses induced by carrageenan in rats. Pharmacol Rep 65: 1272–1280.
115. Thushara RM, Hemshekhar M, Paul M, et al. 2014. Crocin prevents sesamol-induced oxidative stress and apoptosis in human platelets. J Thromb Thrombolysis 38: 321–330.
116. Trantilis PA, Tsoupras G, Polissiou M. 1995. 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 99: 107–111.
117. Tsantarliotou MP, Poutahidis T, Markala D, et al. 2013. Crocetin administration ameliorates endotoxin-induced disseminated intravascular coagulation in rabbits. Blood Coagul Fibrinolysis 24: 305–310.
118. Tseng TH, Chu CY, Huang JM, Shiow SJ, Wang CJ. 1995. Crocetin protects against oxidative damage in rat primary hepatocytes. Cancer Lett 97: 61–67.
119. Umigai N, Tanaka J, Tsuruma K, Shimazawa M, Hara H. 2012. Crocetin, a carotenoid derivative, inhibits VEGF-induced angiogenesis via suppression of p38 phosphorylation. Curr Neurovasc Res 9: 102–109.
120. Urrutia EC, Riverón-Negrete L, Abdullaev F, Del-Angel DS, Martínez NLH, Cruz MEG. 2007. Saffron extract ameliorates oxidative damage and mitochondrial dysfunction in the rat brain. Acta Hortic 739: 359–366.
121. Venkatraman M, Konga D, Peramaiyan R, Ganapathy E, Dhanapal S. 2008. Reduction of mitochondrial oxidative damage and improved mitochondrial efficiency by administration of crocetin against benzo[a]pyrene induced experimental animals. Biol Pharm Bull 31: 1639–1645.
122. Vosooghi S, Mahmoudabady M, Neamati A, Aghababa H. 2013. Preventive effects of hydroalcoholic extract of saffron on hematological parameters of experimental asthmatic rats. Avicenna J Phytomed 3: 279–287.
123. Wang CJ, Lee MJ, Chang MC, Lin JK. 1995. Inhibition of tumor promotion in benzo[a]pyrene-initiated CD-1 mouse skin by crocetin. Carcinogenesis 16: 187–91.
124. Wang CJ, Shiow SJ, Lin JK. 1991. Effects of crocetin on the hepatotoxicity and hepatic DNA binding of aflatoxin B1 in rats. Carcinogenesis 12: 459–462.
125. Wang K, Zhang L, Rao W, et al. 2015. Neuroprotective effects of crocin against traumatic brain injury in mice: Involvement of notch signaling pathway. Neurosci Lett 591: 53–58.
126. Wang Y, Sun J, Liu C, Fang C. 2014. Protective effects of crocetin pretreatment on myocardial injury in an ischemia/reperfusion rat model. Eur J Pharmacol 741: 290–296.
127. Xiong Y, Wang J, Yu H, Zhang X, Miao C. 2015. Anti-asthma potential of crocin and its effect on MAPK signaling pathway in a murine model of allergic airway disease. Immunopharmacol Immunotoxicol 37: 236–243.
128. Xu GL, Li G, Ma HP, Zhong H, Liu F, Ao GZ. 2009. Preventive effect of crocin in inflamed animals and in LPS-challenged RAW 264.7 cells. J Agric Food Chem 57: 8325–8330.
129. Xu GL, Yu SQ, Gong ZN, Zhang SQ. 2005. Study of the effect of crocin on rat experimental hyperlipemia and the underlying mechanisms. China J Chin Meteria Medica 30: 369–372.
130. Yang L, Qian Z, Ji H, et al. 2010. Inhibitory effect on protein kinase C theta by crocetin attenuates palmitate-induced insulin insensitivity in 3 T3-L1 adipocytes. Eur J Pharmacol 642: 47–55.
131. 2+ in the inhibition by crocetin of platelet activity and thrombosis formation. J Agric Food Chem 56: 9429–9433.
132. Yang R, Tan X, Thomas AM, et al. 2006. Crocetin inhibits mRNA expression for tumor necrosis factor-alpha, interleukin-1beta, and inducible nitric oxide synthase in hemorrhagic shock. J Parenter Entera Nutr 30: 297–301.
133. Yang R, Yang L, Shen X, Cheng W, Zhao B, Hamid A. 2012. Suppression of NF-κB pathway by crocetin contributes to attenuation of lipopolysaccharide-induced acute lung injury in mice. Eur J Pharmacol 674: 391–396.
134. Yousefi E, Eskandari A, Gharavi MJ, Khademvatan S. 2014. In vitro activity and cytotoxicity of Crocus sativus extract against leihmania major (MRHO/IR/75/ER). Infect Disord Drug Targets 14: 56–60.
135. Zarinkamar F, Tajik S, Soleimanpour S. 2011. Effects of altitude on anatomy and concentration of crocin, picrocrocin and safranal in Crocus sativus L. Aust J Crop Sci 5: 831–838.
136. Zhang C, Ma J, Fan L, et al. 2015. 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 47: 291–300.
137. Zhang R, Qian ZY, Han XY, Chen Z, Yan JL, Hamid A. 2009. Comparison of the effects of crocetin and crocin on myocardial injury in rats. Chin J Nat Med 7: 223–227.
138. Zheng SG, Zhao MQ, Ren YN, Yang JR, Qian ZY. 2015. Effects of crocetin on VCAM-1 expression in human umbilical vein endothelial cells and monocyte-endothelial cell adhesion. Yao Xue Xue Bao 50: 34–38.
139. Zheng YQ, Liu JX, Wang JN, Xu L. 2007. Effects of crocin on reperfusion induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. Brain Res 1138: 86–94.
140. Zhou C, Bai W, Chen Q, et al. 2015. Protective effect of crocetin against burn-induced intestinal injury. J Surg Res 198: 99–107.
141. Zhu KJ, Yang JS. 2014. Anti-allodynia effect of safranal on neuropathic pain induced by spinal nerve transection in rat. Int J Clin Exp Med 7: 4990–4996.