Beneficial Effects of Hydroalcoholic Extract of Saffron in Alleviating Experimental Autoimmune Diabetes in C57bl/6 Mice
Abstract
Streptozocin (STZ) is a strong alkalizing agent which is capable of destroying the beta cells of the pancreatic islets. Multiple low doses (40 mg/kg, intraperitoneally for 5 consecutive days) prescription of STZ to mice can lead to the T cell-dependent immune response and induction of autoimmune diabetes (AD) with complete similarity to the human type 1 diabetes (T1D). This study has evaluated the effects of hydroalcoholic extract of saffron on the clinical and immunological profile of experimental autoimmune diabetes in C57BL/6 mice. After the establishment of the AD, mice were treated orally with hydroalcoholic extract of saffron (500 mg/kg) for 3 weeks. The results with p<0.05 were considered significant. Obtained data showed that treatment with the hydroalcoholic extract of saffron significantly reduced the incidence of hypoglycemia and restored insulin secretion and histopathological changes in pancreas sections. In addition, treatment with saffron reduced lymphocyte proliferation index in the cells isolated from the pancreas of diabetic mice. Also, the extract of saffron markedly decreased the production of pro-inflammatory interleukin-17 (IL-17) increased anti-inflammatory IL-10 and transforming growth factor-β in the pancreatic cell population. Moreover, the production of proinflammatory nitric oxide and reactive oxygen substances were down-regulated by the saffron extract. It seems that the hydroalcoholic extract of saffron can be considered as a useful strategy in the treatment of type 1 diabetes.
1. Pane JA, Webster NL, Coulson BS. Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells. PLoS Pathogens 2014; 10(3): e1003998.
2. Clark M, Kroger CJ, Tisch RM. Type 1 diabetes: A chronic anti-self-inflammatory response. Front Immunol 2017; 8: 1898.
3. Atalay M, Oksala NK, Laaksonen DE, Khanna S, Nakao C, Lappalainen J, et al. Exercise training modulates heat shock protein response in diabetic rats. J Appl Physiol 2004; 97(2): 605-11.
4. Rostambeigy P, Ghaemi SZ, Shirazi FM, Hashemi N. The Effects of Nutrition Education and Insulin Injection Training on Glycemic Control in Iranian Patients with Type 1 Diabetes. Adv Biores 2014; 5(2):143-7.
5. Rubinstein MR, Genaro AM, Wald MR. Differential effect of hyperglycaemia on the immune response in an experimental model of diabetes in BALB/cByJ and C57Bl/6J mice: Pfarticipation of oxidative stress. Clin Exp Immunol 2013; 171(3): 319-29.
6. Wei L, Lu Y, He S, Jin X, Zeng L, Zhang S, et al. Induction of diabetes with signs of autoimmunity in primates by the injection of multiple-low-dose streptozotocin. Biochem Biophys Res Commun 2011; 412(2): 373-8.
7. Singh R, Kaur N, Kishore L, Gupta GK. Management of diabetic complications: a chemical constituents based approach. J Ethnopharmacol 2013; 150(1): 51-70.
8. Wang K, Tang Z, Zheng Z, Cao P, Shui W, Li Q, et al. Protective effects of Angelica sinensis polysaccharide against hyperglycemia and liver injury in multiple low-dose streptozotocin-induced type 2 diabetic BALB/c mice. Food Funct 2016; 7: 4889-4897.
9. Lee DY, Kim MH, Suh HR, Jung YS, Hwang DY, Kim KS. Comparison of the response using ICR mice derived from three different sources to multiple low-dose streptozotocin-induced diabetes mellitus. Lab Anim Res 2017;33(2):150-156.
10. Amirshahrokhi K, Dehpour AR, Hadjati J, Sotoudeh M, Ghazi-Khansari M. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice. Toxicol Appl Pharmacol 2008; 232(1): 119-24.
11. Rabinovitch A, Suarez-Pinzon WL. Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol 1998; 55(8): 1139-49.
12. Malik AH, Ashraf N. Transcriptome wide identification, phylogenetic analysis, and expression profiling of zinc-finger transcription factors from Crocus sativus L Saffron. Mol Genet Genomics. 2017; 292(3): 619-633.
13. Razavi BM, Hosseinzadeh H. Saffron: a promising natural medicine in the treatment of metabolic syndrome. J Sci Food Agric 2017; 97(6):1679-1685.
14. Boskabady MH, Farkhondeh T. Antiinflammatory, Antioxidant, and Immunomodulatory Effects of Crocus sativus L. and its Main Constituents. Phytother Res 2016; 30(7): 1072-94.
15. Karimi Gh.R. Khalegh Panah P HH. Study of antidepressant effect of aqueous and ethanolic extract of crocus sativus in mice. Iran J Basic Med Sci 2001; 4(3): 11-5.
16. Hosseinzadeh H, Karimi G, Niapoor M. sAntidepressant effect of Crocus sativus L. stigma extracts and their constituents, crocin and safranal, in mice. JMP 2004; 3(11): 48-58.
17. Rezaee R, Hosseinzadeh H. Safranal: From an aromatic natural product to a rewarding pharmacological agent. Iran J Basic Med Sci 2013; 16(1):12-26.
18. Ghazavi A1, Mosayebi G, Salehi H, Abtahi H. Effect of ethanol extract of saffron (Crocus sativus L.) on the inhibition of experimental autoimmune encephalomyelitis in C57bl/6 mice. Pak J Biol Sci 2009; 12(9): 690-5.
19. Najemnikova E, Rodgers CD, Locke M. Altered heat stress response following streptozotocin-induced diabetes. Cell Stress Chaperones 2007; 12(4): 342-52.
20. Dardalhon V, Korn T, Kuchroo VK, Anderson AC. Role of Th1 and Th17 cells in organ-specific autoimmunity. Journal of autoimmunity 2008; 31(3): 252-6.
21. Green EA, Choi Y, Flavell RA. Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity 2002; 16(2): 183-91.
22. Abtahi Froushani SM, Galeh HEG. New insight into the immunomodulatory mechanisms of tretinoin in NMRI mice. Iran J Basic Med Sci 2014; 17(9): 632-637.
23. Shushtari N, Abtahi Froushani SM. Caffeine Augments The Instruction of Anti-Inflammatory Macrophages by The Conditioned Medium of Mesenchymal Stem Cells. Cell j 2017; 19(3): 415-24.
24. Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M, et al. Inhibitory activity on amyloid-β aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J Agric Food Chem 2006; 54(23): 8762-8
25. Liakopoulou-Kyriakides M, Kyriakidis DA. Croscus sativus-biological active constitutents. Stud in Nat Prod Chem 2002; 26: 293-312.
26. Tamaddonfard E, Farshid AA, Hosseini L. Crocin alleviates the local paw edema induced by histamine in rats. Avicenna J Phytomed 2012; 2(2): 97-104.
27. Milajerdi A, Jazayeri S, Bitarafan V, et al. The effect of saffron (Crocus sativus L.) hydro-alcoholic extract on liver and renal functions in type 2 diabetic patients: A double-blinded randomized and placebo control trial. J Nut and Int Meta 2017; 9: 6-11.
28. Kermani T, Zebarjadi M, Mehrad-Majd H, Mirhafez SR, Shemshian M, Ghasemi F, et al. Anti-inflammatory effect of Crocus sativus on the serum cytokines levels in subjects with Metabolic Syndrome: A Randomized, Double-blind, Placebo - controlled trial. Curr Clin Pharmacol 2017; 12(2): 122-126.
29. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.). Exp Biol Med 2002; 227(1):20-5.
30. Loizzo MR, Marrelli M, Pugliese A, Conforti F, Nadjafi F, Menichini F, et al. Crocus cancellatus subsp. damascenus stigmas: chemical profile, and inhibition of α-amylase, α-glucosidase and lipase, key enzymes related to type 2 diabetes and obesity. J Enzyme Inhib Med Chem 2016; 31(2):212-8.
31. Li Y, Liu Y, Chu CQ. Th17 Cells in Type 1 Diabetes: Role in the Pathogenesis and Regulation by Gut Microbiome. Mediators Inflamm 2015; 2015:63847.
32. Abtahi Froushani SM, Delirezh N, Hobbenaghi R, Mosayebi G. Synergistic effects of atorvastatin and all-trans retinoic acid in ameliorating animal model of multiple sclerosis. Immunol Invest 2014; 43(1): 54-68.
33. Kurtys E, Eisel ULM, Verkuyl JM, Broersen LM, Dierckx R, de Vries EFJ. The combination of vitamins and omega-3 fatty acids has an enhanced anti-inflammatory effect on microglia. Neurochem Int 2016; 99: 206-214.
34. Feyzi R, Boskabady Mh, Seyed hosseini Tamijani SM, Rafatpanah H, Rezaei SA. The Effect of Safranal on Th1/Th2 Cytokine Balance. Iran J Immunol 2016; 13(3):263-273.
35. Garetto S, Trovato AE, Lleo A, Sala F, Martini E, Betz AG, et al. Peak inflammation in atherosclerosis, primary biliary cirrhosis and autoimmune arthritis is counter-intuitively associated with regulatory T cell enrichment. Immunobiology 2015; 220(8): 1025-9.
36. Peeri M, Mosalman Haghighi M, Azarbayjani MA, Atashak S, Behrouzi G. Effect of aqueous extract of saffron and aerobic training on hepatic non enzymatic antioxidant levels in streptozotocin-diabetic rats. Archives Des Sciences 2012; 65(10): 525-32.
37. Assimopoulou AN, Sinakos Z, Papageorgiou VP. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res 2005; 19(11): 997-1000.
38. 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(1): 56-61.
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Issue | Vol 18, No 1 (2019) | |
Section | Original Article(s) | |
DOI | https://doi.org/10.18502/ijaai.v18i1.629 | |
Keywords | ||
Crocus sativus L. Inflammation Saffron Type 1 diabetes mellitus |
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