Oxidative stress in diabetic mellitus is a consequence of oxidative stress, which plays a critical role in the pathogenesis of diabetic tissue damage. Receptors for advanced glycation end products and for oxidized low-density lipoproteins (LDL) have critical contribution in oxidative tissue damage. The present study investigated whether anti-diabetic effects of Crocin via modulation of mRNA expression of RAGE and LOX-1 receptors in diabetic rats.
In the current study, high-fat cholesterol (HFC) and streptozotocin (40 mg/kg) used to induce type II diabetes. Experimental groups as follows: (Group 1: control); (Group 2: control treatment [Crocin]); (Group 3: DM [STZ]); (Group 4: DM treatment [STZ + Crocin]); (Group 5; DM + HFC [STZ + HFC]); (Group 6; DM + HFC treatment [STZ + HFC + Crocin]). Crocin (20 mg/kg/day, i.p.) administered in treatment groups for 60 days. Serum glucose and cholesterol levels evaluated on days 5, 30 and 60 after induction of DM. Pancreatic tissue from all group removed on day 60 for histological and RT-PCR analysis.
Application of Crocin significantly decreased serum cholesterol levels on day 60 after induction of DM in diabetic + HFC rats. Moreover, Crocin significantly decreased serum glucose levels on days 30 and 60 both in diabetic and diabetic + HFC rats. Crocin partially prevented the atrophic effects of STZ on both exocrine and endocrine parts of pancreas. Additionally, Crocin significantly decreased LOX-1 and RAGE mRNA expression OF pancreas in diabetic rats.
The current study suggested that Crocin suppressed atrophic change of the pancreas by decrease of LOX-1 and RAGE mRNA expression in diabetic rats.
List of abbreviation
reactive oxygen spacious
advanced glycation end-products
lectin-like oxLDL receptor-1
reverse transcriptase-polymerase chain reaction
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study was supported by a grant from Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Employment or leadership: None declared.
Honorarium: None declare.
Competing interests: None declare.
 Sellamuthu PS, Arulselvan P, Muniappan BP, Fakurazi S, Kandasamy M. Mangiferin from salacia Chinensis prevents oxidative stress and protects pancreatic b-cells in streptozotocin-induced diabetic rats. J Med Food 2013;16:719–27.10.1089/jmf.2012.2480Search in Google Scholar PubMed
 Askary-Ashtiani A, Ghanjal A, Motaqi M, Meftahi GH, Hatef B, Niknam H. The isokinetic and electromyographic assessment of knee muscles strength in the short- and long-term type 2 diabetes. Asian J Sports Med 2016;7:e37008.10.5812/asjsm.37008Search in Google Scholar PubMed PubMed Central
 Kim SH, Hyun SH, Choung SY. Anti-diabetic effect of cinnamon extract on blood glucose in db/db mice. J Ethnopharmacol 2006;104:119–23.10.1016/j.jep.2005.08.059Search in Google Scholar PubMed
 Samarghandian S, Azimi-Nezhad M, Farkhondeh T. Immunomodulatory and antioxidant effects of saffron aqueous extract (Crocus sativus L.) on streptozotocin-induced diabetes in rats. IHJ 2017;69:151–9.10.1016/j.ihj.2016.09.008Search in Google Scholar PubMed PubMed Central
 Matough FA, Budin SB, Hamid ZA, Alwahaibi N, Mohamed J. The role of oxidative stress and antioxidants in diabetic complications. Sultan Qaboos Univ Med J 2012;12:5–18.10.12816/0003082Search in Google Scholar PubMed PubMed Central
 Volpe CM, Villar-Delfino PH, Dos Anjos PMF, Nogueira-Machado JA. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis 2018;9:119.10.1038/s41419-017-0135-zSearch in Google Scholar PubMed PubMed Central
 Sellamuthu PS, Arulselvan P, Kamalraj S, Fakurazi S, Kandasamy M. Protective nature of mangiferin on oxidative stress and antioxidant status in tissues of streptozotocin-induced diabetic rats. ISRN Pharmacol 2013;2013:750109.10.1155/2013/750109Search in Google Scholar PubMed PubMed Central
 Mohamed AK, Bierhaus A, Schiekofer S, Tritschler H, Ziegler R, Nawroth PP. The role of oxidative stress and NF-κB activation in late diabetic complications. BioFactors 1999;10:157–67.10.1002/biof.5520100211Search in Google Scholar PubMed
 Del Turco S, Basta G. An update on advanced glycation endproducts and atherosclerosis. Biofactors 2012;38:266–74.10.1002/biof.1018Search in Google Scholar PubMed
 Nowotny K, Jung T, Hohn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015;5:194–222.10.3390/biom5010194Search in Google Scholar PubMed PubMed Central
 Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J, et al. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol 2019;20:247–60.10.1016/j.redox.2018.09.025Search in Google Scholar PubMed PubMed Central
 Schleicher E, Friess U. Oxidative stress, AGE, and atherosclerosis. Kidney Int 2007;106:S17–S26.10.1038/sj.ki.5002382Search in Google Scholar PubMed
 Lubrano V, Balzan S. LOX-1 and ROS, inseparable factors in the process of endothelial damage. Free Radic Res 2014;48:841–8.10.3109/10715762.2014.929122Search in Google Scholar PubMed
 Kita T, Kume N, Minami M, Hayashida K, Murayama T, Sano H, et al. Role of oxidized LDL in atherosclerosis. Ann N Y Acad Sci 2001;947:199–205.10.1111/j.1749-6632.2001.tb03941.xSearch in Google Scholar PubMed
 Hashtjini MM, Jahromi GP, Meftahi GH. Aqueous extract of saffron administration along with amygdala deep brain stimulation promoted alleviation of symptoms in post-traumatic stress disorder (PTSD) in rats. Avicenna J Phytomed 2018;8:358–69.Search in Google Scholar
 Ghodrat M, Sahraei H, Razjouyan J, Meftahi GH. Effects of a saffron alcoholic extract on visual short-term memory in humans: a psychophysical study. Neurophysiology 2014;46:247–53.10.1007/s11062-014-9436-3Search in Google Scholar
 Hadipour M, Kaka G, Bahrami F, Meftahi GH, Pirzad Jahromi G, Mohammadi A, et al. Crocin improved amyloid beta induced long-term potentiation and memory deficits in the hippocampal CA1 neurons in freely moving rats. Synapse 2018;72:e22026.10.1002/syn.22026Search in Google Scholar PubMed
 Shirali S, Bathaie Z, Nakhjavani M. Effect of crocin on the insulin resistance and lipid profile of streptozotocin-induced diabetic rats. Phytother Res 2013;27:1042–7.10.1002/ptr.4836Search in Google Scholar PubMed
 Rajaei Z, Hadjzadeh MA, Nemati H, Hosseini M, Ahmadi M, Shafiee S. Antihyperglycemic and antioxidant activity of crocin in streptozotocin-induced diabetic rats. J Med Food 2013;16:206–10.10.1089/jmf.2012.2407Search in Google Scholar PubMed
 Yaribeygi H, Sahraei H, Mohammadi AR, Meftahi GH. Saffron (Crocus sativus L.) and morphine dependence: A systematic review article. A J B L S 2014;2:41–5.Search in Google Scholar
 Asalgoo S, Jahromi GP, Hatef B, Sahraei H, Sarshoori J, Sadr S, et al. Saffron (Crocus sativus) aqueous extract reverses the hypothalamus-pituitary-adrenal axis activity in rat model of post-traumatic stress disorder. Rev Bras Farmacogn 2019;29:470–6.10.1016/j.bjp.2019.01.011Search in Google Scholar
 Yaribeygi H, Mohammadi MT, Sahebkar A. Crocin potentiates antioxidant defense system and improves oxidative damage in liver tissue in diabetic rats. Biomed Pharmacother 2018;98:333–7.10.1016/j.biopha.2017.12.077Search in Google Scholar PubMed
 Choudhury H, Pandey M, Hua CK, Mun CS, Jing JK, Kong L, et al. An update on natural compounds in the remedy of diabetes mellitus: A systematic review. J Tradit Complement Med 2018;8:361–76.10.1016/j.jtcme.2017.08.012Search in Google Scholar PubMed PubMed Central
 Moradi B, Abbaszadeh S, Shahsavari S, Alizadeh M, Beyranvand F. The most useful medicinal herbs to treat diabetes. Biomed Res Ther 2018;5:2538–51.10.15419/bmrat.v5i8.463Search in Google Scholar
 King A. The use of animal models in diabetes research. Br J Pharmacol 2012;166:877–94.10.1111/j.1476-5381.2012.01911.xSearch in Google Scholar PubMed PubMed Central
 Skovso S. Modeling type 2 diabetes in rats using high fat diet and streptozotocin. J Diabetes Invest 2014;5:349–58.10.1111/jdi.12235Search in Google Scholar PubMed PubMed Central
 Dogukan A, Sahin N, Tuzcu M, Juturu V, Orhan C, Onderci M, et al. The effects of chromium histidinate on mineral status of serum and tissue in fat-fed and streptozotocin-treated type II diabetic rats. Biol Trace Elem Res 2009;131:124–32.10.1007/s12011-009-8351-8Search in Google Scholar PubMed
 Suman RK, Mohanty IR, Borde MK, Maheshwari U, Deshmukh YA. Development of an experimental model of diabetes co-existing with metabolic syndrome in rats. Adv Pharmacol Sci 2016;2016:11. Article ID 9463476.10.1155/2016/9463476Search in Google Scholar PubMed PubMed Central
 Pirmoradi L, Mohammadi MT, Safaei A, Mesbah F, Dehghani GA. Does the relief of glucose toxicity act as a mediator in proliferative actions of vanadium on pancreatic islet beta cells in streptozocin diabetic rats? IBJ 2014;18:173–80.Search in Google Scholar
 Mohammadi MT, Pirmoradi L, Mesbah F, Safaee A, Dehghani GA. Trophic actions of oral vanadium and improved glycemia on the pancreatic beta-cell ultrastructure of streptozotocin-induced diabetic rats. JOP 2014;15:591–6.Search in Google Scholar
 Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 2000;49:1390–4.10.1053/meta.2000.17721Search in Google Scholar PubMed
 Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocintreated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 2005;52:313–20.10.1016/j.phrs.2005.05.004Search in Google Scholar PubMed
 Hazman O, Aksoy L, Buyukben A. Effects of crocin on experimental obesity and type-2 diabetes. Turk J Med Sci 2016;46:1593–602.10.3906/sag-1506-108Search in Google Scholar PubMed
 Zlatkis A, Zac B, Boyle AJ. A new method for the direct determination of serum cholesterol. J Lab Clin Med 1953;41:486–92.Search in Google Scholar
 Riahi S, Mohammadi MT, Sobhani V, Ababzadeh S. Chronic aerobic exercise decreases lectin-like low density lipoprotein (LOX-1) receptor expression in heart of diabetic rat. Iran Biomed J 2016;20:26–32.Search in Google Scholar
 Hudson BI, Wendt T, Bucciarelli LG, Rong LL, Naka Y, Yan S, et al. Diabetic vascular disease: it’s all the RAGE. Antioxid Redox Signal 2005;7:1588–600.10.1089/ars.2005.7.1588Search in Google Scholar PubMed
 Gupta S, Kataria M, Gupta PK, Murganandan S, Yashroy RC. Protective role of extracts of neem seeds in diabetes caused by streptozotocin in rats. J Ethnopharmacol 2004;90:185–9.10.1016/j.jep.2003.09.024Search in Google Scholar
 Shirali S, Bathaie Z, Nakhjavani M. Effect of Crocin on the insulin resistance and lipid profile of streptozotocin-induced diabetic rats. Phytother Res 2012;27:1042–7.10.1002/ptr.4836Search in Google Scholar
 Sheng L, Qian Z, Zheng S, Xi L. Mechanism of hypolipidemic effect of crocin in rats: Crocin inhibits pancreatic lipase. Eur J Pharmacol 2006;543:116–22.10.1016/j.ejphar.2006.05.038Search in Google Scholar
 Huggins KW, Camarota LM, Howles PN, Hui DY. Pancreatic lipase deficiency minimally affects dietary fat absorption but dramatically decreases dietary cholesterol absorption in mice. J Biol Chem 2003;278:42899–905.10.1074/jbc.M303422200Search in Google Scholar
 Sharma S, Nasir A, Parbhu K, Mursy B, Dev G. Hypoglycemic and hypolipidemic effect of etanolic extract of seeds in alloxan induced diabetic rabbits. J Ethnopharmacol 2003;85:201–6.10.1016/S0378-8741(02)00366-5Search in Google Scholar
 Mohajeri D, Tabrizi BA, Mousavi G, Mesgari M. Anti-diabetic activity of Crocus sativus L. (Saffron) stigma ethanolic extract in alloxan-induced diabetic rats. Res J Biol Sci 2008;3:1102–8.Search in Google Scholar
 Chen M, Nagase M, Fujita T, Narumiya S, Masaki T, Sawamura T. Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium: possible role of LOX-1 ligand and AGE. Biochem Biophys Res Commun 2001;287:962–8.10.1006/bbrc.2001.5674Search in Google Scholar PubMed
 Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I Age Concept Circ Res 1998;37:586–600.Search in Google Scholar
© 2019 Walter de Gruyter GmbH, Berlin/Boston