اثر ورزش و مکمل کروسین بر نشانگرهای بیوژنز میتوکندری و محافظت سلولی در بیماری دیابت با تاکید بر نقش PGC-1α و HSP70: یک مطالعه مروری نظامند
محورهای موضوعی :میثم روزستان 1 , Khalid Mohamadzadeh Salamat 2 * , کمال عزیز بیگی 3 , سید علی حسینی 4
1 - گروه تربیت بدنی و علوم ورزشی، واحد سنندج، دانشگاه آزاد اسلامی، سنندج، ایران
2 - Department of Physical Education, Sa.C., Islamic Azad University, Sanandaj, Iran.
3 - گروه تربیت بدنی و علوم ورزشی، واحد سنندج، دانشگاه آزاد اسلامی، سنندج، ایران
4 - گروه مدیریت ورزش، واحد مرودشت، دانشگاه آزاد اسلامی، مرودشت، ایران.
کلید واژه: تمرین استقامتی, مکمل کروسین, PGC-1α, HSP70, دیابت ,
چکیده مقاله :
هدف: بیوژنز میتوکندری یک چرخه پیچیده است که شامل هماهنگی بین بیان ژن‌های میتوکندری و ژن‌های هسته‌ای، سپس ورود محصولات به اندامک و تداوم گردش این چرخه می‌باشد. نقص میتوکندری و یا نقص در هر یک از مسیرهای درگیر در بیوژنز میتوکندری، می‌تواند منجر به بیماری دیابت شود .یکی از راه های کنترل و مدیریت بیماری دیابت پرداختن به فعالیت های ورزشی می باشد. اگرچه نقش فعالیت های بدنی و آنتی اکسیدان ها بر سلامت قلب نشان داده شده است. اما اثر تعاملی تمرینات مختلف ورزشی همراه با کروسین بر نشانگر های محافظت سلولی بافت قلب به خوبی مشخص نیست. تمرینات ورزشی با شدت متفاوت، با تنظیم بیان ژن‌های دخیل در زایش میتوکندری میوکارد بیماران دیابتی، متابولیسم را در سطح سلولی تنظیم می¬کند. بنابراین هدف مطالعه حاضر بررسی مروری بر اثر تمرینات استقامتی با شدت های مختلف و مکمل کروسین بر نشانگرهای بیوژنز میتوکندری و محافظت سلولی در بیماری دیابت با تاکید بر نقش PGC-1α و HSP70 بود. مواد و روش ها: در مطالعه مروری حاضر، تحقبقات منتشر شده از سال 2010 تا 2024 که در ارتباط با فعالیت های ورزشی، مکمل کروسین، نشانگرهای بیوژنز میتوکندری و محافظت سلولی در بیماری دیابت بودند مورد بررسی قرار گرفتند. جستجوی مطالعات لاتین با استفاده از پایگاه داده های در PubMed، ScienceDirect و Google scholar با کلید واژه های Endurance training،Crocin ،PGC-1α ، HSP70 Diabetes و جستجو در مطالعات فارسی مرتبط در پایگاه های تخصصی فارسی مگیران، SID و گوگل اسکولار، با کلید واژه های ورزش، کروسین، زعفران، بیوژنز میتوکندریایی،PGC-1α ، HSP70انجام شد. از بین تمام مقالات پیدا شده مرتبط ترین آنها که در حدود 91 مقاله مرتبط با کلیدواژه ها بودند ابتدا به دسته-های تمرین+بیوژنز میتوکندریایی، کروسین+بیوژنز میتوکندریایی و تعامل تمرین+کروسین+بیوژنز میتوکندریایی در شرایط دیابت تقسیم شدند. نتایج: از بین 250 مقاله پیدا شده با کلیدواژه های تمرین، بیوژنز میتوکندریایی، کروسین، بیوژنز میتوکندریایی تعداد 91 مقاله که مرتبط با تمرین، کروسین، بیوژنز میتوکندریایی بودند مورد استفاده قرار گرفتند. بررسی نتایج مطالعات به طور کلی نشان داد تمرین استقامتی بیشتر محرک PGC-1α می باشد و کروسین اثرات محدود تری بر بیوژنز میتوکندریایی و اثر آنتی اکسیدانی بیشتری نسبت به تمرین دارد. همچنین تعامل تمرین استقامتی و مکمل کروسین روند بیوژنز میتوکندری را در بیماران دیابتی بهبود می بخشد. نتیجه گیری: به طور کلی به نظر می رسد استفاده از کروسین به عنوان یک آنتی اکسیدان و محرک بالقوه بیوژنز میتوکندریایی از مسیر های جداگانه با تمرین استقامتی می تواند منجر به افزایش نشانگرهای بیوژنز میتوکندریایی مانند PGC-1α, HSP70 در شرایط بیماری دیابت شود. از این رو استفاده از کروسین در کنار تمرینات ورزشی برای کنترل بیماری دیابت و بهبود عملکرد جسمانی توصیه می شود.
Background and Purpose: Mitochondrial biogenesis is a complex cycle that includes the coordination between the expression of mitochondrial genes and nuclear genes, then the entry of products into the organelle and the continuation of this cycle. Mitochondrial defects or defects in any of the pathways involved in mitochondrial biogenesis can lead to diabetes. One of the ways to control and manage diabetes is to engage in sports activities. Although the role of physical activity and antioxidants on heart health has been shown. However, the interactive effect of various sports exercises with crocin on markers of cell protection of heart tissue is not well known. Sports training with different intensity regulates the metabolism at the cellular level by regulating the expression of genes involved in the generation of mitochondria in the myocardium of diabetic patients. Therefore, the aim of this study was to review the effects of endurance training with different intensities and crocin supplementation on mitochondrial biogenesis markers and cell protection in diabetes, emphasizing the role of PGC-1α and HSP70. Materials and methods: In this narrative review, Google Scholar, PubMed, Tormex, Megiran, SID were searched for the keyword’s sports, Crocin, Saffron, mitochondrial biogenesis, PGC-1α, HSP70 in the years between 2000 to 2024. Among all the articles found, the most relevant ones, which were about 70 articles, were first divided into the categories of exercise+mitochondrial biogenesis, crocin+mitochondrial biogenesis, and the interaction of exercise+crocin+mitochondrial biogenesis in diabetes conditions. Results: Among the 1300 articles found with the keywords exercise, mitochondrial biogenesis, crocin, mitochondrial biogenesis, 91 articles related to exercise, crocin, mitochondrial biogenesis were used. The results of the studies generally showed that endurance exercise is more stimulating to PGC-1α and crocin has more limited effects on mitochondrial biogenesis and more antioxidant effect than exercise. Also, the interaction of endurance training and crocin supplementation improves the process of mitochondrial biogenesis in diabetic patients. Conclusion: In general, it seems that the use of crocin as an antioxidant and a potential stimulator of mitochondrial biogenesis from separate pathways with endurance training can lead to an increase in mitochondrial biogenesis markers such as PGC-1α, HSP70 in diabetes conditions. Therefore, it is recommended to use crocin along with exercise to control diabetes and improve physical performance.
1. Chavez, J. A., & Summers, S. A. (2003). Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Archives of biochemistry and biophysics, 419(2), 101-109.
2. Montell, E., Turini, M., Marotta, M., Roberts, M., Noé, V., Ciudad, C. J., ... & Gómez-Foix, A. M. (2001). DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. American Journal of Physiology-Endocrinology and Metabolism, 280(2), E229-E237.
3. Youn, J. Y., Siu, K. L., Lob, H. E., Itani, H., Harrison, D. G., & Cai, H. (2014). Role of vascular oxidative stress in obesity and metabolic syndrome. Diabetes, 63(7), 2344-2355.
4. Summermatter, S., & Handschin, C. (2012). PGC-1α and exercise in the control of body weight. International journal of obesity, 36(11), 1428-1435.
5. Fealy, C. E., Mulya, A., Axelrod, C. L., & Kirwan, J. P. (2018). Mitochondrial dynamics in skeletal muscle insulin resistance and type 2 diabetes. Translational Research, 202, 69-82.
6. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, et al. Transcriptional control of brown fat determination by PRDM16. Cell metabolism. 2007;6(1):38-54.
7. Duan J, Zhang H-Y, Adkins SD, Ren BH, Norby FL, Zhang X, et al. Impaired cardiac function and IGF-I response in myocytes from calmodulindiabetic mice: role of Akt and RhoA. American Journal of Physiology-Endocrinology And Metabolism 2003; 284(2):E366-E76.
8. Turan B, Tuncay E. Enhanced Antioxidant-Defense Preserves Cardiac Dysfunction via Regulation of Cytosolic Levels of Zn and Ca Ions in Hyperglycemic Cardiomyocytes. Free Radical Biology and Medicine 2016;100:S178-S9.
9. Krako Jakovljevic N, Pavlovic K, Jotic A, Lalic, K, Stoiljkovic M, Lukic L, Milicic T, Macesic M, Stanarcic Gajovic J, Lalic NM. Targeting Mitochondria in Diabetes. Int. J. Mol. Sci 2021; 22, 6642.
10. Sergi D, Naumovski N, Heilbronn LK, Abeywardena M, O’Callaghan N, Lionetti L and Luscombe-Marsh N. Mitochondrial (Dys) function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet. Front. Physiol 2019; 10:532.
11. Fathi I, Nourshahi M, Haghparast A, Fallahi HH. Effect of eight-week aerobic continuous and high intensity interval training on levels of SIRT3 in skeletal muscle tissue of Wistar rats. JSEP. 2015; 1277-1289. [In Persian]
12. Mulyani WRW, Sanjiwani MID, Prabawa IPY, Lestari AAW, Wihandani DM, Suastika K, et al. Chaperone-based therapeutic target innovation: Heat shock protein 70 (HSP70) for Type 2 diabetes mellitus. Diabetes, Metab Syndr Obes Targets Ther. 2020;13:559.
13. Gaster M, Rustan AC, Aas V, Beck-Nielsen H. Reduced lipid oxidation in skeletal muscle from type 2 diabetic subjects maybe of genetic origin: Evidence from cultured myotubes. Diabetes 2004; 53:542–548.
14. Hernández-Alvarez MI, Thabit H, Burns N, Shah S, Brema I, Hatunic M, et al. Subjects with early-onset type 2 diabetes show defective activation of the skeletal muscle PGC-1α/mitofusin-2 regulatory pathway in response to physical activity. Diabetes care 2010;33(3):645-51.
15. Ding H, Jiang N, Liu H, Liu X, Liu D, Zhao F, et al. Response of mitochondrial fusion and fission protein gene expression to exercise in rat skeletal muscle. Biochimica et Biophysica Acta (BBA)- General Subjects 2010;1800(3):250-6.
16. Wright DC, Geiger PC, Han D-H, Jones TE, Holloszy JO. Calcium induces increases in peroxisome proliferator-activated receptor γ coactivator-1α and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation. Journal of Biological Chemistry 2007;282(26):18793-9.
17. Tang JE, Hartman JW, Phillips SM. Increased muscle oxidative potential following resistance training induced fiber hypertrophy in young men. Appl Physiol Nutr Metab 2006;31(5):495-501.
18. Ikeda S, Kawamoto H, Kasaoka K, Hitomi Y, Kizaki T, Sankai Y, et al. Muscle type-specific response of PGC-1 alpha and oxidative enzymes during voluntary wheel running in mouse skeletal muscle. J Acta Physiol (Oxf) 2006;188: 217-23.
19. Burgomaster KA, Howarth KR, Phillips SM, Rakobowchuk M, MacDonald MJ, McGee SL, et al. Similar metabolic adaptations durin exercise after low volume sprint interval and traditional endurance training in humans. J Physiol 2008;586(1):151-6.
20. Hodge T, Starnes J, Feger B, Hixson L, Harris MB. Effects of exercise and body temperature on eNOS, SIRT1, SIRT3 and Hsp70 expression in rat plantaris muscles (1164.6). FASEB J. 2014;28:1164–6.
21. Palacios OM, Carmona JJ, Michan S, Chen KY, Manabe Y, Ward III JL, et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle. Aging (Albany NY). 2009;1(9):771.
22. Paulsen G, Hanssen K, Rønnestad B, Kvamme N, Ugelstad I, Kadi F, et al. Strength training elevates HSP27, HSP70 and αB-crystallin levels in musculi vastus lateralis and trapezius. European journal of applied physiology. 2012;112(5):1773-82.
23. Ogawa K, Sanada K, Machida S, Okutsu M, Suzuki K. Resistance exercise training-induced muscle hypertrophy was associated with reduction of inflammatory markers in elderly women. Mediators of inflammation. 2010;2010.
24. Thevis M, Koch A, Sigmund G, Thomas A, Schänzer W. Analysis of octopamine in human doping control samples. Biomedical Chromatography. 2012; 26(5):610-5.
25. Singla RK, Bhat VG. Crocin: an overview. Glo J Pharmaceu Sci 2011; 1: 281-6. 17. Bathaie SZ, Bolhassan A, Tamanoi F. Anticancer effect and molecular targets of saffron carotenoids. Enzymes 2014; 36: 57-86.
26. Hosseini SA, Nik bakht H, Azarbayjani MA. The effect of aqua extract of saffron with resistance training on glycemic indexes of streptozotocin induced diabetic rats. Armaghane Danesh 2013; 18(4): 284-294.
27. Wright DC, Geiger PC, Han D-H, Jones TE, Holloszy JO. Calcium induces increases in peroxisome proliferator-activated receptor γ coactivator-1α and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation. Journal of Biological Chemistry 2007;282(26):18793-9.
28. Schwingshackl L, Missbach B, Dias S, König J, Hoffmann G. Impact of different training modalities on glycaemic control and blood lipids in patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetologia 2014; 57(9):1789-97.
29. Rohde M, Daugaard M, Jensen M H, Helin K, Nylandsted J, Jäättelä M. Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes & development 2005; 19(5): 570-582.
30. Paulsen G, Lauritzen F, Bayer M L, Kalhovde J M, Ugelstad I, Owe SG, et al. Subcellular movement and expression of HSP27, αB-crystallin, and HSP70 after two bouts of eccentric exercise in humans. Journal of applied physiology 2009; 107(2): 570-582.
31. Whitham M, Laing S J, Jackson A, Maassen N, Walsh N P. Effect of exercise with and without a thermal clamp on the plasma heat shock protein 72 response. Journal of applied physiology 2007; 103(4): 1251-1256.
32. Dabidiroshan Z AH, Mousavi S G. Effect of increasing endurance training and weight training session in response to heat shock protein active young women. Journal of Movement Science & Sports 2008; 12(2): 77-86.
33. Marshall H C, Ferguson R A, Nimmo M A. Human resting extracellular heat shock protein 72 concentration decreases during the initial adaptation to exercise in a hot, humid environment. Cell stress & chaperones 2006; 11(2): 129.
34. Ghasemi Kahrizsangi A HMR, Kazemi A, Ravasi A A, Dehkhoda M R. The effect of glucose and glutamine supplementation on serum HSP72 in non-athlete men during four weeks exhausting endurance-intermittent training. Res in Sport Med & Technol 2014; 7(23): 1-12.
35. Aoi W, Ichiishi E, Sakamoto N, Tsujimoto A, Tokuda H, Yoshikawa T. Effect of exercise on hepatic gene expression in rats: a microarray analysis. Life Sci 2004;75(26):3117-28.
36. Ropelle ER, Pauli JR, Prada PO, De Souza CT, Picardi PK, Faria MC, et al. Reversal of diet‐induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS‐1 serine phosphorylation. J Physiol 2006;577(3):997-1007.
37. Corona JC, Duchen MR. PPARγ and PGC-1α as therapeutic targets in Parkinson’s. Neurochem Res 2015;40(2):308-16.
38. Etebari M, Sajjadi SE, Jafarian-Dehkordi A, Panahi M. Antigenotoxic Effects of Methanolic and Aqueous Extracts of Kelussia Odoratissima Mozaffarian against Damage Induced by Methyl Methanesulfonate. Journal of Isfahan Medical School. 2013; 30(215):2062-71.
39. Leick L, Wojtaszewski JF, Johansen ST, Kiilerich K, Comes G, Hellsten Y, et al. PGC-1α is not mandatory for exercise-and training-induced adaptive gene responses in mouse skeletal muscle. American Journal of Physiology-Endocrinology and Metabolism. 2008; 294(2):E463-74.
40. Adhihetty PJ, Uguccioni G, Leick L, Hidalgo J, Pilegaard H, Hood DA. The role of PGC-1alpha on mitochondrial function and apoptotic susceptibility in muscle. American Journal of Physiology. Cell Physiology. 2009; 297(1):C217-25.
41. Farrell PA, Joyner MJ, Caiozzo V. ACSM's advanced exercise physiology. King's College, London: Wolters Kluwer Health Adis (ESP); 2011.
42. Seyydi SM, Tofighi A, Rahmati M, Azar JT. Exercise and Urtica Dioica extract ameliorate mitochondrial function and the expression of cardiac muscle Nuclear Respiratory Factor 2 and Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha in STZ-induced diabetic rats. Gene. 2022;822:146351.
43. Wang SY, Zhu S, Wu J, Zhang M, Xu Y, Xu W, et al. Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy. Journal of Molecular Medicine. 2020;98:245-61.
44. Baghadam M, Azizbeidi K, Baesi K. The Effect Of 8 Weeks Aerobic Training On Cardiac Pgc-1α And Plasma Irisin In Stz-Induced Diabetics’rats. Iranian Journal of Diabetes and Metabolism. 2019;18(5):228-35.[ In Persian]
45. 32.Orazizadeh M, Khorsandi L, Absalan F, Hashemitabar M, Daneshi E. Effect of beta-carotene on titanium oxide nanoparticles-induced testicular toxicity in mice. Journal of Assisted Reproduction and Genetics. 2014; 31(5):561-8.
46. 33.Ordoudi SA, Tsimidou MZ. Measuring antioxidant and prooxidant capacity using the Crocin bleaching assay (CBA). In: Armstrong D, editor. advanced protocols in oxidative stress iii. Methods in molecular biology. New York: Humana Press; 2015.
47. 34.Salem M, Shaheen M, Tabbara A, Borjac J. Saffron extract and Crocin exert anti-inflammatory and anti-oxidative effects in a repetitive mild traumatic brain injury mouse model. Scientific Reports. 2022; 12(1):5004.
48. 35.Goyal S, Arora S, Sharma A, Joshi S, Ray R, Bhatia J, et al. Preventive effect of Crocin of crocus sativus on hemodynamic, biochemical, histopathological and ultrastructural alterations in isoproterenol-induced cardiotoxicity in rats. Phytomedicine. 2010; 17(3-4):227-32.
49. 36- Radmanesh E, Dianat M, Badavi M, Goudarzi G, Mard SA, Radan M. Protective effect of crocin on hemodynamic parameters, electrocardiogram parameters, and oxidative stress in isolated hearts of rats exposed to PM10. Iran J Basic Med Sci. 2022 Apr;25(4):460-467.
50. 37- Munirah MP, Norhayati MN, Noraini M. Crocus Sativus for Insomnia: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2022 Sep 16;19(18):11658.
51. 38- Kocaman G, Altinoz E, Erdemli ME, Gul M, Erdemli Z, Zayman E, Bag HGG, Aydın T. Crocin attenuates oxidative and inflammatory stressrelated periodontitis in cardiac tissues in rats. Adv Clin Exp Med. 2021 May;30(5):517-524.
52. 39- Asghari N, Irani S, Pezeshki-Moddaress M, Zandi M, Mohamadali M. Neuronal differentiation of mesenchymal stem cells by polyvinyl alcohol/Gelatin/ crocin and beta-carotene. Mol Biol Rep. 2022 Apr;49(4):2999-3006.
53. 40- Peyravi A, Yazdanpanahi N, Nayeri H, Hosseini SA. The effect of endurance training with crocin consumption on the levels of MFN2 and DRP1 gene expression and glucose and insulin indices in the muscle tissue of diabetic rats. Journal of Food Biochemistry. 2020; 44(2):e13125.
54. Sato T, Esaki M, Fernandez JM, Endo T. Comparison of the protein-unfolding pathways between mitochondrial protein import and atomic-force microscopy measurements. Proc Natl Acad Sci USA 2005; 102: 17999-8004.
55. Corona JC, Duchen MR. PPARγ and PGC-1α as therapeutic targets in Parkinson's. Neurochemical research. Neurochem Res 2015;40(2):308-16.
56. Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 2006;30:145- 51.
57. Damirchi A, Ebadi B. The effects of the intensity of interval training on mitochondrial dynamics-related proteins in the heart of male rats with myocardial infarction. Journal of Applied Exercise Physiology 2019; 14(28): 159-172.
58. Ghalavand A, Delaramnasab M, Afshounpour M, Zare A. Effects of continuous aerobic exercise and circuit resistance training on fasting blood glucose control and plasma lipid profile in male patients with type II diabetes mellitus. Journal of diabetes and nursing. 2016;4(1):8-19.
59. Liu Y, Lormes W, Wang L, Reissnecker S, Steinacker JM. Different skeletal muscle Hsp70responses to highintensity strength training and low-intensity endurance training. Eur J Appl Physiol 2004; 91(2-3):330-5.
60. Zhu J., Quyyumi AA., WU H., Sako GC., Rott D., Zalles- Ganley A., et al. Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler Thromb Vasc Biol 2013; 23:1055- 1059.
61. Krause M, Heck TG, Bittencourt A, Scomazzon SP, Newsholme P, Curi R, et al. The chaperone balance hypothesis: the importance of the extracellular to intracellular HSP70 ratio to inflammation-driven type 2 diabetes, the effect of exercise, and the implications for clinical management. Mediators of inflammation. 2015;2015.
62. Molvarec A, Rigó J, Nagy B, Walentin S, Szalay J, Füst G, et al. Serum heat shock protein 70 levels are decreased in normal human pregnancy. Journal of reproductive immunology. 2007;74(1):163-9.
63. Chung J, Nguyen A-K, Henstridge DC, Holmes AG, Chan MS, Mesa JL, et al. HSP72 protects against obesity-induced insulin resistance. Proceedings of the National Academy of Sciences. 2008;105(5):1739-44.
64. Nakhjavani M, Morteza A, Khajeali L, Esteghamati A, Khalilzadeh O, Asgarani F, et al. Increased serum HSP70 levels are associated with the duration of diabetes. Cell Stress and Chaperones. 2010;15(6):959-64.
65. Gomez-Cabrera MC, Salvador-Pascual A, Cabo H, Ferrando B, Viña J. Redox modulation of mitochondriogenesis in exercise. Does antioxidant supplementation blunt the benefits of exercise training? Free Radic Biol Med. 2015; 86: 37-46.
66. Mahmudzadeh T, Saghebjoo M, Seghatol Eslami A, Hedayati M. Effect of aerobic training and pistacia atlantica extract consumption on pancreatic β-cells function in streptozotocin-induced diabetic rats. Iran J Diabetes Metab. 2014;13(3):252-62.
67. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brownfat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-8.
68. Woodhead JST, Merry TL. Mitochondrial-derived peptides and exercise. Biochim Biophys Acta Gen Subj. 2021;1865(12):130011.
69. Vettor R, Valerio A, Ragni M, Trevellin E, Granzotto M, Olivieri M, et al. Exercise Training Boosts Enos-Dependent Mitochondrial Biogenesis in Mouse Heart: Role in Adaptation of Glucose Metabolism. Am J Physiol-Endocrinol Metabol 2014; 306(5): E519-E28.
70. Huynh FK, Muoio DM, Hirschey MD. SIRT3 directs carbon traffic in muscle to promote glucose control. Diabetes. 2015;64(9):3058–60.
71. Tashakori Zade M, Mogharnasi M. A study of the effect of 10 weeks of resistance training on HSP70 and insulin resistance in type 2 diabetic women. J Sport Biosci. 2016;8(3):341–51.
72. Hosseini S E, Tavakoli F, Karami M. Medicinal Plants in the Treatment of Diabetes Mellitus. Clin Exc. 2014; 2 (2) :64-89
73. Hosseini S, Nikbakht H, Azarbayjani M. The Effect of Aqua Extract of Saffron with Resistance Training on Glycemic Indexes of Streptozotocin Induced Diabetic Rats. Armaghane danesh. 2013; 18 (4) :284-294.
74. Milajerdi A, Mahmoudi M. Review on the effects of saffron extract and its constituents on factors related to nervous system, cardiovascular and gastrointestinal diseases. Clin Exc. 2014; 3 (1) :108-127.
75. Sing Leung P. The potential of irisin as a therapeutic for diabetes. Future Med. Chem. 2017; 529–532.
76. Singla RK, Bhat VG. Crocin: an overview. Glo J Pharmaceu Sci 2011; 1: 281-6. 17. Bathaie SZ, Bolhassan A, Tamanoi F. Anticancer effect and molecular targets of saffron carotenoids. Enzymes 2014; 36: 57-86.
77. Hosseinzadeh, H., and Nassiri-Asl, M. 2013. Avicenna’s (Ibn Sina) the Canon of Medicine and Saffron (Crocus sativus L.): A Review. Phytotherapy Research 27:475-83.
78. Hosseinzadeh, H., and Nassiri-Asl, M. 2013. Avicenna’s (Ibn Sina) the Canon of Medicine and Saffron (Crocus sativus L.): A Review. Phytotherapy Research 27:475-83.
79. Kianbakht S, Hajiaghaee R. Anti-hyperglycemic effects of saffron and its Active constituents, Crocin and safranal, in alloxan-induced diabetic rats. J Med Plants 2011;10:39-45.
80. 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.
81. Loskutov AV, Beninger CW, Hosfield GL, Sink KC. Development of an improved procedure for extraction and quantitation of safranal in stigmas of Crocus sativus L. using high performance liquid chromatography. Food chem 2000;69:87-95.
82. Sadoughi SD.[Comparing the effect of safranal and crocin on serum levels of adiponectin, lipid profile and glucose in healthy and type one diabetic rats (Persian)]. Pars J Med Sci. 2017; 15(3):49-59.
83. Zar A, Hoseini SA, javedan F, Edalatmanesh MA. [Effect of 15 days cinnamon supplementation on hematocrit and blood pressure response in one session aerobic exercise (Persian)]. Complementary Medicine Journal. 2016; 6(3):1571-82.
84. Azarian F, Farsi S, Hosseini SA, Azarbayjani MA. The effect of endurance training and crocin consumption on anxiety-like behaviors and aerobic power in rats with alzheimer’s. Iranian Journal of Psychiatry and Behavioral Sciences. 2019; 13(4):e89011.
85. Hoseini A, Zar A, Mansouri A. [Effect of aloevera with swimming training on the alanine aminotransferase and aspartate aminotransferase levels of diabetic rats (Persian)]. Iranian Journal of Nutrition Sciences & Food Technology. 2017; 11(4):29-38.
86. Azarian F, Farsi S, Hosseini SA, Azarbayjani MA. Effect of endurance training with saffron consumption on PGC1-α gene expression in hippocampus tissue of rats with alzheimer’s disease. Annals of Military and Health Sciences Research. 2020; 18(1):e99131.
87. Sharma DR, Sunkaria A, Wani WY, Sharma RK, Verma D, Priyanka K, et al. Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway. Neurotoxicology. 2015;51:116-37.
88. Koral J, Oranchuk DJ, Herrera R, Millet GY. Six Sessions of Sprint Interval Training Improves Running Performance in Trained Athletes. conditioning research. 2018;32(3):617-23.
89. 47- Mallikarjuna K, Shanmugam KR, Nishanth K, Wu MC, Hou CW, Kuo CH, et al. Alcohol-induced deterioration in primary antioxidant and glutathione family enzymes reversed by exercise training in the liver of old rats. Alcohol 2010;44:523-9.
90. Moradi A, Hosseini SA, Nikbakht M. Effect of swimming training and crocin consumption on intrinsic apoptosis pathway in muscle tissue of high-fat diet-induced obese rats. Middle East J Rehabil Health Stud 2019: 31;6. (persian)
91. Hassanpour G, Azarbayjani MA, Shakeri N, Abednazari H. The Effect of Interval and Continued Trainings with Crocin on Apoptotic Markers in the Heart Tissue of High-Fat Diet and Streptozotocin Induced Type 2 Diabetic Rats. Rep Health Care 2017: 1;3:58-70. (persian)