Antioxidant, anti-apoptotic, and protective effects of myricitrin and its solid lipid nanoparticle on streptozotocin-nicotinamide-induced diabetic nephropathy in type 2 diabetic male mice

Document Type : Original Article


1 Department of Physiology, Faculty of Medicine, Diabetes Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Physiology, Faculty of Medicine, Cellular and Molecular Research Center, Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Physiology, Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran

4 Department of Anatomical Sciences, Faculty of Medicine, Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

5 Department of Pharmaceutics, Faculty of Pharmacy, Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

6 Department of Physiology, Faculty of Medicine, Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Objective(s): The present study evaluates the protective effects of myricitrin and its solid lipid nanoparticle (SLN) on diabetic nephropathy (DN) induced by streptozotocin-nicotinamide (STZ-NA) in mice.
Materials and Methods: In this experimental study, 108 adult male NMRI mice were divided into 9 groups: control, vehicle, diabetes, diabetes + myricitrin 1, 3, and 10 mg/kg and, diabetes + SLN containing myricitrin 1, 3, and 10 mg/kg. After the experimental period, the plasma and tissue samples were collected for experimental, histopathological, real-time PCR and apoptosis assessments.
Results: Total antioxidant capacity, catalase, glomerular filtration rate, plasma level of albumin, urine (BUN) and, creatinine (Cr) levels decreased, and the kidney weight, intake/output, malondialdehyde, plasma level of BUN and Cr, urine level of sodium, potassium, albumin and glucose, fractional excretions of sodium and potassium, transforming growth factor-β (TGF-β) and nuclear factor kappa B (NF-κB) gene expression, red blood cell accumulation and infiltration of inflammatory cells, and kidney apoptosis increased in untreated diabetic mice compared to the control group, and administration of myricitrin and its SLN recovered all of these changes.
Conclusion: Ultimately, myricitrin and its SLN administration improved DN changes by reducing oxidative stress and increasing antioxidant enzymes level, and these effects were more prominent in the SLN-administered mice.


1. Sagoo MK, Gnudi L. Diabetic nephropathy: is there a role for oxidative stress? free radical biology and medicine 2018.
2. Kandhare AD, Mukherjee A, Bodhankar SL. Antioxidant for treatment of diabetic nephropathy: A systematic review and meta-analysis. Chem Biol Interact 2017; 278:212-221.
3. Qi W, Chen X, Zhang Y, Holian J, Mreich E, Gilbert RE, et al. High glucose induces macrophage inflammatory protein--3α in renal proximal tubule cells via a transforming growth factor-β1 dependent mechanism. Nephrol Dial Transplant 2007; 22:3147-3153.
4. Kaur N, Kishore L, Singh R. Dillenia indica L. Attenuates diabetic nephropathy via inhibition of advanced glycation end products accumulation in STZ-nicotinamide induced diabetic rats. J Tradit Complement Med 2018; 8:226-238.
5. Zhang B, Shen Q, Chen Y, Pan R, Kuang S, Liu G, et al. Myricitrin alleviates oxidative stress-induced inflammation and apoptosis and protects mice against diabetic cardiomyopathy. Sci Rep 2017; 7:44239-44239.
6. Lei Y. Myricitrin decreases traumatic injury of the spinal cord and exhibits antioxidant and anti-inflammatory activities in a rat model via inhibition of COX-2, TGF-β1, p53 and elevation of Bcl-2/Bax signaling pathway. Mol Med Rep 2017; 16:7699-7705.
7. Abourashed EA. Bioavailability of plant-derived antioxidants. Antioxidants 2013; 2:309-325.
8. Tan M-e, He C-h, Jiang W, Zeng C, Yu N, Huang W, et al. Development of solid lipid nanoparticles containing total flavonoid extract from dracocephalum moldavica L. and their therapeutic effect against myocardial ischemia-reperfusion injury in rats. Int J Nanomedicine 2017; 12:3253.
9. Palsamy P, Subramanian S. Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochim Biophys Acta 2011; 1812:719-731.
10. Ghasemi A, Khalifi S, Jedi S. Streptozotocin-nicotinamide-induced rat model of type 2 diabetes. Acta Physiol Hung 2014; 101:408-420.
11. Ahangarpour A, Oroojan AA, Khorsandi L, Kouchak M, Badavi M. Solid lipid nanoparticles of myricitrin have antioxidant and antidiabetic effects on streptozotocin-nicotinamide-induced diabetic model and myotube cell of male mouse. Oxid Med Cell Longev 2018; 2018:7496936-7496936.
12. Ahangarpour A, Oroojan AA, Khorsandi L, Arzani G, Afshari G. Effects of betulinic acid on the male reproductive system of a streptozotocin-nicotinamide-induced diabetic mouse model. World J Mens Health 2016; 34:209-216.
13. Schwanke RC, Marcon R, Meotti FC, Bento AF, Dutra RC, Pizzollatti MG, et al. Oral administration of the flavonoid myricitrin prevents dextran sulfate sodium-induced experimental colitis in mice through modulation of PI3K/Akt signaling pathway. Mol Nutr Food Res 2013; 57:1938-1949.
14. Balarini CM, Oliveira MZT, Pereira TMC, Silva NF, Vasquez EC, Meyrelles SS, et al. Hypercholesterolemia promotes early renal dysfunction in apolipoprotein E-deficient mice. Lipids Health Dis 2011; 10:220-220.
15. Sharma P, Singh R. Effect of momordica dioica fruit extract on antioxidant status in liver, kidney, pancreas, and serum of diabetic rats. Pharmacognosy Res 2014; 6:73-79.
16. Matthesen SK, Larsen T, Vase H, Lauridsen TG, Jensen JM, Pedersen EB. Effect of amiloride and spironolactone on renal tubular function and central blood pressure in patients with arterial hypertension during baseline conditions and after furosemide: a double-blinded, randomized, placebo-controlled crossover trial. Clin Exp Hypertens 2013; 35:313-324.
17. Son MJ, Miura Y, Yagasaki K. Mechanisms for antidiabetic effect of gingerol in cultured cells and obese diabetic model mice. Cytotechnology 2015; 67:641-652.
18. Cui X, Zhou J, Qiu J, Johnson MR, Mrug M. Validation of endogenous internal real-time PCR controls in renal tissues. Am J Nephrol 2009; 30:413-417.
19. Orazizadeh M, Hashemitabar M, Khorsandi L. Protective effect of minocycline on dexamethasone induced testicular germ cell apoptosis in mice. Eur Rev Med Pharmacol Sci 2009; 13:1-5.
20. Sheela N, Jose MA, Sathyamurthy D, Kumar BN. Effect of silymarin on streptozotocin-nicotinamide-induced type 2 diabetic nephropathy in rats. Iran J Kidney Dis 2013; 7:117.
21. Ozougwu J, Obimba K, Belonwu C, Unakalamba C. The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J Physiol Pathophysiol 2013; 4:46-57.
22. Zitouni K, Nourooz-Zadeh J, Harry D, Kerry SM, Betteridge DJ, Cappuccio FP, et al. Race-specific differences in antioxidant enzyme activity in patients with type 2 diabetes: a potential association with the risk of developing nephropathy. Diabetes Care 2005; 28:1698-1703.
23. Procházková D, Boušová I, Wilhelmová N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia 2011; 82:513-523.
24. Dabla PK. Renal function in diabetic nephropathy. World J Diabetes 2010; 1:48.
25. Sitholay PA, Agnihotri MA, Ambad RS. Study of renal function and serum electrolyte in type-2 DM.  Int J Innov Res Med Sci 2017; 2:1149-1153.
26. Datchinamoorthi S, Vanaja R, Rajagopalan B. Evaluation of serum electrolytes in type II diabetes mellitus. Int J Pharm Sci Rev Res 2016; 40:251-253.
27. Schreuder MF, Bökenkamp A, van Wijk JA. Interpretation of the fractional excretion of sodium in the absence of acute kidney injury: A cross-sectional study. Nephron 2017; 136:221-225.
28. Xu ZJ, Shu S, Li ZJ, Liu YM, Zhang RY, Zhang Y. Liuwei dihuang pill treats diabetic nephropathy in rats by inhibiting of TGF-β/SMADS, MAPK, and NF-kB and upregulating expression of cytoglobin in renal tissues. Medicine 2017; 96.
29. Zou J, Yu X, Qu S, Li X, Jin Y, Sui D. Protective effect of total flavonoids extracted from the leaves of Murraya paniculata (L.) jack on diabetic nephropathy in rats. Food Chem Toxicol 2014; 64:231-237.
30. An Y, Xu F, Le W, Ge Y, Zhou M, Chen H, et al. Renal histologic changes and the outcome in patients with diabetic nephropathy. Nephrol Dial Transplant 2014; 30:257-266.
31. Gumustekin M, Tekmen I, Guneli E, Tugyan K, Topcu A, Ergonen A, et al. Short-term melatonin treatment improved diabetic nephropathy but did not affect hemorheological changes in diabetic rats. Die Pharmazie 2007; 62:693-698.
32. Miyajima A, Chen J, Poppas DP, Vaughan ED, Felsen D. Role of nitric oxide in renal tubular apoptosis of unilateral ureteral obstruction. Kidney Int 2001; 59:1290-1303.
33.Sun J, Sun G, Cui X, Meng X, Qin M, Sun X. Myricitrin protects against doxorubicin-induced cardiotoxicity by counteracting oxidative stress and inhibiting mitochondrial apoptosis via ERK/P53 pathway. Evid Based Complement Alternat Med 2016; 2016:6093783.