Genistein preserves the lungs of ovariectomized diabetic rats: addition to apoptotic and inflammatory markers in the lung

Document Type : Original Article


1 Tuberculosis and Lung Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Department of Histology & Embryology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

3 Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

4 Department of Physiology, Hamadan University of Medical Sciences, Hamadan, Iran


Objective(s): The role of isoflavones in pulmonary structure and function during menopause is not well studied. Moreover, the important role of estrogen in the physiological function of respiratory system has been revealed. Genistein, as an isoflavone, mimics estrogenic in diabetic and ovariectomized rats. Here, we hypothesized that genistein would reverse changes in the protein expression levels related to estrogen deficiency in the lung of ovariectomized diabetic rats.
Materials and Methods: Wistar female rats were assigned to four experimental groups (n=10 in each group): sham, rats underwent laparotomy without removing the ovaries; OVX, rats that underwent ovariectomy; OVX.D, rats underwent bilateral ovariectomy and were fed a high-fat diet (HFD); OVX.D.G, ovariectomized diabetic rats with genistein administration (1 mg/kg /day). After ovariectomy, rats continued to feed HFD for a 4-week period. After 4 weeks of HFD feeding, a single dose of 30 mg/kg of streptozotocin was administered in the diabetic group. Genistein was administered for eight weeks. At the end of the experiment, lung tissue was removed and Western blotting technique and hematoxylin-eosin staining were used for evaluation of the lung.
Results: Treatment with genistein significantly decreased inflammatory and apoptotic biomarkers in the ovariectomized diabetic rats compared to non-treated animals (P<0.05). Also, genistein exerted a protective effect in the lung architecture.
Conclusion: Genistein partly reversed ovariectomy-induced changes in apoptotic and inflammatory biomarkers in the lung. Our data suggest that genistein treatment as a natural replacement therapy may prevent the estrogen deficiency effects in the lung of diabetic menopausal women.


1. Sandler M. Is the lung a'target organ'in Diabetes mellitus? Arch Intern Med 1990; 150:1385-1388.
2. Goldman MD. Lung dysfunction in diabetes. Diabetes Care 2003; 26:1915-1918.
3. van den Borst B, Gosker HR, Zeegers MP, Schols AM. Pulmonary function in diabetes: a metaanalysis. Chest 2010; 138:393-406.
4. Wu J, Jin Z, Yan L-J. Redox imbalance and mitochondrial abnormalities in the diabetic lung. Redox Biol 2017; 11:51-59.
5. Dennis RJ, Maldonado D, Rojas MX, Aschner P, Rondón M, Charry L, et al. Inadequate glucose control in type 2 diabetes is associated with impaired lung function and systemic inflammation: a cross-sectional study. BMC Pulm Med 2010; 10:38.
6. Glassberg MK, Choi R, Manzoli V, Shahzeidi S, Rauschkolb P, Voswinckel R, et al. 17β-estradiol replacement reverses age-related lung disease in estrogen-deficient C57BL/6J mice. Endocrinology 2014; 155:441-448.
7. Massaro D, Massaro GD. Estrogen regulates pulmonary alveolar formation, loss, and regeneration in mice. Am J Physiol Lung Cell Mol Physiol 2004; 287:L1154-L9.
8. Bitoska I, Krstevska B, Milenkovic T, Subeska-Stratrova S, Petrovski G, Mishevska SJ, et al. Effects of hormone replacement therapy on insulin resistance in postmenopausal diabetic women. Open Access Maced J Med Sci 2016; 4:83-88.
9. Chen C-L, Weiss NS, Newcomb P, Barlow W, White E. Hormone replacement therapy in relation to breast cancer. Jama 2002; 287:734-741.
10. Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, et al. Hormone replacement therapy and cardiovascular disease. Circulation 2001; 104:499-503.
11. Serock MR, Wells AK, Khalil RA. Modulators of vascular sex hormone receptors and their effects in estrogen-deficiency states associated with menopause. Recent Pat Cardiovasc Drug Discov 2008; 3:165-86.
12. Stephenson T, Setchell K, Kendall C, Jenkins D, Anderson J, Fanti P. Effect of soy protein-rich diet on renal function in young adults with insulin-dependent diabetes mellitus. Clin Nephrol 2005; 64: 1-11.
13. Zhao L, Wang Y, Liu J, Wang K, Guo X, Ji B, et al. Protective effects of genistein and puerarin against chronic alcohol-induced liver injury in mice via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. J Agric Food Chem 2016; 64:7291-7297.
14. Yousefi H, Alihemmati A, Karimi P, Alipour MR, Habibi P, Ahmadiasl N. Effect of genistein on expression of pancreatic SIRT1, inflammatory cytokines and histological changes in ovariectomized diabetic rat. Iran J Basic Med Sci 2017; 20:423-429.
15. Irigoyen M-C, Paulini J, Flores LJ, Flues K, Bertagnolli M, Moreira ED, et al. Exercise training improves baroreflex sensitivity associated with oxidative stress reduction in ovariectomized rats. Hypertension 2005; 46:998-1003.
16. Srinivasan K, Ramarao P. Animal models in type 2 diabetes research: an overview. Indian J Med Res 2007; 125:451-472.
17. Su X, Meng X, Sun C, Liu L, Su B. Intramuscular injection of soluble receptor for advanced glycation endproducts expression vector prevents the development of streptozotocinā€induced diabetes mellitus in rats on high fat diet. J diabetes 2011; 3:309-316.
18. Matori H, Umar S, Nadadur RD, Sharma S, Partow-Navid R, Afkhami M, et al. Genistein, a soy phytoestrogen, reverses severe pulmonary hypertension and prevents right heart failure in rats. Hypertension 2012; 60: 425-430.
19. Faramoushi M, Sasan RA, Sarraf VS, Karimi P. Cardiac fibrosis and down regulation of GLUT4 in experimental diabetic cardiomyopathy are ameliorated by chronic exposures to intermittent altitude. JCVTR 2016; 8:26-33.
20. Elfattah LIA. A comparative study between the effects of dietary soya and estrogen replacement therapy on the lung of ovariectomized albino rats: histological and immunohistochemical study. Egyptian Journal of Histology 2012; 35:34-42.
21. Zhang X, Shan P, Sasidhar M, Chupp GL, Flavell RA, Choi AM, et al. Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium. Am J Respir Cell Mol Biol 2003; 28:305-315.
22. Rayappa SP, Kowluru RA. Role of Raf-1 kinase in diabetes-induced accelerated apoptosis of retinal capillary cells. Int J Biomed Sci 2008; 4:20-28.
23. Zhuang S, Yan Y, Daubert RA, Han J, Schnellmann RG. ERK promotes hydrogen peroxide-induced apoptosis through caspase 3 activation and inhibition of Akt in renal epithelial cells. Am J Physiol Renal Physiol 2007; 292:F440-F447.
24. Tanaka Y, Nakayamada S, Fujimoto H, Okada Y, Umehara H, Kataoka T, et al. H-Ras/mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts. J Biol Chem 2002; 277:21446-21452.
25. Guo J, Gu N, Chen J, Shi T, Zhou Y, Rong Y, et al. Neutralization of interleukin-1 beta attenuates silica-induced lung inflammation and fibrosis in C57BL/6 mice. Arch Toxicol 2013; 87:1963-1973.
26. Falk R, Hacham M, Nyska A, Foley JF, Domb AJ, Polacheck I. Induction of interleukin-1β, tumour necrosis factor-α and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan. J Antimicrob Chemother  2005; 55:713-720.
27. Gurjar MV, Deleon J, Sharma RV, Bhalla RC. Role of reactive oxygen species in IL-1β-stimulated sustained ERK activation and MMP-9 induction. Am J Physiol Heart Circ Physiol 2001; 281:H2568-H2574.
28. Carmo A, Cunha-Vaz J, Carvalho A, Lopes M. L-arginine transport in retinas from streptozotocin diabetic rats: correlation with the level of IL-1β and NO synthase activity. Vision Res 1999; 39:3817-3823.
29. Kim MJ, Lim Y. Protective effect of short-term genistein supplementation on the early stage in diabetes-induced renal damage. Mediators Inflamm 2013; 2013: 510212.
30. Elmarakby AA, Ibrahim AS, Faulkner J, Mozaffari MS, Liou GI, Abdelsayed R. Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. Vascul Pharmacol 2011; 55:149-156.
31. Zhong W-W, Liu Y, Li C-L. Mechanisms of genistein protection on pancreas cell damage in high glucose condition. Intern Med 2011; 50:2129-2134.