Effect of 5, 6-dihydrocyclopenta-1, 2-dithiole-3-thione on the expression of nuclear factor erythroid 2-related factor 2 and hemeoxygenase-1 in retina of type 2 diabetic rats_Chinese Journal of Ocular Fundus Diseases

Authors：

TianMin , ZhouQi ,  LyuHongbin , 李友谊 , 何跃 , 欧阳科

Department of Ophthalmology, The Affiliated Hospital of Luzhou Medical College, Luzhou 646000, China;

Corresponding author：

LyuHongbin, Email: oculistlvhongbin@163.com

Keywords：

Diabetic retinopathy/pathophysiology; NF-E2-related factor 2; Heme oxygenase (decyclizing)

DOI：

10.3760/cma.j.issn.1005-1015.2014.02.016

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Objective To observe the effect of phase Ⅱenzyme inducer 5, 6-dihydrocyclopenta 1, 2-dithiole-3-thione (CPDT) on nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signal pathway and oxidative stress in the retina of type 2 diabetic rats. Methods Thirty-five male Wistar rats were randomly divided into two group, normal group and model group. Model group were further randomly divided into two group, diabetic group and CPDT intervention group. There were 8 rats in the normal group and 27 rats in the model group. Diabetic group and CPDT intervention group were given high fat and high sugar diet for 2 months. After 12 hours of fasting, type 2 diabetic rat model was induced by intraperitoneal injection of low dose of streptozotocin. CPDT was added into the high fat and high sugar diets at 1 week after the diabetic model was established in the CPDT intervention group. Eight weeks after CPDT treatment, blood glucose, serum malondialdehyde (MDA), blood lipid, Nrf2 and hemeoxygenase-1 (HO-1) expression were evaluated. Results Type 2 diabetic model was successfully established in 25 rats, the success rate was 92.6%.The level of blood lipid of diabetic group was higher than those of the normal group (F_TC=65.866, F_TG=25.441, F_LDL-C=38.889; P=0.000). Blood glucose was significant different between all groups (χ²=25.812, P=0.000), and was significantly higher in diabetic group than that in normal group and CPDT intervention group. The serum MDA content was significant different between all groups (F=59.545, P=0.000), and was significantly higher in diabetic group than that in normal group (t=10.523, P=0.000) and CPDT intervention group (t=7.766, P=0.000). The mRNA level of retinal Nrf2 and HO-1 was significant different between all groups (F_Nrf2=19.503, P_Nrf2=0.000;F_HO-1=9.737, P_HO-1=0.001), and was higher in CPDT intervention group than the diabetic group (t_Nrf2=3.399, P_Nrf2=0.002;t_HO-1=2.167, P_HO-1=0.039). The protein level of retinal Nrf2 and HO-1 was significant different between all groups (F_Nrf2=112.823, F_HO-1=119.361; P=0.000), and was higher in CPDT intervention group than the diabetic group (t_Nrf2=6.203, t_HO-1=6.388; P=0.000). Immuno-staining showed that Nrf2 and HO-1 were mainly expressed in retinal ganglion cell layer, inner plexiform layer and inner nuclear layer, and were significant different between all groups (F_Nrf2=16.206, F_HO-1=46.790; P=0.000). They also were higher in CPDT intervention group than the diabetic group (t_Nrf2=3.172, P_Nrf2=0.003;t_HO-1=6.321, P_HO-1=0.000), was higher in diabetic group than that in normal group (t_Nrf2=2.679, P_Nrf2=0.011;t_HO-1=3.482, P_HO-1=0.001). Conclusion CPDT may activate Nrf2/ARE pathway, induce Nrf2 and HO-1 expression, decrease serum MDA and blood glucose, and thus reduce oxidative stress injury in the retina of type 2 diabetic rats.

Citation： TianMin, ZhouQi, LyuHongbin. Effect of 5, 6-dihydrocyclopenta-1, 2-dithiole-3-thione on the expression of nuclear factor erythroid 2-related factor 2 and hemeoxygenase-1 in retina of type 2 diabetic rats. Chinese Journal of Ocular Fundus Diseases, 2014, 30(2): 187-192. doi: 10.3760/cma.j.issn.1005-1015.2014.02.016 Copy

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1. Ceriello A. New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy[J]. Diabetes Care, 2003, 26:1589-1596.
2. Yu X, Kensler T. Nrf2 as a target for cancer chemoprevention[J]. Mutat Res, 2005, 591:93-102.
3. Xu Z, Wei Y, Gong J, et al. NRF2 plays a protective role in diabetic retinopathy in mice[J]. Diabetologia, 2014, 57:204-213.
4. Munday R, Zhang Y, Munday CM, et al. Structure-activity relationships in the induction of phase Ⅱ enzymes by derivatives of 3H-1, 2-dithiole-3-thione in rats[J]. Chem Biol Interact, 160:115-122.
5. Fan J, Xu G, Jiang T, et al. Pharmacologic induction of heme oxygenase-1 plays a protective role in diabetic retinopathy in rats[J]. Invest Ophthalmol Vis Sci, 2012, 53:6541-6556.
6. 牛俊, 皮子凤, 越皓, 等.格列美脲治疗的2型糖尿病大鼠的尿液代谢组学研究[J].高等学校化学学报, 2012, 33:2169-2172.
7. 李宏, 孙琦, 张云, 等.选择性腺苷A2BAR短期治疗糖尿病大鼠模型对胰岛素敏感性的影响[J].中国医学科学院学报, 2010, 32:222-224.
8. 姜兆顺, 赵建芹, 刘元涛, 等.舒洛地特对糖尿病大鼠肾脏病变的保护作用与机制探讨[J].中华肾脏病杂志, 2012, 28:138-142.
9. Liu XY, Li CY, Bu H, et al. The neuroprotective potential of phase Ⅱ enzyme inducer on motor neuron survival in traumatic spinal cord injury in vitro[J]. Cell Mol Neurobiol, 2008, 28:769-779.
10. Li H, Zhang L, Wang F, et al. Attenuation of glomerular injury in diabetic mice with tert-butylhydroquinone through nuclear factor erythroid 2-related factor 2-dependent antioxidant gene activation[J]. Am J Nephrol, 2011, 33:289-297.
11. 谢琳, 唐仕波, 史煜, 等.线粒体DNA氧化损伤对糖尿病大鼠视网膜血管的影响[J].中华眼底病杂志, 2013, 29:30-34.
12. 张民英, 吴晓燕, 王亚冬, 等.αA-晶体蛋白在2型糖尿病大鼠神经视网膜的异常表达[J].中华眼底病杂志, 2010, 26:160-164.
13. Keum YS, Yu S, Chang PP, et al. Mechanism of action of sulforaphane:inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells[J]. Cancer Res, 2006, 66:8804-8813.
14. Kang KW, Lee SJ, Park JW, et al. Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress[J]. Mol Pharmacol, 2002, 62:1001-1010.
15. Stentz FB, Umpierrez GE, Cuervo R, et al. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises[J]. Diabetes, 2004, 53:2079-2086.
16. Kim J, Cha YN, Surh YJ. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders[J]. Mutat Res, 2010, 690:12-23.
17. Wang X, Ye XL, Liu R, et al. Antioxidant activities of oleanolic acid in vitro:possible role of Nrf2 and MAP kinases[J]. Chem Biol Interact, 2010, 184:328-337.

Chinese Journal of Ocular Fundus Diseases

Effect of 5, 6-dihydrocyclopenta-1, 2-dithiole-3-thione on the expression of nuclear factor erythroid 2-related factor 2 and hemeoxygenase-1 in retina of type 2 diabetic rats

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