Diabetes-induced testicular oxidative stress, inflammation, and caspase-dependent apoptosis: the protective role of metformin

Nna, Victor Udo; Bakar, Ainul Bahiyah Abu; Ahmad, Azlina; Mohamed, Mahaneem

doi:10.1080/13813455.2018.1543329

Cited by 52 publications

(40 citation statements)

References 52 publications

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“…Metformin also improved HFD-induced obesity and lipid metabolism by the downstream molecules of AMPK [ 56 ]. In addition, in contrast with the results of other studies [ 57 , 58 , 59 ], metformin treatment did not exert antiapoptotic or anti-inflammatory action in this obese rodent model due to the elevations of apoptosis and inflammation mediators. Examination of a model of autoimmune orchitis (chronic inflammation and infertility) suggested that increasing the content of TNF-α may induce apoptosis of sperm [ 60 ].…”

Section: Discussioncontrasting

confidence: 99%

Metformin Ameliorates Testicular Function and Spermatogenesis in Male Mice with High-Fat and High-Cholesterol Diet-Induced Obesity

et al. 2020

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The aim of this study was to investigate the effects of metformin supplementation on metabolic dysfunction, testicular antioxidant capacity, apoptosis, inflammation and spermatogenesis in male mice with high-fat and high-cholesterol diet-induced obesity. Forty male C57BL/6 mice were fed a normal diet (NC group, n = 10) or a high-fat and high-cholesterol diet (HFC group, n = 30) for 24 weeks, and mice randomly chosen from the HFC group were later treated with metformin for the final 8 weeks of HFC feeding (HFC + Met group, n = 15). Compared with the HFC group, the obese mice supplemented with metformin exhibited improved blood cholesterol, glucose and insulin resistance. The HFC group diminishes in the sperm motility and normal sperm morphology, while the poorer maturity of testicular spermatogenesis was improved by metformin treatment. The HFC group exhibited a higher estradiol level and a lower 17β-HSD protein expression. Further analyses showed that metformin treatment increased the activities of superoxide dismutase, catalase and glutathione peroxidase and reduced lipid peroxidation. Nevertheless, both the HFC and HFC + Met groups exhibited increased expressions of apoptosis and inflammation proteins in the testis. Metformin treatment ameliorated obesity-induced poor testicular spermatogenesis and semen quality through increasing the testosterone level and antioxidant capacity.

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Section: Discussioncontrasting

confidence: 99%

Metformin Ameliorates Testicular Function and Spermatogenesis in Male Mice with High-Fat and High-Cholesterol Diet-Induced Obesity

et al. 2020

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“…It has been reported that testicular germ cells are more susceptible to oxidative damage than somatic cells, because their plasma membrane contains more polyunsaturated fatty acids which are prone to oxidation by free radicals [59]. Therefore, excessive generation of ROS at a rate that outweighs the antioxidant defence system, as observed in DM, and the resulting oxidative stress, triggers germ cell death [6], thus impacting negatively on spermatogenesis and fertility potential [2]. Beyond the testes, oxidative stress may impact negatively on mature spermatozoa in the epididymis during storage.…”

Section: Discussionmentioning

confidence: 99%

“…For each rat, 20 round seminiferous tubules were randomly selected, and their diameters and epithelial heights were measured at ×100 magnification using Image Analyser software (Soft Imaging System, VGA Utilities version 3.67e, Tokyo, Japan). Further, we examined 200 seminiferous tubules for assessment on germ cells loss (either focal or complete) using the ×10 objective, and the result was expressed as a percentage of the total number (200) of seminiferous tubules examined [2,6].…”

Section: Methodsmentioning

confidence: 99%

“…Five micrometre thick testis sections were employed for immunohistochemistry as per our previously described protocol [6]. Heat-mediated antigen retrieval was performed for 5 min, using a pressure cooker containing Tris-EDTA buffer with 0.05% tween 20 (pH 9.0).…”

Section: Methodsmentioning

confidence: 99%

“…In fact, in our previous studies, we found that not only did DM increase testicular oxidative stress [6], but it also increased oxidative stress in the cauda epididymis [2], thus exposing the stored spermatozoa to further risk of oxidative stress. Particularly, down-regulation of nuclear factor erythroid 2-related factor 2/antioxidant response elements (Nrf2/ARE) and up-regulation of nuclear factor kappa B (NF-κB)-mediated inflammation have been reported in the testes of diabetic rats [3,6,7,8].…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Stress, NF-κB-Mediated Inflammation and Apoptosis in the Testes of Streptozotocin–Induced Diabetic Rats: Combined Protective Effects of Malaysian Propolis and Metformin

et al. 2019

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Oxidative stress, inflammation and apoptosis are major complications that trigger organ failure in diabetes mellitus (DM), and are proven to adversely affect the male reproductive system. Clinical and experimental studies have demonstrated the promising protective effects of propolis in DM and its associated systemic effects. Herein, we investigated the effect of Malaysian propolis (MP) on testicular oxidative stress, inflammation and apoptosis in diabetic rats. Further, the possibility of a complementary effect of MP with the anti-hyperglycaemic agent, metformin (Met), was studied with the idea of recommending its use in the event that Met alone is unable to contain the negative effects of DM on the male reproductive system in mind. Male Sprague-Dawley rats were either gavaged distilled water (normoglycaemic control and diabetic control groups), MP (diabetic rats on MP), Met (diabetic rats on Met) or MP+Met (diabetic rats on MP+Met), for 4 weeks. MP decreased oxidative stress by up-regulating (p < 0.05) testicular mRNA levels of nuclear factor erythroid 2-related factor 2, superoxide dismutase, catalase and glutathione peroxidase; increasing (p < 0.05) the activities of antioxidant enzymes; and decreasing (p < 0.05) lipid peroxidation in the testes and epididymis of diabetic rats. Further, MP down-regulated (p < 0.05) testicular mRNA and protein levels of pro-inflammatory mediators (nuclear factor kappa B, inducible nitric oxide synthase, tumour necrosis factor-α and interleukin (IL)-1β), decreased (p < 0.05) the nitric oxide level, and increased (p < 0.05) IL-10 mRNA and protein levels. MP also down-regulated (p < 0.05) Bax/Bcl-2, p53, casapase-8, caspase-9 and caspase-3 genes, and increased (p < 0.05) testicular germ cell proliferation. MP’s effects were comparable to Met. However, the best results were achieved following co-administration of MP and Met. Therefore, we concluded that administration of the MP+Met combination better attenuates testicular oxidative stress, inflammation and apoptosis in DM, relative to MP or Met monotherapy, and may improve the fertility of males with DM.

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The protective effect of metformin against testicular damage in diabetes and prostate cancer model

Aydın

Karabulut-Bulan

Bugan

et al. 2021

Cell Biochemistry & Function

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Individuals with diabetes have an increased risk of breast, colorectal, pancreatic and prostate cancer. Metformin, an oral biguanide used to treat diabetes, has anti-hyperglycaemic, anti-hyperinsulinemic and antioxidant activities. The effects of metformin on testicular tissue damage in cancer and diabetic + cancer rat models were evaluated histologically, immunohistochemically and biochemically. The diabetic model was produced in Copenhagen rats using a single dose of streptozotocin (65 mg/kg), while prostate cancer was induced through subcutaneous inoculation of 2 Â 10 4 Mat-LyLu cells into the animals. At the end of the experimental period, testicular tissues with a close functional relationship to the prostate were collected. Histological evaluation found moderate to severe damage to testes following the diabetes and cancer process. Histopathological and biochemical impairments were observed in the early stage of prostate cancer, which were increased in the diabetic animals. Metformin administration reversed these injuries and provided substantial protection of the testes. In particular, metformin had protective effects on tissue damage, apoptosis, oxidative stress and antioxidant capacity. This suggests that metformin should be further investigated as a targeted protective drug against prostate cancer-related damage to the testes.

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Diabetes-induced testicular oxidative stress, inflammation, and caspase-dependent apoptosis: the protective role of metformin

Cited by 52 publications

References 52 publications

Metformin Ameliorates Testicular Function and Spermatogenesis in Male Mice with High-Fat and High-Cholesterol Diet-Induced Obesity

Metformin Ameliorates Testicular Function and Spermatogenesis in Male Mice with High-Fat and High-Cholesterol Diet-Induced Obesity

Oxidative Stress, NF-κB-Mediated Inflammation and Apoptosis in the Testes of Streptozotocin–Induced Diabetic Rats: Combined Protective Effects of Malaysian Propolis and Metformin

The protective effect of metformin against testicular damage in diabetes and prostate cancer model

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