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In this study, both diabetes and Dunning prostate cancer were induced for the first time in Copenhagen rats in vivo. Thus, the effects of metformin against heart tissue damage of these rats were investigated by biochemical methods. Dunning prostate cancer was induced in Copenhagen rats using high metastatic MAT-LyLu cells. The rats were divided as follows: Control group: only injected with 0.9% NaCl for 14 days; Diabetic group: only injected single dose of streptozotocin (STZ) (65 mg/kg); Cancer group: subcutaneously (s.c) inoculated with 2 x 104 MAT-LyLu cells only; Diabetic + cancer (DC) group: inoculated with 2 x 104 MAT-LyLu cells and STZ injection, Cancer + metformin (CM) group: injected with metformin for 14 days after Mat-LyLu cells application; Diabetic + cancer + metformin (DCM) group: metformin administered for 14 days together with STZ and Mat-LyLu cells. At the end of the experimental period, heart tissues were taken. Reduced glutathione and total antioxidant status levels in heart tissues were decreased, whereas lipid peroxidation, advanced oxidized protein products, nitric oxide, homocysteine, and reactive oxygen species levels, total oxidant status and catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and xanthine oxidase activities increased in the diabetic, cancer and DC groups. Treatment with metformin reversed these effects. In conclusion, the present study shows that metformin has a protective effect against heart tissue damage in STZ-induced diabetic rats with Dunning prostate cancer.

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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The body can host the spread of prostate cancer cells. Metastases from prostate cancer are more frequently seen in the brain, liver, lungs, and lymph nodes. A well‐known antidiabetic drug, metformin, is also known to have antitumor effects. Our study focuses on the evaluation of potential metformin protective effects on brain and cerebellum damage in streptozotocin (STZ)‐induced diabetic and Dunning prostate cancer models. In this investigation, six groups of male Copenhagen rats were created: control, diabetic (D), cancer (C), diabetic + cancer (DC), cancer + metformin, and diabetic + cancer + metformin. The brain and cerebellum tissues of the rats were taken after sacrifice. Oxidative stress markers including reduced glutathione level, lipid peroxidation, glutathione reductase, glutathione peroxidase, glutathione‐S‐transferase, catalase, superoxide dismutase activities, reactive oxygen species, total oxidant and total antioxidant status, lactate dehydrogenase, xanthine oxidase, acetylcholinesterase activities, protein carbonyl contents, nitric oxide and OH‐proline levels, sodium potassium ATPase, carbonic anhydrase, and glucose‐6‐phosphate dehydrogenase activities; glycoprotein levels including hexose, hexosamine, fucose, and sialic acid levels; and histone deacetylase activity as a cancer marker were determined. Oxidative stress markers were impaired and glycoprotein levels and histone deacetylase activity were increased in the D, C, and DC groups. Metformin therapy reversed these effects. Metformin was found to protect the brain and cerebellum of STZ‐induced diabetic rats with Dunning prostate cancer from harm caused by MAT‐Lylu metastatic cells.

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Diabetes is a chronic metabolic disease which lasts for the whole life. Cancer is the second cause of death in the world, according to World Health Organization data. Association of diabetes with cancer is a major health concern. Diabetes and cancer is a serious metabolic disorder with many functional and structural complications as well as having a significant impact both directly and indirectly on all systems (1). Prostate cancer has a great importance for male morbidity and mortality observed both in our country and also in the globe. It is at the second rank among cancer‐related mortality cases. Prostate cancer can be determined as the alteration of the balance between cell proliferation and cell death in the prostate which causes a malign increase of the organ volume. Dunning prostate cancer model is formed by subcutaneous injection of strongly metastatic MAT‐Lylu cells in a Copenhagen rats (2). Experimental diabetes model is widely induced by streptozotocin (STZ). Metformin is a drug that used for the treatment of type 2 diabetes. Besides, the studies related to reduce the risk of cancer of the metformin have recently drawn attention (3). The aim of this study is to investigate the role of metformin on testicular damage in diabetic+prostate cancer model. Male Copenhagen rats were divided into three groups: 1) Control group: % 0.9 physiological saline was received during 14 days, 2) Diabetic+ cancer group: 2x10 4 Mat‐LyLu cells were received after injection of 65 mg/kg STZ. 3) Diabetic+ cancer+metformin group: metformin was received 250 mg/kg during experimental period, following injection of STZ and inocculation of Mat‐LyLu cells. At the end of the experimental period (day 14) testes tissues were taken. Tissues were stained with hematoxylin and eosin and periodic acid‐Schiff reaction and determined the degree of histopathological damage. The degree of histopathological damage in the seminiferous tubules were evaluated as: normal, regressive, degenerative and atrophic (4). Apoptotic cells in testes tissue were detected with TUNEL reaction. Biochemically, serum glucose, glutathione, malondialdehyde, prostate specific antigen levels and testis protein carbonyl levels and myeloperoxidase, xanthine oxidase activities were determined. Testes tissue of the control group presented a normal testicular morphology and regular seminiferous tubules. The histopathological damage score of testicular tissue was significantly increased in diabetic+cancer group compared to control group. The number of regressive and degenerative tubules in diabetic+cancer+metformin group was decreased by metformin treatment. TUNEL positive cells were observed in all groups. The total number of TUNEL positive cells throughout the testes was increased in diabetic+cancer+metformin group compared to diabetic+cancer group. According to biochemical data, serum glutathione levels were decreased in diabetic+cancer group compared to control group. Serum glucose, malondialdehyde, prostate specific antigen levels, and testis protein carbonyl levels and myeloperoxidase and xanthine oxidase activities were increased in diabetic+cancer group. Treatment with metformin reversed these effects. It was indicated that metformin has been shown to be protective against testicular damage in diabetic male rats (5). It was has been reported that metformin was used as protective agent to prevent high‐fat diet induced testicular damage. Metformin inhibits the growth of cancer cell lines which suggests that it also has an inhibitory effect on cancer progression (6). Our results suggest that administration of metformin prevents the testicular damage by ameliorating the oxidative stress parameters and tissue damage. In conclusion, we can say that metformin has a potential protective effect on the testes tissue in diabetes and Dunning prostate cancer model.