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Background Doxorubicin (DOX), is a chemotherapeutic agent, which evokes oxidative stress and cell apoptosis in testicular tissue. It is known that the activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP), leading to apoptosis induced by DOX. The aim of the present study is to investigate whether PARP pathway has a role in DOX-induced testicular damage and infertility utilizing pharmacological PARP-1 inhibitor, PJ34, and PARP-1 knockout mice model. Methods Firstly, we assessed the activation of PARP pathway after DOX-induction at various hours by immunohistochemistry and western blot analysis. Secondly, we evaluated the role of PARP pathway in DOX-induced testicular damage, sperm motility, and fertility with pharmacological inhibition of PARP by using PJ34. Finally, we aimed to correlate a functional relationship between PARP-1 and DOX using PARP-1 knockout mice in DOX-induced testicular damage. Doxorubicin levels in plasma and testis tissue were also assessed. Results In DOX-induced group; PARP-1, PAR and apoptotic pathway protein expressions, increased significantly. In DOX + PJ34 group; PAR, cytochrome c, and AIF levels decreased significantly. Testicular weights, sperm motility, and mean the number of pups per litter decreased in DOX-induced group after 28 days, however they were similar to the control group in DOX-PJ34 group. In PARP-1 KO group, seminiferous tubule morphology was impaired significantly after 28 days of DOX-administration. Conclusions Our study indicates that DOX-induced testicular damage may be related to over-activation of PARP-1. PJ34 application was effective in preventing severe testicular damage caused by DOX-injection and may be considered for fertility protection against DOX-induced testicular damage.

Background: This study aimed to examine the effects of nesfatin-1 on thoracic aorta vasoreactivity and to investigate the inotropic and chronotropic effects of nesfatin-1 on the spontaneous contractions of the isolated rat atria.Methods: Isolated right atria and thoracic aorta were used in organ baths. The reactivity of the thoracic aorta was evaluated by potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP). The effects of nesfatin-1 on the spontaneous contractions of the rat atria were also examined.Results: Nesfatin-1 (0.1–100 ng/ml) produced a concentration-dependent relaxation response in rat thoracic aorta. The relaxant responses to nesfatin-1 were inhibited by the removal of endothelium, NO synthase blocker N-nitro-L-arginine methyl ester (L-NAME, 10−4 M), and soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10–5 M). Nesfatin-1 (10 ng/ml, 30 min) increased the relaxation responses to either ACh or SNP, and the...

The present study was designed to evaluate the cardioprotective effects of nesfatin-1, a novel peptide with anorexigenic properties, in rats with isoproterenol (ISO)-induced myocardial infarction (MI), and to further investigate the role of Akt/GSK-3β signaling pathway in the protective effect of nesfatin-1. To induce MI, ISO was subcutaneously injected into the rats for two consecutive days at a dosage of 85mg/kg/day. ISO-induced myocardial damage was indicated by elevated levels of cardiac specific troponin-T, enhanced myocardial expression of proinflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α), and increased number of cells with apoptotic and necrotic appearance in the myocardial tissue. Levels of p-Akt/Akt and p-GSK-3β/GSK-3β significantly decreased in heart tissue after ISO-induced MI. However, intraperitoneal administration of nesfatin-1 (10μg/kg/day) elicited a significant cardioprotective activity by lowering the levels of cardiac troponin-T and proinflammatory cytokines, indicating the protective effect of nesfatin-1 against ISO-induced MI. The biochemical findings were further confirmed by histopathological examination, which was demonstrated by reduced number of apoptotic and necrotic cells. Moreover, expressions of p-Akt/Akt and p-GSK-3β/GSK-3β in the myocardium of MI group rats were significantly increased by nesfatin-1 administration, suggesting that nesfatin-1, which appears to possess anti-apoptotic and anti-inflammatory properties, may confer protection against ISO-induced MI via an Akt/GSK-3β-dependent mechanism.

The aim of this study was to investigate the effect of resveratrol (RVT) on sildenafil-induced relaxations of isolated corpus cavernosum in non-diabetic and diabetic aged rats. A total of 13 male aged rats (72–80 weeks old) were randomized into two groups including non-diabetic aged rats and diabetic aged rats. Diabetes was induced in aged rats by streptozotocin (single i.p. dose of 45 mg/kg body weight) administration. At the end of the 12th week, corpus cavernosum strips of rats were suspended in an organ bath system. The corpus cavernosum relaxation was evaluated by sildenafil in the presence or absence of RVT (10−4 M) for 45 min. Induction of diabetes resulted in significant inhibition of sildenafil-induced corpus cavernosum relaxation in aged rats. The diminished relaxation in response to sildenafil was significantly improved by acute RVT incubation in both non-diabetic and diabetic aged rats; however, the magnitude of potentiation induced by RVT was more pronounced in diabetic aged rats. The potentiating effect of RVT was significantly inhibited by L-NG-nitroarginine methyl ester (L-NAME, 10−4 M, for 30 min) incubation in both groups. After the L-NAME incubation, the relaxation response of corporal tissues evoked by sildenafil was found to be similar in diabetic and non-diabetic aged rats. RVT improves sildenafil-induced relaxations of corpus cavernosum in both diabetic and non-diabetic aged rats probably by potentiating the activity of NOS, and this effect seems to be more manifest in diabetic aged group.

The cardiovascular benefits of resveratrol (RSV) have been well established by previous experimental and clinical studies. The aim of this study was to investigate the effectiveness of RSV administration on the impaired endothelial function induced by methylglyoxal (MGO), and to elucidate the role of endothelial nitric oxide synthase (eNOS) on its protective effect. Aged Wistar rats (80 weeks old, n = 15) were used in this study. The thoracic aorta was isolated and cut into rings for organ culture. Aortic segments of rats were incubated with MGO (420 µM) in the presence or absence of RSV (30 µM) for 4 h (short-term) or 24 h (long-term). Isometric tension studies were performed by an isolated organ bath in response to acetylcholine (ACh, an endothelium-dependent vasodilator) and sodium nitroprusside (SNP, an endothelium-independent vasodilator). Beside, expressions of eNOS and phospho-eNOS (p-eNOS) (Ser 1177) in thoracic aorta rings were evaluated by immunohistochemistry. Both short-term and long-term MGO incubation significantly inhibited the relaxation response induced by ACh, while the relaxation to SNP was not significantly altered. In addition, eNOS and p-eNOS expressions decreased significantly in arteries incubated with MGO. The impaired endothelial reactivity as well as decreased expressions of eNOS and p-eNOS in MGO-incubated vessels were significantly improved by RSV treatment. Endothelium-dependent vasodilatation of the thoracic aorta was significantly inhibited by MGO administration, and RSV may improve vascular endothelial function. The protective effect of RSV against MGO-induced endothelial dysfunction seems to be via increased eNOS expression and activity.

Objective The aim of this study was to investigate the effect of chronic exendin-4 (Ex-4) treatment on corpus cavernosum (CC) dysfunction in methylglyoxal (MGO) administered rats. Methods Male rats were divided into four groups as control, MGO (75 mg/kg/day in drinking water for 12 weeks), MGO + low-dose Ex-4 (0.1 μg/kg twice daily subcutaneously for 12 weeks concomitant with MGO), and MGO + high-dose Ex-4 (1 μg/kg twice daily subcutaneously for 12 weeks concomitant with MGO). Nitric oxide (NO)-mediated endothelium-dependent and neurogenic CC relaxations were evaluated by acetylcholine (ACh) and electrical field stimulation (EFS), respectively. Apoptosis was determined by TUNEL. Endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), NADPH oxidase subunit gp91phox (NOX2), and Rho kinase (ROCK2) expressions in CC were investigated by immunohistochemistry. Levels of the malondialdehyde (MDA) and advanced oxidation protein products (AOPP) were also measured. Results In MGO administered rats, both endothelium-dependent and neurogenic CC relaxations were significantly impaired as compared to controls. Apoptotic cell death and levels of MDA and AOPP increased significantly in MGO administered rats. eNOS and p-eNOS expressions decreased significantly in MGO group, while gp91phox expressions increased significantly. The diminished relaxation in response to ACh or EFS as well as the changes in expression of proteins in MGO groups were significantly improved by exendin-4 treatment. TUNEL-positive cells, and levels of MDA and AOPP in MGO group rats were also significantly reduced by exendin-4. Conclusion Exendin-4 treatment improves NO-mediated CC relaxations in MGO administered rats probably by inhibiting NADPH oxidase.

Background: The cardiovascular benefits of Resveratrol (RVT) have been well established by previous experimental and clinical studies. Aims: The goal of this study was to test the effectiveness of RVT administration on the impaired endothelial function induced by lipopolysaccharide (LPS), and to elucidate the role of endothelial nitric oxide synthase (eNOS)/Sirtuin 1 (SIRT1) pathway. Study Design: Animal experiment. Methods: Endotoxemia was induced by intraperitoneal injection of 10 mg/kg LPS, and the thoracic aorta was isolated six hours later. RVT was injected intraperitoneally 15 minutes before LPS administration. Six hours after LPS injection, potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP) were used to examine to vascular reactivity and endothelial function. eNOS, phospho-eNOS (p-eNOS) (Ser 1177), and SIRT1 expressions in thoracic aorta were evaluated by Western blot. Results: LPS administration significantly inhibited the relaxation response induced by ACh, while the relaxation to SNP was not significantly altered. Phe- and KCl-induced contractile responses in the thoracic aorta significantly decreased in LPS-injected group. eNOS and p-eNOS expression decreased significantly in arteries obtained from LPS group rats. The impaired vasoreactivity as well as decreased expressions of eNOS, p-eNOS, and SIRT1 in vessels from LPS-injected rats were improved by RVT treatment. Conclusion: The endothelium-dependent vasodilatation of the thoracic aorta was significantly inhibited by LPS administration, and RVT treatment may improve vascular endothelial function. The protective effect of RVT might be associated with increased eNOS expression and activity.