The protective effect of taurine on cyclophosphamide-induced testicular toxicity in rats.

This study aimed to evaluate the protective effect of taurine (TAU) with regard to antioxidant, anti inflammatory and antiapoptotic pathways on cyclophosphamide (CP)-induced testicular toxicity in rats. Forty Sprague-Dawley male rats were used in this experimental study. The CP group animals received a single dose of 200mg/kg CP on Day 8 intraperitoneally (i.p). The other groups were treated with TAU (75, 150 and 300mg/kg) orally for 14 days prior to and following a single i.p injection of CP. Morphometrical analysis and histological examination of testicular tissue were performed. Serum testosterone, LH and FSH levels were measured in serum using commercial ELISA kits. The testicular injury induced by CP was evaluated in terms of oxidative stress, inflammation and apoptosis with a significant inflammatory and apoptotic response and an insignificant oxidative stress. TAU treatment resulted in improvement in body weight gain, oxidative stress, inflammation and apoptosis, some of which were significant. The improvement was more pronounced for antiapoptotic effect of taurine in the testis of CP-treated animals. It was concluded that TAU may prevent and/or treat the testicular toxicity by ameloirating oxidative stress, inflammation and apoptosis.

Are there differences in oxidative stress and inflammatory processes between the autogenous and reactive subtypes of obsessive-compulsive disorder? A controlled cross-sectional study.

OBJECTIVE: To date, no study has investigated whether autogenous and reactive obsessive-compulsive disorder (OCD) types are different entities in terms of oxidative stress and inflammatory processes. The aim of this study is to compare them in terms of these features. METHODS: The study was conducted in subjects with reactive OCD (n=19), autogenous OCD (n=14), and a control group (n=17). All participants were non-smokers. Sociodemographic data were collected and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Obsessive Beliefs Questionnaire (OBQ), and Overvalued Ideas Scale (OVIS) were administered. High-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), paraoxonase (PON1), total oxidant status (TOS), and total antioxidant status (TAS) were measured. RESULTS: There were no significant differences in TAS, TOS, or oxidative stress index (OSI) between the OCD and control groups. PON1 and hs-CRP levels were higher in the OCD group, whereas IL-6 and IL-10 levels were lower. Comparison across the three groups revealed no differences in TAS, TOS, OSI, or PON1 levels; however, hs-CRP was significantly higher while IL-6 and IL-10 were significantly lower in the reactive group compared to controls. CONCLUSION: Our results show that, although inflammatory processes may play a role in OCD, the autogenous and reactive subtypes do not differ from each other in these respects. The classification of OCD into autogenous and reactive subtypes should be reevaluated.

Protective and therapeutic effect of hydrogen sulfide on hemorrhagic cystitis and testis dysfunction induced with cyclophosphamide

Backround/aim: Cyclophosphamide (CP) is a drug used for treatment of many malignant diseases. However, it can cause serious side effects such as hemorrhagic cystitis and male infertility. Hydrogen sulfide (H2S) is a gaseous mediator and is suggested to have antioxidant, antiinflammatory, and antiapoptotic effects. In this study, dose-dependent effects of H2S donor sodium hydrosulfide (NaHS) on cyclophosphamide-induced hemorrhagic cystitis and testicular dysfunction were investigated in rats. Material and methods: Rats were divided into 5 groups (n = 8): control, CP, NaHS25 µmol/kg, NaHS50 µmol/kg, and NaHS100 µmol/ kg. After treatment for 7 days intraperitoneally (ip), a single ip dose of CP 200 mg/kg was given on the 8th day. Then, treatment was continued for 7 days. In bladder and testicular tissues, IL 6, IL 10, cGMP, NO, H2S, FSH, LH, and testosterone levels were measured by ELISA. Histopathological examination with H&E staining, as well as immunohistochemical staining for acrolein in bladder and caspase-3 and APAF-1 in testis were performed. Results: NaHS prevented the increased IL 6 and IL 10 values induced by CP as well as prevented the decrease in cGMP values associated with CP. There was no significant change in FSH values, but the LH value, which increased with CP, decreased with 25, 50, and 100 µmol/kg NaHS. In contrast, testosterone decreased in the CP group and increased in the treatment groups. NaHS was effective in many biochemical and histopathological parameters at 25 and 50 µmol/kg doses, and this effect decreased at 100 µmol/kg dose. Conclusion: H2S has a protective and therapeutic effect on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide. It can be suggested that H2S is a promising molecule in facilitating cancer treatment.

Relationship Between Gonadal Hormone Levels and Symptom Severity in Female Patients With Schizophrenia.

Objective: It is thought that sex-specific differences in schizophrenia may be associated with gonadal hormones, especially estrogen. This study aimed to investigate the relationship between follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol, and progesterone serum levels and symptom severity during the menstrual cycle in female patients with schizophrenia. Methods: Serum samples were taken in the follicular and periovulatory phases from 32 female patients with schizophrenia; and FSH, LH, prolactin, estradiol, and progesterone levels were performed. Simultaneously, the patients were administered positive and negative symptom scale (PANSS), Calgary depression scale for schizophrenia (CDSS), and Hamilton anxiety rating scale (HAM-A). Results: PANSS (z = -2.52, P < .001), HAM-A (z = -3.60, P < .001), and CDSS (z = -2.52, P = .012) scores were lower in the periovulatory phase than in the follicular phase. Negative correlations between FSH and PANSS positive symptom subscale (r = -0.393, P = .035), and between prolactin and PANSS total score (r = -0.406, P = .029) were detected. Conclusion: Hypoestrogenism should be studied more in patients with schizophrenia. Studies with large samples evaluating FSH, LH, prolactin, and progesterone together with estrogen are needed to be able to safely use gonadal hormones, which may be related to schizophrenia symptom severity, especially in patients who do not respond adequately to treatment.

Inflammation and Oxidative Stress in Deficit Schizophrenia.

INTRODUCTION: Differences in parameters related to inflammatory and oxidative stress in deficit (DS) and nondeficit schizophrenia (non-DS) may support the DS/non-DS categorization of schizophrenia. For DS patients, non-DS patients, and for healthy controls, this study aims to evaluate the serum levels of: proinflammatory cytokines of interleukin (IL) 1ß, tumor necrosis factor (TNF) α, Interferon (IFN) γ, IL-12, and IL-17; anti-inflammatory cytokines of IL-10, IFN-α, and transforming growth factor (TGF) ß; and antioxidant biomarkers of paraoxonase1 (PON1) and Total Antioxidant Capacity (TAOC). METHOD: Serum IL-1ß, TNF-α, IFN-γ, IL-12, IL-17, IL-10, IFN-α, TGF-ß, PON1 and TAOC levels were measured and performed in DS (n=26), non-DS (n=28), and healthy control (n=28) groups. RESULTS: Patients in the DS group had higher IL-17 levels than the non-DS group did. TGF-ß values for both patient groups were significantly higher than those of the controls. PON1 and TAOC values for both patient groups were significantly lower than those of the controls. CONCLUSION: Our findings may be evidence for the consideration that DS reflects a coherent entity within schizophrenia. Increased levels of IL-17 from pro-inflammatory cytokines may be related with DS.

Do Resveratrol and Dehydroepiandrosterone Increase Diminished Ovarian Reserve?

OBJECTIVE: In this study, the aim is to observe changes induced by dehydroepiandrosterone (DHEA) and resveratrol (RES) in diminished ovarian follicles that was induced by 4-vinylcyclohexenediepoxide (VCD). MATERIALS AND METHODS: Twenty four Wistar albino female rats were divided into 3 groups: control, DHEA and RES. Unilateral oophorectomy was performed in control group to remove the right ovary of 4 rats and the left ovary of 4 rats. After administration of 160 mg/kg VCD, remaining ovaries were removed. Following the same VCD treatment, in DHEA and RES groups, 60 mg/kg DHEA and 20 mg/kg RES were given for 45 days respectively and residual ovaries were removed. Hematoxylin-eosin and TUNEL staining were performed. Follicle stimulating hormone (FSH), estradiol (E2) and anti-mullerian hormone (AMH) values were measured. RESULTS: In control group, VCD-induced apoptosis in follicles increased the TUNEL-positive cell counts (p<0.001) with decreased number of follicles. On the other hand, DHEA significantly increased all three follicle types in the ovaries and decreased apoptosis (p<0.001). The decreased follicle number in all three follicle types after VCD treatment were found to be significantly increased after RES treatment (p<0.001). Apoptosis in the follicles was significantly decreased by RES administration (p<0.001). FSH values were found to be increased with VCD and to reach control values with DHEA and RES. E2 values significantly decreased with VCD, but significantly increased with RES and DHEA. CONCLUSION: Both DHEA and RES may improve VCD-induced diminished ovarian reserve. DHEA and RES increased the number of primary, primordial and growing follicles, with no significant difference between them.

Alagebrium and Complications of Diabetes Mellitus.

Glycation is the process of linking a sugar and free amino groups of proteins. Cross-linking of glycation products to proteins results in the formation of cross-linked proteins that inhibit the normal functioning of the cell. Advanced glycation end products (AGEs) are risk molecules for the cell aging process. These ends products are increasingly synthesized in diabetes and are essentially responsible for diabetic complications. They accumulate in the extracellular matrix and bind to receptors (receptor of AGE [RAGE]) to generate oxidative stress and inflammation. particularly in the cardiovascular system. Treatment methods targeting the AGE system may be of clinical importance in reducing and preventing the complications induced by AGEs in diabetes and old age. The AGE cross-link breaker alagebrium (a thiazolium derivative) is the most studied anti-AGE compound in the clinical field. Phase III clinical studies with alagebrium have been successfully conducted, and this molecule has positive effects on cardiovascular hypertrophy, diabetes, hypertension, vascular sclerotic pathologies, and similar processes. However, the mechanism is still not fully understood. The primary mechanism is that alagebrium removes newly formed AGEs by chemically separating α-dicarbonyl carbon-carbon bonds formed in cross-linked structures. However, it is also reported that alagebrium is a methylglyoxal effective inhibitor. It is not yet clear whether alagebrium inhibits copper-catalyzed ascorbic acid oxidation through metal chelation or destruction of the AGEs. It is not known whether alagebrium has a direct association with RAGEs. The safety profile is favorably in humans, and studies have been terminated due to financial insufficiency and inability to license as a drug.

The therapeutic potential of amifostine on cyclophosphamide-induced testicular dysfunction in rats: An experimental study.

BACKGROUND: Cyclophosphamide (CP) is a well-known alkylating anticancer agent used in the treatment of various malignant and non-malignant tumors. CP may also cause a variety of adverse effects, including reproductive toxicity. Amifostine is known as a cytoprotective drug having antioxidant properties. OBJECTIVE: To evaluate the possible beneficial effects of amifostine on testicular toxicity induced by CP in rats. MATERIALS AND METHODS: A total of 35 Sprague-Dawley rats were used in this experimental study. The CP group animals received a single dose of 200 mg/kg CP on Day 8 by intraperitoneal injection and were left untreated for the following seven days. The two remaining groups of animals were treated with 200 mg/kg/day amifostine (AMF 200) and 400 mg/kg/day amifostine (AMF 400) for seven days prior to and following a single intraperitoneal injection of CP. Morphometrical analysis and histological examination of testicular tissue were performed. Serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels were measured in serum using commercial ELISA kits. The epidydimal sperm count was determined. RESULTS: The tubular epithelial height in the testis was significantly higher in the AMF400 group compared to other groups (p < 0.001). Animals in the AMF400 group showed minimal debris in the tubules, no Sertoli cell damage, and the Johnsen scores were slightly higher in the AMF400 group. The epididymal sperm count was significantly lower in the CP-administered animals compared to the control animals and was significantly higher in the AMF200 and AMF400 groups compared to the CP group (p = 0.006, and p = 0.019 respectively). CONCLUSION: Amifostine, at a dose of 400 mg/kg, may have a protective effect on testicular damage induced by CP in rats.

Protective role of resveratrol on testicular germ cells in mice with testicular toxicity.

OBJECTIVE: The aim of the present study was to investigate the possible beneficial effects of resveratrol in mice subjected to vinyl cyclohexene dieposide (VCD) -induced testicular toxicity. MATERIAL AND METHODS: A total of thirty- six Swiss albino male mice aged 28-days were used in the present study. The study was composed of two stages where mice which received or did not receive VCD (320 mg/kg/day) were administered resveratrol. The animals were assigned into control and resveratrol-treated groups in the first stage and into groups of VCD- and VCD+resveratrol-treated groups in the second stage. At the end of the experiments, relative testicular weight (TW/BW) and dry/wet weight of testis (TDW/TWW) were calculated. Histological analysis by hematoxylin and eosin (H&E) staining and immunohistochemical staining by BAX and Bcl-2 were performed. Serum testosterone, LH and FSH levels were measured by a commercially available ELISA kit. RESULTS: Resveratrol caused a dose-dependent increase in TW/BW and decrease in TDW/TWW (p<0.05). Resveratrol at a dose of 20 mg/kg resulted in an improvement in testosterone, LH and FSH levels in mice with VCD-induced testicular toxicity (p<0.001). Resveratrol also improved apoptotic index and epithelial cell height of testicular seminipherous tubuli significantly after VCD exposure (p<0.001). CONCLUSION: Results of the present study suggest that resveratrol can be used as a protective and/or therapeutic agent particularly for cases with male infertility caused by testicular toxicity.

Functional Effects of Alagebrium (ALT-711)-Isolated Rat Carotid Artery.

OBJECTIVE: In our study, the effects of glycosylated protein cross-link breaker, alagebrium was investigated on isolated rat carotid artery using myography. Alagebrium showed vasodilator effect on carotid artery rings; particularly, this effect was significantly increased in endothelium-intact rings. MATERIALS AND METHODS: To clarify the vasodilator mechanism of alagebrium, different antagonists such as N(G)-Nitro-L-arginine methyl ester (L-NAME), glibenclamide, indomethacin, metoprolol, propranolol, tetraethylammonium, and calcium channel activator BAYK-8644 were used to reverse this effect. RESULTS: Relaxation% responses to alagebrium were more significantly increased in intact endothelium than in denuded arteries. Blocking vasodilation related to channels (K-ATP, PGI2, BKca) and receptors (ß1, ß2) did not reverse the relaxation response to alagebrium. Vasodilator response to alagebrium was only slightly decreased after L-NAME incubation and significantly decreased after BAYK-8644 incubation. CONCLUSION: Results of present study suggest that the mechanism of alagebrium-induced vasodilator effect may include the blockage of L-type calcium channels and partially of the nitric oxide synthase enzyme.

The Effect of P-Glycoprotein Inhibition and Activation on the Absorption and Serum Levels of Cyclosporine and Tacrolimus in Rats.

BACKGROUND: Permeability glycoprotein (P-glycoprotein or P-gp) plays an important role in the intestinal absorption of the immunosuppressive agents: cyclosporine and tacrolimus. OBJECTIVES: The aim of this study was to determine how the intestinal absorption of cyclosporine and tacrolimus is affected when they are used with P-gp activating or inhibiting agents. MATERIAL AND METHODS: In in vitro experiments, everted parts of rat small intestines were used to evaluate the effects of verapamil (a P-gp inhibitor) and rifampicin (a P-gp inducer) on the intestinal absorption of cyclosporine and tacrolimus. In in vivo experiments, the effects of verapamil and rifampicin on the plasma concentrations of cyclosporine and tacrolimus were evaluated. RESULTS: In in vitro experiments, the absorption of cyclosporine and tacrolimus from the small intestine increased in a time-dependent manner when the drugs were administered with or without verapamil or rifampicin. There was no difference in the absorption of cyclosporine ± verapamil/rifampicin between the jejunum and ileum; however, ileal absorption of tacrolimus + rifampicin was significantly higher than jejunal absorption (p < 0.05). Plasma concentrations of cyclosporine and tacrolimus were significantly increased when they were co-administered with verapamil (p < 0.001) and significantly decreased when co-administered with rifampicin (p < 0.05). CONCLUSIONS: P-gp may play an important role in the absorption of immunosupressive drugs, and it may contribute to drug-drug interactions thay may lead to inadequate drug response or toxicity.

Evaluation of Cisplatin Neurotoxicity in Cultured Rat Dorsal Root Ganglia via Cytosolic Calcium Accumulation.

BACKGROUND: Calcium homeostasis is considered to be important in antineoplastic as well as in neurotoxic adverse effects of cisplatin. AIMS: This study aimed to investigate the role of Ca(2+) in cisplatin neurotoxicity in cultured rat dorsal root ganglia (DRG) cells. STUDY DESIGN: Cell culture study. METHODS: DRG cells prepared from 1-day old Sprague-Dawley rats were used to determine the role of Ca(2+) in the cisplatin (10-600 µM) neurotoxicity. The cells were incubated with cisplatin plus nimodipine (1-3 µM), dizocilpine (MK-801) (1-3 µM) or thapsigargin (100-300 nM). Toxicity of cisplatinon DRG cells was determined by the MTT assay. RESULTS: The neurotoxicity of cisplatin was significant when used in high concentrations (100-600 µM). Nimodipine (1 µM) but not MK-801 or thapsigargin prevented the neurotoxic effects of 200 µM of cisplatin. CONCLUSION: Voltage-dependent calcium channels may play a role in cisplatin neurotoxicity.

Effects of tadalafil on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide in rats.

INTRODUCTION: The protective and/or therapeutic potential of tadalafil (TDL) on cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) and testicular dysfunction in rats was evaluated. MATERIALS AND METHODS: The animals except from the control group were divided into four groups and treated with saline, or 1, 5 or 10 mg/kg TDL orally (CP, TDL1, TDL5 and TDL10 groups, respectively) before and after CP injection. Body and organ weights, sperm count, cGMP, nitric oxide (NO), IL-6 and IL-10 levels in serum and bladder tissue, and serum testosterone (T), LH and FSH levels were determined. The histological analysis of bladder and testis was performed and the number of apoptotic cells was determined. RESULTS AND CONCLUSION: The CP group had decreased cGMP and NO levels in the bladder, serum T level (p < 0.05) and sperm count (p < 0.001) and higher IL-6 levels in serum and bladder (p < 0.01). Treatment with TDL resulted in increased cGMP (p < 0.001), NO (p < 0.05) and serum T (p < 0.05) levels. Histological analysis of the CP group showed severe HC in bladder and testicular damage. TDL-treated animals showed a dose-dependent improvement in all of these histological impairments. In conclusion, a selective inhibitor of phosphodiesterase-5 enzyme, TDL, showed a protective and/or therapeutic effect on CP-induced HC and testicular dysfunction in rats.

Relation of bosentan, iloprost, and sildenafil with growth factor levels in monocrotaline-induced pulmonary hypertension.

It is believed that growth factors play an important role in vascular remodeling that is evident in pulmonary hypertension (PH) pathogenesis. In the present study, the vascular endothelial growth factor (VEGF) levels in serum and pulmonary artery samples of rats have been analyzed with monocrotaline (MCT)-induced PH after treatments with iloprost, bosentan, and sildenafil. Serum VEGF and pulmonary artery VEGF levels were found to be significantly lower in MCT groups compared with control groups and significantly higher in treatment groups compared with MCT groups. In conclusion, treatment strategies directed at increasing VEGF levels may be reasonable in PH management.

The role of inflammation and COX-derived prostanoids in the effects of bradykinin on isolated rat aorta and urinary bladder.

Bradykinin, a vasoactive peptide, increases during inflammation and induces the formation of prostaglandins through specific receptor activation. Two types of receptors mediate the biological effects of bradykinin, B(1) and B(2) receptors. Although B(2) receptors are present in most tissues, B(1) receptors are expressed after inflammatory stimuli or tissue injury. Bradykinin has a high affinity for B(2) and a low affinity for B(1) receptors, whereas the opposite occurs for des-Arg(9)-bradykinin. Recently, it has been reported that nonsteroidal anti-inflammatory drugs have different inhibitory activities on cyclooxygenase isozymes, COX-1, COX-2, and COX-3. In the present study, we have investigated the contributions of different COX isozyme inhibitions and inflammation on bradykinin-induced effects of isolated rat aorta and urinary bladder smooth muscle contractions. Male Sprague-Dawley rats weighing 200-250 g were used in the study. The vasodilatory responses to bradykinin (1 nM-1 µM) were studied on isolated rat aorta rings contracted with norepinephrine (0.1 µM) following incubation with dipyrone (100, 700, and 2,000 µM). The relaxant responses of dipyrone (100, 700, and 2,000 µM) were also compared on the isolated rat urinary bladder contracted with bradykinin (n = 8). A bacterial lipopolysaccharide was used for the induction of inflammation (n = 8). The levels of PGE(2), PGF(1α), TXB(2), nitric oxide synthase (NOS), IL-10, and TNF-α were all determined in both the plasma and the perfusate of the aorta preparations (n = 5). The vasodilatory activities of bradykinin and des-Arg9-bradykinin were significantly increased upon the inhibition of COX-3 (dipyrone at 100 µM). These effects disappeared in the inflamed group. PGE(2), PGF1α, and TXB(2) were significantly high, but NOS activity was low in the aorta perfusate after the inhibition of COX-3. Dipyrone showed the relaxant activity of the urinary bladder contracted with bradykinin. The vasodilatory activity of des-Arg(9)-bradykinin was in the inflamed group but not in the non-inflamed group. Bradykinin did not contract urinary bladder in inflamed group. The results suggest that COX-induced products may play an important role in the bradykinin-induced rat aortic smooth muscle relaxations.