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Öğe The broad-spectrum chemokine inhibitor NR58-3.14.3 suppresses the implantation and survival of human endometrial implants in the nude mice endometriosis model(Springer Heidelberg, 2007) Kayisli, Umit A.; Berkkanoglu, Murat; Zhang, Lufang; Kizilay, Gulnur; Arici, AydinMany chemokines likely contribute to the pathogenesis of endometriosis. The authors hypothesize that the broad-spectrum chemokine inhibitor NR58-3.14.3 may prevent ectopic human endometrium implantation and growth. After placing human endometrium fragments into the peritoneal cavity, ovariectomized athymic nude mice (n = 31) receiving intramuscular estradiol valerate were randomly assigned to daily intraperitoneal injections of either phosphate-buffered saline or NR58-3.14.3. Fourteen days later, the implant number and volume, proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) index, and MTT cell viability were assessed in the implants. NR58-3.14.3 reduced the total number (45%) and total volume (81%) of endometriotic lesions (P < .05) and revealed a lower PCNA and higher TUNEL index in ectopic implants compared with controls (P < .05). NR58-3.14.3 treatment did not affect endometrial cell proliferation in vitro. NR58-3.14.3, by possibly regulating cell survival, can reduce the number and size of ectopic implants in vivo, supporting the potential use of chemokine inhibitors in novel therapies for endometriosis.Öğe Changes in nociceptin/orphanin FQ levels in rat brain regions after acute and chronic cannabinoid treatment in conjunction with the development of antinociceptive tolerance(Wiley-Blackwell, 2016) Ulugol, Ahmet; Topuz, Ruhan D.; Gunduz, Ozgur; Kizilay, Gulnur; Karadag, Hakan C.It has been indicated that acute and chronic morphine administrations enhance nociceptin/orphanin FQ (N/OFQ) levels in the brain, which might play role in the development of tolerance to the antinociceptive effect of morphine. Accordingly, N/OFQ receptor (NOP) antagonists have been shown to prevent the development of antinociceptive tolerance to morphine. Our aim is to observe whether cannabinoids, similarly to opioids, enhance N/OFQ levels in pain-related brain regions and whether antagonism of NOP receptors attenuates the development of tolerance to the antinociceptive effect of cannabinoids. Hot plate and Tail flick tests are used to assess the antinociceptive response in Sprague-Dawley rats. N/OFQ levels are measured in cortex, amygdala, hypothalamus, periaqueductal gray, nucleus raphe magnus and locus coeruleus of rat brains using Western blotting and immunohistochemistry. Within 9 days, animals became completely tolerant to the antinociceptive effect of the cannabinoid agonist WIN 55,212-2 (2, 4, 6 mg/kg, i.p.). Chronic administration of JTC-801, a NOP receptor antagonist, at a dose that exerted no effect on its own (1 mg/kg, i.p.), attenuated development of tolerance to the antinociceptive effect of WIN 55,212-2 (4 mg/kg, i.p.). Western blotting and immunohistochemistry results showed that N/OFQ levels significantly increased in amygdala, periaqueductal gray, nucleus raphe magnus and locus coeruleus of rat brains when WIN 55,212-2 was combined with JTC-801. We hypothesize that, similar to opioids, chronic cannabinoid + NOP antagonist administration may enhance N/OFQ levels and NOP receptor antagonism prevents development of tolerance to cannabinoid antinociception.Öğe Does Oral Monosodium Glutamate Have a Cochleotoxic Effect? An Experimental Study(Karger, 2022) Guven, Selis Gulseven; Ersoy, Onur; Topuz, Ruhan Deniz; Bulut, Erdogan; Kizilay, Gulnur; Uzun, CemIntroduction: The effect of orally consumed monosodium glutamate (MSG), which is a common additive in the food industry, on the cochlea has not been investigated. The present study aimed to investigate the possible cochleotoxic effects of oral MSG in guinea pigs using electrophysiological, biochemical, and histopathological methods. Methods: Thirty guinea pigs were equally divided into control and intervention groups (MSG 100 mg/kg/day; MSG 300 mg/kg/day). At 1 month, 5 guinea pigs from each group were sacrificed; the rest were observed for another month. Electrophysiological measurements (distortion product otoacoustic emission [DPOAE] and auditory brainstem response [ABR]), glutamate levels in the perilymph and blood samples, and histopathological examinations were evaluated at 1 and 2 months. Results: Change in signal-to-noise ratio at 2 months was significantly different in the MSG 300 group at 0.75 kHz and 2 kHz (p = 0.013 and p = 0.044, respectively). There was no statistically significant difference in ABR wave latencies of the guinea pigs given MSG compared to the control group after 1 and 2 months; an increase was noted in ABR thresholds, although the difference was not statistically significant. In the MSG groups, moderate-to-severe degeneration and cell loss in outer hair cells, support cells, and spiral ganglia, lateral surface junction irregularities, adhesions in stereocilia, and partial loss of outer hair cell stereocilia were noted. Conclusion: MSG, administered in guinea pigs at a commonly utilized quantity and route of administration in humans, may be cochleotoxic.Öğe The Effect of Ceftriaxone in Valproic Acid-Induced Mouse Model of Autism(Tabriz Univ Medical Sciences & Health Services, 2022) Gur, Gamze; Topuz, Ruhan Deniz; Kizilay, GulnurPurpose: Autism is a multifactorial neurodevelopment disease and it has not been disclosed as a hypoglutamatergic or hyperglutamathergic disease. Ceftriaxone is an antibiotic that increases glutamate transporter-1 (GLT-1) expression in the brain in chronic use. In our study we aimed to investigate the effects of different doses of ceftriaxone in postnatal period in male mice exposed to valproic acid (VPA) at 12.5th day of pregnancy.Methods: A total of 96 BALB/c male mice were divided into 12 groups (n = 8 animals per group). Ceftriaxone (50, 100, 200 mg/kg/d) or saline was given to the male offsprings born from pregnant mice administered VPA and/or saline, between days 47 and 55. Dihydrokainic acid (10 mg/kg), a GLT-1 inhibitor, was administered intraperitoneally to evaluate whether GLT-1 mediates the effect of ceftriaxone. Three chamber sociability and social interaction test and the rota rod test were performed in all groups on days 54 and 55. GLT-1 levels in the hippocampus were measured by immunohistochemistry (IHC) and western blotting (WB).Results: In our study, autism-like behaviors were observed in male offsprings that were exposed to VPA in the intrauterine period. Chronic ceftriaxone administration has no curative effect on behavioral impairment seen in autism.Conclusion: Our results show that ceftriaxone did not exert significant therapeutic effect on VPA-induced mouse model of autism.Öğe Effects of Cannabinoid Modulation on Hypothalamic Nesfatin-1 and Insulin Resistance(Wolters Kluwer Medknow Publications, 2019) Kaya, Oktay; Yilmaz, Makbule Elif; Bayram, Sinasi; Gunduz, Ozgur; Kizilay, Gulnur; Ozturk, LeventBoth nesfatin-1 and cannabinoid systems involved in the regulation of sleep, metabolism, and food intake. The relationship between cannabinoid system and nesfatin-1 levels remains to be elucidated. This study investigated nesfatin-1 and insulin resistance in 72-h rapid eye movement (REM) sleep-deprived mice under the effects of cannabinoid, and cannabinoid receptors CB1R and CB2R blocking. Sixty mice were exposed to 72-h sleep deprivation. Groups and drug administrations were as follows: Group 1 (control) received injection of vehicle. Group 2 received WIN 55,212,2. Group 3 received AM251 (CB1R antagonist) followed by WIN 55,212,2 injection. Group 4 received SR144528 (CB2R antagonist) followed by WIN 55,212,2 injection. Group 5 received only AM251. Group 6 received only SR144528. Blood samples were collected 1 h after drug administration and prepared for biochemical measurements. Glucose levels were measured by glucometer, whereas insulin and nesfatin-1 levels were measured by ELISA. Central nesfatin-1 was also assessed using immunohistochemistry. One-way analysis of variance together with post hoc Tukey's test was used for inter-group comparisons. Serum nesfatin-1 levels were comparable in all study groups. Brain nesfatin-1 immune-positive cell count was lower in WIN group compared to controls. The administration of CB1R or CB2R antagonist prevented reduction in nesfatin-1-positive cell count. Insulin resistance was higher in WINCB2 and CB2 groups than in control and WINCB1 groups. Cannabinoid treatment reduced nesfatin-1 immunoreactivity in the central nervous system and this effect was prevented by either CB1R or CB2R antagonist pretreatment. Insulin resistance might be related to CB2 receptor activation which was independent from central nesfatin-1 immunoreactivity.Öğe Effects of Curcumin on Apoptosis and Oxidoinflammatory Regulation in a Rat Model of Acetic Acid-Induced Colitis: The Roles of c-Jun N-Terminal Kinase and p38 Mitogen-Activated Protein Kinase(Mary Ann Liebert, Inc, 2013) Topcu-Tarladacalisir, Yeter; Akpolat, Meryem; Uz, Yesim Hulya; Kizilay, Gulnur; Sapmaz-Metin, Melike; Cerkezkayabekir, Aysegul; Omurlu, Imran KurtThe present study evaluated the effects of curcumin on epithelial cell apoptosis, the immunoreactivity of the phospho-c-Jun N-terminal kinase (JNK) and phospho-p38 mitogen-activated protein kinases (MAPKs) in inflamed colon mucosa, and oxidative stress in a rat model of ulcerative colitis induced by acetic acid. Rats were randomly divided into three groups: control, acetic acid, and acetic acid + curcumin. Curcumin (100 mg/kg per day, intragastrically) was administered 10 days before the induction of colitis and was continued for two additional days. Acetic acid-induced colitis caused a significant increase in the macroscopic and microscopic tissue ranking scores as well as an elevation in colonic myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, and the number of apoptotic epithelial cells in colon tissue compared to controls. In the rat colon, immunoreactivity of phospho-p38 MAPK was increased, whereas the phospho-JNK activity was decreased following the induction of colitis. Curcumin treatment was associated with amelioration of macroscopic and microscopic colitis sores, decreased MPO activity, and decreased MDA levels in acetic acid-induced colitis. Furthermore, oral curcumin supplementation clearly prevented programmed cell death and restored immunreactivity of MAPKs in the colons of colitic rats. The results of this study suggest that oral curcumin treatment decreases colon injury and is associated with decreased inflammatory reactions, lipid peroxidation, apoptotic cell death, and modulating p38- and JNK-MAPK pathways.Öğe Effects of electroacupuncture at ST36 and BL20 on the diabetic rat testis(Sage Publications Ltd, 2023) Kizilay, Gulnur; Ersoy, Onur; Bozer, Cuneyt; Demirtas, Selim; Cikmaz, Selman; Yilmaz, AliObjective: We aimed to evaluate the effects of electroacupuncture (EA) at ST36 and BL20 on the testicular tissues in a rat model of diabetes and to explore the mechanisms of action. Methods: A total of 34 male Sprague-Dawley rats were allocated to a control group (n = 10), diabetes (D) group (n = 12) or diabetes + acupuncture (DA) group (n = 12). To model diabetes, rats in groups D and DA received an intraperitoneal injection of a single dose of 35 mg/kg streptozotocin (STZ) dissolved in citrate buffer (pH = 4.5; 0.1 M) after 2 weeks of high-fat diet administration. Under xylazine/ketamine anesthesia, stainless steel needles (30 mm x 0.25 mm) were inserted bilaterally at ST36 and BL20. The needles were connected to an EA device via cables, and EA was applied for 30 min (15 Hz frequency and 0.2-1 mA intensity) twice a week for 5 weeks. Results: The effects of EA at ST36 and BL20 on blood glucose levels and body weight, biochemical parameters, histopathological, morphometric and immunohistochemical findings, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis were evaluated. A significant decrease was detected in DA versus D groups in blood glucose levels, basement membrane thickness and apoptotic cell/tubule indices. In addition, there was a significant increase in the Johnsen scores, seminiferous tubule diameters, serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone, proliferation indices, and sex hormone-binding globulin (SHBG) and insulin-like peptide 3 (INSL3) immunoreactivities. Conclusion: EA had multiple positive effects on blood glucose homeostasis and testicular structure/function in this rat model of diabetes. EA may be effective at preventing or eliminating histopathological damage in the diabetic testis.Öğe THE EFFECTS OF METHYLEUGENOL ON THE LIVER, KIDNEY AND SMALL INTESTINE AND ON THE ANTIOXIDANT ENZYMES IN RATS(Parlar Scientific Publications (P S P), 2009) Kaboglu, Aysegul; Ertan, Figen; Kizilay, GulnurMethyleugenol is a natural, widely used constituent of foods. cosmetics, soaps and shampoos. The purpose of this study was to evaluate the effects of methyleugenol on the liver, kidney and small intestine. Methyleugenol was given by gavage to rats for ten days at doses of 10 mg/kg and 30 mg/kg. In liver, widening of the sinusoidal area, necrotic and hypertrophic hepatocytes, cytoplasmic vacuolization in hepatocytes, degeneration of endothelium, mononuclear cell infiltration, and picnotic nuclei were observed. In kidney, loosing of glomerulus, mononuclear cell infiltration, focal bleeding around tubules, degenerative tubules, epithelial membrane degeneration, hypertrophic epithelial cells, and accumulation of material in proximal tubules were observed. In small intestine, increased mitotic figures in the base of villi, edema in connective tissue, connective-epithelial tissue separation, diminished connective tissue in lamina propria, a foam-like appearance, and leukocyte infiltration were observed. There were no significant changes in superoxide dismutase (SOD) and catalase (CAT) activity, but glutathione peroxidase (GPX) activity was significantly increased in the kidney and small intestine at 30 mg/kg (p<0.05). The amount of total protein was significantly increased in liver (p<0.05). but not changed in the kidney and small intestine. We concluded that the toxic effects of methyleugenol must be evaluated in greater detail.Öğe Expression and regulation of c-Jun N-terminal kinase (JNK) in endometrial cells in vivo and in vitro(Springer, 2008) Kizilay, Gulnur; Cakmak, Hakan; Yen, Chih-Feng; Atabekoglu, Cem; Arici, Aydin; Kayisli, Umit AliJNK(c-Jun N-terminal kinase) is one of the main types of mitogen-activated protein kinases. JNK modulates inflammation and apoptosis in response to stress. Our hypothesis is that temporal and spatial changes in JNK activity regulate inflammation in human endometrium and that fluctuation in estrogen and progesterone levels may play a role in JNK activation. Therefore, we aimed to determine total-(t-) and active-(phosphorylated, p-) JNK expression in endometrial tissues in vivo by immunohistochemistry, and in vitro by immunocytochemistry and Western blot analysis. Immunohistochemistry revealed moderate cytoplasmic and nuclear t-JNK immunoreactivity, and mostly nuclear p-JNK immunoreactivity throughout the menstrual cycle and early pregnancy. The highest p- and t-JNK immunoreactivity was detected in late secretory phase (P < 0.05). We observed that endometrial stromal cell (ESC)s showed a significant increase in p-JNK expression following 48 h of estrogen combined with progesterone (E-2 + P-4) withdrawal from the culture conditions, compared to control and non-withdrawal groups (P < 0.05). Upon treatment with JNK inhibitor SP600125, we observed a significantly decreased interleukin (IL)-8 level (P < 0.05) in the presence and absence of E-2. These results demonstrate that JNK expression increases during the late secretory phase when the inflammatory response is highest. Inhibition of IL-8 expression by SP600125 suggests that JNK is involved in regulation of proinflammatory mediators of endometrium.Öğe In vivo effects of curcumin and deferoxamine in experimental endometriosis(Wroclaw Medical Univ, 2017) Kizilay, Gulnur; Uz, Yesim Hulya; Seren, Gulay; Ulucam, Enis; Yilmaz, Ali; Cukur, Ziya; Kayisli, Umit AliBackground. Endometriosis is one of the most common chronic gynecological diseases. Objectives. The aim of the study was to examine the effects of curcumin and/or deferoxamine on cell proliferation in a rat model of endometriosis. Material and methods. Thirty female 12-week-old albino Wistar rats, weighing 200-250 g, were used in this study. All the rats underwent ovariectomy and 0.1-mg beta-estradiol 17-valerate pellets were placed intraperitoneally. An experimental model of endometriosis was created in all the animals. To create the experimental model, an approximately 1-cm long section of the uterus was taken, primarily from the right horn of the uterus. Autologous fragments were then placed between the peritoneum and muscle. The animals were divided into 3 groups: Group A, treated only with the vehicle used for curcumin and deferoxamine; group B, treated with curcumin (100 mg/kg body weight); and group C, treated with deferoxamine + curcumin (100 mg/kg body weight). After biopsy samples were obtained, the sections were stained with hematoxylin and eosin. Immunostaining for cytokeratin-7 and proliferating cell nuclear antigen (PCNA) was performed. Blood iron levels were measured using a Perkin Elmer AAnalyst 800 Atomic Absorption Spectrophotometer. Results. The endometrial implant size increased in Group A, but treatment with curcumin (p = 0.01) and deferoxamine + curcumin (p = 0.007) reduced the implant size. In ectopic endometrial epithelial cells, there were significant decreases in PCNA immunoreactivity between groups A and B (p = 0.044) and between groups A and C (p = 0.033). Conclusions. Treatment with curcumin alone and/or in combination with deferoxamine contributed to a reduction in implant size and cell proliferation in a rat endometriosis model. Iron-chelating agents may act in the same manner when used in women with endometriosis; however, further studies from different perspectives are still needed.Öğe Increased c-Jun N-terminal kinase activation in human endometriotic endothelial cells(Springer, 2011) Uz, Yesim Hulya; Murk, William; Bozkurt, Idil; Kizilay, Gulnur; Arici, Aydin; Kayisli, Umit AliEndometriosis is a common inflammatory gynecological disease characterized by the presence of endometrial tissue outside of the uterine cavity. The c-Jun N-terminal kinase (JNK) is a subfamily of the mitogen-activated protein kinases (MAPKs) involved in cellular processes ranging from cytokine expression to apoptosis, and is activated in response to inflammation and cellular stress. We hypothesized that inflammatory cytokines in the peritoneal microenvironment increase JNK MAPK activity in endometriotic endothelial cells, and that human endometrial endothelial cells (HEECs) may be involved in inflammatory pathogenesis of endometriosis. Thus, we evaluated the expression of the total- and phosphorylated-(phospho)-JNK in endometrial and endometriotic endothelial cells in vivo, and in HEECs treated with normal fperitoneal fluid (NPF), endometriotic peritoneal fluid (EPF), and the inflammatory cytokines interleukin-1beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) in vitro. Phospho-JNK immunoreactivity in HEECs in normal endometrium was significantly higher in the early proliferative and late secretory phases compared to other phases. Both eutopic and ectopic HEECs from the early secretory phase also revealed higher phospho-JNK immunoreactivity, compared to their respective cycle-matched normal HEECs. Moreover, HEECs treated with EPF showed significantly higher phospho-JNK levels compared to that in HEECs treated with NPF. In conclusion, our in vivo and in vitro findings suggest that increased phosphorylation of JNK in HEECs from women with endometriosis is likely due to high level of IL-1 beta and TNF-alpha in peritoneal fluid; this in turn may up-regulate inflammatory cytokine expression and thus play a role in the pathogenesis of endometriosis.Öğe MAPK immunoreactivity in streptozotocin-induced diabetic rat testis(Acta Cirurgica Brasileira, 2014) Donmez, Yeliz Bozdemir; Kizilay, Gulnur; Topcu-Tarladacalisir, YeterPURPOSE: To evaluate the alterations of two mitogen-activated protein kinases (MAPK)s, extracellular signal regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK), in the testes of male rats with experimental diabetes. METHODS: Twenty males Sprague-Dawley rats were randomly divided into a control group (n=8) and a diabetes group (administration of 40 mg/kg/day streptozotocin (STZ) for five sequential days, n=12). After six weeks, testicular biopsy samples were obtained for light microscopy and immunohistochemical methods. RESULTS: The PCNA (proliferating cell nuclear antigen) index was significantly decreased in the diabetes group (p=0.004) when compared to the control group. Both total (t)-ERK and phosphor (p)-ERK immunoreactivities were significantly decreased in the diabetes group (p=0.004, p<0.001, respectively). The t-JNK immunoreactivity was unchanged in both groups (p=0.125), while p-JNK immunoreactivity was significantly increased in the diabetic group (p=0.002). CONCLUSIONS: The decrease of androgen levels in the course of diabetes may contribute to the decrease of the immunoreactivities of t-ERK and p-ERK. JNK may be activated due to the changes in various cytokines and chemochines that participate in the oxidative stress process of diabetes. Therefore, testicular apoptosis may occur and lead to infertility associated with diabetes.Öğe Progestin-inflammatory cytokine interactions affect matrix metalloproteinase-1 and-3 expression in term decidual cells: Implications for treatment of chorioamnionitis-induced preterm delivery(Endocrine Soc, 2008) Oner, Ceyda; Schatz, Frederick; Kizilay, Gulnur; Murk, William; Buchwalder, Lynn F.; Kayisli, Umit A.; Arici, AydinContext: Chorioamnionitis (CAM)-elicited preterm delivery (PTD) is associated with elevated amniotic fluid levels of IL-1 beta and TNF-alpha. We hypothesized that IL-1 beta and TNF-alpha may induce matrix metalloproteinase (MMP)-1 and MMP-3 activity to promote PTD by degrading decidual and fetal membranes and cervical extracellular matrix. Objective: Our objective was to evaluate: 1) MMP-1 and MMP-3 expression in decidual sections from uncomplicated term, idiopathic preterm, and CAM-complicated deliveries, and 2) the separate and interactive effects of IL-1 beta, TNF-alpha, medroxyprogesterone acetate (MPA), and a p38 MAPK inhibitor (SB203580) on MMP-1 and MMP-3 expression in term decidual cells (DCs). Interventions and Main Outcome Measures: Decidua were immunostained for MMP-1 and MMP-3. Cultured term DCs were incubated with estradiol (E2) or E2 plus MPA with or without IL-1 beta or TNF-alpha with or without S13203580. ELISA and Western blotting assessed secreted MMP-1 and MMP-3 levels, quantitative real-time RT-PCR assessed mRNA levels, and substrate gel zymography was used to determined MMP-1 and MMP-3 proteolytic activity. Results: MMP-1 and MMP-3 immunostaining was more prominent in CAM-complicated decidua vs. control preterm and term decidual specimens (P < 0.05). Compared with basal outputs by DCs incubated with E2, TNF-a enhanced MMP-1 and MMP-3 secretion by 14 +/- 3- and 9 +/- 2-fold, respectively, and IL-1 beta increased MMP-1 and MMP-3 secretion by 13 +/- 3- and 19 +/- 2-fold, respectively (P < 0.05). Addition of MPA lowered basal MMP-1 and MMP-3 outputs by 70%, whereas the TNF-alpha- and IL-1 beta-enhanced MMP-1 and MMP-3 levels were blunted by more than 50% (P < 0.05). SB203580 suppressed TNF-alpha- and IL-1 beta-induced MMP-1 and MMP-3 secretion by severalfold. Western blotting confirmed the ELISA results, and mRNA levels corresponded with MMP-1 and MMP-3 protein levels. MMP-1 and MMP-3 proteolytic activity was confirmed by substrate gel zymography. Conclusion: Augmented DC-expressed MMP-1 and MMP-3 in CAM-complicated pregnancies may promote PTD via decidual, fetal membrane, and cervical extracellular matrix degradation. Effects of progestin-p38 MAPK signaling inhibition on cytokine-enhanced MMP-1 and MMP-3 expression in term DCs suggest alternative mechanisms to prevent CAM-induced PTD.Öğe Protective effect of sildenafil on liver injury induced by intestinal ischemia/reperfusion(W B Saunders Co-Elsevier Inc, 2013) Inan, Mustafa; Uz, Yesim Hulya; Kizilay, Gulnur; Topcu-Tarladacalisir, Yeter; Sapmaz-Metin, Melike; Akpolat, Meryem; Aydogdu, NurettinBackground: This study evaluated the protective effect of sildenafil on liver injury induced by intestinal ischemia-reperfusion. Methods: Forty female Sprague Dawley rats were divided into 4 groups: sham-control (SC), ischemia (I), ischemia-reperfusion (IR), and ischemia-reperfusion+ sildenafil (SIL; sildenafil gavaged at 50 mg/kg before operating). A 2-h ischemia-reperfusion was performed by clamping the superior mesenteric artery. Liver function, plasma alanine (ALT) and aspartate (AST) aminotransferase, and intestinal and liver malondialdehyde (MDA) were measured at the end of the experiment. Intestinal and liver tissue damage was examined by histology. Liver samples were immunologically stained for endothelial nitric oxide synthase (eNOS) and proliferating cell nuclear antigen (PCNA). Results: The ALT and AST levels were highest in the IR group and were lower in the SIL group (p<0.05). Intestinal MDA levels were statistically higher in the IR group than in the SC, I and SIL groups. Liver MDA levels were significantly higher in the IR group than in the I and SC groups (p<0.05) and higher than in the SIL group (p>0.05). Intestinal damage based on Chiu scoring was more severe in the IR than in the SIL group (p<0.05). Sildenafil reduced damage and also increased eNOS and PCNA immunoreactivity in liver tissue. Conclusions: Sildenafil shows a protective effect on intestinal ischemia-reperfusion-induced liver injury, possibly by decreasing vascular resistance through increased nitric oxide levels. (C) 2013 Elsevier Inc. All rights reserved.Öğe Role of JNK, TGF-?1, Akt, IL-1? and INSL-3 in proanthocyanidin protection against apoptosis in diabetic rat testis(Taylor & Francis Ltd, 2022) Kizilay, Gulnur; Bayram, Sinasi; Ersoy, Onur; Cerkezkayabekir, Aysegul; Sapmaz-Metin, Melike; Karaca, TuranWe investigated how proanthocyanidin treatment altered c-Jun N-terminal kinases, transforming growth factor beta 1, serine/threonine-specific protein kinase, interleukin 1 beta and insulin-like 3 expression in the testis of diabetic rats. We used 24 Wistar albino male rats divided into four groups. Group 1 was untreated control. Group 2 was treated with 40 mg/kg streptozotocin (STZ) for 5 days. Group 3 was treated with 40 mg/kg STZ + 250 mg/kg proanthocyanidin once daily for six weeks. Group 4 was treated with 40 mg/kg STZ + 250 mg/kg proanthocyanidin. Superoxide dismutase activity was reduced in groups 3 and 4 compared to group 2. Glutathione peroxidase activity was increased significantly in groups 3 and 4 compared to groups 1 and 2. Catalase activity was decreased in group 4 compared to group 2. We found that proanthocyanidin increased cell proliferation in diabetic testis. Phospho-JNK and TGF-beta 1 immunostaining was decreased groups 3 and 4 compared to group 2, while p-Akt immunostaining was increased in groups 3 and 4. The number of IL-1 beta immunostained cells in groups 3 and 4 was decreased compared to group 2. INSL-3 immunostaining was increased significantly in group 3 compared to group 2. Our findings indicate that proanthocyanidin ameliorated diabetes related testicular dysfunction. Proanthocyanidin contributes to a balanced oxidant-antioxidant status, and balanced proliferation and apoptosis activity in the germinal cells.Öğe The short-term effects of single toxic citric acid doses on mouse tissues - Histopathological study(Parlar Scientific Publications (P S P), 2008) Aktac, Tulin; Kaboglu, Aysegul; Kizilay, Gulnur; Bakar, ElvanIn this study, the acute-toxic effects of citric acid, a food preservative, were histopathologically investigated on the liver and kidney tissues of mice. A LD25 (480 mg/kg body weight) dose of citric acid was given by intraperitoneal injection, and after ten days several necrotic changes were observed in both tissues by light and electron microscopy. Citric acid treatment caused loosing and combining of hepatocyte membranes; cytoplasmic vacuolization in hepatocytes; picnotic nuclei; mononuclear cell infiltration in small areas, and degeneration of blood vessel endothelium in liver; damaging of cell membrane; picnotic nuclei and hypertrophy of lining epithelium of tubules; disappearing of basal membrane and fusing of tubules in kidney. It also caused a decrease in numbers and volume of mitochondria and increase in secondary lysosomes, disorganization and loss of mitochondrial cristae in both tissues, invagination of nucleus membrane in liver, disorder of basal infoldings, swelling in endoplasmic reticulum sacs and loss of junctional complex as well as partial separation of tubule cells in kidney. The results suggest that citric acid dose level has toxic effects in mice, and additional toxic properties must be examined in detail.Öğe Sitagliptin and fucoidan prevent apoptosis and reducing ER stress in diabetic rat testes(Wiley, 2021) Kizilay, Gulnur; Ersoy, Onur; Cerkezkayabekir, Aysegul; Topcu-Tarladacalisir, YeterSitagliptin increases the levels of incretin hormones and stimulates a decrease in blood glucose levels, by blocking the DPP4 enzyme. We have very limited information about impact of sitagliptin on male genital system and relationship between sitagliptin/diabetes/ER. Fucoidan can be effective in blood glucose homeostasis. We goal to explain of the effect of sitagliptin and introduce an approach of fucoidan treatment in experimental diabetes in male rats. Fifty-eight Wistar albino rats were divided into C-control group and D-diabetes group: 60 mg/kg streptozotocin intraperitoneal (i.p.); DS group: STZ + 10 mg/kg sitagliptin intragastric (i.g.); DF group: STZ + 100 mg/kg fucoidan i.p.; and DSF group: STZ + 10 mg/kg sitagliptin + 100 mg/kg fucoidan. A significant decrease was detected when DS, DF and DSF groups compared to group D in blood glucose levels, basement membrane thickness and also apoptotic cell/tubule index, pJNK, caspase 3, caspase 12, GRP78, CHOP and DPP4. Sitagliptin and fucoidan have been found to be effective in blood glucose homeostasis and reducing the expression of certain proteins that lead to apoptosis and especially the proteins in the ER stress pathway. Therefore, we think that both sitagliptin and fucoidan can be effective in preventing or eliminating histopathological damages in diabetic testicular tissues, and their treatment effects can be used more.Öğe Ultrastructural changes in rat liver by methyleugenol and evaluation of some biochemical parameters(Tubitak Scientific & Technological Research Council Turkey, 2010) Cerkezkayabekir, Aysegul; Kizilay, Gulnur; Ertan, FigenThe present study investigated the effect of methyleugenol, a food flavoring and fragrance agent, on the livers of laboratory rats. Doses of 10 and 30 mg/kg/day of methyleugenol (in 0.5% methylcellulose) were administered intragastrically (IG) to 2 dose groups for 10 days alongside a control group (n = 10 for each group). Gains in body weight were not statistically significant for either dose. Lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) activities decreased (P < 0.05) for both dose groups, but AST (aspartate aminotransferase) activity decreased significantly (P < 0.05) only in the 30 mg/kg/day methyleugenol dose group. Alanine aminotransferase (ALT) activity did not change significantly in either group. The total amount of glucose remained unchanged, but glycogen in the liver decreased significantly (P < 0.05) in the 30 mg/kg/day methyleugenol dose group. There was also an increase of swelling in the smooth endoplasmic reticulum sacs (sER), electron dense accumulations in the sER, cytoplasmic vacuolization, a slight increase of mitochondria and lysosomes, and invaginations in the nucleus membranes of hepatocytes. Extensions in bile canaliculi and increasing microvilli of bile canaliculi in the liver were also observed. These findings indicate the ultrastructural toxic effect of methyleugenol on rat livers in 10 and 30 mg/kg/day doses. Therefore, we may speculate that the toxic effect of methyleugenol needs to be examined in detail.Öğe Vitamin E modulates apoptosis and c-jun N-terminal kinase activation in ovarian torsion-detorsion injury(Academic Press Inc Elsevier Science, 2013) Sapmaz-Metin, Melike; Topcu-Tarladacalisir, Yeter; Uz, Yesim Hulya; Inan, Mustafa; Omurlu, Imran Kurt; Cerkezkayabekir, Aysegul; Kizilay, GulnurThe aim of this study was to evaluate the role of vitamin E in follicular degeneration and to assess histopathological and biochemical changes following ischemia-reperfusion (IR) injury in rat ovaries. Twenty-eight Wistar albino rats were randomly divided into four groups: sham, 4 h torsion, 24 h detorsion, and a vitamin E group. Thirty minutes before detorsion, a single dose of 200 mg/kg vitamin E was administered intraperitoneally. The ovarian histology score was determined, serum levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were measured. The apoptosis of granulosa cells and the phospho-c-jun N-terminal kinase (p-JNK) and phospho-p38 (p-p38) immunoreactivities of these cells were determined. MDA and MPO levels were significantly increased in the torsion and detorsion groups. Hemorrhage, edema, and congestion were also apparent in these groups. In addition, the apoptotic index and the immunoreactivity of p-JNK were highest in the detorsion group, which also showed marked follicular degeneration. However, p-p38 activity was not affected by torsion-detorsion (TD) induction. Vitamin E ameliorated TD-induced histological alterations. It also decreased serum levels of MDA and MPO, reduced the activity of p-JNK in the ovaries, and reduced numbers of apoptotic follicular cells. In conclusion, these data indicate that vitamin E attenuated ovarian follicular degeneration by inhibiting the immunoreactivity of p-JNK and reducing the apoptosis of granulosa cells. (c) 2013 Elsevier Inc. All rights reserved.
