Browsing by Author "Gül, Zülfiye"
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Item Assessment of neuron-specific enolase, S100B and malondialdehyde levels in serum and vitreous of patients with proliferative diabetic retinopathy(Springer, 2020-01) Asadova, Vusala; Gül, Zülfiye; Büyükuysal, Rıfat Levent; Yalçınbayır, Özgür; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Göz Hastalıkları Anabilim Dalı.; 0000-0002-7311-5277; AAH-1657-2021; AAH-6625-2021; 6602686612; 8702056700Purpose To assess the vitreous and serum levels of neuron-specific enolase (NSE), S100B and malondi-aldehyde (MDA) in proliferative diabetic retinopathy (PDR) cases and investigate the correlation between preoperative and postoperative anatomical and clinical features. Materials and methods The study group included patients who had pars plana vitrectomy (PPV) for PDR. The control group included non-diabetic individuals who underwent PPV surgery for vitreoretinal interface disorders. Samples of serum were taken from all participants preoperatively, while vitreous samples were taken during the PPV. Vitreous and serum levels of NSE, S100B and MDA were measured, and comparisons were made between the groups. Results The study group consisted of 56 eyes of 56 cases with PDR. The control group consisted of 20 eyes of 20 cases. The concentrations of vitreous NSE, S100B and MDA were significantly higher than the control group (p < 0.0001, p < 0.05, p < 0.001, respectively). Serum levels were statistically different for NSE and S100B (p < 0.05). Conclusion Our results clearly show that vitreous levels of S100B, NSE and MDA and serum concentrations of NSE and S100B increased significantly in patients with PDR. The findings may possibly indicate neurodegeneration and oxidative stress; therefore, these markers may have a diagnostic value in patients with PDR.Item The association between olfaction and taste functions with serum ghrelin and leptin levels in obese women(Mary Ann Liebert, 2019-09) Uygun, Burçin; Kıyıcı, Sinem; Özmen, Suay; Gül, Zülfiye; Sığırlı, Deniz; Çavun, Sinan; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Dahili Tıp Bilimleri/Tıbbi Farmakoloji.; AAA-7472-2021; AAC-9702-2019; 24482063400; 6507468595Purpose: To investigate the olfaction and taste functions in obese female patients and the association between serum ghrelin and leptin levels compared with healthy controls. Methods: Fifty-two obese women, who have a body mass index >30 kg/m(2), and 15 healthy women were included in the study. After 8 hrs fasting, blood samples were taken for serum biochemical parameters, ghrelin, and leptin level measurement. For the quantitative assessment of olfactory function, all participants underwent an N-butanol threshold test and odor identification test using 12 Sniffin' Sticks (R) fragrance sticks. The gustatory function was tested by administering a whole-mouth above threshold test using sucrose solutions. Results: The sucrose taste threshold score in obese women was significantly higher than the controls (P = 0.004). We found positively significant correlation between serum ghrelin levels and n-butanol threshold scores in obese women (r = 0.300, P = 0.031). N-butanol smell threshold was not significantly different between the two groups (P = 0.149), while the Sniffin' Sticks smell test scores were significantly lower in obese women compared with the controls (P = 0.007). Serum leptin levels were also significantly higher in obese women (P < 0.001) although there was no significant difference in serum ghrelin levels between the two groups (P = 0.768). There was no correlation between serum leptin levels and Sniffin' Sticks scores, n-butanol, and sucrose taste threshold scores in obese women. Conclusions: These results might suggest that leptin, which is an anorexigenic peptide, may have a negative effect on taste and smell functions. More studies are warranted to elucidate the exact role of ghrelin secretion on olfaction and taste functions.Publication Biochemical changes in hemolymph of spinning and non-spinning silkworm larvae, bombyx mori (l., 1758) (Lepidoptera: Bombycidae), reared on fresh mulberry leaves: Possible reasons for non-spinning syndrome(Ege Üniversitesi, 2020-01-01) Şahan, Ümran; Gül, Zülfiye; Büyükuysal, Levent Rıfat; ŞAHAN, ÜMRAN; BÜYÜKUYSAL, RİFAT LEVENT; Bursa Uludağ Üniversitesi/Ziraat Fakültesi/Zootekni Bölümü; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı; AAH-2966-2021; IKI-0689-2023Non-spinning syndrome in Bombyx mori (L., 1758) (Lepidoptera: Bombycidae) is a serious issue for the sericulture industry. Determination of urea metabolism as an important parameter at the onset of spinning has shown the need for examining the role of urea metabolism in the non-spinning syndrome. The aim of this study was to investigate role of urea metabolism in the non-spinning syndrome by evaluating urease activity and L-arginine concentrations in the silkworm hemolymph and mulberry leaves. Additionally, urea concentrations were determined in hemolymph samples. Urease activities in hemolymph samples were almost twice as high in spinning larvae (SL) than in non-spinning larvae, 25 +/- 5.8 vs 10.9 +/- 2.4 units/l (P < 0.05). Urea concentrations in the SL hemolymph decreased significantly from day 5 (137 +/- 13 mg/l) to day 7 (97 +/- 17 mg/l) of the fifth instar (P < 0.01), it remained almost constant in NSL hemolymph (149 +/- 19 to 167 +/- 4 mg/l). Additionally, L-arginine concentrations in hemolymph samples obtained from NSL of 4.55 +/- 0.48 mM were significantly higher than in SL at 2.72 +/- 0.45 mM (P < 0.01). Changes in urease activity and L-arginine concentrations in hemolymph were similarly observed in mulberry leaves. These results suggested that changes in urea metabolism may cause or contribute to non-spinning syndrome in silkworms.Item Brain slice viability determined under normoxic and oxidative stress conditions: Involvement of slice quantity in the medium(Taylor & Francis, 2020-03-03) Gül, Zülfiye; Büyükuysal, M. Çağatay; Büyükuysal, R. Levent; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; AAH-1657-2021; 6602686612Objective: In vitro acute adult brain slice methods are instruments in developing our knowledge of the nervous system. Optimization of this method for obtaining high-quality brain slices is extremely important in terms of consistency and reliability of the experimental results. Although some important topics such as slice thickness, temperature, and composition of the physiological medium have been studied for optimization, involvement of slice quantity in medium on tissue viability has not been investigated yet. Methods: Different number of slices (1, 3, or 6 slices) were incubated under normoxic or some prooxidant stress conditions induced by oxygen-glucose deprivation (OGD), H2O2, FeSO4+ ascorbic acid, or menadione to evaluate the effect of slice density on tissue viability. Results:Slice quantity in the normoxic incubation medium caused a significant increase in 2,3,5-triphenyltetrazolium chloride (TTC) staining intensity of the slices. Similarly, increase in the slice quantity in the medium also protected the slices against either OGD, H2O2, FeSO4, or menadione-induced decrease in TTC staining. In addition to TTC staining, lactate dehydrogenase leakage or malondialdehyde and reactive oxygen species production under normoxic or ischemia-like conditions were also attenuated by increasing slice quantity in the medium. Conclusion: These results show that when using brain slices method for investigating the structural and functional features of brain at the molecular and cellular levels, both slice quantity in the medium and incubation volume should be considered first. Increasing slice quantity or decreasing incubation volume probably causes an increase in the concentration of endogenous substance(s) involved in neuroprotection.Item Chlorogenic acid enhances abdominal skin flap survival based on epigastric artery in nondiabetic and diabetic rats(Lippincott Williams & Wilkins, 2014-06-06) Bağdaş, Deniz; Etöz, Betül Çam; Gül, Zülfiye; Özyiğit, Musa Özgür; Çinkılıç, Nilüfer; İnan, Sevda; Büyükcoşkun, Naciye İsbil; Özlük, Kasım; Gürün, Mine Sibel; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; Uludağ Üniversitesi/Tıp Fakültesi/Fizyoloji Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Eczacılık Anabilim Dalı.; Uludağ Üniversitesi/Veteriner Fakültesi/Patoloji Anabilim Dalı.; Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü.; 0000-0002-3595-6286; 0000-0001-8138-5851; 0000-0002-8872-0074; AAF-9939-2020; AAH-5296-2021; E-3364-2018; AAR-6478-2021; AAH-1692-2021; AAG-8716-2019; AAH-2873-2021; 15062425700; 56427863700; 56086542900; 6507338060; 26533892300; 56320836200; 6603128152; 6602676331; 55664349700Previous studies showed that chlorogenic acid (CGA) accelerates wound healing via its antioxidant activity. We aimed to investigate the effect of CGA in an experimental epigastric abdominal skin flap model in nondiabetic and diabetic rats. Rats were firstly divided into 2 groups: nondiabetic and diabetic. Diabetes was induced by streptozotocin. Then, 4 subgroups were created for each group: vehicle as well as 0.2 mg/0.5 mL, 1 mg/0.5 mL, and 5 mg/0.5 mL CGA treatments. Right epigastric artery-based abdominal skin flaps were elevated and sutured back into their original position. Chlorogenic acid or vehicle was injected once into the femoral arteries by leaving the epigastric artery as the single artery feeding the flaps during the injection. On postoperative day 7, flap survivals were evaluated, and the rats were killed. Distal flap tissues were collected for histopathological and biochemical assays. Chlorogenic acid showed greater flap survival in both nondiabetic and diabetic rats. Capillary density was increased, and necrosis was reduced in the CGA-treated rats. Chlorogenic acid decreased malondialdehyde levels as well as increased reduced glutathione and superoxide dismutase levels in the flap tissues. This study showed that CGA significantly improved flap survival by its antioxidant activities with intra-arterial local injections.Item (E)-3-furan-2-yl-N-phenylacrylamide (PAM-4) decreases nociception and emotional manifestations of neuropathic pain in mice by α7 nicotinic acetylcholine receptor potentiation(Taylor and Francis, 2021-07-27) Rabha, Younis; Han-Shen, Tae; Ortells, Marcelo O.; Arias, Hugo R.; Bağdaş, Deniz; Gül, Zülfiye; Sevdar, Gülce; Cavun, Sinan; Gürün, Mine Sibel; Uludağ Üniversitesi/Tıp Fakültesi/Sinir Bilimleri ve Nöroloji; 0000-0003-0307-3486; 0000-0001-5050-095X; JCN-7924-2023; AAC-9702-2019; DVX-8040-2022; 57226240379; 6507468595; 55664349700Clinical intervention of pain is often accompanied by changes in affective behaviors, so both assays of affective and sensorial aspects of nociception play an important role in the development of novel analgesics. Although positive allosteric modulation (PAM) of alpha 7 nicotinic acetylcholine receptors (nAChRs) has been recognized as a novel approach for the relief of sensorial aspects of pain, their effects on affective components of pain remain unclear. Therefore, we investigated whether PAM-4, a highly selective alpha 7-nAChR PAM, attenuates inflammatory and neuropathic pain, as well as the concomitant depressive/anxiety comorbidities. The anti-nociceptive activity of PAM-4 was assessed in mice using the formalin test and chronic constriction injury (CCI)-induced neuropathic pain model. The anxiolytic- and antidepressant-like activity of PAM-4 was evaluated using the marble burying test and forced swimming test. Acute systemic administration of PAM-4 dose-dependently reversed formalin-induced paw licking behavior and CCI-induced mechanical allodynia without development of any motor impairment. PAM-4 reversed the decreased swimming time and number of buried marbles in CCI-treated mice, suggesting that this ligand attenuates chronic pain-induced depression-like behavior and anxiogenic-like effects. The effects of PAM-4 were inhibited by the alpha 7-selective antagonist methyllycaconitine, indicating molecular mechanism mediated by alpha 7-nAChRs. Indeed, electrophysiological recordings showed the PAM-4 enhances human alpha 7 nAChRs with higher potency and efficacy compared to rat alpha 7 nAChRs. These findings suggest that PAM-4 reduces both sensorial and affective behaviors induced by chronic pain in mice by alpha 7-nAChR potentiation. PAM-4 deserves further investigations for the management of chronic painful conditions with comorbidities.Item Effect of rainbow trout (Oncorhynchus mykiss) seminal plasma on the post-thaw quality of ram semen cryopreserved in a soybean lecithin-based or egg yolk-based extender(Elsevier, 2015-11-15) Üstüner, Burcu; Alcay, Selim; Toker, M. Berk; Nur, Zekariya; Gökce, Elif; Sonat, Füsun Ak; Gül, Zülfiye; Duman, Muhammed; Cenize, Cafer; Uslu, Aydın; Saığrkaya, Hakan; Soylu, Mustafa Kemal; Uludağ Üniversitesi/Veteriner Fakültesi/Üreme ve Suni Tohumlama Anabilim Dalı.; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; Uludağ Üniversitesi/Veteriner Fakültesi/Su Hayvanları Hastalıkları Anabilim Dalı.; 0000-0001-7707-2705; 0000-0002-1438-221X; 0000-0002-8872-0074; 0000-0002-7678-3289; AAH-2635-2021; T-1697-2019; AAH-8821-2021; AAF-9939-2020; AAG-7238-2021; 18937724600; 56099810300; 56480349200; 6508060684; 56779799700; 26428428000; 56086542900; 55568071100; 57070339500; 57069822700; 6602400461; 7003293300The aim of the current study was to evaluate the effects of different concentrations of rainbow trout seminal plasma (RTSP) (0.1%, 1% and 10%) in extenders containing either egg yolk or lecithin for use in Awassi ram semen cryopreservation. Pooled sperm were diluted in a two-step dilution method to a final concentration of 1/5 (semen/extender) in egg yolk or lecithin extender containing no RTSP, 0.1%, 1% or 10% RTSP (v/v). Semen samples were assessed for sperm motility, plasma membrane integrity [hypoosmotic swelling test (HOST) and Hoechst 33258] and defective acrosomes [FITC-conjugated Pisum sativum agglutinin (PSA-FITC)] at the following five time points: after dilution with extender A; after equilibration; and post-thaw at 0 h, 3 h and 5 h. Malondialdehyde (MDA) was examined only after thawing. Freezing and thawing procedures (dilution, equilibration and post-thaw incubation at Oh, 3 h and 5 h) negatively affected the motility (P<0.001) and acrosome integrity (P<0.001). Additionally, freezing and thawing negatively affected the plasma membrane integrity, as determined by the HOST and Hoechst 33258 (P<0.001). The extender group affected the motility (P<0.001) and the HOST results (P<0.001). Levels of MDA in the egg yolk extender with 1% RTSP group were significantly lower than in the lecithin control group (P<0.05). In conclusion, the egg yolk extender groups that were supplemented with 10% and 1% RTSP provided greater cryoprotective effects for semen survivability during 5 h incubation than the other extender groups.Item The effects of menthol-nicotine usage on gastric mucosal damage and the investigation of possible mechanisms(Wiley, 2016-09) Şahintürk, Serdar; Gül, Zülfiye; Çam, Betül; Bağdaş, Deniz; Büyükcoşkun, Naciye İsbil; Özlük, Kasım; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Fizyoloji Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Birimi.; AAH-1692-2021; AAF-9939-2020; CGO-3719-2022; DQA-8365-2022; EOB-5882-2022Item Effects of systemic chlorogenic acid on random-pattern dorsal skin flap survival in diabetic rats(Pharmaceutical Soc Japan, 2014-03) Bağdaş, Deniz; Çam, Betül Etöz; İnan, Sevda; Çinkılıç, Nilüfer; Özyiğit, Musa Özgür; Gül, Zülfiye; Büyükcoşkun, Naciye; Özlük, Kasım; Gürün, Mine Sibel; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Birimi.; Uludağ Üniversitesi/Tıp Fakültesi/Fizyoloji Anabilim Dalı.; Uludağ Üniversitesi/Veterinerlik Fakültesi/Klinik Öncesi Bilimler Bölümü.; Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü.; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0002-3595-6286; 0000-0001-8138-5851; 0000-0002-8872-0074; AAF-9939-2020; AAH-5296-2021; AAH-2873-2021; AAH-1692-2021; E-3364-2018; AAG-8716-2019; 15062425700; 24179406800; 56320836200; 26533892300; 6507338060; 56086542900; 55665951400; 6602676331; 55664349700There has been considerable interest in understanding the effects of antioxidants in flap survival during diabetes. Previous studies showed that chlorogenic acid (CGA) exhibits potent antioxidant effects. We aimed to determine the effects of systemic CGA treatment on skin flap survival in an experimental random-pattern dorsal skin flap model in diabetic rats. Twenty-eight male Wistar rats were divided into four groups: phosphate buffered saline (PBS)-treated or CGA-treated nondiabetic rats, PBS-treated or CGA-treated diabetic rats. Diabetes was induced by streptozotocin (45 mg/kg). Caudally based bipedicled dorsal skin flaps were elevated. CGA (100 mg/kg) or PBS (mL/kg; as vehicle) was administered intraperitoneally once daily. On postoperative day 7, flap survival, regional blood perfusion and microangiography were evaluated. The malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and nitric oxide (NO) levels were evaluated from the flap tissue. Capillary density and vascular endothelial growth factor (VEGF) expression were assessed. Harmful effects of diabetes on flap survival were observed. CGA attenuated these effects and allowed greater survival and blood perfusion. CGA decreased MDA and NO levels and increased GSH and SOD levels. CGA elevated capillary density and VEGF expression. This study showed that peripherally administered CGA significantly improved flap survival in diabetic and nondiabetic rats.Item Exenatide treatment causes suppression of serum fasting ghrelin levels in patients with type 2 diabetes mellitus(Bioscientifica Ltd, 2017-12-07) Güçlü, Metin; Kıyıcı, Sinem; Gül, Zülfiye; Çavun, Sinan; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; 0000-0002-8872-0074; AAF-9939-2020; 56086542900; 6507468595Aim: In the present study, we investigated the long-term effects of exenatide treatment on serum fasting ghrelin levels in patients with type 2 diabetes mellitus. Methods: Type 2 diabetic patients, who were using metformin with and without the other antihyperglycemic drugs on a stable dose for at least 3 months, were enrolled in the study. BMI>35 kg/m(2) and HbA1c>7.0% were the additional inclusion criteria. Oral antihyperglycemic drugs, other than metformin, were stopped, and metformin treatment was continued at 2000 mg per day. Exenatide treatment was initiated at 5 mu g per dose subcutaneously (sc) twice daily, and after one month, the dose of exenatide was increased to 10 mu g twice daily. Changes in anthropometric variables, glycemic control, lipid parameters and total ghrelin levels were evaluated at baseline and following 12 weeks of treatment. Results: Thirty-eight patients (male/female = 7/31) entered the study. The mean age of patients was 50.5 +/- 8.8 years with a mean diabetes duration of 8.5 +/- 4.9 years. The mean BMI was 41.6 +/- 6.3 kg/m(2) and the mean HbA1c of patients was 8.9 +/- 1.4%. The mean change in the weight of patients was -5.6 kg and the percentage change in weight was -5.2 +/- 3.7% following 12 weeks of treatment. BMI, fasting plasma glucose and HbA1c levels of patients were decreased significantly (P < 0.001 and P < 0.001; respectively), while there was no change in lipid parameters. Serum fasting ghrelin levels were significantly suppressed following 12 weeks of exenatide treatment compared with baseline values (328.4 +/- 166.8 vs 245.3 +/- 164.8 pg/mL) (P = 0.024). Conclusion: These results suggest that the effects of exenatide on weight loss may be related with the suppression of serum fasting ghrelin levels, which is an orexigenic peptide.Item Exenatide treatment causes suppression of serum ghrelin levels following mixed meal test in obese diabetic women(Hindawi, 2016-01-21) Topyıldız, Figen; Kıyıcı, Sinem; Güçlü, Metin; Kısakol, Gürcan; Gül, Zülfiye; Sıgırlı, Deniz; Çavun, Sinan; Uludağ Üniversitesi/Tıp Fakültesi/Eczacılık Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Biyoistatistik Anabilim Dalı.; 0000-0002-8872-0074; AAF-9939-2020; AAA-7472-2021; AAC-9702-2019; 56086542900; 24482063400; 6507468595Aim. To investigate the effect of exenatide treatment on serum ghrelin levels in obese female patients with type 2 diabetes mellitus. Methods. Fourteen female patients with type 2 diabetes mellitus being treated with metformin and exenatide were enrolled. A mixed meal test was applied to the patients while continuing with their daily medications. Blood samples were taken before and at 60, 120, and 180 minutes following mixed meal test to measure serum total ghrelin, glucose, and insulin levels. The following week, exenatide treatment of the patients was paused for 24 hours and the same experimental procedures were repeated. Results. Serum ghrelin levels were suppressed significantly at 180 minutes with exenatide treatment compared with baseline (294.4 +/- 57.5 versus 234.5 +/- 59.4 pg/mL) (p < 0.001). Serum ghrelin levels at 180 minutes were statistically different when percentage change in serum ghrelin levels after mixed meal tests with and without exenatide usage were compared (p = 0.001). Estimated total area under the curve values for serum ghrelin concentrations was also significantly lower with exenatide compared with omitted treatment (p = 0.035). Conclusion. These results suggest that the effect of exenatide on weight loss may be related with the suppression of serum ghrelin levels, which is an orexigenic peptide.Item Freeze-dried egg yolk based extenders containing various antioxidants improve post-thawing quality and incubation resilience of goat spermatozoa(Elsevier, 2016-03-21) Alçay, Selim; Gökçe, Elif; Toker, M. Berk; Önder, N. Tekin; Üstüner, Burcu; Uzabacı, Ender; Gül, Zülfiye; Çavuş, Seda; Uludağ Üniversitesi/Veteriner Fakültesi/Üreme ve Suni Tohumlama Anabilim Dalı.; Uludağ Üniversitesi/Veteriner Fakültesi/Biyoistatistik Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; 0000-0001-5141-0008; 0000-0002-7678-3289; 0000-0002-9634-0055; 0000-0002-8872-0074; AAF-9939-2020; AAG-7238-2021; 56099810300; 56779799700; 56480349200; 55670728900; 18937724600; 55347697800; 56086542900; 57188685710The aim of this study was to evaluate different antioxidants-supplemented freeze-dried egg yolk based extenders for the post-thawing quality and incubation resilience of goat spermatozoa. Pooled semen were diluted in a two-step dilution method to a final concentration of 1/5 (semen/extender) in control and antoxidant supplemented freeze-dried extenders (methionine, cysteamine and butylated hydroxytoluene). Semen samples were assessed for sperm motility, plasma membrane functional integrity using hypoosmotic swelling test (HOST), damaged acrosome using FITC-Pisum sativum agglutinin (PSA-FITC) and DNA integrity using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Membrane lipid peroxidation status was also analyzed using the malondialdehyde (MDA) concentration. In the study, antioxidant supplemented freeze-dried egg yolk based extenders have beneficial effect on goat sperm parameters. In addition, we achieved a higher quality in post thawed goat semen even after 6 h incubation when the extender was supplemented by 5 mM BHT or cysteamine.Publication Glutamate-induced modulation in energy metabolism contributes to protection of rat cortical slices against ischemia-induced damage(Lippincott Williams & Wilkins, 2021-01-13) Gül, Zülfiye; Büyükuysal, R. Levent; BÜYÜKUYSAL, RİFAT LEVENT; 0000-0002-8872-0074; AAH-1657-2021Objectives: Glutamate excitotoxicity contributes to neurodegeneration during cerebral ischemia. Recent studies in the protective effect of glutamate against ischemia and hypoxia have shown the need for questioning the role of glutamate in energy metabolism during ischemia. Current study investigates the effect of glutamate on energy substrate metabolites such as alpha-ketoglutarate, lactate, and pyruvate release during control, oxygen-glucose deprivation (OGD), and reoxygenation (REO) conditions. Methods: The effects of 0.5 and 2 mM glutamate on spontaneous alpha-ketoglutarate, lactate, and pyruvate release were tested in vitro, on acute rat cortical slices. Alpha-ketoglutarate, lactate, and pyruvate levels were determined by HPLC with UV detector. Results: We observed that glutamate added into medium significantly increased alpha-ketogluarate release under control conditions. Although OGD and REO also had a glutamate-like effect, only REO-induced rise further enhanced by glutamate. In contrast to alpha-ketoglutarate, both OGD and REO conditions caused significant declines in pyruvate and lactate outputs. While OGD and REO-induced declines in pyruvate outputs were further potentiated, lactate output was not altered by glutamate added into the medium. Glutamate and alpha-ketoglutarate, moreover, also ameliorated OGD- and REO-induced losses in 2,3,5-triphenyltetrazolium chloride staining with a similar degree. Conclusion: These results indicate that glutamate probably increases alpha-ketoglutarate production as an alternative energy source for use in the TCA cycle under energy-depleted conditions. Thus, increasing the alpha-ketoglutarate production may represent a new therapeutic intervention for neurodegenerative disorders, including cerebral ischemia.Item High glutamate attenuates S100B and LDH outputs from rat cortical slices enhanced by either oxygen-glucose deprivation or menadione(Springer, 2014-03-28) Demircan, Celaleddin; Gül, Zülfiye; Büyükuysal, Rıfat Levent; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0002-8872-0074; AAF-9939-2020; AAH-1657-2021; 55399735400; 56086542900; 6602686612One hour incubation of rat cortical slices in a medium without oxygen and glucose (oxygen-glucose deprivation, OGD) increased S100B release to 6.53 +/- A 0.3 ng/ml/mg protein from its control value of 3.61 +/- A 0.2 ng/ml/mg protein. When these slices were then transferred to a medium containing oxygen and glucose (reoxygenation, REO), S100B release rose to 344 % of its control value. REO also caused 192 % increase in lactate dehydrogenase (LDH) leakage. Glutamate added at millimolar concentration into the medium decreased OGD or REO-induced S100B release and REO-induced LDH leakage. Alpha-ketoglutarate, a metabolic product of glutamate, was found to be as effective as glutamate in decreasing the S100B and LDH outputs. Similarly lactate, 2-ketobutyrate and ethyl pyruvate, a lipophilic derivative of pyruvate, also exerted a glutamate-like effect on S100B and LDH outputs. Preincubation with menadione, which produces H2O2 intracellularly, significantly increased S100B and LDH levels in normoxic medium. All drugs tested in the present study, with the exception of pyruvate, showed a complete protection against menadione preincubation. Additionally, each OGD-REO, menadione or H2O2-induced mitochondrial energy impairments determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining and OGD-REO or menadione-induced increases in reactive oxygen substances (ROS) determined by 2,7-dichlorofluorescin diacetate (DCFH-DA) were also recovered by glutamate. Interestingly, H2O2-induced increase in fluorescence intensity derived from DCFH-DA in a slice-free physiological medium was attenuated significantly by glutamate and alpha-keto acids. All these drug actions support the conclusion that high glutamate, such as alpha-ketoglutarate and other keto acids, protects the slices against OGD- and REO-induced S100B and LDH outputs probably by scavenging ROS in addition to its energy substrate metabolite property.Item Impact of menthol on oral nicotine consumption in female and male sprague dawley rats(Oxford University Press, 2019-02-05) Bağdaş, Deniz; Gül, Zülfiye; Scott, Michael M.; Tyndale, Rachel F.; Damaj, M. Imad; Cam, Betül; Büyükuysal, Levent; Gürün, Mine Sibel; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; AAH-1657-2021; CGO-3719-2022; DVX-8040-2022; 56427863700; 6602686612; 55664349700Introduction: One of the preferable flavors in oral nicotine delivery systems is menthol which masks the harshness of tobacco. However, possible interactions between oral menthol and nicotine on intake and preference remain unclear. Therefore, we aimed to determine the impact of menthol on oral nicotine consumption. Methods: Adult Sprague Dawley female and male rats (n = 8 per group) were given a choice of water or drug solution by using two-bottle free choice paradigm for 2 weeks: vehicle (5% ethanol), nicotine (20 mg/L), menthol (1 g/L) and mentholated nicotine groups. At the end of the study, plasma nicotine levels were determined. Results: When rats were given a choice of nicotine or water, nicotine intake was similar between female and male rats. Menthol addition to nicotine solution significantly increased nicotine intake and preference in male but not female rats without a considerable effect on total fluid intake and body weight change in either sex. The average nicotine intake in male rats was 0.5 +/- 0.05 and 1.4 +/- 0.12 mg/kg/day for nicotine and menthol-nicotine combination (p <.05), respectively. The average nicotine intake in female rats was 0.6 +/- 0.05 and 0.6 +/- 0.03 mg/kg/day for nicotine and mentholnicotine combination (p >.05), respectively. Plasma nicotine levels were not significantly different between the groups in either male (nicotine group: 20.8 +/- 4.9, mentholated nicotine group: 31.9 +/- 3.2 ng/mL) or female (nicotine group: 24.0 +/- 3.3, mentholated nicotine group: 17.8 +/- 2.9 ng/mL) rats (p >.05). Conclusions: Menthol increases oral nicotine consumption in male, but not female, rats.Item In vivo systemic chlorogenic acid therapy under diabetic conditions: Wound healing effects and cytotoxicity/genotoxicity profile(Pergamon-Elsevier Science, 2015-07) Bağdaş, Deniz; Etöz, Betül Cam; Gül, Zülfiye; Ziyanok, Sedef; İnan, Sevda; Turaçözen, Özge; Gül, Nihal; Topal, Ayşe B.; Çinkılıç, Nilüfer; Taş, Sibel; Özyiğit, Musa Özgür; Gürün, Mine Sibel; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; Uludağ Üniversitesi/Tıp Fakültesi/Fizyoloji Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; Uludağ Üniversitesi/Fen ve Edebiyat Fakültesi/Biyoloji Bölümü.; Uludağ Üniversitesi/Veteriner Fakültesi/Patoloji Anabilim Dalı.; Uludağ Üniversitesi/Veteriner Fakültesi/Cerrahi Anabilim Dalı.; 0000-0002-8872-0074; 0000-0002-3595-6286; 0000-0001-8138-5851; AAR-6478-2021; AAF-9939-2020; AAG-8716-2019; E-3364-2018; ABE-6873-2020; AAH-4272-2021; AAH-2873-2021; AAH-5296-2021; 15062425700; 56427863700; 56086542900; 9735158200; 56320836200; 56320248500; 8387784600; 56357211200; 26533892300; 7004343411; 6507338060; 55664349700Oxidative stress occurs following the impairment of pro-oxidant/antioxidant balance in chronic wounds and leads to harmful delays in healing progress. A fine balance between oxidative stress and endogenous antioxidant defense system may be beneficial for wound healing under redox control. This study tested the hypothesis that oxidative stress in wound area can be controlled with systemic antioxidant therapy and therefore wound healing can be accelerated. We used chlorogenic acid (CGA), a dietary antioxidant, in experimental diabetic wounds that are characterized by delayed healing. Additionally, we aimed to understand possible side effects of CGA on pivotal organs and bone marrow during therapy. Wounds were created on backs of streptozotocin-induced diabetic rats. CGA (50 mg/kg/day) was injected intraperitoneally. Animals were sacrificed on different days. Biochemical and histopathological examinations were performed. Side effects of chronic antioxidant treatment were tested. CGA accelerated wound healing, enhanced hydroxyproline content, decreased malondialdehyde/nitric oxide levels, elevated reduced-glutathione, and did not affect superoxide dismutase/catalase levels in wound bed. While CGA induced side effects such as cyto/genotoxicity, 15 days of treatment attenuated blood glucose levels. CGA decreased lipid peroxidation levels of main organs. This study provides a better understanding for antioxidant intake on diabetic wound repair and possible pro-oxidative effects.Item K channel blockage with 3,4-diaminopyridine potentiates the effect of L-DOPA on dopamine release in striatal slices prepared from 6-OHDA pre-treated rats(Springer, 2020-08-24) Gül, Zülfiye; Duyu, Gözde; Altınbaş, Burçin; Büyükuysal, Rıfat Levent; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0003-0749-2426; AAH-1657-2021; 6602686612Although L-DOPA revolutionized in the treatment of Parkinson's disease, most patients developed motor complications after several years of treatment. Adjunctive therapy to L-DOPA with drugs related to dopaminergic signaling may reduce its dose without decreasing the therapeutic efficiency and thus ameliorates its adverse effects. It has been shown that 3,4-diaminopyridine (3,4-DAP), a K channel blocker, increased dopamine release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The current study investigates whether 3,4-DAP may enhance L-DOPA-induced dopamine (DA) release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The effects of L-DOPA and 3,4-DAP on spontaneous DA and DOPAC release were tested in vitro, on acute rat striatal slices prepared from non-treated and 6-hydroxydopamine-pre-treated rats. DA and DOPAC levels were determined by HPLC methods. When 3,4-diaminopyridine was combined with L-DOPA, the observed effect was considerably greater than the increases induced by L-DOPA or 3,4-DAP alone in normoxic and neurodegenerative conditions produced by FeSO4 and 6-hydroxydopamine. Furthermore, L-DOPA plus 3,4-DAP also ameliorated DOPAC levels in neurodegenerative conditions. These data indicate that 3,4 DAP plus L-DOPA activates striatal dopaminergic terminals by increasing the DA release and, thus, could be considered as a promising finding in treatment of acute and chronic injury in dopaminergic neurons.Item Kisspeptin’in gelişimsel döneme bağlı olarak dişi sıçanlarda medial preoptik bölgede in vitro noradrenalin salıverilmesi üzerine etkisi(Bursa Uludağ Üniversitesi, 2020-08-07) Gül, Zülfiye; Büyükuysal, Rıfat Levent; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0003-0749-2426Üçüncü ventrikülün rostral periventriküler bölgesinde lokalize olan kisspeptin nöronlarının, ovulasyon öncesi LH salıverilmesinden sorumlu olan GnRH nöronlarının major stimülatörü olduğu son yıllarda yapılan çalışmalar ile ortaya konmuştur. GnRH salıverilmesinin bir diğer ana modülatörü ise noradrenerjik sistemdir. Kisspeptinerjik ve noradrenerjik nöronların medial preoptik bölgedeki (MPB) yerleşimleri çok yakınlık göstermekle birlikte, bu iki sistem arasındaki ilişkinin yapılacak çalışmalar ile aydınlatılmasına ihtiyaç duyulmaktadır. Yapılan bu çalışma gelişim dönemi farklı dişi Sprague Dawley sıçanların MPB’sinden hazırlanan beyin dilimleri kullanılarak kisspeptinin noradrenalin (NA) salıverilmesi üzerine direk etkisinin olup olmadığını ortaya koymak amacı ile yapılmıştır. Oksijenlenmiş Krebs solüsyonu içeren inkübasyon kuyucuklarına yerleştirilen dilimler preinkübasyon dönemi ardından 60 dakika boyunca kisspeptin (40 ve 400 μM) ile inkübe edildi. İnkübasyon periyodu sonrasında inkübasyon ortamı salınan NA düzeylerinin belirlenmesi amacıyla kullanıldı. Salıverilmenin Ca2+ ile ilişkisini incelemek amacıyla Ca2+’suz Krebs solüsyonu ve hücre dışı Ca2+ şelasyonu için 400 μM BAPTA kullanıldı. Prepubertal, adölesan ve yetişkin dişi sıçanların MPB’den elde edilen dilimlerin 40 ve 400 μM kisspeptin ile inkübasyonu prepubertal dönemdeki dilimlerden NA salıverilmesini etkilemezken, adölesan ve yetişkin sıçanlarda ise salıverilmenin anlamlı olarak arttığı gözlendi. Ca2+’un ortamdan uzaklaştırılmasının kisspeptin kaynaklı NA salıverilmesinde anlamlı bir düşüşe (p‹0.05) neden olması veziküler salım mekanizmasının ekstrasellüler Ca+2 iyonlarına bağımlı olduğunu göstermiştir. Kisspeptinin NA salıverilmesini direkt olarak uyarabildiğini gösteren bu bulgular, söz konusu peptidin NA salıverilmesi üzerinden GnRH salıverilmesini indirekt olarak modüle edebileceğini düşündürmektedir.Item Normoksik ve iskemik koşullarda inkübe edilen sıçan kortikal dilimlerinin ttc ile boyanması: Inkübasyon koşullarının boyanma üzerine etkisi(Uludağ Üniversitesi, 2017-10-26) Gül, Zülfiye; Büyükuysal, Rıfat Levent; Uludağ Üniversitesi/Sağlık Bilimleri Enstitüsü/Tıbbi Farmakoloji Anabilim Dalı.Amaç: Deneysel iskemi ve benzeri durumlarda meydana gelen beyin hasarının büyüklüğünün doğru bir şekilde gösterilmesi, hasar mekanizmasının açıklanması ve yeni terapötik yaklaşımlar geliştirilmesi açısından oldukça önemlidir. İnfarkt alanının belirlenmesi amacı ile en fazla tercih edilen yöntemlerden biri beyin kesitlerinin 2,3,5-trifeniltetrazolium klorür (TTC) ile boyanmasıdır. Ancak, değişik deneysel prosedürler kullanılması ile bu boyamada farklı sonuçlar elde edildiği literatürde görülmektedir. Biz bu çalışmayı; inkübasyon ortamındaki dilim sayısının TTC boyama yoğunluğu üzerine etkisini ve bunun hasarlanma ile ilgili diğer parametreler için de söz konusu olup olmadığını incelemek amacıyla planlandık. Metod: Dişi Sprague Dawley sıçanlardan hazırlanan kortikal dilimler (0,4 mm) 2 ml inkübasyon ortamına 1,3,6 dilim olacak şekilde yerleştirildiler. 60 dakikalık preinkübasyon periyodundan sonra dilimler normoksik koşullar yanında, in vitro iskemi, H2O2 (1 mM), FeSO4 (0,1 mM) + askorbik asid veya menadion (1 mM) içeren 4 farklı oksidatif stres modellerinde inkübe edildiler. İnkübasyon sonunda dilimler %0,5 TTC ile boyandı. Doku hasarının tespiti için aynı deney koşullarında, ortama salıverilen LDH yanında, doku MDA ve ROS düzeyleri ölçüldü. Bulgular: Normoksik koşullarda inkübe edilen dilimlerin TTC boyanma yoğunluğunun ortamdaki dilim sayısı arttıkça fazlalaştığı gözlendi. Benzer şekilde hasarlanma ile ilgili diğer parametreler de dilim sayısı artışından olumlu etkilendi.Dört farklı oksidatif stres modeli ile indüklenen TTC boyanma yoğunluğundaki azalma, 1 dilim inkübe edilen grupta en yüksek iken 6 dilim içeren grupta bu azalma anlamlılık düzeyine ulaşmadı. Doku MDA ve ROS düzeyleri ile ortama salınan LDH düzeylerindeki değişikliklerin de, TTC boyanma yoğunluğundaki değişikliklerle yüksek derece korelasyon gösterdiğini tespit edildi. Sonuç: Bu çalışmadan elde edilen sonuçlar, inkübasyon ortamındaki dilim sayısının, normoksik ve oksidatif stres koşullarda deney sonuçlarını etkileyebileceğini açıkca göstermektedir. Bu etkinin mekanizmasını tez çalışması kapsamında çalışılmamış olmakla birlikte, etkinin inkübasyon ortamına salınan endojen nöroprotektif maddelerin konsanstrasyonlarındaki değişiklik ile ilişkili olduğunu düşünmekteyiz.Item Pharmacologic overview of chlorogenic acid and its metabolites in chronic pain and inflammation(Bentham Science, 2020) Meade, Julie; Gül, Zülfiye; Bağdaş, Deniz; Cam, Betül; Cinkılıç, Nilüfer; Gürün, Mine Sibel; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Anabilim Dalı.; 0000-0002-3595-6286; AAH-5296-2021; CGO-3719-2022; DVX-8040-2022; 56427863700; 26533892300; 55664349700Background: Natural phenolic compounds in medicinal herbs and dietary plants are antioxidants which play therapeutic or preventive roles in different pathological situations, such as oxidative stress and inflammation. One of the most studied phenolic compounds in the last decade is chlorogenic acid (CGA), which is a potent antioxidant found in certain foods and drinks. Objective: This review focuses on the anti-inflammatory and antinociceptive bioactivities of CGA, and the putative mechanisms of action are described. Ethnopharmacological reports related to these bioactivities are also reviewed. Materials and Methods: An electronic literature search was conducted by authors up to October 2019. Original articles were selected. Results: CGA has been shown to reduce inflammation and modulate inflammatory and neuropathic pain in animal models. Conclusion: The consensus of the literature search was that systemic CGA may facilitate pain management via bolstering antioxidant defenses against inflammatory insults.