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Papers by SELDAĞ BEKPINAR
Journal of Proteome Research, 2014
Aortic aneurysm is a complex multifactorial disease, and its molecular mechanism is not understoo... more Aortic aneurysm is a complex multifactorial disease, and its molecular mechanism is not understood. In thoracic aortic aneurysm (TAA), the expansion of the aortic wall is lead by extracellular matrix (ECM) degeneration in the medial layer, which leads to weakening of the aortic wall. This dilatation may end in rupture andif untreateddeath. The aortic media is composed of vascular smooth muscle cells (VSMCs) and proteins involved in aortic elasticity and distensibility. Delineating their functional and quantitative decrease is critical in elucidating the disease causing mechanisms as well as the development of new preventive therapies. Laser microdissection (LMD) is an advanced technology that enables the isolation of the desired portion of tissue or cells for proteomics analysis, while preserving their integrity. In our study, the aortic media layers of 36 TAA patients and 8 controls were dissected using LMD technology. The proteins isolated from these tissue samples were subjected to comparative proteomic analysis by nano-LC-MS/MS, which enabled the identification of 352 proteins in aortic media. Among these, 41 proteins were differentially expressed in the TAA group with respect to control group, and all were downregulated in the patients. Of these medial proteins, 25 are novel, and their association with TAA is reported for the first time in our study. Subsequent analysis of the data by ingenuity pathway analysis (IPA) shows that the majority of differentially expressed proteins were found to be cytoskeletal-associated proteins and components of the ECM which are critical in maintaining aortic integrity. Our results indicate that the protein expression profile in the aortic media from TAA patients differs significantly from controls. Further analysis of the mechanism points to markers of pathological ECM remodeling, which, in turn, affect VSMC cytosolic structure and architecture. In the future, the detailed investigation of the differentially expressed proteins may provide insight into the elucidation of the pathological processes underlying aneurysms.
Diabetes Research and Clinical Practice, 2014
Aims: We aimed to investigate the pharmacological efficiency of metformin on asymmetric dimethyla... more Aims: We aimed to investigate the pharmacological efficiency of metformin on asymmetric dimethylarginine (ADMA) metabolism in inflammation caused by the lipopolysaccharide (LPS)/D-galactosamine (D-GalN) treatment. Methods: Adult Sprague-Dawley rats were injected LPS/D-GalN intraperitoneally. One half of the animals was injected metformin (250 mg kg À1 body mass for one week) prior to LPS/D-GalN treatment. Six hours after the LPS/D-GalN injection, livers were removed, and used for the measurements of dimethylarginine dimethylaminohydrolase (DDAH) and myeloperoxidase (MPO) activities, glutathione (GSH), ADMA and arginine levels. Liver tissues were examined histopathologically. The Kruskal-Wallis (posthoc Mann-Whitney U) test was used for the statistics. LPS/D-GalN injections caused liver injury as evidenced by the activities of aminotransferases and arginase. GSH level and DDAH activity were decreased in the liver. Metformin pretreatment alleviated the activity of serum enzymes, and attenuated histopathological lesions caused by LPS/D-GalN injections. LPS/D-GalN-induced inflammation, as confirmed by the increased MPO activity, created an asymmetrical distribution of arginine and ADMA between the tissue and plasma. Metformin decreased tissue ADMA level while it restored the DDAH activity and GSH. Conclusion: Our findings showed that metformin administration for one week has a potency to protect liver through regulating ADMA metabolism in LPS/D-GalN-induced injury.
Genetic Testing and Molecular Biomarkers, 2012
Cyclooxygenase-2 (COX-2) is the inducible isoenzyme of COX that leads to increased production of ... more Cyclooxygenase-2 (COX-2) is the inducible isoenzyme of COX that leads to increased production of prostaglandins and thromboxane, the mediators of inflammation. Controversial data regarding COX levels or activities in the placentas of women with preeclampsia have led us to examine whether a single nucleotide polymorphism (SNP) in the COX-2 gene is associated with the onset of preeclampsia. Two polymorphisms in the promoter region of COX-2 gene were examined by the polymerase chain reaction and restriction fragment length polymorphism in 128 controls and 74 preeclamptic patients. Genotype distribution and allelic frequencies for-765G/C polymorphism of COX-2 gene were significantly different between patients and controls (p = 0.000 and p = 0.042, respectively). The odds ratio (OR) for preeclampsia risk associated to the-765G allelic variant was 4.07 (95% confidence interval [CI]: 0.89-18.56). The AA genotype of the-1195 A/G variant was present at a significantly higher frequency among all preeclamptic subjects (p = 0.000 v 2 : 13.4, OR: 3.44, 95% CI: 1.74-6.77). A moderate linkage was observed between the-765G and-1195A variants (D 0 : 0.201; r 2 : 0.003). These findings suggest that SNPs,-765G/C and-1195 A/G, on the promoter region of COX-2 gene may reduce the risk of preeclampsia, possibly by affecting the rate of gene expression.
Advances in peritoneal dialysis. Conference on Peritoneal Dialysis, 2005
In the present study, we used high sensitivity C-reactive protein (hs-CRP) analysis in combinatio... more In the present study, we used high sensitivity C-reactive protein (hs-CRP) analysis in combination with lipid screening [which has been reported to be a more valuable risk marker than other novel markers such as homocysteine (Hcy) and lipoprotein a] to perform cardiovascular risk assessment in peritoneal dialysis (PD) and hemodialysis (HD) patients. We selected 9 PD patients, 10 HD patients, and 9 control subjects for the study. In those patients, we determined levels of serum lipids, hs-CRP, Hcy, vitamin B12, folic acid, and leptin. Patients on PD had a significantly elevated hs-CRP concentration (3.14 +/- 0.79 mg/L) and ratio of total cholesterol (TC) to high density lipoprotein (HDL) cholesterol (4.71 +/- 0.40), and their cardiovascular risk was found to be three times that of control subjects. In HD patients, the elevation of hs-CRP was more profound (5.66 +/- 1.30), but their TC:HDL ratio fell within the normal range (3.18 +/- 0.13). However, a cardiovascular risk assessment of...
Canadian journal of physiology and pharmacology, Jan 10, 2017
Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dy... more Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dysfunction and cardiovascular complication in renal disease. Gentamicin (GM), a commonly used antibiotic exhibits a toxic effect on renal proximal tubules. Prevention of its nephrotoxicity is important. Therefore, we investigated whether heme oxygenase (HO)-1 induction influenced kidney and vascular function in GM-administered rats. GM (100 mg/kg/day; ip) was given to rats alone or together with hemin (20 mg/kg/alternate days; ip.) for 14 days. Plasma and kidney L-arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) as well as kidney 4-hydroxynonenal (HNE) levels and myeloperoxidase (MPO) activity were measured. Histopathologic examinations of kidney and relaxation and contraction responses of aorta were also examined. GM increased serum SDMA, urea nitrogen (BUN), and creatinine levels and caused histopathologic alterations in kidney. GM elevated HO-1 protein...
Pharmacological Research, 2005
Leukocyte arylsulphatase A (AS-A) was shown to be significantly high in newly-diagnosed breast ca... more Leukocyte arylsulphatase A (AS-A) was shown to be significantly high in newly-diagnosed breast cancer patients. Previous reports imply a connection between serum interleukin-6 (IL-6) and breast cancer, possibly through a modulation of enzymes involved in estrogen synthesis. Abnormal distribution of heparan sulphate proteoglycans (HSPGs) in malignant breast epithelial cells suggests that they play a key role in the regulation of cell growth. Estradiol is believed to be effective in modulating glycosaminoglycans (GAGs) and their depolymerizing enzymes. Therefore, in this study, attempts were made to evaluate the activity of leukocyte arylsulphatase A, serum interleukin-6, urinary GAGs and heparan sulphate (HS) in response to tamoxifen (TAM) therapy in mastectomised breast cancer patients. Thirty-four patients (aged 30-82 years) were administered TAM (20 mg twice daily). Blood and urine samples of each patient were collected three times (at the beginning, and in third and sixth month of TAM therapy), and biochemical parameters were measured. There was no difference between baseline leukocyte AS-A activity and that measured after three months. At the end of six months, enzyme activity was significantly higher than the former values (p = 0.022), but within the reference intervals reported in the literature. Although this increase might imply a normalization, the duration of TAM therapy is not long enough to make a decision about either regression or aggravation of the disease. TAM did not have any effect on serum IL-6, urinary HS and GAG levels which may be due to insensitivity of these variables to TAM during the short period of therapy. Both urinary GAG and HS levels measured at sixth month exhibited a positive correlation with the baseline level of leukocyte AS-A (p = 0.005 and 0.009, respectively), suggesting that positive responses to the drug might be seen in patients with low AS-A activity.
The Journal of Toxicological Sciences, 2012
We examined the role of nitrergic, glutamatergic and gamma-aminobutyric acid (GABA)ergic systems ... more We examined the role of nitrergic, glutamatergic and gamma-aminobutyric acid (GABA)ergic systems in the mechanism(s) underlying lithium induced acute toxicity. With this aim, lithium (18 mEq/kg, i.p.) intoxicated rats were observed for 3 hr recording their clinical signs and death. Lithium exposure at the dose used produced central nervous system (CNS) depression. Pre-treatment of N w-nitro-L-arginine methyl ester (L-NAME) a nonselective nitric oxide synthase inhibitor (10 mg/kg, i.p.), 7-nitroindazole (7-NI) a selective neuronal nitric oxide synthase inhibitor (25 mg/kg, i.p.), nitric oxide precursor L-arginine (1,000 mg/kg, i.p.) and MK-801 a noncompetitive antagonist of N-methyl-D-aspartic acid class of glutamate receptors (0.5 mg/kg, i.p.) all increased CNS depression and mortality in lithium group however, no change was seen in GABA receptor agonist GABA (1,000 mg/kg, i.p.) or D-arginine (1,000 mg/kg, i.p.) a biologically inactive enantiomer of L-arginine pre-treated rats. Glutamic acid decarboxylase (GAD) enzyme activity was measured in hippocampus, cerebral cortex and cerebellum of the different groups of animals. GAD enzyme activity reduced in cerebral cortex but not altered in hippocampus or cerebellum by lithium as compared to the control (saline) group. We conclude that an interaction with nitrergic and glutamatergic systems may have a role in the acute toxicity of lithium in rats.The inhibition of glutamate metabolism may arise from this interaction and the involvement of GABA-ergic system should be further investigated in this toxicity.
Journal of Proteome Research, 2014
Aortic aneurysm is a complex multifactorial disease, and its molecular mechanism is not understoo... more Aortic aneurysm is a complex multifactorial disease, and its molecular mechanism is not understood. In thoracic aortic aneurysm (TAA), the expansion of the aortic wall is lead by extracellular matrix (ECM) degeneration in the medial layer, which leads to weakening of the aortic wall. This dilatation may end in rupture andif untreateddeath. The aortic media is composed of vascular smooth muscle cells (VSMCs) and proteins involved in aortic elasticity and distensibility. Delineating their functional and quantitative decrease is critical in elucidating the disease causing mechanisms as well as the development of new preventive therapies. Laser microdissection (LMD) is an advanced technology that enables the isolation of the desired portion of tissue or cells for proteomics analysis, while preserving their integrity. In our study, the aortic media layers of 36 TAA patients and 8 controls were dissected using LMD technology. The proteins isolated from these tissue samples were subjected to comparative proteomic analysis by nano-LC-MS/MS, which enabled the identification of 352 proteins in aortic media. Among these, 41 proteins were differentially expressed in the TAA group with respect to control group, and all were downregulated in the patients. Of these medial proteins, 25 are novel, and their association with TAA is reported for the first time in our study. Subsequent analysis of the data by ingenuity pathway analysis (IPA) shows that the majority of differentially expressed proteins were found to be cytoskeletal-associated proteins and components of the ECM which are critical in maintaining aortic integrity. Our results indicate that the protein expression profile in the aortic media from TAA patients differs significantly from controls. Further analysis of the mechanism points to markers of pathological ECM remodeling, which, in turn, affect VSMC cytosolic structure and architecture. In the future, the detailed investigation of the differentially expressed proteins may provide insight into the elucidation of the pathological processes underlying aneurysms.
Diabetes Research and Clinical Practice, 2014
Aims: We aimed to investigate the pharmacological efficiency of metformin on asymmetric dimethyla... more Aims: We aimed to investigate the pharmacological efficiency of metformin on asymmetric dimethylarginine (ADMA) metabolism in inflammation caused by the lipopolysaccharide (LPS)/D-galactosamine (D-GalN) treatment. Methods: Adult Sprague-Dawley rats were injected LPS/D-GalN intraperitoneally. One half of the animals was injected metformin (250 mg kg À1 body mass for one week) prior to LPS/D-GalN treatment. Six hours after the LPS/D-GalN injection, livers were removed, and used for the measurements of dimethylarginine dimethylaminohydrolase (DDAH) and myeloperoxidase (MPO) activities, glutathione (GSH), ADMA and arginine levels. Liver tissues were examined histopathologically. The Kruskal-Wallis (posthoc Mann-Whitney U) test was used for the statistics. LPS/D-GalN injections caused liver injury as evidenced by the activities of aminotransferases and arginase. GSH level and DDAH activity were decreased in the liver. Metformin pretreatment alleviated the activity of serum enzymes, and attenuated histopathological lesions caused by LPS/D-GalN injections. LPS/D-GalN-induced inflammation, as confirmed by the increased MPO activity, created an asymmetrical distribution of arginine and ADMA between the tissue and plasma. Metformin decreased tissue ADMA level while it restored the DDAH activity and GSH. Conclusion: Our findings showed that metformin administration for one week has a potency to protect liver through regulating ADMA metabolism in LPS/D-GalN-induced injury.
Genetic Testing and Molecular Biomarkers, 2012
Cyclooxygenase-2 (COX-2) is the inducible isoenzyme of COX that leads to increased production of ... more Cyclooxygenase-2 (COX-2) is the inducible isoenzyme of COX that leads to increased production of prostaglandins and thromboxane, the mediators of inflammation. Controversial data regarding COX levels or activities in the placentas of women with preeclampsia have led us to examine whether a single nucleotide polymorphism (SNP) in the COX-2 gene is associated with the onset of preeclampsia. Two polymorphisms in the promoter region of COX-2 gene were examined by the polymerase chain reaction and restriction fragment length polymorphism in 128 controls and 74 preeclamptic patients. Genotype distribution and allelic frequencies for-765G/C polymorphism of COX-2 gene were significantly different between patients and controls (p = 0.000 and p = 0.042, respectively). The odds ratio (OR) for preeclampsia risk associated to the-765G allelic variant was 4.07 (95% confidence interval [CI]: 0.89-18.56). The AA genotype of the-1195 A/G variant was present at a significantly higher frequency among all preeclamptic subjects (p = 0.000 v 2 : 13.4, OR: 3.44, 95% CI: 1.74-6.77). A moderate linkage was observed between the-765G and-1195A variants (D 0 : 0.201; r 2 : 0.003). These findings suggest that SNPs,-765G/C and-1195 A/G, on the promoter region of COX-2 gene may reduce the risk of preeclampsia, possibly by affecting the rate of gene expression.
Advances in peritoneal dialysis. Conference on Peritoneal Dialysis, 2005
In the present study, we used high sensitivity C-reactive protein (hs-CRP) analysis in combinatio... more In the present study, we used high sensitivity C-reactive protein (hs-CRP) analysis in combination with lipid screening [which has been reported to be a more valuable risk marker than other novel markers such as homocysteine (Hcy) and lipoprotein a] to perform cardiovascular risk assessment in peritoneal dialysis (PD) and hemodialysis (HD) patients. We selected 9 PD patients, 10 HD patients, and 9 control subjects for the study. In those patients, we determined levels of serum lipids, hs-CRP, Hcy, vitamin B12, folic acid, and leptin. Patients on PD had a significantly elevated hs-CRP concentration (3.14 +/- 0.79 mg/L) and ratio of total cholesterol (TC) to high density lipoprotein (HDL) cholesterol (4.71 +/- 0.40), and their cardiovascular risk was found to be three times that of control subjects. In HD patients, the elevation of hs-CRP was more profound (5.66 +/- 1.30), but their TC:HDL ratio fell within the normal range (3.18 +/- 0.13). However, a cardiovascular risk assessment of...
Canadian journal of physiology and pharmacology, Jan 10, 2017
Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dy... more Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dysfunction and cardiovascular complication in renal disease. Gentamicin (GM), a commonly used antibiotic exhibits a toxic effect on renal proximal tubules. Prevention of its nephrotoxicity is important. Therefore, we investigated whether heme oxygenase (HO)-1 induction influenced kidney and vascular function in GM-administered rats. GM (100 mg/kg/day; ip) was given to rats alone or together with hemin (20 mg/kg/alternate days; ip.) for 14 days. Plasma and kidney L-arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) as well as kidney 4-hydroxynonenal (HNE) levels and myeloperoxidase (MPO) activity were measured. Histopathologic examinations of kidney and relaxation and contraction responses of aorta were also examined. GM increased serum SDMA, urea nitrogen (BUN), and creatinine levels and caused histopathologic alterations in kidney. GM elevated HO-1 protein...
Pharmacological Research, 2005
Leukocyte arylsulphatase A (AS-A) was shown to be significantly high in newly-diagnosed breast ca... more Leukocyte arylsulphatase A (AS-A) was shown to be significantly high in newly-diagnosed breast cancer patients. Previous reports imply a connection between serum interleukin-6 (IL-6) and breast cancer, possibly through a modulation of enzymes involved in estrogen synthesis. Abnormal distribution of heparan sulphate proteoglycans (HSPGs) in malignant breast epithelial cells suggests that they play a key role in the regulation of cell growth. Estradiol is believed to be effective in modulating glycosaminoglycans (GAGs) and their depolymerizing enzymes. Therefore, in this study, attempts were made to evaluate the activity of leukocyte arylsulphatase A, serum interleukin-6, urinary GAGs and heparan sulphate (HS) in response to tamoxifen (TAM) therapy in mastectomised breast cancer patients. Thirty-four patients (aged 30-82 years) were administered TAM (20 mg twice daily). Blood and urine samples of each patient were collected three times (at the beginning, and in third and sixth month of TAM therapy), and biochemical parameters were measured. There was no difference between baseline leukocyte AS-A activity and that measured after three months. At the end of six months, enzyme activity was significantly higher than the former values (p = 0.022), but within the reference intervals reported in the literature. Although this increase might imply a normalization, the duration of TAM therapy is not long enough to make a decision about either regression or aggravation of the disease. TAM did not have any effect on serum IL-6, urinary HS and GAG levels which may be due to insensitivity of these variables to TAM during the short period of therapy. Both urinary GAG and HS levels measured at sixth month exhibited a positive correlation with the baseline level of leukocyte AS-A (p = 0.005 and 0.009, respectively), suggesting that positive responses to the drug might be seen in patients with low AS-A activity.
The Journal of Toxicological Sciences, 2012
We examined the role of nitrergic, glutamatergic and gamma-aminobutyric acid (GABA)ergic systems ... more We examined the role of nitrergic, glutamatergic and gamma-aminobutyric acid (GABA)ergic systems in the mechanism(s) underlying lithium induced acute toxicity. With this aim, lithium (18 mEq/kg, i.p.) intoxicated rats were observed for 3 hr recording their clinical signs and death. Lithium exposure at the dose used produced central nervous system (CNS) depression. Pre-treatment of N w-nitro-L-arginine methyl ester (L-NAME) a nonselective nitric oxide synthase inhibitor (10 mg/kg, i.p.), 7-nitroindazole (7-NI) a selective neuronal nitric oxide synthase inhibitor (25 mg/kg, i.p.), nitric oxide precursor L-arginine (1,000 mg/kg, i.p.) and MK-801 a noncompetitive antagonist of N-methyl-D-aspartic acid class of glutamate receptors (0.5 mg/kg, i.p.) all increased CNS depression and mortality in lithium group however, no change was seen in GABA receptor agonist GABA (1,000 mg/kg, i.p.) or D-arginine (1,000 mg/kg, i.p.) a biologically inactive enantiomer of L-arginine pre-treated rats. Glutamic acid decarboxylase (GAD) enzyme activity was measured in hippocampus, cerebral cortex and cerebellum of the different groups of animals. GAD enzyme activity reduced in cerebral cortex but not altered in hippocampus or cerebellum by lithium as compared to the control (saline) group. We conclude that an interaction with nitrergic and glutamatergic systems may have a role in the acute toxicity of lithium in rats.The inhibition of glutamate metabolism may arise from this interaction and the involvement of GABA-ergic system should be further investigated in this toxicity.