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Öğe A new biological marker candidate in female reproductive system diseases: Matrix metalloproteinase with thrombospondin motifs (ADAMTS)(Galenos Yayincilik, 2014) Demircan, Kadir; Comertoglu, Ismail; Akyol, Sumeyya; Yigitoglu, Beyza Nur; Sarikaya, EsmaPlaying a key role in the pathophysiology of many diseases, A Disintegrin-like and Metalloproteinase with Thrombospondin type-1 motif (ADAMTS) proteinases have been attracted more attention in obstetrics and gynecology. First discovered in 1997, this zinc-dependent proteinase family has 19 members today. These enzymes, which are located in the extracellular matrix (ECM), have a lot of very important functions, like matrix formation and resorption, angiogenesis, ovulation, and coagulation. In addition, in the pathogenesis of cancer, inflammation, arthritis, and connective tissue diseases, ADAMTS proteinases have crucial roles. The purpose of this review is to collect previous studies about obstetrics and gynecology that are related to ADAMTS enzymes and discuss the subject in many aspects to give an idea to the investigators who are interested in the subject.Öğe A novel association between TGF?1 and ADAMTS4 in coronary artery disease: A new potential mechanism in the progression of atherosclerosis and diabetes(Turkish Soc Cardiology, 2015) Ulucay, Safiye; Cam, Fethi Sirri; Batir, Muhammed Burak; Sutcu, Recep; Bayturan, Ozgur; Demircan, KadirObjective: Coronary artery disease is characterized by atherosclerosis in the vessel wall. Recently, it has been thought that increasing LDL-binding capacity of subendothelial proteoglycan fragments that are formed by protease activity can be responsible for the initiation of atherosclerosis. ADAMTS4 is a member of the versican-degrading proteinases. In vitro studies demonstrated that TGF beta inhibits the expression of ADAMTS4 in macrophages. In this study, we aimed to investigate the role and association between TGF beta 1 and ADAMTS4 in coronary artery disease. Methods: A total of 84 cases with atheroma plaque and 72 controls without plaque were analyzed. The severity of disease was determined by Gensini score. TGF beta 1 gene polymorphisms were genotyped by the PCR-RFLP method. TGF beta 1 and ADAMTS4 serum levels were measured by ELISA method. Statistical analyses of genotypes and their relationship with serum levels were performed by chi-square, student t test and ANOVA. Results: ADAMTS4 levels were higher in cases compared with controls (p < 0.05). In the patient group, ADAMTS4 levels were higher than in controls and correlated with TGF beta 1 serum levels (r = 0.29; p < 0.05) and severity of disease (r = 0.20; p < 0.05). The TGF beta 1 gene CCA haplotype was associated with 3.3-fold increase in coronary artery disease (OR = 3.26 95% CI 1.22-8.68; p < 0.05). Unexpectedly, ADAMTS4 serum levels were also higher in diabetic cases (p = 0.05). Conclusion: This study has demonstrated that ADAMTS4 may be responsible for the pathogenesis of atherosclerosis. This is the first report about the association between ADAMTS4 and TGF beta 1 serum levels in the progression of atherosclerosis in CAD. Furthermore, it is seen that TGF beta 1 haplotype can cause a genetic susceptibility to CAD in the Turkish population. To our knowledge, this is also the first report suggesting higher serum ADAMTS4 levels in diabetic patients.Öğe ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse(Elsevier Ireland Ltd, 2013) Demircan, Kadir; Yonezawa, Tomoko; Takigawa, Tomoyuki; Topcu, Vehap; Erdogan, Serpil; Ucar, Fatma; Armutcu, FerahADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are involved in a variety of biological processes such as angiogenesis, cancer and arthritis. ADAMTSs appears to be responsible for the cleavage of proteoglycans in several tissues including brain and cartilage. Chondroitin sulfate proteoglycans (CSPGs) maintains the integrity of the brain extracellular matrix and major inhibitory contributors for glial scar and neural plasticity. The activity of aggrecanases in the central nervous system (CNS)has been reported. ADAMTSs are an enzyme degrading CSPGs in the brain. However, there is a little knowledge regarding ADAMTSs in the CNS. We investigated the expression levels of ADAMTSs mRNAs by RT-PCR after spinal cord injury in mouse. Transcripts encoding 4 of the 19 known ADAMTSs were evaluated in the mouse spinal cord following injury. ADAMTS1, -5 and -9 expression levels were found to be upregulated. No change was observed in ADAMTS4 expression. By means of immunohistochemistry, ADAMTSs were detected in the astrocytes implying its cellular source in SCI. Western blot analyses indicated that aggrecanase-generated proteoglycan fragments are produced after SCI. (c) 2013 Elsevier Ireland Ltd. All rights reserved.Öğe ADAMTS4 and ADAMTS5 Knockout Mice Are Protected from Versican but Not Aggrecan or Brevican Proteolysis during Spinal Cord Injury(Hindawi Ltd, 2014) Demircan, Kadir; Topcu, Vehap; Takigawa, Tomoyuki; Akyol, Sumeyya; Yonezawa, Tomoko; Ozturk, Gulfer; Ugurcu, VeliThe chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50-60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4-/-, Adamts5-/-, and wt mice but not in the sham-operated group. By contrast Adamts4-/- and Adamts5-/- mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4-/- mice' spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4-/- or Adamts5-/- mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI.Öğe Alterations in ADAMTS12 gene expression in salivary glands of radioiodine-131-administered rats(Lippincott Williams & Wilkins, 2016) Sadic, Murat; Korkmaz, Meliha; Gultekin, Salih S.; Demircan, KadirPurposeThe aim of this study was to evaluate the alterations in ADAMTS12 expression after radioiodine-131 (RAI)-induced salivary gland damage.Materials and methodsA total of 30 Wistar male albino rats (26045g, 6 months old) were studied for ADAMTS12 gene expression levels and histological changes in the parotid and submandibular salivary glands of rats after the administration of RAI. A series of healthy rats were used as controls. A 3mCi (111MBq) dose of RAI was administered to rats in group 1 (n=6), group 2 (n=6), group 3 (n=6), and group 4 (n=6) to induce salivary gland damage. Evaluations were performed at 24h in controls and at 4, 24h, 7, and 30 days after the administration of RAI. Quantitative and statistical analyses were carried out.ResultsIn RAI-administered groups, the mean values of ADAMTS12 gene expression showed a distinct suppression over time for the parotid gland (groups 1-4: 0.38, 0.11, 0.10, and 0.18, respectively; P<0.05), but the values remained similar over time for the submandibular gland (groups 1-4: 1.59, 1.57, 1.03, and 1.00, respectively; P>0.05) compared with the controls. Histological evaluation indicated that RAI-administered groups had significant common nuclear coarsening and focal subnuclear vacuolization, but not in the control samples. Histological changes were more prominent in the parotid gland samples.ConclusionAlterations in ADAMTS12 gene expression may play a role in RAI-induced salivary gland damage in rats. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.Öğe Differentially regulated ADAMTS1, 8, 9, and 18 in pancreas adenocarcinoma(Termedia Publishing House Ltd, 2017) Kilic, Murat Ozgur; Aynekin, Busra; Bozer, Mikdat; Kara, Adem; Haltas, Hacer; Icen, Duygu; Demircan, KadirIntroduction: Despite recent diagnostic and therapeutic improvements, pancreas cancer remains one of the highly lethal cancers. The extracellular matrix (ECM) is a physiological barrier that limits the spread of cancer cells into surrounding tissues and distant organs. Disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) is a family of 19 proteases, which is involved in various biological processes such as ECM remodelling and anti-angiogenesis. Aim: To investigate the expression of ADAMTS1, 8, 9, and 18 proteinases in pancreas adenocarcinoma and its nodal metastasis. Material and methods: The immunostaining status of ADAMTS1, 8, 9, and 18 were investigated in formalin-fixed paraffin-embedded samples of 25 patients who underwent pancreaticoduodenectomy for an adenocarcinoma located at the head of the pancreas. Results: In semi-quantitive grading pathologically, ADAMTS1, 8, 9, and 18 were found to be highly stained in all cancerous pancreas samples compared with normal pancreas. In addition, the immune positivity of ADAMTS1, 9, and 18 was found to be higher in metastatic lymph nodes than in non-metastatic lymph tissue. Tumour size was correlated with ADAMTS9 and 18 expressions in cancerous pancreas. Conclusions: According to the data obtained from the study, we suggest that these four ADAMTSs may have significant roles in the tumorigenesis and nodal spread of pancreas adenocarcinoma.Öğe Early Induction of ADAMTS1,-4,-5 and-9 in IL-Stimulated Mouse Astrocytes(Turkish Neurosurgical Soc, 2014) Abali, Osman; Gokce, Emre Cemal; Cemil, Berker; Erdogan, Bulent; Yonezawa, Tomoko; Demircan, KadirAIM: Astrocytes and extracellular matrix molecules have important roles in regulating synaptic functions between neurons in the central nervous system. However, under pathological conditions, these constituents are activated to form glial scar that is thought to be harmful for neuronal regeneration. The aim of this study was to evaluate the expression pattern of ADAMTS1, -4, -5 and -9 in IL-1 stimulated astrocyte cultures obtained from postnatal day zero mouse brains. MATERIAL and METHODS: Real time PCR analyses were performed. RESULTS: An overexpression of ADAMTS1, -4, -5 and -9 at the 3-h time point after IL-1 stimulation was found. IL-1 stimulation induced aggrecaneses and this effect was time dependent. Maximum increase was detected at 3-h (six fold increase). Interestingly the expression of ADAMTS1 and -4 appeared to be at the highest expression level but the ADAMTS5 and ADAMTS9 expression level was much weaker (three times and two times respectively). CONCLUSION:To the best of our knowledge, this is the first report demonstrating induction of ADAMTS in IL-1 induced astrocytes. Aggrecanases may play a role in tissue destruction in the progression of central nervous system (CNS) injury and they are differentially expressed in mouse CNS, suggesting a critical role in the pathogenesis of CNS injury. This can be a very crucial aetiologic factor for some neuropsychiatric disorders.Öğe Emerging roles of ADAMTS metalloproteinases in regenerative medicine and restorative biology(Tubitak Scientific & Technological Research Council Turkey, 2016) Armutcu, Ferah; Demircan, KadirADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteinases degrade proteoglycans and thereby have the potential to alter tissue architecture and regulate cellular function. Recent studies about the roles of these enzymes have produced new perspectives for the molecular mechanisms behind regenerative biology with clinical potential to generate therapeutic targets to resolve tissue injury. ADAMTS enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their dysregulation has been implicated in disease-related processes such as inflammation and fibrosis. Increasing evidence indicates that they may be of key significance in the physiological and pathological central nervous system. In this review, we summarize what is currently known about the roles of ADAMTS proteins in tissue repair and regeneration as well as in the pathogenesis of other important biological processes and diseases including arthritis, atherosclerosis, and cancer.Öğe Evaluation of ADAMTS Levels in Patients with Chronic and Aggressive Periodontitis(Federation Amer Soc Exp Biol, 2016) Demircan, Kadir; Tayman, Ayse; Bayram, Nezihe Asli; Demir, Berrin Tugtag; Karagoz, Zehra Firat; Fistik, Tuba; Kurga, Sivge[Abstract Not Available]Öğe Expression of ADAMTS2 and ADAMTS5 in the salivary gland of rats after radioiodine therapy(Lippincott Williams & Wilkins, 2018) Sadic, Murat; Demirel, Koray; Halacli, Sevil O.; Karakok, Emre; Koca, Gokhan; Ekinci, Ozgur; Demircan, KadirObjectiveThe aim of this study was to investigate the presence of ADAMTS2 and ADAMTS5 in the salivary gland (SG) of rats after high-dose radioiodine therapy.MethodsA total of 36 male Wistar albino rats were used for this study. Thirty-six male rats were divided randomly into six groups: control and five radioactive iodine (RAI) treatment groups of six rats each. All animals were killed. The evaluation of biodistribution and histopathological studies were carried out on the SGs removed. Real-time PCR and immunohistochemical analysis were carried out to determine mRNA and protein expression levels of ADAMTS genes. Differences between the groups were evaluated statistically.ResultsIn RAI-treated groups, ADAMTS2 and ADAMTS5 gene expression was observed to increase, whereas there was no mRNA or protein expression in the control group. There were statistically significant increases in the mRNA expression of ADAMTS2 (all RAI-administered groups in parathyroid gland and at 4, 24, and 48h in submandibular gland) and ADAMTS5 (all RAI-administered groups, except on the 30th day in the parathyroid gland and all RAI groups in submandibular gland). Through immunohistochemical analysis, the staining pattern in the extracellular source was also observed in the overexpressed ADAMTS2 and ADAMTS5 groups. Nuclear coarsening and partial focal subnuclei vacuolization were determined in all RAI-administered groups with histopathological examinations.ConclusionAn increase in the mRNA expression levels of ADAMTS2 and ADAMTS5 genes was detected in the RAI-administered groups. These results suggested that ADAMTS2 and ADAMTS5 genes might play a role in radiation exposure and radioiodine-induced SG changes.Öğe Hypoxia causes important changes of extracellular matrix biomarkers and ADAMTS proteinases in the adriamycin-induced renal fibrosis model(Wiley, 2019) Armutcu, Ferah; Demircan, Kadir; Yildirim, Umran; Namuslu, Mehmet; Yagmurca, Murat; Celik, Hueseyin T.Aim Renal fibrosis is a common cause of renal dysfunction with chronic kidney diseases. This process is characterized by excessive production of extracellular matrix (ECM) or inhibition of ECM degradation. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteinases, which are widely presented in mammals, have very critical roles in ECM remodelling. We aimed to study the role of ADAMTS proteinases and some of the ECM markers in the pathogenesis of renal fibrosis and to investigate the effects of hypoxia on these biomarkers. Methods In addition to the control group, Adriamycin (ADR) treated rats were divided into four groups as ADR, sham and two hypoxia groups. Renal nephropathy was assessed biochemical assays, pathological and immunohistochemical staining methods. The expression of ADAMTSs and mRNA were determined using Western blotting and real-time PCR, respectively. Results Renal dysfuntion and tissue damage in favour of ECM accumulation and renal fibrosis were observed in the ADR group. This was approved by remarkable changes in the expression of ADAMTS such as increased ADAMTS-1, -12 and -15. In addition, it was found that hypoxia and duration of hypoxia enhanced markers of tubulointerstitial fibrosis in the rat kidney tissues. Also, expression differences especially in ADAMTS-1, -6 and -15 were observed in the hypoxia groups. The variable and different expression patterns of ADAMTS proteinases in the ADR-induced renal fibrosis suggest that ADAMTS family members are involved in the development and progression of fibrosis. Conclusion The expression changes of ADAMTS proteinases in kidney and association with hypoxia have potential clues to contribute to the early diagnosis and treatment options of renal fibrosis.Öğe Immunohistochemical Determination of HIF, TSP-1, ADAMTS1, and ADAMTS8 Expressions in the Brains of Alzheimer's Disease Patients: A Preliminary Autopsy Study(Erciyes Univ Sch Medicine, 2016) Inanir, Nursel Turkmen; Eren, Filiz; Fedakar, Recep; Eren, Bulent; Demircan, Kadir; Gurses, Murat Serdar; Ural, MustafaObjective: Alzheimer's disease (AD) is a progressive neurodegenerative disease that mostly affects the elderly population. Recent studies performed in AD highlight the pathophysiological relevance of disintegrin and metalloproteinase with thrombospondin type 1-like motifs (ADAMTS) genes and their products, namely hypoxia inducible factor-1 (HIF-1) and thrombospondin-1 (TSP-1). Thus, the aim of this study was to describe and identify the distribution, characteristics, and any changes in the expression and immunoreactivity for HIF-1, TSP-1, and ADAMTS1 and 8 in AD brains. Materials and Methods: Nine patients who were autopsied in the Council of Forensic Medicine, Bursa Morgue Department in 2013, were selected. All patients were sent for autopsy to the Morgue Department within 8 h after death. At the autopsy, tissue samples of the organs were obtained for histopathological examination for determining the cause of death. Among these, two patients were clinically diagnosed with AD. Results: Immunohistochemical staining was performed, and the staining intensity/extensity was evaluated using a semi-quantitative scoring system. Median distribution (extensity) scores of the immunohistochemical staining were estimated as 2 for HIF-1, 0.67 for TSP-1, 3.11 for ADAMTS1, and 2.78 for ADAMTS8. Intensity scores were estimated as 1.22 for HIF-1, 0.56 for TSP-1, 3 for ADAMTS1, and 2.11 for ADAMTS8. Conclusion: Our study suggests that ADAMTS1 and ADAMTS8 expressions are not specific for AD. To understand and provide definitive data on all aspects of metalloproteinases, extracellular matrix proteins, and transcriptional factor effects to AD, further studies are needed, where other metalloproteinases and related molecules/enzymes should be studied.Öğe Isolation of Human Glioblastoma Multiforme Primary Cells and analysis of CD133+(Federation Amer Soc Exp Biol, 2015) Yukselten, Yunus; Yildiz, Dilara Akcora; Demircan, Kadir; Sunguroglu, Asuman; Ugur, Hasan[Abstract Not Available]Öğe PRKCA, PTPN1 and ZYX Are Possible Markers to Target CD133+GBM Stem Cells(Federation Amer Soc Exp Biol, 2016) Ozkanca, Seyma; Bal, Merve Gulsen; Yukselten, Yunus; Yildiz, Dilara Akcora; Ugur, Hasan Caglar; Demircan, Kadir; Sunguroglu, Asuman[Abstract Not Available]Öğe PXN and TRIO are elevated in CD133+GSCs transcriptomically(Federation Amer Soc Exp Biol, 2016) Sunguroglu, Asuman; Bunsuz, Merve; Yukselten, Yunus; Bal, Merve Gulsen; Ozkanca, Seyma; Yildiz, Dilara Akcora; Demircan, Kadir[Abstract Not Available]Öğe The gene expression and protein profiles of ADAMTS and TIMP in human chondrosarcoma cell lines induced by insulin: The potential mechanisms for skeletal and articular abnormalities in diabetes(Modestum Ltd, 2020) Akyol, Sumeyya; Karagoz, Zehra; Inan, Nuran Dingil; Butun, Ilknur; Benli, Ismail; Demircan, Kadir; Yigitoglu, Muhammet RamazanBackground: The delay in wound healing, decrease in the long bones resilience to fracture, and delay in fracture healing are among common complications diabetes mellitus (DM) patients, and they still remain as challenging issues to be solved. The mechanism has not been fully understood yet, but high sugar and/or insulin deficiency or unresponsiveness to insulin in blood are potential causes to blame. Extracellular matrix degradation/remodeling is one of the important mechanisms whereby cell differentiation, bone remodeling and wound repair can be regulated. A disintegrin and metalloproteinase with a thrombospondin type 1 motif (ADAMTS) proteins play important roles in cartilage/bone metabolism. This study aimed to determine whether ADAMTS/Tissue inhibitors of metalloproteinases (TIMP) proteins were affected by insulin application in OUMS-27 (chondrosarcoma) cells. Material and Methods: OUMS-27 cells were induced by 10 mu g/mL insulin for 1, 3, 7, and 11 days. Cells were harvested, mRNA and protein extractions were performed. Total mRNA and cDNA levels were measured by qRT-PCR and protein levels were detected by WB. Results: ADAMTS1,5, and 7 levels were significantly decreased, while TIMP-3 levels were detected increased (mRNA/protein concentrations). Conclusion: Pathologies and disturbances of cartilage/bone metabolism, delayed fracture healing in particular, in patients with DM may result from insulin deficiency. ADAMTS genes that play a role in healing process are increased during insulin deficiency, which consequently interrupts healing process by causing cartilage extracellular matrix (ECM) degradation.Öğe The investigation of the role of proteoglycans and ADAMTS levels in fetal membranes in physiopathological process of gestational diabetes(Churchill Livingstone, 2017) Ozler, Sibel; Demircan, KadirAbout 2-5% of all pregnant women develop gestational diabetes mellitus (GDM) during pregnancy and its prevalence has increased markedly within the last decade. GDM is a metabolic syndrome produced by various degrees of carbohydrate intolerance during pregnancy. Various risk factors such as obesity, genetics, environmental factors, and hypertension have been described previously. Maternal and fetal complications occur in around 7% of pregnant women with GDM. In these patients, a relation between proteoglycans and ADAMTS proteases located in extracellular matrix in fetal membranes (placenta, cord, amnion) and complicated pregnancies has already been determined by various animal experiments. Changes in expression, structure and function of ADAMTS proteases and proteoglycans in fetal membranes lead to alteration in the structure of extracellular matrix. If we can establish a balance between these proteoglycans and ADMTS proteases or determine the changes in their structure and functions, it will be possible to predict the risk in high risk pregnancies at early weeks and to initiate treatment early or to follow the target population regularly. In addition, prevention or reduction of maternal and fetal complications may be possible. For this purpose, ADAMTS and proteoglycans the synthesis of which is too much or less, may be targeted and if we would be able to determine and prevent the changes in their levels in the early period of pregnancy, the development of GDM and its complications may be prevented or decreased. Thus, we may identify a marker for early diagnosis and treatment and reduce prematurity, which is the most common cause of fetal death. Fetal and maternal complications, and especially treatment and care costs of prematurity, may also be decreased. (C) 2016 Published by Elsevier Ltd.Öğe The potential link of COMP-ADAMTS and Aggrecanase-ADAMTS Genes with Osteoarthrit(Federation Amer Soc Exp Biol, 2016) Demircan, Kadir; Gurlu, Gulsum; Guven, Kubra Nur; Fistik, Tuba; Cakirbay, Hasim; Yanik, Burcu[Abstract Not Available]Öğe The Role of IL33 in Glioblastoma Multiforme(Federation Amer Soc Exp Biol, 2015) Demircan, Kadir; Yukselten, Yunus; Bal, Merve; Bunsuz, Merve; Yildiz, Dilara Akcora; Sunguroglu, Asuman; Ugur, Hasan[Abstract Not Available]
