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Öğe A(2A) adenosine receptors regulate multiple organ failure after hemorrhagic shock in mice(Lippincott Williams and Wilkins, 2022) Keleştemur, Taha; Németh, Zoltán H.; Pacher, Pal; Antonioli, Luca; Haskó, GyörgyTrauma hemorrhagic shock (T/HS) is a clinical condition that causes multiple organ failure that needs rapid intervention. Restricted oxygen at the cellular level causes inflammation and subsequent cell death. Adenosine triphosphate is the universal intracellular energy currency and an important extracellular inflammatory signaling molecule. Adenosine, an endogenous nucleotide formed as a result of the breakdown of adenosine triphosphate, is also released during T/HS. Adenosine binds to four G protein-coupled receptors (A1R, A2a, A2b, A3R) called adenosine receptors or P1 receptors. In the present study, we evaluated the effect of activation, inactivation, and genetic absence of A2aR (A2aR-/- mice) on T/HS-induced multiple organ failure. Wild-type mice were pretreated (30 min before shock induction) with an agonist or antagonist and then subjected to T/HS by withdrawing arterial blood and maintaining the blood pressure between 28 and 32 mm Hg. A2aR-/- mice were subjected to T/HS in the absence of pharmacologic treatment. Neutrophil sequestration was assessed by detecting myeloperoxidase, and Evans blue dye (EBD) method was used to analyze lung permeability. Blood and lung inflammatory cytokine levels were determined by sandwich enzyme-linked immunosorbent assay. The liver enzymes aspartate aminotransferase and alanine aminotransferase were determined spectrophotometrically from plasma. Activation of the apoptotic cascade was evaluated using a mouse apoptosis array. Our results demonstrate that the selective A2aR agonist CGS21680 decreases lung neutrophil sequestration, lung proinflammatory cytokines IL-6 and TNF-?, and bronchoalveolar lavage EBD. Pretreatment with the selective antagonist ZM241385 and genetic blockade in A2aR-/- mice increased neutrophil sequestration, proinflammatory cytokine levels, and bronchoalveolar lavage fluid EBD. The myeloperoxidase level in the lung was also increased in A2aR-/- mice. We observed that antiapoptotic markers decreased significantly with the absence of A2aR in the lung and spleen after T/HS. In conclusion, our data demonstrate that activation of A2aR regulates organ injury and apoptosis in the setting of T/HS.Öğe Adenosine metabolized from extracellular ATP ameliorates organ injury by triggering A2BR signaling(NLM (Medline), 2023) Keleştemur, Taha; Németh, Zoltán H.; Pacher, Pal; Beesley, Jennet; Robson, Simon C.; Eltzschig, Holger K.; Haskó, GyörgyBACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A2BR. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to A2BRs in regulating the host's response to T/HS. METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A2BR) and conditional knockout (intestinal epithelial cell-specific deficient VillinCre-A2BRfl/fl) mice. At 3 three hours after resuscitation, blood and tissue samples were collected to analyze organ injury. RESULTS: T/HS upregulated the expression of CD39, CD73, and the A2BR in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and A2BR mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and A2BR knockout (KO) exacerbated lung injury, inflammatory cytokines, and chemokines as well as macrophage and neutrophil infiltration and accumulation in the lung. Agonists reduced the levels of the liver enzymes aspartate transferase and alanine transaminase in the blood, whereas antagonist administration or CD39, CD73, and A2BR KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient VillinCre-A2BRfl/fl mice showed increased intestinal injury compared to their wild-type VillinCre controls. CONCLUSION: In conclusion, the CD39-CD73-A2BR axis protects against T/HS-induced multiple organ failure.Öğe Advanced imaging techniques in neurological diseases(Wiley, 2019) Keleştemur, Taha[Abstract Not Available]Öğe Beyin felci sonrası meydana gelen plastisite ile ilgili patofizyolojik süreçlerin ileri mikroskopi teknikleriyle incelenmesi(İstanbul Medipol Üniversitesi Sağlık Bilimleri Enstitüsü, 2017) Keleştemur, Taha; Kılıç, ErtuğrulBeyin felci insanlarda en fazla motor fonksiyon bozukluklarına neden olan hastalıktır. Beyin felci sonrası post-iskemik fazda beynin endojen onarım mekanizmalarının etkinleştirilerek fonksiyonel olarak iyileşmesi, rehabilitasyon ve beyin plastisitesini uyaran tedaviler ile mümkün olabilmektedir. Post-iskemik fazda beyin felcinin iyileşmesi, kortikal ve subkortikal seviyede nöronal ağın yeniden organize edilmesiyle gerçekleşmektedir. Böylece fonksiyonel olmayan nöronal ağ, aktive edilip yeni bağlantılar ile güçlendirilerek hasarlı bölge çevresi ve beynin farklı bölgeleri ile iletişimi sağlanmaktadır. Beyin felci sonrasında hasarlı dokunun yeniden şekillendirilmesinde iskemik olmayan hemisferde (kontralateral) aksonal yapılanma (projeksiyon) gibi değişiklikler beynin, iskemik beyin felci sonrası oluşan yeni duruma hazırlanmasına ve fonksiyonel iyileşmeye katkıda bulunmaktadır. Daha önce bu konu ile ilgili yapılmış olan deneysel çalışmalar ipsilateral ve kontralateral hemisferlerde bu süreçlerin birbirinden bağımsız olarak geliştiğini göstermektedir. Ayrıca bu süreçlerin nasıl koordine edildiğine dair bilgiler yetersiz kalmaktadır. Bu tezin amacı kapsamında farelerde 30 dakikalık beyin felci uygulamasını takiben akut patofizyolojik değişikliklerin tamamlandıgı 3. günde sinaptik reoganizasyonların ve projeksiyonların üç boyutlu olarak belirlenmesi için hayvanların motor kortekslerine yeşil floresan ve kırmızı floresan ifade eden viral vektör enjeksiyonları yapıldı. Enjeksiyondan sonra 30. günde hayvanlar sakrifiye edilip beyinleri çıkartılarak 1 mm'lik bloklar halinde veya bütün beyin dokusu şeffaflaştırılıp, lazer taramalı konfokal mikroskop, multi foton mikroskop ve ışık perdeli mikroskop kullanılarak görüntülenerek hasar sonrası meydana gelen aksonal projeksiyonların 3 boyutlu haritalandırılması yapıldı. Sonuç olarak, şeffaflaştırma tekniğinin kullanılması ve bunun yanında viral vektör enjeksiyonlarının yapılması beyin felci patofizyolojisinin daha iyi anlaşılması, hasardan sonra meydana gelen plastisitenin kortiko spinal yolların daha iyi belirlenmesi ve son olarak geliştirilecek tedavi yöntemlerinin etkinliklerinin yorumlanmasına katkı sağlayacağı düşünülmektedir.Öğe Effect of circadian rhythm protein BMAL1 on neuronal damage(Wiley, 2017) Beker, Mustafa Çağlar; Serel, Elif; Karaçay, Reyda; Altunay, Serdar; Dilden, Aysun; Çağlayan, Ahmet Burak; Keleştemur, Taha; Çağlayan, Berrak; Yalçın, Esra; Kılıç, Ertuğrul[Abstract Not Available]Öğe Effect of P2X7 receptor on activation of microglia and IL1 beta following ischemia(Wiley, 2017) Çağlayan, Berrak; Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Yalçın, Esra; Beker, Merve; Keleştemur, Taha; Şahin, Fikrettin; Kılıç, Ertuğrul[Abstract Not Available]Öğe Effects of circadian rhythm on brain injury and related molecular mechanisims(Wiley-Blackwell, 2016) Beker, Mustafa Çağlar; Çağlayan, Ahmet Burak; Keleştemur, Taha; Çağlayan, Berrak; Yalçın, Esra; Dalay, Arman; Altunay, Serdar; Sertel, Elif; Kılıç, Ertuğrul[Abstract Not Available]Öğe Effects of neurotrophic factors cdnf and manf on brain plasticity and repair after brain ischemia(Wiley-Blackwell, 2016) Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Çağlayan, Berrak; Altunay, Serdar; Dalay, Arman; Dilden, Aysun; Sertel, Elif; Keleştemur, Taha; Yalçın, Esra; Kılıç, Ülkan; Saarma, Mart; Kılıç, Ertuğrul[Abstract Not Available]Öğe Effects of normobaric oxygen and melatonin on reperfusion injury: Role of cerebral microcirculation(Impact Journals, 2015) Beker, Mustafa; Çağlayan, Ahmet Burak; Keleştemur, Taha; Ça?layan, Berrak; Yalçın, Esra; Yulu?, Burak; Kılıç, Ülkan; Hermann, Dirk Matthias; Kılıç, ErtuğrulIn order to protect the brain before an irreversible injury occurs, penumbral oxygenation is the primary goal of current acute ischemic stroke treatment. However, hyperoxia treatment remains controversial due to the risk of free radical generation and vasoconstriction. Melatonin is a highly potent free radical scavenger that protects against ischemic stroke. Considering its anti-oxidant activity, we hypothesized that melatonin may augment the survival-promoting action of normobaric oxygen (NBO) and prevent brain infarction. Herein, we exposed mice to 30 or 90 min of intraluminal middle cerebral artery occlusion (MCAo) and evaluated the effects of NBO (70% or 100% over 90 min), administered either alone or in combination with melatonin (4 mg/ kg, i.p.), on disseminate neuronal injury, neurological deficits, infarct volume, blood-brain barrier (BBB) permeability, cerebral blood flow (CBF) and cell signaling. Both NBO and particularly melatonin alone reduced neuronal injury, neurological deficits, infarct volume and BBB permeability, and increased post-ischemic CBF, evaluated by laser speckle imaging (LSI). They also improved CBF significantly in the ischemic-core and penumbra, which was associated with reduced IgG extravasation, DNA fragmentation, infarct volume, brain swelling and neurological scores. Levels of phosphorylated Akt, anti-apoptotic Bcl-xL, pro-apoptotic Bax and endothelial nitric oxide synthase (NOS) were re-regulated after combined oxygen and melatonin delivery, whereas neuronal and inducible NOS, which were increased by oxygen treatment, were not influenced by melatonin. Our present data suggest that melatonin and NBO are promising approaches for the treatment of acute-ischemic stroke, which encourage proof-of-concept studies in human stroke patients.Öğe Effects of normobaric oxygen and melatonin treatment on newborn hypoxia plasiticity(Wiley, 2017) Keleştemur, Taha; Beker, Mustafa Çağlar; Çağlayan, Ahmet Burak; Çağlayan, Berrak; Dalay, Arman; Altunay, Serdar; Yalçın, Esra; Sertel, Elif; Dilden, Aysun; Kılıç, Ertuğrul[Abstract Not Available]Öğe Effects of repetitive transcranial magnetic stimulation on motor activity and neuronal survival after spinal cord injury(Wiley, 2017) Dalay, Arman; Balçıkanlı, Zeynep; Altunay, Serdar; Keleştemur, Taha; Tancan, Emre; Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Kılıç, Ertuğrul[Abstract Not Available]Öğe Efficacy of one-hour negative pressure wound therapy and magnetic field energy in wound healing(MA Healthcare Ltd, 2024) Özer, Aysel Yıldız; Keskin, İlknur; Keleştemur, Taha; Aytürk, Nilüfer; Ersavaş, Cenk; Günal, Mehmet YalçınObjective: Wound healing is an important aspect of health but needs further research to identify the effects and interactions of different treatment approaches on healing. The aims of this study were to investigate the effectiveness of one-hour negative pressure wound therapy (NPWT) and compare histological differences between one-hour NPWT and magnetic field energy (MFE) in rats on early-stage wound healing, wound size and angiogenesis. Method: Standardised wounds were created on Wistar rats that were allocated and divided into NPWT, MFE and control groups. Both treatments were applied for 1 hour/day for 10 days. Wound size, histological changes and wound area blood flow were assessed. Results: The wound size of all groups was similar on days 0, 2 and 10. The MFE group s wound size was smaller than the NPWT group on days 4, 6 and 8 (p.Öğe Evaluation of components of the extracellular purinergic signaling system in human sepsis(2024) Lovászi, Marianna; Németh, Zoltán H.; Keleştemur, Taha; Sánchez, Itzel V.; Antonioli, Luca; Pacher, Pál; Wagener, Gebhard; Haskó, GyörgyObjective: Extracellular purines such as adenosine triphosphate (ATP), uridine triphosphate (UTP), and uridine diphosphate (UDP) and the ATP degradation product adenosine are biologically active signaling molecules, which accumulate at sites of metabolic stress in sepsis. They have potent immunomodulatory effects by binding to and activating P1 or adenosine and P2 receptors on the surface of leukocytes. Here we assessed the levels of extracellular purines, their receptors, metabolic enzymes, and cellular transporters in leukocytes of septic patients. Methods: Peripheral blood mononuclear cells (PBMCs), neutrophils, and plasma were isolated from blood obtained from septic patients and healthy control subjects. Ribonucleic acid was isolated from cells, and mRNA levels for purinergic receptors, enzymes, and transporters were measured. Adenosine triphosphate, UTP, UDP, and adenosine levels were evaluated in plasma. Results: Adenosine triphosphate levels were lower in septic patients than in healthy individuals, and levels of the other purines were comparable between the two groups. Levels of P1 and P2 receptors did not differ between the two patient groups. mRNA levels of ectonucleoside triphosphate diphosphohydrolase (NTPDase) 1 or CD39 increased, whereas those of NTPDase2, 3, and 8 decreased in PBMCs of septic patients when compared with healthy controls. CD73 mRNA was lower in PBMCs of septic than in healthy individuals. Equilibrative nucleoside transporter (ENT) 1 mRNA concentrations were higher and ENT2, 3, and 4 mRNA concentrations were lower in PBMCs of septic subjects when compared with healthy subjects. Concentrative nucleoside transporter (CNT) 1 mRNA levels were higher in PBMCs of septic versus healthy subjects, whereas the mRNA levels of CNT2, 3, and 4 did not differ. We failed to detect differences in mRNA levels of purinergic receptors, enzymes, and transporters in neutrophils of septic versus healthy subjects. Conclusion: Because CD39 degrades ATP to adenosine monophosphate (AMP), the lower ATP levels in septic individuals may be the result of increased CD39 expression. This increased degradation of ATP did not lead to increased adenosine levels, which may be explained by the decreased expression of CD73, which converts AMP to adenosine. Altogether, our results demonstrate differential regulation of components of the purinergic system in PBMCs during human sepsis.Öğe Evaluation of components of the extracellular purinergic signaling system in human sepsis(2024) Lovászi, Marianna; Németh, Zoltán H.; Keleştemur, Taha; Sánchez, Itzel V.; Antonioli, Luca; Pacher, Pál; Wagener, Gebhard; Haskó, GyörgyObjective: Extracellular purines such as adenosine triphosphate (ATP), uridine triphosphate (UTP), and uridine diphosphate (UDP) and the ATP degradation product adenosine are biologically active signaling molecules, which accumulate at sites of metabolic stress in sepsis. They have potent immunomodulatory effects by binding to and activating P1 or adenosine and P2 receptors on the surface of leukocytes. Here we assessed the levels of extracellular purines, their receptors, metabolic enzymes, and cellular transporters in leukocytes of septic patients. Methods: Peripheral blood mononuclear cells (PBMCs), neutrophils, and plasma were isolated from blood obtained from septic patients and healthy control subjects. Ribonucleic acid was isolated from cells, and mRNA levels for purinergic receptors, enzymes, and transporters were measured. Adenosine triphosphate, UTP, UDP, and adenosine levels were evaluated in plasma. Results: Adenosine triphosphate levels were lower in septic patients than in healthy individuals, and levels of the other purines were comparable between the two groups. Levels of P1 and P2 receptors did not differ between the two patient groups. mRNA levels of ectonucleoside triphosphate diphosphohydrolase (NTPDase) 1 or CD39 increased, whereas those of NTPDase2, 3, and 8 decreased in PBMCs of septic patients when compared with healthy controls. CD73 mRNA was lower in PBMCs of septic than in healthy individuals. Equilibrative nucleoside transporter (ENT) 1 mRNA concentrations were higher and ENT2, 3, and 4 mRNA concentrations were lower in PBMCs of septic subjects when compared with healthy subjects. Concentrative nucleoside transporter (CNT) 1 mRNA levels were higher in PBMCs of septic versus healthy subjects, whereas the mRNA levels of CNT2, 3, and 4 did not differ. We failed to detect differences in mRNA levels of purinergic receptors, enzymes, and transporters in neutrophils of septic versus healthy subjects. Conclusion: Because CD39 degrades ATP to adenosine monophosphate (AMP), the lower ATP levels in septic individuals may be the result of increased CD39 expression. This increased degradation of ATP did not lead to increased adenosine levels, which may be explained by the decreased expression of CD73, which converts AMP to adenosine. Altogether, our results demonstrate differential regulation of components of the purinergic system in PBMCs during human sepsis.Öğe Evaluation of effects of UNC2025 on the traumatic brain injury(Wiley, 2022) Keleştemur, Taha; Çelik, Süleyman; Daşdelen, Muhammed Furkan; Kılıç, Ertuğrul[Abstract Not Available]Öğe Evidence that activation of P2X7R does not exacerbate neuronal death after optic nerve transection and focal cerebral ischemia in mice(Academic Press Inc Elsevier Science, 2017) Çağlayan, Berrak; Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Yalçın, Esra; Beker, Merve; Keleştemur, Taha; Sertel, Elif; Öztürk, Gürkan; Kılıç, Ülkan; Şahin, Fikrettin; Kılıç, ErtuğrulConflicting data in the literature about the function of P2X7R in survival following ischemia necessitates the conductance of in-depth studies. To investigate the impacts of activation vs inhibition of the receptor on neuronal survival as well as the downstream signaling cascades, in addition to optic nerve transection (ONT), 30 min and 90 min of middle cerebral artery occlusion (MCAo) models were performed in mice. Intracellular calcium levels were assessed in primary cortical neuron cultures. Here, we show that P2X7R antagonist Brilliant Blue G (BBG) decreased DNA fragmentation, infarct volume, brain swelling, neurological deficit scores and activation of microglial cells after focal cerebral ischemia. BBG also significantly increased the number of surviving retinal ganglion cells (RGCs) after ONT and the number of surviving neurons following MCAo. Importantly, receptor agonist BzATP resulted in increased activation of microglial cells and induced phosphorylation of ERK,AKT and JNK. These results indicated that inhibition of P2X7R with BBG promoted neuronal survival, not through the activation of survival kinase pathways, but possibly by improved intracellular Ca2+ overload and decreased the levels of Caspase 1, IL-1 beta and Bax proteins. On the other hand, BzATP-mediated increased number of activated microglia and increased survival kinase levels in addition to increased caspase-1 and IL-1 beta levels indicate the complex nature of the P2X7 receptor-mediated signaling in neuronal injury.Öğe Evidence that melatonin downregulates Nedd4-1 E3 ligase and its role in cellular survival(Academic Press Inc Elsevier Science, 2019) Yalçın, Esra; Beker, Mustafa Çağlar; Türkseven, Şeyma; Çağlayan, Berrak; Gürel, Büşra; Kılıç, Ülkan; Çağlayan, Ahmet Burak; Kalkan, Rabia; Baykal, Ahmet Tarık; Keleştemur, Taha; Kılıç, ErtuğrulIndolamine melatonin structurally resembles non-covalent proteasome inhibitors; however, the role of ubiquitin proteasome system (UPS) in neuronal survival and how melatonin carries out UPS inhibition remain largely unknown. With the use of melatonin treated cells, we evaluated the expression of Nedd4-1, an E3 ligase, how melatonin regulates its activity and its relationship with neuronal survival. Nedd4-1 was upregulated in the hypoxic condition in both control and Nedd4-1 overexpressed cells and melatonin treatment reversed its expression in both normoxic and hypoxic conditions, which was associated with increased cellular survival. Melatonin had no effect on the expression of Nedd4-1 at mRNA level. However, when melatonin was administered along with protein synthesis inhibitor cycloheximide, protein level of Nedd4-1 was further reduced, indicating that melatonin possibly downregulates Nedd4-1 after its synthesis. Notably, co-immunoprecipitation analyses followed by Liquid chromatography Mass Spectrometry (LC-MS/MS) revealed that melatonin may dissociate ribosomal proteins, such as RS19, RL23A, and nucleophosmin from Nedd4-1, while 40S ribosomal protein S7 and 60S ribosomal protein L35 came into contact with Nedd4-1 upon melatonin treatment. By using IPA analyses, we obtained further data indicated novel target molecules of melatonin in hypoxic conditions, including OTOF, SF3B2, IPO5, ST13, FGFR3, Mxl/Mx2, playing roles in RNA splicing and trafficking, growth factor and interferon signaling. Here, we described a new insight into the role of melatonin in UPS functioning by proposing a molecular mechanism through which melatonin regulates Nedd4-1.Öğe Evidence that osteogenic and neurogenic differentiation capability of epidural adipose tissue-derived stem cells was more pronounced than in subcutaneous cells(Tübitak Scientific & Technical Research Council Turkey, 2020) Solmaz, Bilgehan; Şahin, Ali; Keleştemur, Taha; Kılıç, Ertuğrul; Kaptanoğlu, ErkanBackground/aim: The management of dura-related complications, such as the repairment of dural tears and reconstruction of large dural defects, remain the most challenging subjects of neurosurgery. Numerous surgical techniques and synthetic or autologous adjuvant materials have emerged as an adjunct to primary dural closure, which may result in further complications or side effects. Therefore, the subcutaneous autologous free adipose tissue graft has been recommended for the protection of the central nervous system and repairment of the meninges. In addition, human adipose tissue is also a source of multipotent stem cells. However, epidural adipose tissue seems more promising than subcutaneous because of the close location and intercellular communication with the spinal cord. Herein, it was aimed to define differentiation capability of both subcutaneous and epidural adipose tissue-derived stem cells (ASCs). Materials and methods: Human subcutaneous and epidural adipose tissue specimens were harvested from the primary incisional site and the lumbar epidural space during lumbar spinal surgery, and ASCs were isolated. Results: The results indicated that both types of ASCs expressed the cell surface markers, which are commonly expressed stem cells; however, epidural ASCs showed lower expression of CD90 than the subcutaneous ASCs. Moreover, it was demonstrated that the osteogenic and neurogenic differentiation capability of epidural adipose tissue-derived ASCs was more pronounced than that of the subcutaneous ASCs. Conclusion: Consequently, the impact of characterization of epidural ASCs will allow for a new understanding for dural as well as central nervous system healing and recovery after an injury.Öğe Inhibition but not activation of neuronal P2X7 receptors plays roles in brain injury after optic nerve transaction and focal cerebral ischemia(Wiley-Blackwell, 2014) Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Kılıç, Ülkan; Keleştemur, Taha; Çağlayan, Berrak; Kılıç, Ertuğrul[Abstract Not Available]Öğe Inhibition but not activation of neuronal P2X7 receptors plays roles in brain injury after optic nerve transaction and focal cerebral ischemia(Springer Heidelberg, 2014) Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Kılıç, Ülkan; Keleştemur, Taha; Çağlayan, Berrak; Kılıç, Ertuğrul[Abstract Not Available]
