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4. Photocatalytically Active Graphitic Carbon Nitride as an Effective and Safe 2D Material for In Vitro and In Vivo Photodynamic Therapy

Author

Taheri, Hadiseh, Unal, Mehmet Altay, Sevim, Melike, Gurcan, Cansu, Ekim, Okan, Ceylan, Ahmet, Syrgiannis, Zois, Christoforidis, Konstantinos C., Bosi, Susanna, Ozgenc, Ozge, Gomez, Manuel Jose, Turktas Erken, Mine, Soydal, Cigdem, Eroglu, Zafer, Bitirim, Ceylan Verda, Cagin, Umut, Ari, Fikret, Ozen, Asuman, Kucuk, Ozlem, Delogu, Lucia Gemma, Prato, Maurizio, Metin, Onder, Yilmazer, Acelya, Taheri, Hadiseh, Unal, Mehmet Altay, Sevim, Melike, Gurcan, Cansu, Ekim, Okan, Ceylan, Ahmet, Syrgiannis, Zois, Christoforidis, Konstantinos C., Bosi, Susanna, Ozgenc, Ozge, Gomez, Manuel Jose, Turktas Erken, Mine, Soydal, Cigdem, Eroglu, Zafer, Bitirim, Ceylan Verda, Cagin, Umut, Ari, Fikret, Ozen, Asuman, Kucuk, Ozlem, Delogu, Lucia Gemma, Prato, Maurizio, Metin, Onder, and Yilmazer, Acelya

Abstract

Thanks to its photocatalytic property, graphitic carbon nitride (g-C3N4) is a promising candidate in various applications including nanomedicine. However, studies focusing on the suitability of g-C3N4 for cancer therapy are very limited and possible underlying molecular mechanisms are unknown. Here, it is demonstrated that photoexcitation of g-C3N4 can be used effectively in photodynamic therapy, without using any other carrier or additional photosensitizer. Upon light exposure, g-C3N4 treatment kills cancer cells, without the need of any other nanosystem or chemotherapeutic drug. The material is efficiently taken up by tumor cells in vitro. The transcriptome and proteome of g-C3N4 and light treated cells show activation in pathways related to both oxidative stress, cell death, and apoptosis which strongly suggests that only when combined with light exposure, g-C3N4 is able to kill cancer cells. Systemic administration of the mesoporous form results in elimination from urinary bladder without any systemic toxicity. Administration of the material significantly decreases tumor volume when combined with local light treatment. This study paves the way for the future use of not only g-C3N4 but also other 2D nanomaterials in cancer therapy.

Published
2020

5. Beta(3)-Adrenergic Receptor Activation Plays An Important Role In The Depressed Myocardial Contractility Via Both Elevated Levels Of Cellular Free Zn2+ And Reactive Nitrogen Species

Author

Tuncay, Erkan, Olgar, Yusuf, Durak, Aysegul, Degirmenci, Sinan, Bitirim, Ceylan Verda, and Turan, Belma

Abstract

Role of (3)-AR dysregulation, as either cardio-conserving or cardio-disrupting mediator, remains unknown yet. Therefore, we examined the molecular mechanism of (3)-AR activation in depressed myocardial contractility using a specific agonist CL316243 or using (3)-AR overexpressed cardiomyocytes. Since it has been previously shown a possible correlation between increased cellular free Zn2+ ([Zn2+](i)) and depressed cardiac contractility, we first demonstrated a relation between (3)-AR activation and increased [Zn2+](i), parallel to the significant depolarization in mitochondrial membrane potential in rat ventricular cardiomyocytes. Furthermore, the increased [Zn2+](i) induced a significant increase in messenger RNA (mRNA) level of (3)-AR in cardiomyocytes. Either (3)-AR activation or its overexpression could increase cellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels, in line with significant changes in nitric oxide (NO)-pathway, including increases in the ratios of pNOS3/NOS3 and pGSK-3/GSK-3, and PKG expression level in cardiomyocytes. Although (3)-AR activation induced depression in both Na+- and Ca2+-currents, the prolonged action potential (AP) seems to be associated with a marked depression in K+-currents. The (3)-AR activation caused a negative inotropic effect on the mechanical activity of the heart, through affecting the cellular Ca2+-handling, including its effect on Ca2+-leakage from sarcoplasmic reticulum (SR). Our cellular level data with (3)-AR agonism were supported with the data on high [Zn2+](i) and (3)-AR protein-level in metabolic syndrome (MetS)-rat heart. Overall, our present data can emphasize the important deleterious effect of (3)-AR activation in cardiac remodeling under pathological condition, at least, through a cross-link between (3)-AR activation, NO-signaling, and [Zn2+](i) pathways. Moreover, it is interesting to note that the recovery in ER-stress markers with (3)-AR agonism in hyperglycemic cardiomyocytes is favored. Therefore, how long and to which level the (3)-AR agonism would be friend or become foe remains to be mystery, yet.

Published
2019

6. Increased free Zn2+correlates induction of sarco(endo)plasmic reticulum stressviaaltered expression levels of Zn2+-transporters in heart failure

Author

Olgar, Yusuf, primary, Durak, Aysegul, additional, Tuncay, Erkan, additional, Bitirim, Ceylan Verda, additional, Ozcinar, Evren, additional, Inan, Mustafa Bahadir, additional, Tokcaer-Keskin, Zeynep, additional, Akcali, Kamil Can, additional, Akar, Ahmet Ruchan, additional, and Turan, Belma, additional

Published
2018
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7. Increased free Zn2+ correlates induction of sarco(endo)plasmic reticulum stress <italic>via</italic> altered expression levels of Zn2+‐transporters in heart failure.

Author

Olgar, Yusuf, Durak, Aysegul, Tuncay, Erkan, Bitirim, Ceylan Verda, Ozcinar, Evren, Inan, Mustafa Bahadir, Tokcaer‐Keskin, Zeynep, Akcali, Kamil Can, Akar, Ahmet Ruchan, and Turan, Belma

Subjects
HEART failure, ENDOPLASMIC reticulum, ZINC transporters, CARRIER proteins, GENE expression, PREVENTION
Abstract

Abstract: Zn2+‐homoeostasis including free Zn2+ ([Zn2+]i) is regulated through Zn2+‐transporters and their comprehensive understanding may be important due to their contributions to cardiac dysfunction. Herein, we aimed to examine a possible role of Zn2+‐transporters in the development of heart failure (HF) via induction of ER stress. We first showed localizations of ZIP8, ZIP14 and ZnT8 to both sarcolemma and S(E)R in ventricular cardiomyocytes (H9c2 cells) using confocal together with calculated Pearson's coefficients. The expressions of ZIP14 and ZnT8 were significantly increased with decreased ZIP8 level in HF. Moreover, [Zn2+]i was significantly high in doxorubicin‐treated H9c2 cells compared to their controls. We found elevated levels of ER stress markers, GRP78 and CHOP/Gadd153, confirming the existence of ER stress. Furthermore, we measured markedly increased total PKC and PKCα expression and PKCα‐phosphorylation in HF. A PKC inhibition induced significant decrease in expressions of these ER stress markers compared to controls. Interestingly, direct increase in [Zn2+]i using zinc‐ionophore induced significant increase in these markers. On the other hand, when we induced ER stress directly with tunicamycin, we could not observe any effect on expression levels of these Zn2+ transporters. Additionally, increased [Zn2+]i could induce marked activation of PKCα. Moreover, we observed marked decrease in [Zn2+]i under PKC inhibition in H9c2 cells. Overall, our present data suggest possible role of Zn2+ transporters on an intersection pathway with increased [Zn2+]i and PKCα activation and induction of HF, most probably via development of ER stress. Therefore, our present data provide novel information how a well‐controlled [Zn2+]ivia Zn2+ transporters and PKCα can be important therapeutic approach in prevention/treatment of HF. [ABSTRACT FROM AUTHOR]

Published
2018
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8. Genetic and epigenetic effect of estrogen on mesenchymal stem cell maintenance and differentiation

Author

Bitirim, Ceylan Verda, Yuluğ, Işık, Akçalı, Kamil Can, Moleküler Biyoloji ve Genetik Anabilim Dalı, and Yuluğ, Işık G.

Subjects
Estrogen replacement therapy, Hormone therapy, Mesenchymal stem cells, Stem cells, Genetics, QH588.S83 B58 2013, Genetik, Biology, Biyoloji
Abstract

Mezenkimal kök hücreler (MKH) kemik, yağ, kıkırdak, sinir ve karaciğer hücrelerine dönüşebilme potansiyeli olan, immün reaksiyon oluşturma özelliği olmayan hücrelerdir. Bu özellikler kök hücreleri doku mühendisliği ve hücre tedavisi alanları için yeni bir umut haline getirdi. Hücre transplantasyonunda kullanılmak üzere ideal yüzey üretmek için pek çok çalışma yürütüldü. Son yıllarda farklı fiziksel, kimyasal ve elektriksel özelliklerinden dolayı karbon nanotüpler (KNT) yeni biyomateryal yüzeyler olarak tanımlandı. Östrojen hormonunun mezenkimal kök hücre devamlılığı, çoğalması ve farklılaşması üzerine etkileri rapor edilmiştir. Fakat östrojenin biyomateryal yüzey üzerindeki mezenkimal kök hücrenin devamlılıgındaki ve mezenkimal kök hücre farklılaşmasındaki genetik ve epigenetik rolü tam olarak araştırılmamıştır. Bu nedenle, bu çalışmada östrojenin karbon nantüp üzerine ekilen kök hücrelerin devamlılığındaki ve adipojenik, östeojenik ve kondrojek farklılaşmaya katılan anahtar transkripsiyon faktörlerinin genetik ve epigenetik regülasyonundaki rolünü araştrmak amaçlanmıştır. Sonuçlarımız östrojenin çok duvarlı karbon nanotüpler üzerindeki MKHlerin canlılıgını arttırıcı etkisini göstermiştir. Ayrıca hücre canlılıgı ve KNT materyalin üzerine yapışan MKH sayısının passajlama ile azaldıgını gösterdik. Bu çalışmada östrojenin MKH farklılaşmasının genetik ve epigenetik regülasyonuna etkisini gösterebildik. Östrojen tedavisi, normal dişi ve overi alınmış dişiden alınan MKH?de temel adipojenik transkripsiyon faktörler olan C/EBP?, FABP4, PPAR?, Adipsinin gen ifadesini azaltırken, anahtar transkripsiyon faktörü olan RUNX2 nin ifadesini arttırır. Bu sonucun östrojenin adipojenik farklılaşma üzerine baskılayıcı etkisini, östeojenik farklılaşma üzerine arttırıcı etkisini gösterdiği söylenebilir. PPAR? ve diğer transkripsiyon faktörü ETS1 proteinlerinin hücresel lokalizasyonunun östrojen yokluguna bağlı değişimi ayrıca gösterilmiştir. Diğer modifiye histonlar arasında, H3K27me2, H3K27me3 ve H3K36me2 protein düzeylerinin östrojen tedavisinden sonra azaldığını bulduk. Ek olarak, kromatin immünopresipitasyon analizleri H3K27me2, H3K27me3 ve ER? düzeylerinin C/EBP?, FABP4, PPAR?, Adipsin ve RUNX2 promotörleri üzerinde östrojen tedavisi sonucu arttıgını gösterdi. Bisülfit sekanslama analizleri östrojen yoklugunda C/EBP? ve PPAR? promotörleri üzerinde DNA hipermetilasyonu görülürken, ER? promotöründe CpG hipometilsayonu görüldü. Sonuç olarak, östrojen MKH devamlılıgı ve farklılaşmasında epigenetik ve genetik değişimlere yol açar. Östrojenin temel transkripsiyon faktölerinin regülasyonundaki etkisinin anlaşılması obezite, osteoporoz ve osteoartirit gibi kronik hastalıkların tedavisi için yeni ipuçları yaratır. Mesenchymal stem cells (MSCs) have the potential to differentiate into multiple cell types and immune privileged characteristics. These features make MSCs a hope in tissue engineering and cell based treatment applications. Tremendous amount of studies were carried out in order to produce an ideal biomaterial as a scaffold for cell transplantation. In recent studies, carbon nanotubes (CNT) were identified as a novel scaffold array due to their unique physical, chemical and electrical properties among the other biomaterials.The effect of estrogen hormone on the regulation of MSC maintenance, proliferation and differentiation was reported. However, its role in maintenance of MSCs on scaffold materials such as CNTs and the genetic and epigenetic regulation of MSC differentiation have not fully been elucidated. Therefore our aim was to examine the possible role of estrogen in the MSCs? maintenance seeded on CNT surfaces and genetic and epigenetic regulation of the key transcription factors involved in adipogenic, osteogenic and chondrogenic differentiaton of MSCs. Our results revealed the enhanced effect of estrogen on the viability of MCSs which were seeded and incubated on multiwalled carbon nanotubes (MWCNT). In addition we demonstrated that passaging causes decrease of cell viability and the number of attached cells on CNT materials. We have also shown the effect of estrogen on the epigenetic and genetic regulation of MSC differentiation. Estrogen treatment decreased the expression of major adipogenic transcription factors; C/EBP?, FABP4, PPAR?, Adipsin and increased key osteogenic transcription factor RUNX2 in MSCs from both normal female and ovariectomized rats, suggesting inhibitory and stimulatory effect of estrogen on adipogenesis and osteogenesis respectively. We have also shown that the subcellular localization of PPAR? and ETS1 is changed in response to estrogen deficiency. Among modified histones, we found that H3K27me2, H3K27me3 and H3K36me2 protein levels were reduced after estrogen treatment both in female and ovariectomized animals. In addition, ChIP analysis showed that estrogen treatment caused an increase in H3K27me2, H3K27me3 and ER? levels at the promoters of C/EBP?, FABP4, PPAR?, Adipsin and RUNX2. Bisulfite sequencing analysis revealed that in the absence of estrogen, DNA hypermethylation was established in C/EBP? and PPAR? promoters whereas in ER? promoters CpG hypomethylation was observed after estrogen treatment. In conclusion, estrogen causes epigenetic and genetic changes in maintenace and differentiation of MSCs. Understanding the effect of estrogen on the genetic and epigenetic regulation of the major transcription factors may lead to clues for new treatment in chronic diseases such as obesity, osteoporosis and ostearthiritis. 175

Published
2013

9. Increased free Zn 2+ correlates induction of sarco(endo)plasmic reticulum stress via altered expression levels of Zn 2+ -transporters in heart failure.

Author

Olgar Y, Durak A, Tuncay E, Bitirim CV, Ozcinar E, Inan MB, Tokcaer-Keskin Z, Akcali KC, Akar AR, and Turan B

Subjects
Adult, Animals, Case-Control Studies, Cation Transport Proteins metabolism, Cations, Divalent, Cell Line, Doxorubicin pharmacology, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress drug effects, Gene Expression Regulation, Heart Failure metabolism, Heart Failure pathology, Heart Failure surgery, Heart Ventricles drug effects, Heart Ventricles metabolism, Heart Ventricles pathology, Heat-Shock Proteins genetics, Heat-Shock Proteins metabolism, Humans, Male, Middle Aged, Myoblasts drug effects, Myoblasts metabolism, Myoblasts pathology, Myocytes, Cardiac cytology, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Protein Kinase C-alpha genetics, Protein Kinase C-alpha metabolism, Rats, Sarcoplasmic Reticulum drug effects, Transcription Factor CHOP genetics, Transcription Factor CHOP metabolism, Tunicamycin pharmacology, Zinc Transporter 8 metabolism, Cation Transport Proteins genetics, Heart Failure genetics, Heart Transplantation, Sarcoplasmic Reticulum metabolism, Zinc metabolism, Zinc Transporter 8 genetics
Abstract

Zn 2+ -homoeostasis including free Zn 2+ ([Zn 2+ ] i ) is regulated through Zn 2+ -transporters and their comprehensive understanding may be important due to their contributions to cardiac dysfunction. Herein, we aimed to examine a possible role of Zn 2+ -transporters in the development of heart failure (HF) via induction of ER stress. We first showed localizations of ZIP8, ZIP14 and ZnT8 to both sarcolemma and S(E)R in ventricular cardiomyocytes (H9c2 cells) using confocal together with calculated Pearson's coefficients. The expressions of ZIP14 and ZnT8 were significantly increased with decreased ZIP8 level in HF. Moreover, [Zn 2+ ] i was significantly high in doxorubicin-treated H9c2 cells compared to their controls. We found elevated levels of ER stress markers, GRP78 and CHOP/Gadd153, confirming the existence of ER stress. Furthermore, we measured markedly increased total PKC and PKCα expression and PKCα-phosphorylation in HF. A PKC inhibition induced significant decrease in expressions of these ER stress markers compared to controls. Interestingly, direct increase in [Zn 2+ ] i using zinc-ionophore induced significant increase in these markers. On the other hand, when we induced ER stress directly with tunicamycin, we could not observe any effect on expression levels of these Zn 2+ transporters. Additionally, increased [Zn 2+ ] i could induce marked activation of PKCα. Moreover, we observed marked decrease in [Zn 2+ ] i under PKC inhibition in H9c2 cells. Overall, our present data suggest possible role of Zn 2+ transporters on an intersection pathway with increased [Zn 2+ ] i and PKCα activation and induction of HF, most probably via development of ER stress. Therefore, our present data provide novel information how a well-controlled [Zn 2+ ] i via Zn 2+ transporters and PKCα can be important therapeutic approach in prevention/treatment of HF., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Published
2018
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