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YILMAZ, BETÜL

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YILMAZ

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BETÜL

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2012 - 201992020 - 202412
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    PublicationOpen Access
    Cytotoxicity of Different Nano Composite Resins on Human Gingival and Periodontal Ligament Fibroblast Cell Lines: An In Vitro Study
    (MDPI, 2020-03-01) YILMAZ GÖLER, AYŞE MİNE; Kavuncu, Gamze; Yilmaz, Ayse Mine; Yilmaz, Betul Karademir; Atali, Pinar Yilmaz; Altunok, Elif Cigdem; Kuru, Leyla; Agrali, Omer Birkan
    The aim of this study is to determine the cytotoxicity of three different nano composite resins (CRs) on human gingival fibroblast (hGF) and periodontal ligament fibroblast (hPDLF) cell lines. These CRs selected were nanohybrid organic monomer-based Admira Fusion (AF), nanohybrid Bis-(acryloyloxymethyl) tricyclo [5.2.1.0.sup.2,6] decane-based Charisma Topaz (CT), and supra nano filled resin-based Estelite Quick Sigma (EQS). MTT assay was performed to assess the cytotoxicity of CRs at 24 h and one week. AF and EQS applied on hGF cells at 24 h and one week demonstrated similar cytotoxic outcomes. Cytotoxicity of CT on hGF cells at one week was higher than 24 h (p = 0.04). Cytotoxicity of CT on hGF cells was higher at 24 h (p = 0.002) and one week (p = 0.009) compared to control. All composites showed higher cytotoxicity on hPDLF cells at one week than the 24 h (AF; p = 0.02, CT; p = 0.02, EQS; p = 0.04). AF and EQS demonstrated lower cytotoxicity on hPDLF cells than the control group at 24 h (AF; p = 0.01, EQS; p = 0.001). CT was found more cytotoxic on hPDLF cells than the control (p = 0.01) and EQS group (p = 0.008) at one week. The cytotoxicity of CRs on hGF and hPDLF cells vary, according to the type of composites, cell types, and exposure time.
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    PublicationOpen Access
    Molecular cardiotoxic effects of proteasome inhibitors carfilzomib and ixazomib and their combination with dexamethasone involve mitochondrial dysregulation
    (2023-01-01) YILMAZ, BETÜL; JANNUZZI A. T., Korkmaz N. S., GÜNAYDIN AKYILDIZ A., Arslan Eseryel S., Karademir Yilmaz B., ALPERTUNGA B.
    With the development and approval of new proteasome inhibitors, proteasome inhibition is increasingly recognized in cancer therapy. Besides successful anti-cancer effects in hematological cancers, side effects such as cardiotoxicity are limiting effective treatment. In this study, we used a cardiomyocyte model to investigate the molecular cardiotoxic mechanisms of carfilzomib (CFZ) and ixazomib (IXZ) alone or in combination with the immunomodulatory drug dexamethasone (DEX) which is frequently used in combination therapies in the clinic. According to our findings, CFZ showed a higher cytotoxic effect at lower concentrations than IXZ. DEX combination attenuated the cytotoxicity for both proteasome inhibitors. All drug treatments caused a marked increase in K48 ubiquitination. Both CFZ and IXZ caused an upregulation in cellular and endoplasmic reticulum stress protein (HSP90, HSP70, GRP94, and GRP78) levels and DEX combination attenuated the increased stress protein levels. Importantly, IXZ and IXZ-DEX treatments caused upregulation of mitochondria fission and fusion gene expression levels higher than caused by CFZ and CFZ-DEX combination. The IXZ-DEX combination reduced the levels of OXPHOS proteins (Complex II–V) more than the CFZ-DEX combination. Reduced mitochondrial membrane potential and ATP production were detected with all drug treatments in cardiomyocytes. Our findings suggest that the cardiotoxic effect of proteasome inhibitors may be due to their class effect and stress response and mitochondrial dysfunction may be involved in the cardiotoxicity process.
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    PublicationOpen Access
    Potential role of proteasome on c-jun related signaling in hypercholesterolemia induced atherosclerosis
    (ELSEVIER SCIENCE BV, 2014) SÖZEN, AHMET ERDİ; Sozen, Erdi; Karademir, Betul; Yazgan, Burak; Bozaykut, Perinur; Ozer, Nesrin Kartal
    Atherosclerosis and its complications are major causes of death all over the world. One of the major risks of atherosclerosis is hypercholesterolemia. During atherosclerosis, oxidized low density lipoprotein (oxLDL) regulates CD36-mediated activation of c-jun amino terminal kinase-1 (JNK1) and modulates matrix metalloproteinase (MMP) induction which stimulates inflammation with an invasion of monocytes. Additionally, inhibition of proteasome leads to an accumulation of c-jun and phosphorylated c-jun and activation of activator protein-1 (AP-1) related increase of MMP expression. We have previously reported a significant increase in cluster of differentiation 36 (CD36) mRNA levels in hypercholesterolemic rabbits and shown that vitamin E treatment prevented the cholesterol induced increase in CD36 mRNA expression. In the present study, our aim is to identify the signaling molecules/transcription factors involved in the progression of atherosclerosis following CD36 activation in an in vivo model of hypercholesterolemic (induced by 2% cholesterol containing diet) rabbits. In this direction, proteasomal activities by fluorometry and c-jun, phospo c-jun, JNK1, MMP-9 expressions by quantitative RT-PCR and immunoblotting were tested in aortic tissues. The effects of vitamin E on these changes were also investigated in this model. As a result, c-jun was phosphorylated following decreased proteasomal degradation in hypercholesterolemic group. MMP-9 expression was also increased in cholesterol group rabbits contributing to the development of atherosclerosis. In addition, vitamin E showed its effect by decreasing MMP-9 levels and phosphorylation of c-jun. (C) 2014 The Authors. Published by Elsevier B.V.
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    PublicationOpen Access
    Controlled Release of Metformin Hydrochloride from Core-Shell Nanofibers with Fish Sarcoplasmic Protein
    (MDPI, 2019-10-10) YILMAZ, BETÜL; Sena, Su; Sumeyra, Korkmaz Nalan; Ulkugul, Guven; Sema, Arslan; Betul, Karademir; Muge, Sennaroglu Bostan; Sayip, Eroglu Mehmet; Muhammet, Uzun; Cevriye, Kalkandelen; Mahir, Mahirogullari; Titu, Aurel Mihail; Ficai, Anton; Ficai, Denisa; Gunduz, Oguzhan
    Background and Objectives: A coaxial electrospinning technique was used to produce core/shell nanofibers of a polylactic acid (PLA) as a shell and a polyvinyl alcohol (PVA) containing metformin hydrochloride (MH) as a core. Materials and Methods: Fish sarcoplasmic protein (FSP) was extracted from fresh bonito and incorporated into nanofiber at various concentrations to investigate the influence on properties of the coaxial nanofibers. The morphology, chemical structure and thermal properties of the nanofibers were studied. Results: The results show that uniform and bead-free structured nanofibers with diameters ranging from 621 nm to 681 nm were obtained. A differential scanning calorimetry (DSC) analysis shows that FSP had a reducing effect on the crystallinity of the nanofibers. Furthermore, the drug release profile of electrospun fibers was analyzed using the spectrophotometric method. Conclusions: The nanofibers showed prolonged and sustained release and the first order kinetic seems to be more suitable to describe the release. MTT assay suggests that the produced drug and protein loaded coaxial nanofibers are non-toxic and enhance cell attachment. Thus, these results demonstrate that the produced nanofibers had the potential to be used for diabetic wound healing applications.
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    PublicationOpen Access
    Next-generation grade and survival expression biomarkers of human gliomas based on algorithmically reconstructed molecular pathways
    (2022-07-01) YILMAZ, BETÜL; Zolotovskaia M. A., Kovalenko M. A., Tkachev V. S., Simonov A. M., Sorokin M., Kim E., Kuzmin D., Karademir-Yilmaz B., Buzdin A. A.
    In gliomas, expression of certain marker genes is strongly associated with survival and tumor type and often exceeds histological assessments. Using a human interactome model, we algorithmically reconstructed 7494 new-type molecular pathways that are centered each on an individual protein. Each single-gene expression and gene-centric pathway activation was tested as a survival and tumor grade biomarker in gliomas and their diagnostic subgroups (IDH mutant or wild type, IDH mutant with 1p/19q co-deletion, MGMT promoter methylated or unmethylated), including the three major molecular subtypes of glioblastoma (proneural, mesenchymal, classical). We used three datasets from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas, which in total include 527 glioblastoma and 1097 low grade glioma profiles. We identified 2724 such gene and 2418 pathway survival biomarkers out of total 17,717 genes and 7494 pathways analyzed. We then assessed tumor grade and molecular subtype biomarkers and with the threshold of AUC > 0.7 identified 1322/982 gene biomarkers and 472/537 pathway biomarkers. This suggests roughly two times greater efficacy of the reconstructed pathway approach compared to gene biomarkers. Thus, we conclude that activation levels of algorithmically reconstructed gene-centric pathways are a potent class of new-generation diagnostic and prognostic biomarkers for gliomas.
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    PublicationOpen Access
    Resveratrol: French paradox revisited
    (FRONTIERS MEDIA SA, 2012) YILMAZ, BETÜL; Catalgol, Betul; Batirel, Saime; Taga, Yavuz; Ozer, Nesrin Kartal
    Resveratrol is a polyphenol that plays a potentially important role in many disorders and has been studied in different diseases. The research on this chemical started through the French paradox, which describes improved cardiovascular outcomes despite a high-fat diet in French people. Since then, resveratrol has been broadly studied and shown to have antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic effects, with those on oxidative stress possibly being most important and underlying some of the others, but many signaling pathways are among the molecular targets of resveratrol. In concert they may be beneficial in many disorders, particularly in diseases where oxidative stress plays an important role. The main focus of this review will be the pathways affected by resveratrol. Based on these mechanistic considerations, the involvement of resveratrol especially in cardiovascular diseases, cancer, neurodegenerative diseases, and possibly in longevity will be is addressed.
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    PublicationOpen Access
    Exploring the anticancer effects of brominated plastoquinone analogs with promising cytotoxic activity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction
    (2022-06-01) YILMAZ GÖLER, AYŞE MİNE; YILMAZ, BETÜL; Jannuzzı A. T., Yılmaz Göler A. M., Bayrak N., Yıldız M., Yıldırım H., Yılmaz B., Shilkar D., Jayaprakash Venkatesan R., Jayaprakash V., Tuyun A. F.
    Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possibleBrPQ5interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity ofBrPQ5was assessed, and IC50values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects ofBrPQ5on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed thatBrPQ5caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However,BrPQ5did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.
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    PublicationOpen Access
    Propolis-Based Nanofiber Patches to Repair Corneal Microbial Keratitis
    (MDPI, 2021-04-28) ŞAHİN, ALİ; Ulag, Songul; Ilhan, Elif; Demirhan, Ramazan; Sahin, Ali; Yilmaz, Betul Karademir; Aksu, Burak; Sengor, Mustafa; Ficai, Denisa; Titu, Aurel Mihail; Ficai, Anton; Gunduz, Oguzhan
    In this research, polyvinyl-alcohol (PVA)/gelatin (GEL)/propolis (Ps) biocompatible nanofiber patches were fabricated via electrospinning technique. The controlled release of Propolis, surface wettability behaviors, antimicrobial activities against the S. aureus and P. aeruginosa, and biocompatibility properties with the mesenchymal stem cells (MSCs) were investigated in detail. By adding 0.5, 1, and 3 wt.% GEL into the 13 wt.% PVA, the morphological and mechanical results suggested that 13 wt.% PVA/0.5 wt.% GEL patch can be an ideal matrix for 3 and 5 wt.% propolis addition. Morphological results revealed that the diameters of the electrospun nanofiber patches were increased with GEL (from 290 nm to 400 nm) and Ps addition and crosslinking process cause the formation of thicker nanofibers. The tensile strength and elongation at break enhancement were also determined for 13 wt.% PVA/0.5 wt.% GEL/3 wt.% Ps patch. Propolis was released quickly in the first hour and arrived at a plateau. Cell culture and contact angle results confirmed that the 3 wt.% addition of propolis reinforced mesenchymal stem cell proliferation and wettability properties of the patches. The antimicrobial activity demonstrated that propolis loaded patches had antibacterial activity against the S. aureus, but for P. aeruginosa, more studies should be performed.
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    PublicationOpen Access
    Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
    (ELSEVIER, 2020-05) YILMAZ GÖLER, AYŞE MİNE; Jannuzzi, Ayse Tarbin; Arslan, Sema; Yilmaz, Ayse Mine; Sari, Gulce; Beklen, Hande; Mendez, Lucia; Fedorova, Maria; Arga, Kazim Yalcin; Yilmaz, Betul Karademir; Alpertunga, Buket
    Proteasome inhibitors have great success for their therapeutic potential against hematologic malignancies. First generation proteasome inhibitor bortezomib induced peripheral neuropathy is considered as a limiting factor in chemotherapy and its second-generation counterpart carfilzomib is associated with lower rates of neurotoxicity. The mitochondrial toxicity (mitotoxicity) hypothesis arises from studies with animal models of bortezomib induced peripheral neuropathy. However, molecular mechanisms are not fully elucidated and the role of mitotoxicity in bortezomib and carfilzomib induced neurotoxicity has not been investigated comparatively. Herein, we characterized the neurotoxic effects of bortezomib and carfilzomib at the molecular level in human neuronal cells using LC-MS/MS analysis, flow cytometry, RT-qPCR, confocal microscopy and western blotting. We showed that bortezomib and carfilzomib affected the human neuronal proteome differently, and bortezomib caused higher proteotoxic stress via protein oxidation, protein K48-ubiquitination, heat shock protein expression up-regulation and reduction of mitochondria membrane potential. Bortezomib and carfilzomib did not affect the gene expression levels related to mitochondrial dynamics (optic atrophy 1; OPA1, mitofusin 1; MFN1, mitofusin 2; MFN2, fission 1; FIS1, dynamin-related protein 1; DRP1) and overall mitophagy rate whereas, PINK1/Parkin mediated mitophagy gene expressions were altered with both drugs. Bortezomib and carfilzomib caused downregulation of the contents of mitochondrial oxidative phosphorylation complexes, voltage-dependent anion channel 1 (VDAC1) and uncoupling protein 2 (UCP2) similarly. Our findings suggest that, both drugs induce mitotoxicity besides proteotoxic stress in human neuronal cells and the higher incidence of neurotoxicity with bortezomib than carfilzomib is not directly related to mitochondrial pathways.
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    PublicationOpen Access
    Protective effects of vitamin E against hypercholesterolemia-induced age-related diseases
    (BMC, 2012-01) YILMAZ, BETÜL; Catalgol, Betul; Ozer, Nesrin Kartal
    Hypercholesterolemia is a major risk factor for age-related diseases such as atherosclerosis and Alzheimer's disease (AD). Changes in human plasma cholesterol levels results from the interaction between multiple genetic and environmental factors. The accumulation of excess cholesterol in blood vessels leads to atherosclerosis. Many studies on this field show that differential expression of oxidative stress-related proteins, lipid metabolism-related enzymes, and receptors response to atherogenic diet. Additionally, excess brain cholesterol has been associated with increased formation and deposition of amyloid-beta peptide from amyloid precursor protein which may contribute to the risk and pathogenesis of AD. To consider genetically, more than 50 genes have been reported to influence the risk of late-onset AD. Some of these genes might be also important in cholesterol metabolism and transport. Epidemiological studies have shown an association between high intake and high serum concentrations of antioxidant vitamins like vitamin E and lower rates of ischemic heart diseases. It has been known that vitamin E also inhibits smooth muscle cell proliferation by non-antioxidant mechanism. On the basis of the previous results, vitamin E has been accepted as an important protective factor against hypercholesterolemia-induced age-related diseases.