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YILMAZ, BETÜL

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YILMAZ

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BETÜL

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2020 - 202430
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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
    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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    Molecular signatures in acute myeloid leukemia: from diagnosis to targeted therapy and drug repositioning
    (Springer, 2022-01-01) YILMAZ, BETÜL; ARĞA, KAZIM YALÇIN; KELEŞOĞLU N., YILMAZ B., ARĞA K. Y.
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    Design and fabrication of electrospun polycaprolactone/chitosan scaffolds for ligament regeneration
    (PERGAMON-ELSEVIER SCIENCE LTD, 2021) İNAN, AHMET TALAT; Saatcioglu, Elif; Ulag, Songul; Sahin, Ali; Yilmaz, Betul Karademir; Ekren, Nazmi; Inan, Ahmet Talat; Palaci, Yuksel; Ustundag, Cem Bulent; Gunduz, Oguzhan
    Tendon and ligament impairments are among the most familiar injuries of the knee with acute or chronic pain conditions. The defects of anterior cruciate ligament (ACL) stay a known clinical problem. In the present study, the electrospinning method was used to fabricate 10wt.%PCL/(1, 3, 5)wt.%Chitosan (CS) appropriate and biocompatible scaffolds with a similar connective ligament geometry and structure. 10wt.%PCL/3wt.%CS demonstrated higher tensile strength value (0.58854 MPa) than other scaffolds in the tensile test. Moreover, 10wt.%PCL/3wt.%CS scaffolds had high mesenchymal stem cells (MSCs) viability value for all incubation periods. Swelling and degradation behaviours of the ligament-like scaffolds were examined in vitro for 15 days. Results reported that the highest swelling ratio was observed with CS addition for 10wt.%PCL/5wt.%CS scaffolds which value nearly reached to the 270% ratio. Scanning electron microscope proved the geometry of the scaffolds, which were suitable for ligament-like tissue. Attachment of MSCs on the scaffolds proved the network-like structure of the cells on the scaffolds.
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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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    The potential use of natural products to negate hepatic, renal and neuronal toxicity induced by cancer therapeutics
    (PERGAMON-ELSEVIER SCIENCE LTD, 2020) YALÇIN, AHMET SUHA; Prsa, Patrik; Karademir, Betul; Bicim, Gokhan; Mahmoud, Hatem; Dahan, Inbal; Yalcin, A. Suha; Mahajna, Jamal; Milisav, Irina
    Different types of chemotherapeutics are used for cancer treatment. These drugs act on several signal pathways, lead to programmed cell death, and damage cancer cells. Although many specific mechanisms of action have been suggested for chemotherapeutics, there are still gaps in understanding their effects. They may affect different components of the cell, particularly proteins with specific functions, such as enzymes. Recently, targeted and immuno therapies were introduced for treatment of different cancers. However, many cancer patients still depend on traditional and well-known drugs. Doxorubicin and platinum-based drugs are among the most frequently used chemotherapeutics. They are highly cytotoxic for cancer cells, but they also act on healthy cells. Hence, it is crucial to understand the mechanisms involved in order to decrease their side effects. Natural products, many of which are also available over-the-counter, may be considered to decrease various cancer drug-induced side effects. This review focuses on the use of these compounds to overcome side effects of chemotherapeutics, primarily doxorubicin and cisplatin, in the liver, kidney, and neuronal systems.
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    Glioblastoma cell adhesion properties through bacterial cellulose nanocrystals in polycaprolactone/gelatin electrospun nanofibers
    (ELSEVIER SCI LTD, 2020) YILMAZ, BETÜL; Unal, Semra; Arslan, Sema; Yilmaz, Betul Karademir; Kazan, Dilek; Oktar, Faik Nuzhet; Gunduz, Oguzhan
    Glioblastoma (GBM), the most common and extremely lethal type of brain tumor, is resistant to treatment and shows high recurrence rates. In the last decades, it is indicated that standard two-dimensional (2D) cell culture is inadequate to improve new therapeutic strategies and drug development. Hence, well-mimicked three-dimensional (3D) tumor platforms are needed to bridge the gap between in vitro and in vivo cancer models. In this study, bacterial cellulose nano-crystal (BCNC) containing polycaprolactone (PCL) /gelatin (Gel) nanofibrous composite scaffolds were successfully fabricated by electrospinning for mimicking the extracellular matrix of GBM tumor. The fiber diameters in the nanofibrous matrix were increased with an increased concentration of BCNC. Moreover, fiber morphology changed from the smooth formation to the beaded formation by increasing the concentration of the BCNC suspension. In-vitro biocompatibilities of nanofibrous scaffolds were tested with U251 MG glioblastoma cells and improved cell adhesion and proliferation was compared with PCL/Gel. PCL/Gel/BCNC were found suitable for enhancing axon growth and elongation supporting communication between tumor cells and the microenvironment, triggering the process of tumor recurrence. Based on these results, PCL/Gel/BCNC composite scaffolds are a good candidate for biomimetic GBM tumor platform.