Person: YILMAZ, BETÜL
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YILMAZ
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BETÜL
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Publication Open 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 KartalAtherosclerosis 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.Publication Open Access Resveratrol: French paradox revisited(FRONTIERS MEDIA SA, 2012) YILMAZ, BETÜL; Catalgol, Betul; Batirel, Saime; Taga, Yavuz; Ozer, Nesrin KartalResveratrol 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.Publication Open 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, BuketProteasome 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.Publication Open Access Nrf2 silencing to inhibit proteolytic defense induced by hyperthermia in HT22 cells(ELSEVIER SCIENCE BV, 2016-08) YILMAZ, BETÜL; Bozaykut, Perinur; Ozer, Nesrin Kartal; Karademir, BetulNrf2 pathway has been known to be protective against cancer progression however recent studies have revealed that the antioxidant activity of Nrf2 contributes to chemotherapy resistance. For many years, hyperthermia has been used as an additional therapy to increase the efficiency of chemotherapy and radiotherapy. Besides the positive effects of hyperthermia during treatment procedure, thermotolerance has been found to develop against heat treatment. Although the involved molecular mechanisms have not been fully clarified, heat shock proteins (HSP) and proteasome activity are known to be involved in the acquisition of thermotolerance. The aim of this study was to investigate the potential beneficial effects of combining hyperthermia with Nrf2 silencing to inhibit molecular mechanisms leading to induction of defense mechanisms in transcription level. Following heat treatment of HT22 cells, HSP70 and the proteasome levels and as well as proteasome activity were found to be elevated in the nucleus. Our results demonstrated that Nrf2 silencing reduced defense mechanisms against heat treatment both in antioxidant and proteolytic manner and Nrf2 may be a potential target for therapeutic approach in order to improve the beneficial effects of hyperthermia in cancer therapy. (C) 2016 The Authors. Published by Elsevier B.V.