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 Metadata only Redox Regulation and Cancer Therapy(BENTHAM SCIENCE PUBL LTD, 2018) YALÇIN, AHMET SUHA; Yalcin, A. Suha; Karademir, BetulPublication Metadata only Cellular Protection and Therapeutic Potential of Tocotrienols(BENTHAM SCIENCE PUBL LTD, 2011) YILMAZ, BETÜL; Catalgol, Betul; Batirel, Saime; Ozer, Nesrin KartalTocotrienols, components belonging to vitamin E members, are used as potent therapeutics in the treatment of several diseases. Recent studies suggested tocotrienol to have better activity in many situations compared to tocopherols. Tocotrienols have been shown to lower the atherogenic apolipoprotein B and lipoprotein plasma levels. Additionally, tocotrienols with their anti-tumor effect together with anti-angiogenic and anti-thrombotic effects may serve as effective agents in cancer therapy. Besides these effects, some properties such as water insolubility and low stability limit the usage of tocotrienols in the clinic. However recent studies tried to increase the bioavailability with esterification and combination use. These efforts for the clinical usage of tocotrienols which may help them to take a wide place in the clinic and additional studies are needed to identify their therapeutical mechanisms.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 Metadata only CD36 expression in peripheral blood mononuclear cells reflects the onset of atherosclerosis(WILEY, 2018) SÖZEN, AHMET ERDİ; Yazgan, Burak; Sozen, Erdi; Karademir, Betul; Ustunsoy, Seyfettin; Ince, Umit; Zarkovic, Neven; Ozer, Nesrin KartalTogether with complex genetic and environmental factors, increased serum cholesterol and ox-LDL levels are considered as major triggering factors of atherosclerosis. Mononuclear cell infiltration to the arterial wall and uptake of ox-LDL, which is facilitated by CD36 receptor through an uncontrolled manner, play a key role in foam cell formation followed by atherogenesis development. The aim of this study was to analyze if CD36 expression in peripheral blood mononuclear cells reflect its aortic tissue level in hypercholesterolemia. In this study, CD36 protein expression was evaluated in aortic specimens of cholesterol or cholesterol plus Vitamin E treated animals in relation to the immunohistochemical analyses for the HNE-protein adducts, as well as for smooth muscle actin and vimentin. The CD36 mRNA expression was determined by RT-PCR in PBMC of hypercholesterolemic rabbits and hypercholesterolemic versus normocholesterolemic individuals. Immunohistochemistry findings revealed that smooth muscle actin, smooth muscle vimentin, HNE-protein conjugates, and CD36 protein expressions were significantly increased in aorta of hypercholesterolemic group where foam cells were present. High cholesterol diet significantly induced CD36 mRNA expression in both rabbit aorta and PBMCs, while positive correlation between aortic and PBMC CD36 expression has been found. In addition, consistent with the rabbit model, CD36 mRNA expression levels in human PBMCs were significantly higher in hypercholesterolemic patients than in normocholesterolemic individuals. Taken together, these results demonstrate that the CD36 mRNA levels of PBMCs could reflect the CD36 mRNA levels in aorta and could be used as a biomarker for diagnosis of atherosclerotic burden. (c) 2018 BioFactors, 44(6):588-596, 2018Publication 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 Metadata only 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, IrinaDifferent 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.Publication Metadata only Molecular Function of Tocopherols in Age Related Diseases(BENTHAM SCIENCE PUBL LTD, 2014) YILMAZ, BETÜL; Karademir, Betul; Ozer, Nesrin KartalTocopherols, with a phytyl side chain in its chroman ring, belong to vitamin E family and have several effects on organisms. They are also classified as therapeutics against different types of human diseases. Especially important roles in cell signaling and gene regulatory mechanisms make tocopherols crucial as therapeutic agents. Aging is accompanied with several degenerative disorders including cardiovascular, neuronal and metabolic diseases. The role of free radical damage in aging has been identified and tocopherols were shown to be involved in age related disorders. Recent studies and future directions will be focused in this review regarding the molecular functions of tocopherols.Publication Metadata only Basic mechanisms in endoplasmic reticulum stress and relation to cardiovascular diseases(ELSEVIER SCIENCE INC, 2015) SÖZEN, AHMET ERDİ; Sozen, Erdi; Karademir, Betul; Ozer, Nesrin KartalThe folding process is an important step in protein synthesis for the functional shape or conformation of the protein. The endoplasmic reticulum (ER) is the main organelle for the correct folding procedure, which maintains the homeostasis of the organism. This process is normally well organized under unstressed conditions, whereas it may fail under oxidative and ER stress. The unfolded protein response (UPR) is a defense mechanism that removes the unfolded/misfolded proteins to prevent their accumulation, and two main degradation systems are involved in this defense, including the proteasome and autophagy. Cells decide which mechanism to use according to the type, severity, and duration of the stress. If the stress is too severe and in excess, the capacity of these degradation mechanisms, proteasomal degradation and autophagy, is not sufficient and the cell switches to apoptotic death. Because the accumulation of the improperly folded proteins leads to several diseases, it is important for the body to maintain this balance. Cardiovascular diseases are one of the important disorders related to failure of the UPR. Especially, protection mechanisms and the transition to apoptotic pathways have crucial roles in cardiac failure and should be highlighted in detailed studies to understand the mechanisms involved. This review is focused on the involvement of the proteasome, autophagy, and apoptosis in the UPR and the roles of these pathways in cardiovascular diseases. (C) 2014 Elsevier Inc. All rights reserved.Publication Metadata only Effects of vitamin E on peroxisome proliferator-activated receptor gamma and nuclear factor-erythroid 2-related factor 2 in hypercholesterolemia-induced atherosclerosis(ELSEVIER SCIENCE INC, 2014) SÖZEN, AHMET ERDİ; Bozaykut, Perinur; Karademir, Betul; Yazgan, Burak; Sozen, Erdi; Siow, Richard C. M.; Mann, Giovanni E.; Ozer, Nesrin KartalAtherosclerosis and associated cardiovascular complications such as stroke and myocardial infarction are major causes of morbidity and mortality. We have previously reported a significant increase in mRNA levels of the scavenger receptor CD36 in aortae of cholesterol-fed rabbits and shown that vitamin E treatment attenuated increased CD36 mRNA expression. In the present study, we further investigated the redox signaling pathways associated with protection against atherogenesis induced by high dietary cholesterol and correlated these with CD36 expression and the effects of vitamin E supplementation in a rabbit model. Male albino rabbits were assigned to either a control group fed with a low vitamin E diet alone or a test group fed with a low vitamin E diet containing 2% cholesterol in the absence or presence of daily intramuscular injections of vitamin E (50 mg/kg). To elucidate the mechanisms by which vitamin E supplementation alters the effects of hypercholesterolemia in rabbit aortae, we measured peroxisome proliferator-activated receptor gamma (PPAR gamma), ATP-binding cassette transporter A1 (ABCA1), and matrix metalloproteinase-1 (MMP-1) mRNA levels by quantitative RT-PCR and the expression of MMP-1, nuclear factor-erythroid 2-related factor 2 (Nrf2), and glutathione S-transferase alpha (GST alpha) protein by immunoblotting. The increased MMP-1 and decreased GSTa expression observed suggests that a cholesterol-rich diet contributes to the development of atherosclerosis, whereas vitamin E supplementation affords protection by decreasing MMP-1 and increasing PPAR gamma, GSTa, and ABCA1 levels in aortae of rabbits fed a cholesterol-rich diet. Notably, protein expression of Nrf2, the antioxidant transcription factor, was increased in both the cholesterol-fed and the vitamin E-supplemented groups. Although Nrf2 activation can promote CD36-mediated cholesterol uptake by macrophages, the increased induction of Nrf2-mediated antioxidant genes is likely to contribute to decreased lesion progression. Thus, our study demonstrates that Nrf2 can mediate both pro- and antiatherosclerotic effects. (C) 2014 Elsevier Inc. All rights reserved.