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A preliminary proteomic evaluation of smooth muscle cells in thoracic aortic aneurysms
(The Scientific and Technological Research Council of Turkey, 2014) Açılan Ayhan, Ceyda; Baykal, Betül; Serhatlı, Müge; Kaçar, Ömer; Adıgüzel, Zelal; Taş, Serpil; Baysal, Kemal; Baykal, Ahmet Tarık
Aortic aneurysm is characterized as localized degeneration of the aorta leading to advanced weakening and widening of the vessel. While the exact mechanisms have yet to be determined, current studies indicate that the degradation of extracellular matrix (ECM) proteins and apoptosis of vascular smooth muscle cells (SMCs) may result in extendibility, dilation, and rupture of the vessel. Within the aortic wall, SMCs are implicated as key components involved in disease development, as numerous molecular changes have been reported to occur. Most current studies involve either investigation of proteins constituting a group or pathway in SMCs, or analyses of the whole aortic tissue. In order to determine which proteins are important in the development of thoracic aortic aneurysms (TAAs), we performed comparative proteomic analyses using cultured SMCs from TAAs versus controls. Label-free nano LC-MS/MS analysis of cell extracts resulted in the identification of 256 proteins, 26 of which were differentially regulated by >= 1.4-fold. Both previously described and new proteins were identified that were involved in oxidative stress, ECM formation, energy metabolism, or the 14-3-3 pathway. Among these, differential expression of SerpinH1, a protease inhibitor for collagenases, was further verified via immunoblotting. Here we have attempted to shed light on the cellular mechanisms of TAAs.
A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line
(Elsevier Science, 2015) Yerlikaya, Azmi; Okur, Emrah; Baykal, Ahmet Tarık; Acılan, Ceyda; Boyacı, İhsan; Ulukaya, Engin
The 26S proteasome is a proteolytic enzyme found in both cytoplasm and nucleus. In this study, we examined the differential expression of proteasome inhibitor bortezomib-induced proteins in p53-deficient 4T1 cells. It was found that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24 h. Next, we analyzed the expression of intracellular proteins in response to treatment with 100 nM bortezomib for 24 h by label-free LC-MS/MS. These analyses showed that Hsp70, the 26S proteasome non-ATPase regulatory subunit 14 and sequestosome 1 were increased at least 2 fold in p53-deficient 4T1 cells. The proteins identified by label-free LC-MS/MS were then analyzed by Ingenuity Pathway Analysis (IPA) Tool to determine biological networks affected by inhibition of the 26S proteasome. The analysis results showed that post-translational modifications, protein folding, DNA replication, energy production and nucleic acid metabolism were found to be among the top functions affected by the 26S proteasome inhibition. The biological network analysis indicated that ubiquitin may be the central regulator of the pathways modulated after bortezomib-treatment. Further investigation of the mechanism of the proteins modulated in response to the proteasomal inhibition may lead to the design of more effective and novel therapeutic strategies for cancer. Biological significance Although the proteasome inhibitor bortezomib is approved and used for the treatment of human cancer (multiple myeloma), the mechanism of action is not entirely understood. A number of studies showed that proteasome inhibitors induced apoptosis through upregulation of tumor suppressor protein p53. However, the role of tumor suppressor protein p53 in bortezomib-induced apoptosis is controversial and not well-understood. The tumor suppressor p53 is mutated in at least 50% of human cancers and is strongly induced by proteasomal inhibition. Some also reported that the proteasome inhibitor can induce apoptosis in a p53-independent manner. Also, it is reported that Noxa, a target of p53, is induced in response to proteasomal inhibition in a p53-independent manner. However, we have also previously reported that neither Puma nor Noxa are induced by proteasomal inhibition in p53-null 4T1 breast cancer cells, which is commonly used for in vivo breast cancer tumor models. The current results provided additional targets of proteasome inhibitor bortezomib and may therefore help in understanding the p53-independent mechanism of apoptosis induction by proteasome inhibitors. In addition, the results presented in this current study report for the first time that proteasomal subunit Psmd14, anti-apoptotic GRP78, anti apoptotic protein Card10, Dffb, Traf3 and Trp53bp2 are regulated and overexpressed in response to proteasome inhibitor bortezomib in p53-deficient 4T1 cells. Therefore, novel therapeutic strategies targeting these anti-apoptotic or pro-apoptotic proteins as well as inhibiting the proteasome simultaneously may be more effective against cancer cells. The proteins identified here present new avenues for the development of anti-cancer drugs.
Alzheimer hastalığında yaşa bağlı hipokampusteki protein profil değişimi ile meydana gelen farklılıklar ve ilişkili yolakların transgenik 5XFAD fare modeli üzerinde incelenmesi
(İstanbul Medipol Üniversitesi Sağlık Bilimleri Enstitüsü, 2016) Arzuman, Ayşegül Sümeyye; Ozansoy, Mehmet; Baykal, Ahmet Tarık
Alzheimer Hastalığı en yaygın görülen demaslardan biridir. Fakat, hastalığın mekanizması ve hastalıkla ilgili biyobelirteçler henüz tam olarak açıklığa kavuşmamıştır. Bu çalışmada, 5xFAD transgenik fare modeli ve onların kontrolleri kullanarak hastalığın temel mekanizmasını anlamak için farklı yaş gruplarında proteomic çalışması yapılarak değişim gösteren proteinleri, yolakları ve farklı yaş grupları arasındaki protein ilişkilerine bakılmış ve hastalığın gelişimini incelemek hedeflenmiştir. İki farklı yaş grubunda, farklı protein tanımlanması ve ekspresyonlarının belirlenmesi için kütle spektrometresi tabanlı protemik teknolojisi kullanılmıştır. Üç ve altı aylık 5xFAD trasgenik fare modeli hipokampusünde istatistiksel anlamlı olarak değişen toplam 137 protein tanımlanmıştır. Bu proteinlerin 15 tanesi 3 aylık dokuya, 122 tanesi ise 6 aylık hipokampus dokusuna aittir. Bunlara ek olarak, biyoinformatik yazılımlar kullanılarak tanımlanan proteinlerin hangi proteinler tarafından düzenlendiği. Bu çalışmanın amacı, yaşa bağlı olarak değişen 5xFAD hipokampus bölgesindeki protein değişiklerini inceleyip Alzheimer hastalığının temel mekanizmasını anlamaya çalışmaktır. Sonuç olarak; bu çalışmada elde ettiğimiz veriler bize gösterdiki 3. ayda değişim gösteren proteinler 6. aydaki yolaklardaki bozulmalara sebep olduğu gözlemlenmiştir. En çok etkilenen yolak ise mikrotübül bozukluk olarak belirlenmiştir.
Beyin ekstrasellüler matriksinin nörodejenerasyondaki rolünün alzheimer fare modelinde araştırılması
(İstanbul Medipol Üniversitesi Sağlık Bilimleri Enstitüsü, 2017) Gürel, Büşra; Öztürk, Gürkan; Baykal, Ahmet Tarık
Alzheimer hastalığında (AD), sinaptik yanıt mekanizmalarının ve sinaptik bağlantı stabilitesinin hasar gördüğü bilinmektedir. Son yıllarda yapılan çalışmalar, nöron ve glialar tarafından üretilen bazı ekstrasellüler matriks bileşenlerinin, bu iki mekanizma üzerinde etkili olduğunu göstermiştir. Çalışmanın amacı, Alzheimer's hastalığının başlangıç ve gelişim evrelerinde, hastalık modeli olan 5XFAD farelerden elde edilen hipokampal ekstrasellüler matriks örneklerinde proteom profilini analiz ederek, nörodejenereasyon oluşumu ile ilgili bu evrelere ait protein seviyesindeki değişimleri ve posttranslasyonel modifikasyon değişimlerini tanımlamaktır. Bunlara ek olarak, sağlıklı ve Alzheimer's hastası bireylerden alınan beyin-omurilik sıvıları ve post mortem beyin dokusu örneklerinin proteom analizi yapılarak, hastalığın gelişiminde rol alan temel yolakları belirlemektir. Fareler 3 (3m), 6 (6m) ve 12 (12m) aylık iken, Morris Su Tankı deneyleri ile hafıza testlerini takiben, intraserebral mikrodiyaliz "push-pull" yöntemi ile hipokampal ekstrasellüler matriks örnekleri toplandı. Örneklerin protein ekspresyon profilleri nanoLC-MS/MS yöntemi kullanılarak analiz edildi. Kütle spektrometrisi ile elde edilen ham data, Progenesis QI yazılımı ile işlenerek protein tanımlamaları gerçekleştirildi. 3,6 ve 12 aylık ECM örneklerinde sırasıyla 251, 213 ve 238 protein tanımlandı. Bunlardan sırasıyla 68, 41 ve 33 protein istatistiksel olarak anlamlı (p<0.05) en az 1.4 kat ekspresyon değişikliği gösterdi. Beyin-omurilik sıvılarının analizinde 204ü anlamlı değişen 1041 protein, postmortem doku analizlerinde 311i anlamlı değişen 1737 protein tanımlandı. Anlamlı değişiklik gösteren proteinler, Ingenuity Pathway Analysis (IPA) yazılımı ile analiz edilerek ilgili yolaklar tespit edildi.
Biochemical and proteomic analysis of a potential anticancer agent: Palladium(II) saccharinate complex of terpyridine acting through double strand break formation
(American Chemical Society, 2014) Adıgüzel, Zelal; Baykal, Ahmet Tarık; Kaçar, Ömer; Yılmaz, Veysel Turan; Ulukaya, Engin; Açılan, Ceyda
Metal based chemotherapeutic drugs are widely used as an effective method to defeat various cancers. In this study, the mechanism of action of a novel therapeutic agent, [Pd(sac)(terpy)](sac)center dot 4H(2)O (sac = saccharinate, and terpy = 2,2':6',2 ''-terpyridine) was studied. To better understand the proteomic changes in response to this agent, we performed nano LC-MS/MS analyses in human breast cancer cells (MDA-MB-231). Thirty proteins were identified to be differentially expressed more than 40% after drug treatment. Many cellular pathways were affected, including proteins involved in DNA repair, apoptosis, energy metabolism, protein folding, cytoskeleton, pre-mRNA maturation, or protein translation. The changes in protein expression were further verified for XRCC5, which plays a role in double strand break (DSB) repair, and ubiquitin, which is involved in protein degradation and apoptosis. The elevated XRCC5 levels were suggestive of increased DSBs. The presence of DSBs was confirmed by smearing of plasmid DNA in vitro and induction of gamma H2AX foci in vivo. There was also increased intracellular reactive oxygen species (ROS) formation, as detected by 2',7'-dichlorofluorescein diacetate (DCFDA) staining. Scavenging ROS by N-acetylcysteine rescued cell death in response to Pd(II) treatment, potentially explaining how the Pd(II) complex damaged the DNA. The details of this analysis and the significance will be discussed during the scope of this work.
Comparison of protein expression profile of limb regeneration between neotenic and metamorphic axolotl
(Elsevier, 2020) Sibai, Mustafa; Altuntaş, Ebru; Süzek, Barış Ethem; Şahin, Betül; Parlayan, Cüneyd; Öztürk, Gürkan; Baykal, Ahmet Tarık; Demircan, Turan
The axolotl (Ambystoma mexicanum) salamander, a urodele amphibian, has an exceptional regenerative capacity to fully restore an amputated limb throughout the life-long lasting neoteny. By contrast, when axolotls are experimentally induced to metamorphosis, attenuation of the limb's regenerative competence is noticeable. Here, we sought to discern the proteomic profiles of the early stages of blastema formation of neotenic and metamorphic axolotls after limb amputation by employing LC-MS/MS technology. We quantified a total of 714 proteins and qRT-PCR for selected genes was performed to validate the proteomics results and provide evidence for the putative link between immune system activity and regenerative potential. This study provides new insights for examination of common and distinct molecular mechanisms in regeneration-permissive neotenic and regeneration-deficient metamorphic stages at the proteome level.
Data for a proteomic analysis of p53-independent induction of apoptosis by bortezomib
(Elsevier, 2014) Yerlikaya, Azmi; Okur, Emrah; Baykal, Ahmet Tarık; Acılan, Ceyda; Boyacı, İhsan; Ulukaya, Engin
This data article contains data related to the research article entitled, "A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line" by Yerlikaya et al. [1]. The research article presented 2-DE and nLC-MS/MS based proteomic analysis of proteasome inhibitor bortezomib-induced changes in the expression of cellular proteins. The report showed that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24. h. In addition, the report demonstrated that Hsp70, the 26S proteasome non-ATPase regulatory subunit 14 and sequestosome 1 were increased at least 2 fold in p53-deficient 4T1 cells. The data here show for the first time the increased expressions of Card10, Dffb, Traf3 and Trp53bp2 in response to inhibition of the 26S proteasome. The information presented here also shows that both Traf1 and Xiap (a member of IAPs) are also downregulated simultaneously upon proteasomal inhibition. The increases in the level of Card10 and Trp53bp2 proteins were verified by Western blot analysis in response to varying concentrations of bortezomib for 24. h.
Deneysel çalışmalarda çevresel değişikliğe maruz kalan Fasciola Hepatica'nın salgıladığı protein miktarlarının bir ileri proteomik yaklaşımla incelenmesi
(Türkiye Parazitoloji Derneği, 2014) Haçarız, Orçun; Baykal, Ahmet Tarık
Amaç: Ana konakçıdan çıkarıldıktan sonra çevresel değişikliğe maruz kalan Fasciola hepatica'nın salgıladığı protein miktarlarını bir ileri proteomik yaklaşımla incelemek.Yöntemler: Son konakçıdan toplanan ergin F. hepatica parazitleri doğrudan fosfat tamponlu su (FTS, oda sıcaklığında) içerisine konuldu ve 37°C'de 2 saat bekletildi (Enstitü'ye 1 saat içerisinde getirildikten sonra). Daha sonra, FTS, bir revize F. hepatica protein veri bankası (Universal Protein Resource; UniProt) ve veri bağımsız edinim yöntemi ile ileri bir proteomik yöntem (yüksek başarımlı sıvı kromatografisine bağlı, elektriksel püskürtme ile iyonlaştırma ve dört kutup zaman bazlı ölçüm içeren kütle spektrometresi sistemi; nanoUPLC-ESI-QTOF-MS) kullanılarak incelendi.Bulgular: Parazitlerle bekletilme sonrası FTS'nin proteomik analizinde, cathepsin L protease 1, fatty acid binding protein 1 ve 2, thioredoxin peroxidase (TPx), ve kunitz type proteinase inhibitor tanımlandı. Fasciola hepatica TPx miktarı, bu çalışmada tanımlanan diğer proteinlerin miktarlarına göre yaklaşık olarak 2-6 kat daha fazla bulundu (p<0,01).Sonuç: Çevresel değişiklikten kaynaklanan parazit üzerindeki stres, TPx salınımının uyarılması ile ilişkili olabilir. İleri proteomik yaklaşımların uygulanması, parazit-konakçı etkileşiminin aydınlatılmasında ve parazite karşı etkili korunma yöntemlerinin geliştirilmesinde yararlı veriler sağlayabilir.
Detailed tail proteomic analysis of axolotl (Ambystoma mexicanum) using an mRNA-seq reference database
(Wiley, 2017) Demircan, Turan; Keskin, İlknur; Dumlu, Seda Nilgün; Aytürk, Nilüfer; Avşaroğlu, Mahmut Erhan; Akgün, Emel; Öztürk, Gürkan; Baykal, Ahmet Tarık
Salamander axolotl has been emerging as an important model for stem cell research due to its powerful regenerative capacity. Several advantages, such as the high capability of advanced tissue, organ, and appendages regeneration, promote axolotl as an ideal model system to extend our current understanding on the mechanisms of regeneration. Acknowledging the common molecular pathways between amphibians and mammals, there is a great potential to translate the messages from axolotl research to mammalian studies. However, the utilization of axolotl is hindered due to the lack of reference databases of genomic, transcriptomic, and proteomic data. Here, we introduce the proteome analysis of the axolotl tail section searched against an mRNA-seq database. We translated axolotl mRNA sequences to protein sequences and annotated these to process the LC-MS/MS data and identified 1001 nonredundant proteins. Functional classification of identified proteins was performed by gene ontology searches. The presence of some of the identified proteins was validated by in situ antibody labeling. Furthermore, we have analyzed the proteome expressional changes postamputation at three time points to evaluate the underlying mechanisms of the regeneration process. Taken together, this work expands the proteomics data of axolotl to contribute to its establishment as a fully utilized model.
Determination of stage specific markers for liver fibrosis in hepatitis B: A comparative tissue proteomic study
(Elsevier Science B.V., 2016) Katrinli, Şeyma; Özdil, Kamil; Şahin, Aslı; Öztürk, Oğuzhan; Kır, Gözde; Baykal, Ahmet Tarık; Saraç, Ömer Sinan; Sökmen, Mehmet; Dinler Doğanay, Gizem; Doğanay, Hamdi Levent
Background and Aims: Chronic Hepatitis B infection is one of themajor causes of liver cirrhosis and around 600,000 people dieannually worldwide. The virus itself is non-cytopathic and the liverdamage is due to host immune reaction. Thus liver damage pathwaysmight differ in chronic HBV and comprehensive tissue proteomicanalysis is missing in literature. To estimate which patient withchronic hepatitis B will develop rapidly fibrosis or cirrhosis is yet athorny issue and requires a vast recognition of cellular pathwaysinvolved in fibrosis. The aim of this study is to enlighten pathwaysassociated with liver fibrosis in HBV infection for leading up to newtherapeutic targets and diagnostic biomarkers.
Early stage alterations in CA1 extracellular region proteins indicate dysregulation of IL6 and iron homeostasis in the 5XFAD Alzheimer's disease mouse model
(Ios Press, 2018) Gürel, Büşra; Cansev, Mehmet; Sevinç, Cansu; Keleştemur, Seda; Öcalan, Büşra; Çakır, Ayşen; Aydın, Sami; Kahveci, Nevzat; Ozansoy, Mehmet; Taşkapılıoğlu, Özlem; Ulus, İsmail Hakkı; Karayel Başar, Merve; Şahin, Betül; Tüzüner, Mete Bora; Baykal, Ahmet Tarık
In recent years, an increasing number of research papers revealed that the compositional and volumetric alterations in the extracellular matrix are the consequences of aging and may be related to Alzheimer's disease (AD). In this study, we aimed to demonstrate the alterations in hippocampal extracellular fluid proteins in vivo using the 5XFAD mouse model. Samples were obtained from hippocampi of 5XFAD mice (n = 6) and their non-transgenic littermates by intracerebral push-pull perfusion technique at 3 months of age, representing the pre-pathological stage of the AD. Proteins in the hippocampal perfusates were analyzed by Ultra Performance Liquid Chromatography-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UPLC-ESI-qTOF-MS/MS). 178 proteins were identified and 19 proteins of them were found to be statistically significantly altered (p <= 0.05, fold change>= 40%, unique peptide count>= 3) in the hippocampal CA1 extracellular fluid of the 5XFAD mouse model. Ingenuity pathway analysis of the protein expression results identified IL6 as an upstream regulator. The upregulation of IL6 was validated by immunohistochemical staining of the hippocampus and cortex of the 5XFAD mice prior to A beta plaque formation. Furthermore, the iron level in the hippocampus was measured by inductively coupled plasma-mass spectrometry as IL6 is mentioned in several studies to take part in iron homeostasis and inflammation and found to be increased in 5XFAD mice hippocampus. Alterations in extracellular matrix proteins in addition to increasing amount of hippocampal IL6 and iron in the early stages of AD may reveal inflammation-mediated iron dyshomeostasis in the early stages of neurodegeneration.
Evaluation of apoptotic molecular pathways for smooth muscle cells isolated from thoracic aortic aneurysms in response to oxidized sterols
(Springer, 2014) Adıgüzel, Zelal; Arda, Nazlı; Kaçar, Ömer; Serhatlı, Müge; Gezer Taş, Serpil; Baykal, Ahmet Tarık; Baysal, Kemal; Açılan, Ceyda
Oxysterols, oxygenated derivatives of cholesterol, are found abundantly in the plasma and atherosclerotic plaques, a common risk factor for thoracic aortic aneurysms (TAAs). Among the oxysterols, namely 7-ketocholesterol (7-KC) and 25-hydroxycholesterol (25-OHC), lead both to induction of reactive oxygen species (ROS) in cells and to apoptosis in smooth muscle cells (SMCs) probably due to increased oxidative stress. Since loss of SMCs through apoptosis is a major event in TAA formation, it is important to understand the molecular pathways of apoptosis in response to ROS in TAAs. Very little is known about the effect of oxysterols on TAA SMCs. Therefore, we investigated molecular pathways participating in the oxysterol induced cell death of TAAs. Our results showed that TAA SMCs died mainly as a result of apoptosis as suggested by cellular shrinkage, blebbing, DNA condensation/fragmentation in response to oxysterol treatment. There was no significant difference in oxysterol induced cell death between TAA and control SMCs. Addition of antioxidant molecules prevented cell death, hence ROS appears to be involved in the apoptosis of these cells. While oxysterol treatment increased caspase 3 activity, cell death was not rescued in its absence. Efficient silencing of other targets including apoptotic proteins (p53, Bax), and survival proteins (Akt1, Akt2) showed that apoptosis can occur through p53, and Bax independent pathways. Silencing Akt1 or Akt2 did not lead to further cell death. These results indicate that oxysterols can induce several cell death pathways in TAA SMCs.
Evidence that melatonin downregulates Nedd4-1 E3 ligase and its role in cellular survival
(Academic Press Inc Elsevier Science, 2019) Yalçın, Esra; Beker, Mustafa Çağlar; Türkseven, Şeyma; Çağlayan, Berrak; Gürel, Büşra; Kılıç, Ülkan; Çağlayan, Ahmet Burak; Kalkan, Rabia; Baykal, Ahmet Tarık; Keleştemur, Taha; Kılıç, Ertuğrul
Indolamine melatonin structurally resembles non-covalent proteasome inhibitors; however, the role of ubiquitin proteasome system (UPS) in neuronal survival and how melatonin carries out UPS inhibition remain largely unknown. With the use of melatonin treated cells, we evaluated the expression of Nedd4-1, an E3 ligase, how melatonin regulates its activity and its relationship with neuronal survival. Nedd4-1 was upregulated in the hypoxic condition in both control and Nedd4-1 overexpressed cells and melatonin treatment reversed its expression in both normoxic and hypoxic conditions, which was associated with increased cellular survival. Melatonin had no effect on the expression of Nedd4-1 at mRNA level. However, when melatonin was administered along with protein synthesis inhibitor cycloheximide, protein level of Nedd4-1 was further reduced, indicating that melatonin possibly downregulates Nedd4-1 after its synthesis. Notably, co-immunoprecipitation analyses followed by Liquid chromatography Mass Spectrometry (LC-MS/MS) revealed that melatonin may dissociate ribosomal proteins, such as RS19, RL23A, and nucleophosmin from Nedd4-1, while 40S ribosomal protein S7 and 60S ribosomal protein L35 came into contact with Nedd4-1 upon melatonin treatment. By using IPA analyses, we obtained further data indicated novel target molecules of melatonin in hypoxic conditions, including OTOF, SF3B2, IPO5, ST13, FGFR3, Mxl/Mx2, playing roles in RNA splicing and trafficking, growth factor and interferon signaling. Here, we described a new insight into the role of melatonin in UPS functioning by proposing a molecular mechanism through which melatonin regulates Nedd4-1.
Generating a detailed protein profile of Fasciola hepatica during the chronic stage of infection in cattle
(Wiley-Blackwell, 2014) Haçarız, Orçun; Baykal, Ahmet Tarık; Akgün, Mete; Kavak, Pınar; Sağıroğlu, Mahmut Şamil; Sayers, Gearoid Patrick
Fasciola hepatica is a trematode helminth causing a damaging disease, fasciolosis, in ruminants and humans. Comprehensive proteomic studies broaden our knowledge of the parasite's protein profile, and provide new insights into the development of more effective strategies to deal with fasciolosis. The objective of this study was to generate a comprehensive profile of F. hepatica proteins expressed during the chronic stage of infection in cattle by building on previous efforts in this area. The approach included an improved sample preparation procedure for surface and internal layers of the parasite, the application of nano-UPLC-ESI-qTOF-MS (nano-ultra-performance LC and ESI quadrupole TOF MS) integrated with different acquisition methods and in silico database search against various protein databases and a transcript database including a new assembly of publically available EST. Of a total of 776 identified proteins, 206 and 332 were specific to the surface and internal layers of the parasite, respectively. Furthermore, 238 proteins were common to both layers, with comparative differences of 172 proteins detected. Specific proteins not previously identified in F. hepatica, but shown to be immunomodulatory or potential drug targets for other parasites, are discussed.
Hepatitis B virus e antigen (HBeAg) may have a negative effect on dendritic cell generation
(Elsevier, 2014) Hatipoğlu, İbrahim; Ercan, Duygu; Açılan, Ceyda; Başalp, Aynur; Durali, Deniz; Baykal, Ahmet Tarık
Hepatitis B virus (HBV) continues to be a serious worldwide health problem despite the use of protective HBV vaccines and therapeutic regimens against chronic HBV infection. Chronic HBV patients cannot induce sufficient immune responses against the virus. HBV and its antigens are believed to suppress immune responses during chronic infection. Hence, studying the role of HBV in immune suppression is very important for the development of alternative therapeutic strategies for HBV infections. In the present study, we investigated the effect of Hepatitis B virus e antigen (HBeAg) on the generation of bone marrow derived dendritic cells (BMDCs) and the stimulation of plasmacytoid DCs (pDCs). In the presence of HBeAg, the ratio of BMDCs was decreased, but the ratio of CD11b(+)Ly6G(+) immature myeloid cells was increased. The expression of 47 proteins was also changed during HBeAg treatment; however, CpG-induced MHC-II expression on pDCs was not affected. Our results indicate that HBeAg may have a negative effect on the generation of DCs from bone morrow precursors. (C) 2014 Elsevier GmbH. All rights reserved.
Identification of ApoA1, HPX and POTEE genes by omic analysis in breast cancer
(Spandidos Publications, 2014) Çine, Naci; Baykal, Ahmet Tarık; Sünnetçi, Deniz; Cantürk, Zafer; Serhatlı, Müge; Savlı, Hakan
Breast cancer is the most common cancer among women and accounts for 23% of all female types of cancers. It is well recognized that breast cancer represents a heterogeneous group of tumors, and the molecular events involved in the progression to cancer remain undetermined. Moreover, available prognostic and predictive markers are not sufficient for the accurate determination of the risk for many breast cancer patients. Thus, it is necessary to discover new molecular markers for accurate prediction of clinical outcome and individualized therapy. In the present study, we performed omics-based whole-genome trancriptomic and whole proteomic profiling with network and pathway analyses of breast tumors to identify gene expression patterns related to clinical outcome. A total of 20 samples from tumors and 14 normal appearing breast tissues were analyzed using both gene expression microarrays and LC-MS/MS. We identified 585 downregulated and 413 upregulated genes by gene expression microarrays. Among these genes, HPX, POTEE and ApoAl were the most significant genes correlated with the proteomic profile. Our data revealed that these identified genes are closely related to breast cancer and may be involved in robust detection of disease progression.
Interaction of melatonin and Bmal1 in the regulation of PI3K/AKT pathway components and cellular survival
(Nature Publishing Group, 2019) Beker, Mustafa Çağlar; Çağlayan, Berrak; Çağlayan, Ahmet Burak; Kelestemur, Taha; Yalçın, Esra; Çağlayan, Aysun; Kılıç, Ülkan; Baykal, Ahmet Tarık; Reiter, Russel J.; Kılıç, Ertuğrul
The circadian rhythm is driven by a master clock within the suprachiasmatic nucleus which regulates the rhythmic secretion of melatonin. Bmal1 coordinates the rhythmic expression of transcriptome and regulates biological activities, involved in cell metabolism and aging. However, the role of Bmal1 in cellular- survival, signaling, its interaction with intracellular proteins, and how melatonin regulates its expression is largely unclear. Here we observed that melatonin increases the expression of Bmal1 and both melatonin and Bmal1 increase cellular survival after oxygen glucose deprivation (OGD) while the inhibition of Bmal1 resulted in the decreased cellular survival without affecting neuroprotective effects of melatonin. By using a planar surface immunoassay for PI3K/AKT signaling pathway components, we revealed that both melatonin and Bmal1 increased phosphorylation of AKT, ERK-1/2, PDK1, mTOR, PTEN, GSK-3 alpha beta, and p70S6K. In contrast, inhibition of Bmal1 resulted in decreased phosphorylation of these proteins, which the effect of melatonin on these signaling molecules was not affected by the absence of Bmal1 . Besides, the inhibition of PI3K/AKT decreased Bmal1 expression and the effect of melatonin on Bmal1 after both OGD in vitro and focal cerebral ischemia in vivo. Our data demonstrate that melatonin controls the expression of Bmal1 via PI3K/AKT signaling, and Bmal1 plays critical roles in cellular survival via activation of survival kinases.
mTor Is a signaling hub in cell survival: A mass-spectrometry-based proteomics investigation
(American Chemical Society, 2014) Tang, Zhi; Baykal, Ahmet Tarık; Gao, Hui; Quezada, Hernan Concha; Zhang, Haiyan; Bereczki, Erika; Serhatlı, Müge; Baykal, Betül; Acıoğlu, Çiğdem; Wang, Shan; Ioja, Eniko; Ji, Xinying; Zhang, Yan; Guan, Zhizhong; Winblad, Bengt; Pei, Jin-Jing
mTor plays a central role in controlling protein homeostasis and cell survival. Recently, we have demonstrated that perturbations of mTor signaling are implicated in Alzheimer's disease (AD) and that mTor complex 1 (mTorC1) is involved in the formation of toxic phospho-tau. Therefore, we employed mass-spectrometry-based proteomics to identify specific protein expression changes in relation with cell survival in human neuroblastoma SH-SYSY cells expressing genetically modified mTor. Cell death in SH-SYSY cells was induced by moderate serum deprivation. Using flow cytometry we observed that up-regulated mTor complex 2 (mTorC2) increases the number of viable cells. By using a combination approach of proteomic and enrichment analysis we have identified several proteins (Thioredoxin-dependent peroxide reductase, Peroxiredoxin-5, Cofilin 1 (non-muscle), Annexin A5, Mortalin, and 14-3-3 protein zeta/delta) involved in mitochondrial integrity, apoptotosis, and pro-survival functions (caspase inhibitor activity and anti-apoptosis) that were significantly altered by mTor activity modulation. The major findings of this study are the implication of mTorC2 but not mTorC1 in cell viability modulation by activating the pro-survival machinery. Taken together, these results suggest that up-regulated mTorC2 might be playing an important role in promoting cell survival by suppressing the mitochondria-caspase-apoptotic pathway in vitro.
Neonatal neurodegeneration in alzheimer's disease transgenic mouse model
(IOS Press, 2018) Mazi, Aişe Rümeysa; Arzuman, Ayşegül Sümeyye; Gürel, Büşra; Şahin, Betül; Tüzüner, Mete Bora; Ozansoy, Mehmet; Baykal, Ahmet Tarık
Alzheimer's disease (AD) is a progressive disorder characterized by a variety of molecular pathologies causing cortical dementia with a prominent memory deficit. Formation of the pathology, which begins decades before the diagnosis of the disease, is highly correlated with the clinical symptoms. Several proteomics studies were performed using animal models to monitor the alterations of the brain tissue proteome at different stages of AD. However, proteome changes in the brain regions of newborn transgenic mouse model have not been investigated yet. To this end, we analyzed protein expression alterations in cortex, hippocampus and cerebellum of transgenic mice carrying five familial AD mutations (5XFAD) at neonatal day-1. Our results indicate a remarkable difference in protein expression profile of newborn 5XFAD brain with region specific variations. Additionally, the proteins, which show similar expression alteration pattern in postmortem human AD brains, were determined. Bioinformatics analysis showed that the molecular alterations were mostly related to the cell morphology, cellular assembly and organization, and neuroinflammation. Moreover, morphological analysis revealed that there is an increase in neurite number of 5XFAD mouse neurons in vitro. We suggest that, molecular alterations in the AD brain exist even at birth, and perhaps the disease is silenced until older ages when the brain becomes vulnerable.
Proteomic analysis of kidney preservation solutions prior to renal transplantation
(Public Library Science, 2016) Çoşkun, Abdurrahman; Baykal, Ahmet Tarık; Kazan, Dilek; Akgöz, Müslüm; Şenal Öztuğ, Merve; Berber, İbrahim; Titiz, İzzet; Bilsel, Gökhan; Kilercik, Hakan; Karaosmanoğlu, Kübra; Çiçek, Müslüm; Yurtsever, İlknur; Yazıcı, Cevat
One of the main issues in kidney transplantation is the optimal functional preservation of the organ until its transplantation into the appropriate recipient. Despite intensive efforts, the functional preservation period remains limited to hours. During this time, as a result of cellular injury, various proteins, peptides, and other molecules are released by the organ into the preservation medium. In this study, we used proteomic techniques to analyze the protein profiles of preservation solutions in which organs had been preserved prior to their transplantation. Samples were obtained from the preservation solutions of 25 deceased donor kidneys scheduled for transplantation. The protein profiles of the solutions were analyzed using 2D gel electrophoresis/MALDI-TOF and LC-MS/MS. We identified and quantified 206 proteins and peptides belonging to 139 different groups. Of these, 111 proteins groups were belonging to kidney tissues. This study used proteomic techniques to analyze the protein profiles of organ preservation solutions. These findings will contribute to the development of improved preservation solutions to effectively protect organs for transplantation.

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