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Publication Open Access A proximity mapping journey into the biology of the mammalian centrosome/cilium complex(Multidisciplinary Digital Publishing Institute (MDPI), 2020) Department of Molecular Biology and Genetics; Arslanhan, Melis Dilara; Gülensoy, Dila; Karalar, Elif Nur Fırat; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 206349The mammalian centrosome/cilium complex is composed of the centrosome, the primary cilium and the centriolar satellites, which together regulate cell polarity, signaling, proliferation and motility in cells and thereby development and homeostasis in organisms. Accordingly, deregulation of its structure and functions is implicated in various human diseases including cancer, developmental disorders and neurodegenerative diseases. To better understand these disease connections, the molecular underpinnings of the assembly, maintenance and dynamic adaptations of the centrosome/cilium complex need to be uncovered with exquisite detail. Application of proximity-based labeling methods to the centrosome/cilium complex generated spatial and temporal interaction maps for its components and provided key insights into these questions. In this review, we first describe the structure and cell cycle-linked regulation of the centrosome/cilium complex. Next, we explain the inherent biochemical and temporal limitations in probing the structure and function of the centrosome/cilium complex and describe how proximity-based labeling approaches have addressed them. Finally, we explore current insights into the knowledge we gained from the proximity mapping studies as it pertains to centrosome and cilium biogenesis and systematic characterization of the centrosome, cilium and centriolar satellite interactomes.Publication Open Access Antiviral activity of an N-allyl acridone against dengue virus(BioMed Central, 2015) Mazzucco, Maria B.; Talarico, Laura B.; Carro, Ana C.; Fascio, Mirta L.; D'Accorso, Norma B.; Garcia, Cybele C.; Damonte, Elsa B.; N/A; Vatansever, Sezen; PhD Student; Graduate School of Sciences and EngineeringBackground: Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. In a previous screening assay, we identified a group of N-allyl acridones as effective virus inhibitors. Here, the antiviral activity and mode of action targeted to viral RNA replication of one of the most active DENV-2 inhibitors was further characterized. Results: The compound 10-allyl-7-chloro-9(10H)-acridone, designated 3b, was active to inhibit the in vitro infection of Vero cells with the four DENV serotypes, with effective concentration 50% (EC50) values in the range 12.5-27.1 mu M, as determined by virus yield inhibition assays. The compound was also effective in human HeLa cells. No cytotoxicity was detected at 3b concentrations up to 1000 mu M. Mechanistic studies demonstrated that virus entry into the host cell was not affected, whereas viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR. The addition of exogenous guanosine together with 3b rescued only partially the infectivity of DENV-2. Conclusions: The acridone derivative 3b selectively inhibits the infection of Vero cells with the four DENV serotypes without a direct interaction with the host cell or the virion but interfering specifically with the intracellular virus multiplication. The mode of antiviral action for this acridone apparently involves the cellular enzyme inosine-monophospahe dehydrogenase together with another still unidentified target related to DENV RNA synthesis.Publication Open Access Application of microneedle patches for drug delivery; doorstep to novel therapies(Sage, 2022) Nazary Abrbekoh, F.; Salimi, L.; Saghati, S.; Amini, H.; Fathi Karkan, S.; Moharamzadeh, K.; Rahbarghazi R.; Sokullu, Emel; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 163024In the past decade, microneedle-based drug delivery systems showed promising approaches to become suitable and alternative for hypodermic injections and can control agent delivery without side effects compared to conventional approaches. Despite these advantages, the procedure of microfabrication is facing some difficulties. For instance, drug loading method, stability of drugs, and retention time are subjects of debate. Besides, the application of novel refining fabrication methods, types of materials, and instruments are other issues that need further attention. Herein, we tried to summarize recent achievements in controllable drug delivery systems (microneedle patches) in vitro and in vivo settings. In addition, we discussed the influence of delivered drugs on the cellular mechanism and immunization molecular signaling pathways through the intradermal delivery route. Understanding the putative efficiency of microneedle patches in human medicine can help us develop and design sophisticated therapeutic modalities.Publication Open Access Applications, challenges and prospects of mesenchymal stem cell exosomes in regenerative medicine(BioMed Central, 2021) Rezabakhsh, Aysa; Rahbarghazi Reza; Sokullu, Emel; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 163024Recent advances in the identification and application of different stem cell types have offered alternative therapeutic approaches for clinicians. The lack of successful engraftment, migration into the injured site, loss of functionality and viability, ethical issues, shortage of donated allogeneic stem cells and the possibility of transmission of infectious are the main challenges associated with direct cell transplantation. The discovery and research on exosomes have led to the rise of hopes for the alleviation of different pathologies in regenerative medicine. Exo are nano-sized extracellular vesicles (40–150 nm) and released by each type. These nanoparticles participate in cell-to-cell communication in a paracrine manner. It is thought that the application of Exo can circumvent several drawbacks related to whole-cell therapies. Because of their appropriate size and stability, Exo are touted as therapeutic bullets transferring signaling factors into the acceptor cells in a paracrine manner. Despite these advantages, technologies associated with Exo isolation and purification are challenging because of heterogeneity in exosomal size and cargo. The lack of standard GMP-grade protocols is the main hurdle that limits the extensive application of Exo in the clinical setting. Here, the authors aimed to inspire a logical and realistic vision about problems associated with Exo application in regenerative medicine.Publication Open Access beta III-Tubulin: a novel mediator of chemoresistance and metastases in pancreatic cancer(Impact Journals, 2015) McCarroll, Joshua A.; Sharbeen, George; Liu, Jie; Youkhana, Janet; Goldstein, David; McCarthy, Nigel; Limbri, Lydia F.; Dischl, Dominic; Ceyhan, Gueralp O.; Johns, Amber L.; Biankin, Andrew V.; Kavallaris, Maria; Phillips, Phoebe A.; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, beta-tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of beta-tubulins in pancreatic cancer are unknown. We measured the expression of different beta-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence beta III-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of beta III-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that beta III-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing beta III-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of beta III-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that beta III-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients.Publication Open Access Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress(Impact Journals, 2016) Liu, Huaping; Lucia Leon; Annicchiarico, Clara; Munoz-Pinedo, Cristina; Barredo, Julio; Leclerc, Guy; Merchan, Jaime; Liu, Xiongfei; Lampidis, Theodore J.; Kurtoğlu, Metin; Graduate School of Health SciencesUnregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mtor. Inhibition of mtor results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eif2 alpha. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types.Publication Open Access DICER governs characteristics of glioma stem cells and the resulting tumors in xenograft mouse models of glioblastoma(Impact Journals, 2016) Mansouri, Sheila; Singh, Sanjay; Alamsahebpour, Amir; Burrell, Kelly; Li, Mira; Ekinci, Can; Koch, Elizabeth; Chang, Jeffery T.; Wouters, Bradly; Aldape, Kenneth; Zadeh, Gelareh; N/A; Karabörk, Merve; Solaroğlu, İhsan; Undergraduate Student; Faculty Member; School of Medicine; N/A; 102059The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently decreased in a variety of malignancies. We characterized the role of DICER in glioblastoma (GB), specifically demonstrating its effects on the ability of glioma stem-like cells (GSCs) to form tumors in a mouse model of GB. DICER silencing in GSCs reduced their stem cell characteristics, while tumors arising from these cells were more aggressive, larger in volume, and displayed a higher proliferation index and lineage differentiation. The resulting tumors, however, were more sensitive to radiation treatment. Our results demonstrate that DICER silencing enhances the tumorigenic potential of GSCs, providing a platform for analysis of specific relevant miRNAs and development of potentially novel therapies against GB.Publication Open Access Emerging role of exosomes in the pathology of chronic obstructive pulmonary diseases; destructive and therapeutic properties(BioMed Central, 2022) Rahbarghazi, Reza; Rajabi, Hadi; Konyalılar, Nur; Erkan, Sinem; Mortazavi, Deniz; Korkunç, Seval Kübra; Kayalar, Özgecan; Bayram, Hasan; PhD Student; Researcher; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; 4890Chronic obstructive pulmonary disease (COPD) is known as the third leading cause of human death globally. Enhanced chronic inflammation and pathological remodeling are the main consequences of COPD, leading to decreased life span. Histological and molecular investigations revealed that prominent immune cell infiltration and release of several cytokines contribute to progressive chronic remodeling. Recent investigations have revealed that exosomes belonging to extracellular vesicles are involved in the pathogenesis of COPD. It has been elucidated that exosomes secreted from immune cells are eligible to carry numerous pro-inflammatory factors exacerbating the pathological conditions. Here, in this review article, we have summarized various and reliable information about the negative role of immune cell-derived exosomes in the remodeling of pulmonary tissue and airways destruction in COPD patients.
Publication Metadata only First extensor compartment morphology and clinical significance: a cadaver series study(Korean Association of Anatomists, 2023) Coşkun, Osman; Ok, Fatma; Şahin, Büşra; Gürses, İlke Ali; Faculty Member; School of Medicine; 235485The first extensor compartment of the wrist is a distinctly variable anatomical area. Anatomical variations in this region contribute to the pathophysiology and treatment failure of de Quervain's disease, which is a kind of tenosynovitis that develops in the first extensor compartment of the wrist. We aim to describe the first extensor compartment morphology, to evaluate the septum frequency, location of the septum, and the number of tendons of abductor pollicis longus (APL) and extensor pollicis brevis muscles (EPB). First extensor compartment of 87 wrists of 45 cadavers were dissected. The presence or absence of septum and number of tendon slips of APL and EPB revealed. The proximal and distal widths of the compartments were measured. Septums were detected in 60.9% (n=53) of the wrists. Incomplete (distal) and complete (proximal) septa were present in 35.6% (n=31) and 25.3% (n=22) of the cases. Only 26.4% of the wrists had a single slip of APL tendon. The Remaining had multiple slips. The median inner width of the proximal and distal compartments in all wrists were calculated as in the order of 9.11±1.14 mm and 8.55±1.12 mm. We believe that understanding the anatomy of the first extensor compartment in the Turkish population would be helpful to surgeons, radiologists, and physiotherapists to diagnose and manage de Quervain's disease.Publication Open Access Generation of integration-free induced pluripotent stem cells from a patient with Familial Mediterranean Fever (FMF)(Elsevier, 2015) Gül, Ahmet; Department of Molecular Biology and Genetics; Fidan, Kerem; Kavaklıoğlu, Gülnihal; Ebrahimi, Ayyub A.; Özlü, Can; Ay, Nur Zeynep; Ruacan, Ayşe Arzu; Önder, Tamer Tevfik; Master Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; Graduate School of Sciences and Engineering; N/A; N/A; N/A; N/A; N/A; 38250; 42946Fibroblasts from a Familial Mediterranean Fever (FMF) patient were reprogrammed with episomal vectors by using the Neon Transfection System for the generation of integration-free induced pluripotent stem cells (iPSCs). The resulting iPSC line was characterized to determine the expression of pluripotency markers, proper differentiation into three germ layers, the presence of normal chromosomal structures as well as the lack of genomic integration. A homozygous missense mutation in the MEFV gene (p.Met694Val), which lead to typical FMF phenotype, was shown to be present in the generated iPSC line.