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Publication Open Access An examination of the putative role of melatonin in exosome biogenesis(Frontiers, 2021) Amini, Hassan; Rezabakhsh, Aysa; Hassanpour, Mehdi; Hashemzadeh, Shahriar; Ghaderi, Shahrouz; Rahbarghazi, Reza; Reiter, Russel J.; Heidarzadeh, Morteza; Sokullu, Emel; PhD Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences; N/A; 163024During the last two decades, melatonin has been found to have pleiotropic effects via different mechanisms on its target cells. Data are abundant for some aspects of the signaling pathways within cells while other casual mechanisms have not been adequately addressed. From an evolutionary perspective, eukaryotic cells are equipped with a set of interrelated endomembrane systems consisting of intracellular organelles and secretory vesicles. Of these, exosomes are touted as cargo-laden secretory vesicles that originate from the endosomal multivesicular machinery which participate in a mutual cross-talk at different cellular interfaces. It has been documented that cells transfer various biomolecules and genetic elements through exosomes to sites remote from the original cell in a paracrine manner. Findings related to the molecular mechanisms between melatonin and exosomal biogenesis and cargo sorting are the subject of the current review. The clarification of the interplay between melatonin and exosome biogenesis and cargo sorting at the molecular level will help to define a cell's secretion capacity. This review precisely addresses the role and potential significance of melatonin in determining the efflux capacity of cells via the exosomal pathway. Certain cells, for example, stem cells actively increase exosome efflux in response to melatonin treatment which accelerates tissue regeneration after transplantation into the injured sites.
Publication Metadata only Antioxidant activity of CAPE (caffeic acid phenethyl ester) in vitro can protect human sperm deoxyribonucleic acid from oxidative damage(Elsevier, 2018) Ayla, Sule; Tunali, Gulden; Bilgic, Bulent E.; Sofuoglu, Kenan; Ozdemir, A. Arman; Tanriverdi, Gamze; Ozdemir, Semra; Soner, B. Cem; Ozturk, Bahar; Aslan, Esra Guler; Seckin, Ismail; N/A; Karahüseyinoğlu, Serçin; Faculty Member; School of Medicine; 110772Purpose: Sperm processing (e.g., centrifugation) used in preparation for assisted reproduction can result in excessive generation of reactive oxygen species (ROS) and potential sperm damage. The use of antioxidants during sperm processing has been shown to prevent iatrogenic sperm damage, including DNA damage. In this study, we evaluated the effect of caffeic acid phenethyl ester (CAPE) on oxidative stress mediated sperm dysfunction and DNA damage. Methods: Semen samples were obtained to liquefy at room temperature. After centrifugation and washing protocols, spermatozoa were incubated in a single step supplemented medium with either of 10, 50 or 100 mu mol/L CAPE for 2 hours at 36 degrees C. After incubation period, MDA levels of seminal plasma were measured. The fragmentation in sperm DNA was detected by light microscopy via use of an aniline blue assay, while ultrastructural morphology was analyzed by transmission electron microscopy. Results: Significant increase has been observed in percent chromatin condensation (assessed by aniline blue staining) and Malondialdehyde (Mmol/L) in oligoasthenoteratozoospermia group before the centrifugation (0.57 +/- 0.15). Incubation of samples with 100 mu mol/L CAPE after centrifugation resulted in a significantly lower percent chromatin condensation compared to samples incubated without CAPE (0.42 +/- 0.12) (P < 0.0033). Incubation of all samples with CAPE (10 mu mol/L, 50 mu mol/L, 100 mu mol/L.) after centrifugation resulted in a significantly lower percentage of Malondialdehyde levels. Conclusions: The data suggests that preincubation of spermatozoa with the antioxidant CAPE offers protection against oxidative DNA damage in vitro.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 Metadata only Application of exosomes for the alleviation of COVID-19-related pathologies(Wiley, 2022) Rezabakhsh, Aysa; Mahdipour, Mahdi; Nourazarian, Alireza; Habibollahi, Paria; Avcı, Çığır Biray; Rahbarghazi, Reza; Sokullu, Emel; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 163024The pandemic of COVID-19 caused worldwide concern. Due to the lack of appropriate medications and the inefficiency of commercially available vaccines, lots of efforts are being made to develop de novo therapeutic modalities. Besides this, the possibility of several genetic mutations in the viral genome has led to the generation of resistant strains such as Omicron against neutralizing antibodies and vaccines, leading to worsening public health status. Exosomes (Exo), nanosized vesicles, possess several therapeutic properties that participate in intercellular communication. The discovery and application of Exo in regenerative medicine have paved the way for the alleviation of several pathologies. These nanosized particles act as natural bioshuttles and transfer several biomolecules and anti-inflammatory cytokines. To date, several approaches are available for the administration of Exo into the targeted site inside the body, although the establishment of standard administration routes remains unclear. As severe acute respiratory syndrome coronavirus 2 primarily affects the respiratory system, we here tried to highlight the transplantation of Exo in the alleviation of COVID-19 pathologies.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 C-Abl is not activated in DNA damage-induced and Tap63-mediated oocyte apoptosis in human ovary(Springer, 2018) Department of Molecular Biology and Genetics; N/A; N/A; Bildik, Gamze; Ayhan, Ceyda Açılan; Şahin, Gizem Nur; Karahüseyinoğlu, Serçin; Öktem, Özgür; Teaching Faculty; PhD Student; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; Graduate School of Health Sciences; N/A; N/A; N/A; 110772; 102627There is a controversy in literature as to whether c-Abl is crucial for the induction of TAp63-mediated apoptosis and whether that inhibition of c-Abl with imatinib, which was designed to inhibit the oncogenic kinase BCR-ABL and c-kit, protects oocytes from chemotherapy-induced apoptosis in mice. No human data are available on this issue. We therefore aimed to explore whether genomic damage induced by chemotherapy drug cisplatin activates c-Abl along with TAp63 and the inhibition of c-Abl with imatinib prevents cisplatin-induced oocyte death and follicle loss in human ovary. Exposure to cisplatin induced DNA damage, activated TAp63 and SAPK/JNK pathway, and triggered apoptosis in the oocytes and granulosa cells. However, TAp63 activation after cisplatin was not associated with any increase in the expression of c-Abl. Imatinib did not prevent cisplatin-induced apoptosis of the granulosa cells or oocytes. Moreover, treatment with this drug resulted in the formation of bizarre shaped follicles lacking oocytes and increased follicular atresia by inducing apoptosis of granulosa cells and oocytes. Similar toxic effects were observed when ovarian tissue samples were incubated with a c-kit antagonist drug anti-CD117, but not with another c-Abl tyrosine kinase inhibitor GNF-2, which lacks an inhibitory action on c-kit. Intraperitoneal administration of imatinib to the xenografted animals produced similar histomorphological abnormalities in the follicles in human ovarian grafts and did not prevent cisplatin-induced follicle loss when co-administered with cisplatin. Our findings provide, for the first time, a molecular evidence for ovarian toxicity of this drug in human. Furthermore, this study together with two previous case reports of a severely compromised ovarian response to gonadotropin stimulation and premature ovarian failure in patients, while receiving imatinib, further heighten the concerns about its potential gonadotoxicity on human ovary and urge caution in its use in young female patients.Publication Metadata only Cell scientist to watch - Elif Nur Fırat-Karalar(Company Biologists Ltd, 2019) Breuer, Manuel; N/A; Department of Molecular Biology and Genetics; Karalar, Elif Nur Fırat; N/A; Faculty Member; Department of Molecular Biology and Genetics; N/A; College of Sciences; N/A; 206349N/APublication Open Access Clock regulation of metabolites reveals coupling between transcription and metabolism(Elsevier, 2017) Sancar, Aziz; Krishnaiah, Saikumari Y.; Wu, Gang; Altman, Brian J.; Growe, Jacqueline; Rhoades, Seth D.; Coldren, Faith; Venkataraman, Anand; Olarerin-George, Anthony O.; Francey, Lauren J.; Mukherjee, Sarmistha; Girish, Saiveda; Selby, Christopher P.; Ubeydullah, E.R.; Sianati, Bahareh; Sengupta, Arjun; Anafi, Ron C.; Baur, Joseph A.; Dang, Chi V.; Hogenesch, John B.; Weljie, Aalim M.; Department of Chemical and Biological Engineering; Kavaklı, İbrahim Halil; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 40319; N/AThe intricate connection between the circadian clock and metabolism remains poorly understood. We used high temporal resolution metabolite profiling to explore clock regulation of mouse liver and cell-autonomous metabolism. In liver, similar to 50% of metabolites were circadian, with enrichment of nucleotide, amino acid, and methylation pathways. In U2 OS cells, 28% were circadian, including amino acids and NAD biosynthesis metabolites. Eighteen metabolites oscillated in both systems and a subset of these in primary hepatocytes. These 18 metabolites were enriched in methylation and amino acid pathways. To assess clock dependence of these rhythms, we used genetic perturbation. BMAL1 knockdown diminished metabolite rhythms, while CRY1 or CRY2 perturbation generally shortened or lengthened rhythms, respectively. Surprisingly, CRY1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite from transcriptional rhythms, with potential impact on nutrient sensing in vivo. These results provide the first comprehensive views of circadian liver and cell-autonomous metabolism.