Biology subjects

Sahin, F.

Publications and source records attributed to Sahin, F..

5 recordsLinked to original sources

bioRxiv2024

Boosting Proteasome Activity: A Novel Mechanism of NMDAR Blockers Against Neurodegeneration

NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimers and Parkinsons. In a mouse model, ketamine administration notably altered brain synaptic protein profiles within two hours, downregulating proteins linked to neurodegenerative conditions. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling--a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, crucial as proteasome activity declines with age leading to protein aggregation and disease symptoms. The elucidation of the mechanistic pathways underlying the therapeutic effects of NMDAR antagonists holds promise for developing new treatment strategies for brain diseases, including schizophrenia, Alzheimers, and Parkinsons.

neuroscience↗

bioRxiv2020

Gamma-irradiated SARS-CoV-2 vaccine candidate, OZG-38.61.3, confers protection from SARS-CoV-2 challenge in human ACEII-transgenic mice

The SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A, oral polio vaccine, and smallpox proved to be reliable approaches for immunization for prolonged periods. During the pandemic, we produced an inactivated SARS-CoV-2 vaccine candidate, having the advantages of being manufactured rapidly and tested easily in comparison with recombinant vaccines. In this study, an inactivated virus vaccine that includes a gamma irradiation process for the inactivation as an alternative to classical chemical inactivation methods so that there is no extra purification required has been optimized. The vaccine candidate (OZG-38.61.3) was then applied in mice by employing the intradermal route, which decreased the requirement of a higher concentration of inactivated virus for proper immunization, unlike most of the classical inactivated vaccine treatments. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 1013 or 1014 viral copy per dose) of OZG-38.61.3 was initially determined in Balb/c mice. This was followed by testing the immunogenicity and protective efficacy of OZG-38.61.3. Human ACE2-encoding transgenic mice were immunized and then infected with a dose of infective SARS-CoV-2 virus for the challenge test. Findings of this study show that vaccinated mice have lower SARS-CoV-2 viral copy number in oropharyngeal specimens along with humoral and cellular immune responses against the SARS-CoV-2, including the neutralizing antibodies similar to those shown in Balb/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.

immunology↗

bioRxiv2020

Preliminary report of preclinical efficacy and safety analysis of gamma-irradiated inactivated SARS-CoV-2 vaccine candidates, SK-01 version 1 and OZG-3861 version 1

COVID-19 outbreak caused by SARS-CoV-2 created an unprecedented health crisis since there is no vaccine for this novel virus. Therefore, SARS-CoV-2 vaccines have become crucial for reducing morbidity and mortality. In this study, in vitro and in vivo safety and efficacy analyzes of lyophilized vaccine candidates inactivated by gamma-irradiation were performed. The candidate vaccines in this study were OZG-3861 version 1 (V1), an inactivated SARS-CoV-2 virus vaccine, and SK-01 version 1 (V1), a GM-CSF adjuvant added vaccine. The candidate vaccines were applied intradermally to BALB/c mice to assess toxicity and immunogenicity. Preliminary results in vaccinated mice are reported in this study. Especially, the vaccine models containing GM-CSF caused significant antibody production with neutralization capacity in absence of the antibody-dependent enhancement feature, when considered in terms of T and B cell responses. Another important finding was that the presence of adjuvant was more important in T cell in comparison with B cell response. Vaccinated mice showed T cell response upon restimulation with whole inactivated SARS-CoV-2 or peptide pool. This study shows that the vaccines are effective and leads us to start the challenge test to investigate the gamma-irradiated inactivated vaccine candidates for infective SARS-CoV-2 virus in humanized ACE2+ mice.

immunology↗

bioRxiv2020

Neurons from human mesenchymal stem cells display both spontaneous and stimuli responsive activity

Mesenchymal stem cells are one of the promising tissue specific stem cell source for neural tissue regeneration applications. Previous studies on human mesenchymal stem cell (hMSC) derived neurons have been limited and not statisfactory in terms of neuronal activity. In this study, we analysed the functionality of bone marrow hMSCs differentiated into neural protein expressing cells by a single step cytokine based induction protocol. Neurons from both primary hMSCs and hMSC cell line displayed spontaneous activity ([≥]75%) as demonstrated by Ca++ imaging. Furthermore, when electrically stimulated, hMSC induced neurons (hMd-Neuron) matched the response of a typical neuron in the process of maturation. Our results reveal that enriched neurothrophic factors enhance differentiation capacity of bone marrow hMSCs into high yielding functional neurons with spontaneous activity and mature into electrophysiologically active state. hMd-Neurons have the potential to be used as a tool for disease modelling of neuropathologies and neural differentiation studies.

neuroscience↗

bioRxiv2018

c-Myc inhibition is critical for HSC expansion and Rad51 expression

c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence. Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion. Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34low HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclin-dependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo. In addition, c-Myc inhibition upregulates major HDR modulator Rad51 expression in hematopoietic cells. Besides, c-Myc inhibition does not alter proliferation kinetics of endothelial cells, fibroblasts or adipose derived mesenchymal stem cells, however; it limits bone marrow derived mesenchymal stem cell proliferation. We further demonstrate that a cocktail of c-Myc inhibitor 10074-G5 along with tauroursodeoxycholic acid (TUDCA) and i-NOS inhibitor L-NIL provides a robust HSC maintenance and expansion ex vivo as evident by induction of all stem cell antigens analyzed. Intriguingly, the cocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL improves HDR related gene expression. These findings provide tools to improve ex vivo HSC maintenance and expansion, autologous HSC transplantation and gene editing through modulation of HSC glycolytic and HDR pathways.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC=\"FIGDIR/small/403584_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (65K):\norg.highwire.dtl.DTLVardef@a34597org.highwire.dtl.DTLVardef@12dcc37org.highwire.dtl.DTLVardef@1ba68edorg.highwire.dtl.DTLVardef@13edbfd_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG HighlightsO_LIc-Myc inhibition induces ex vivo murine and human hematopoietic stem and progenitor cell proliferation and in vivo murine HSC pool\nC_LIO_LIc-Myc inhibition downregulates CDKIs and glycolytic gene expression in hematopoietic cells\nC_LIO_LIc-Myc inhibition do not cause apparent changes to endothelial cells, fibroblasts, or AD-MSCs but it limits BM-MSC proliferation\nC_LIO_LIc-Myc inhibition along with TUDCA and L-NIL improves HSC maintenance and expansion as evident by induction of all HSC surface antigens analyzed\nC_LIO_LIc-Myc inhibition alone upregulates major HDR modulator Rad51 expression in hematopoietic cells\nC_LIO_LICocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL improves HDR and S-phase related gene expression\nC_LI

cell biology↗