Fırtına Karagonlar, Zeynep
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Karagonlar, Zeynep Firtina
Firtina, Zeynep
Karagonlar, Zeynep Fırtına
Karagonlar, Zeynep F.
Firtina Karagonlar, Zeynep
Firtina, Zeynep
Karagonlar, Zeynep Fırtına
Karagonlar, Zeynep F.
Firtina Karagonlar, Zeynep
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zeynep.firtina@ieu.edu.tr
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05.08. Genetics and Bioengineering
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336
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376
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8
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17.68
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19.79
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8
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3
| Journal | Count |
|---|---|
| 2024 Medical Technologies Congress -- OCT 10-12, 2024 -- Bodrum, TURKIYE | 1 |
| Alternatives to Laboratory Animals | 1 |
| Bıochemıcal And Bıophysıcal Research Communıcatıons | 1 |
| Cancer Scıence | 1 |
| Cells | 1 |
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Now showing 1 - 10 of 19
Article Citation - WoS: 10Citation - Scopus: 11Upconversion Properties of Tm3+-Er3+ Co-Doped Layered Perovskites and In-Vitro Cytotoxicity of Their Exfoliated Nanomaterials(Elsevier, 2021) Gunay, Bensu; Sariyar, Ece; Unal, Ugur; Karagonlar, Zeynep Firtina; Saglam, Ozge; Firtina Karagonlar, ZeynepThe upconversion behavior of Er3+/Tm3+ co-doped Ruddlesden-Popper type K(2)Ln(2)Ti(3)O(10) layered perovskites was investigated. The lanthanide pair was selected for achieving 980 nm-driven green, red, and NIR emission. The perovskites having different dopant compositions were synthesized by a conventional solid-state procedure by substitution of La3+ ions in the host lattice. Moreover, the single nanosheets having approximately 1.8 nm thickness and 2 mu m lateral size were obtained via chemical exfoliation. The non-doped and co-doped layered materials and the nanosheets derived from these materials were characterized by X-ray diffraction, Scanning Electron Microscopy, Atomic Force Microscopy and custom-made experimental set-up of upconversion emission spectroscopy. According to the XRD profiles, the perovskites had the layered orientation and water molecules in the interlayer domain because of their hygroscopic nature. The co-doped layered perovskites presented twophoton excited green and red emissions, identified as S-4(3/2) -> (4)I(15/2 )with H-2(11/2) -> (4)I(15/2 )and F-4(9/2) -> I-4(15/2) of the Er3+ transitions with a NIR emission. The intensity of red to green ratio emission of the materials increased with respect to the co-dopant concentration. The nanosheets' upconversion emission was weak in the visible region compared to their layered morphology. On the other hand, the NIR emission based on H-3(4) -> H-3(6) transition of the Tm3+ ions was preserved despite the acid and solvent treatments to break apart the layered orientation. MTT assay and Calcein/PI staining were conducted to evaluate cytotoxicity of non-doped and Er3+/Tm3+ co-doped K(2)Ln(2)Ti(3)O(10) perovskites and their exfoliated nanosheets on HEK 293 and HepG2 cell lines. Both assays indicated that although cell viability decreases with increasing concentration, good cell viability was observed at even 100 mu g/mL. In addition to their excellent luminescent and optical features, the nanomaterials also demonstrated low cytotoxicity increasing the potential for their use in laser-based biological applications.Master Thesis 2d Perovskite Nanosheets for Multifunctional Device Fabrication and Biological Applications(İzmir Ekonomi Üniversitesi, 2021) Günay, Bensu; Sağlam, Özge; Karagonlar, Zeynep FırtınaBu tezin amaçları, frekans yükseltme özelliğine sahip nanolevhalar kullanılarak yapılandırılmış çok işlevli bir cihaz tasarımı ve biyolojik uygulamalar için iki boyutlu nanolevhaların biyouyumluluğunun araştırılmasıdır. K2Ln2Ti3O10 yapıda katmanlı perovskitler frekans yükseltme ile kırmızı ışıma elde edebilmek için farklı sitokiyometrik oranlarda Tm3+/Er3+ iyonları ile katkılandırılarak sentezlenmiştir. 2.5% Tm3+-20% Er3+ ile katkılı katmanlı malzemenin yanal boyutu 300 nm ile 2.5 µm arasında elde edilmiştir. Nanolevhaların kalınlığı 2-3 nm arasında belirlenmiştir ve tek nanolevhaların başarılı bir şekilde elde edildiği gösterilmiştir. Frekans yükseltme özelliğine sahip Tm3+/Yb3+ ve Er3+/Yb3+ ile katkılı nanolevhalar katman-katman tekniği ile 20 kez kaplanmıştır ve hazırlanan filmler sırasıyla 1G4 ›3H6 geçişi ile mavi ışıma ve 4S3/2›4I15/2 ve 2H11/2›4I15/2 geçişleri ile yeşil ışımalar göstermiştir. Öte yandan, Tm3+/Er3+ ortak katkılı nanolevha yapılı filmler, frekans yükseltme işlemi sırasında kırmızı ve yeşil emisyon sergilemiştir. Er3+/Yb3+ ortak katkılı nanolevhaların biriktirilmiş filmleri durumunda, yeşil ve kırmızı frekans yükseltme emisyonlarında iki foton süreçleri yer almıştır. 60 katman ile üretilen filmler ayrıca üç farklı nanolevhalar kullanılarak hazırlanmıştır. Film oluştururken nanolevhaların kombinasyonu CIE diagramında beyaz emisyon sergilemiştir. Ayrıca nanolevhaların sitotoksisitesi HepG2 ve HEK 293 hücre hatları kullanılarak analiz edilmiştir. HEK 293 hücre hattı için Tm3+/Er3+ katkılı katmanlı malzemenin toksisitesi %45,7 iken, nanolevhaların toksisitesi %73,6 olarak belirlenmiştir.Article Citation - WoS: 24Citation - Scopus: 22Lgr5/R-spo1 Axis Promotes Stemness and Aggressive Phenotype in Hepatoblast-Like Hepatocellular Carcinoma Cell Lines(Elsevier Science Inc, 2021) Akbari, Soheil; Kunter, Imge; Azbazdar, Yagmur; Ozhan, Gunes; Atabey, Nese; Karagonlar, Zeynep Firtina; Erdal, Esra; Firtina Karagonlar, ZeynepLeucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a newly defined stem cell marker in endoderm-derived organs such as the small intestine, colon and pancreas. Recently, LGR5 was demonstrated to be an important factor in liver regeneration and stem cell maintenance. Moreover, LGR5 expression is highly upregulated in various cancers including hepatocellular carcinoma. Herein, we demonstrate that LGR5 expression is specifically observed in certain subset of HCC cell lines with ?hepatoblast-like? appearance, characterized by the expression of liver fetal/progenitor markers. Notably, the activation of the canonical Wnt pathway significantly increases the expression of LGR5 in this subset of cell lines, whereas it does not cause any induction of LGR5 expression in mesenchymal like cell lines SNU-475 and SNU-449. Furthermore, we showed that treatment of the hepatoblast-like HCC cell lines HuH-7 and Hep3B with LGR5 ligand R-Spo1 significantly amplifies the induction of LGR5 expression, the phosphorylation of LRP6 and ?-catenin resulting in enhanced TCF/LEF activity either alone or in combination with Wnt3a. Consistently, the silencing of the LGR5 gene attenuates the co-stimulatory effect of R-Spo1/Wnt3a on TCF/LEF activity while overexpression of LGR5 enhances it. On the contrary, overexpression of LGR5 does not change TCF/LEF activity induced by R-Spo1/Wnt3a in mesenchymal-like HCC line, SNU-449. Importantly, LGR5-overexpressing cells have increased expression of several Wnt target genes and stemness-related genes including EpCAM and CK19 upon R-Spo1/Wnt3a treatment. LGR5-overexpressing cells also have increased spheroid forming, migration and invasion abilities and stimulation with R-Spo1/Wnt3a augments these abilities of LGR5-overexpressing cells. In addition, ectopic overexpression of LGR5 significantly increases cell proliferation rate independent of R-Spo1/Wnt3a stimulation. Moreover, in vitro tubulogenesis assay demonstrates that treatment with R-Spo1/Wnt3a enhances the sprouting of capillary tubules in only LGR5overexpressing cells. Finally, R-Spo1/Wnt3a significantly promotes dissemination of LGR5-overexpressing cells in vivo in a zebrafish xenograft model. Our study unravels a tumor-promoting role for LGR5 through activation of canonical Wnt/?-catenin signaling in the hepatoblast-like HCCs. In conclusion, our results suggest that LGR5/RSpo1/Wnt3a generates an axis that mediates the acquisition of aggressive phenotype specifically in hepatoblastlike subset of HCCs and might represent a valuable target for treatment of HCC tumors with aberrant activation of Wnt/?-catenin pathway.Article Citation - WoS: 5Citation - Scopus: 5Modelling the Sorafenib-Resistant Liver Cancer Microenvironment by Using 3-D Spheroids(SAGE Publications Inc., 2023) Sarıyar, E.; Fırtına Karagonlar, ZeynepLiver cancer is the third leading cause of cancer-related mortality, and hepatocellular carcinoma (HCC) is the most common form of liver cancer, and it usually occurs in the setting of chronic liver disease and cirrhosis. For patients with advanced HCC, systemic treatment is the first choice — however, resistance occurs frequently. Sorafenib was the first tyrosine kinase inhibitor approved for advanced HCC, and resistance to the therapy is a serious concern. When sorafenib therapy fails in a patient, it can be challenging to decide whether they can undergo a second-line therapy, and to determine which therapy they will be able to tolerate. Thus, physiologically relevant in vitro preclinical models are crucial for screening potential therapies, and 3-D tumour spheroids permit studies of tumour pathobiology. In this study, a drug-resistant 3-D tumour spheroid model was developed, based on sorafenib-resistant hepatocellular carcinoma cells, LX2 stellate cells and THP-1 monocytes. Model tumour spheroids that were formed with the sorafenib-resistant cells demonstrated lower diffusion of doxorubicin and exhibited increased resistance to regorafenib. Moreover, in the sorafenib-resistant spheroids, there was increased presence of CD68-positive cells and a reduction in inflammatory marker secretion. The sorafenib-resistant cell line-derived spheroids also showed a higher expression of FGF-19, PDGF-AA and GDF-15, which are known to be involved in malignancies. This multi-cell type spheroid model represents a potentially useful system to test drug candidates in a microenvironment that mimics the drug-resistant tumour microenvironment in HCC. © The Author(s) 2023.Article Citation - WoS: 2Citation - Scopus: 2Liraglutide Modulates Cyclooxygenase and α7 Acetylcholine Receptors: in Vitro and in Silico Insights Into Its Anti-Inflammatory Role in LPS-Induced Inflammation in Raw 264.7 Macrophages(Springer, 2025) Baris, Elif; Portakal, Huseyin Saygin; Aslan, Arda; Karagonlar, Zeynep Firtina; Tosun, Metiner; Firtina Karagonlar, ZeynepLiraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is well-established for its metabolic benefits, including glycemic control and weight loss. Beyond these roles, it exhibits significant anti-inflammatory properties, though the mechanisms remain underexplored. This study investigates the anti-inflammatory effects of liraglutide in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. Results demonstrate that increasing concentrations of liraglutide suppresses LPS-elevated prostaglandin E2 (PGE2), 6-keto prostaglandin F1 alpha (6-keto-PGF1 alpha, a stable prostacyclin metabolite) and thromboxane A2 (TXA2), similar to that observed with conventional anti-inflammatory agents, ibuprofen and celecoxib. Mechanistic exploration reveals that liraglutide's anti-inflammatory action is dually-modulated by cyclooxygenase (COX) and nicotinic acetylcholine receptor (nAChR) signaling. The application of non-selective, non-competitive nAChR antagonist or selective and potent alpha 7-nAChR antagonist, mecamylamine (MEC) and methyllycaconitine (MLA), respectively, highlights the involvement of cholinergic pathways in liraglutide's activity. Based on in silico molecular docking analyses, liraglutide exhibits favorable binding affinities to COX-1, COX-2, prostacyclin synthase (PGIS), and alpha 7nAChRs, supporting its potential multi-target anti-inflammatory effects. These findings suggest that the therapeutic potential of liraglutide may go beyond metabolic regulation and may be promising for conditions in which metabolic and inflammatory pathways converge, including inflammation and modulation of cholinergic signaling.Article Citation - WoS: 1Citation - Scopus: 1Thyroid Hormone T3 Augments the Cytotoxicity of Sorafenib in Huh7 Hepatocellular Carcinoma Cells by Suppressing Akt Expression(Wolters Kluwer Medknow Publications, 2024) Uyulgan, S.; Köse, S.N.; Kıpçak, A.; Başkan, Y.; Dağlar, G.; Karagonlar, Z.F.; Yandım, C.; Kose, Sila NazBackground and Objectives: Hepatocellular carcinoma (HCC) is a primary cancer that poorly responds to treatment. Molecular cancer studies led to the development of kinase inhibitors, among which sorafenib stands out as a multi-kinase inhibitor approved by FDA for first line use in HCC patients. However, the efficiency of sorafenib was shown to be counteracted by numerous subcellular pathways involving the effector kinase AKT, causing resistance and limiting its survival benefit. On the way of breaking such resistance mechanisms and increase the efficiency of sorafenib, deeper understanding of hepatocellular physiology is essential. Thyroid hormones were shown to be metabolized in liver and inevitably affect the molecular behaviour of hepatocytes. Interestingly, thyroid hormone T3 was also demonstrated to be potentially influential in liver regeneration and treatment with this hormone reportedly led to a decrease in HCC tumor growths. In this study, we aimed to uncover the impact of T3 hormone on the cytotoxic response to sorafenib in HCC in vitro. Materials and Methods: We pre-treated the HCC cell line Huh-7 with T3 prior to sorafenib exposure both in 2D and 3D culture. We checked cell viability with MTT assay in 2D culture and measured the sizes of 3D spheroids with bright-field microscopy followed by a surface analysis with ImageJ. We also performed scratch assay to measure cell migration as well as western blot and qPCR to uncover affected pathways. Results: We observed an additive effect to sorafenib’s cytotoxicity both in 2D and 3D culture. Cell migration assay also confirmed our finding and pointed out a benefit of T3 hormone in HCC cell migration. Western blot experiments showed that T3 exerts its additive effect by suppressing AKT expression upon sorafenib treatment both at protein and gene expression levels. Conclusion: Our results open a promising new avenue in increasing sorafenib’s cytotoxicity where thyroid hormone T3 is utilized to modulate AKT expression to combat resistance, and warrant further studies in the field. © 2024 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow.Master Thesis Α7 Nachr Aracılıklı Kolinerjik Anti-inflamatuar Yolak Aktivasyonunun Regorafenib Direncine Etkisinin Belirlenmesi(2025) Sezan, Sıla; Karagonlar, Zeynep Fırtına; Barış, ElifHepatoselüler karsinom (HCC), agresif doğası, yüksek metastatik potansiyeli ve sınırlı tedavi seçenekleri nedeniyle küresel bir sağlık sorunu olmaya devam etmektedir. İleri evre HCC için ikinci basamaktaki tedavi olan regorafenib, umut vaat etse de, direnç mekanizmaları nedeniyle etkinliği sınırlıdır. Ortaya çıkan kanıtlar, tümör mikroçevresinin (TME), inflamasyonun ve tümörle ilişkili makrofajların (TAM'ler) direnç mekanizmalarındaki kritik rolünü vurgulamaktadır. Bu çalışma, HCC'de regorafenib direncinin üstesinden gelmede kolinerjik anti-inflamatuar yolak (CAP) içindeki α7 nikotinik asetilkolin reseptörünün (α7 nAChR) ve aktivasyonunun rolünü araştırmaktadır. Regorafenib dirençli Huh7 (RRC) hücrelerini ve polarize M1 ve M2 makrofajlarını içeren 2D kültür ve 3D sferoid modelleri kullanarak, regorafenib ile kombine edilen bir α7 nAChR ligandı olan kolinin etkilerini inceledik. Bulgularımız, kolinin regorafenibin etkinliğini artırdığını, RRC hücrelerinin canlılığını, migrasyonunu ve çoğalmasını azalttığını, aynı zamanda M1 makrofaj polarizasyonunu teşvik ettiğini göstermektedir. RRC hücrelerinde artmış α7 nAChR ekspresyonu ve kalsiyum alışverişi gözlemlendi, bu da direnç mekanizmalarındaki kritik rolünü ortaya koymaktadır. Ek olarak, kombine tedavi, NF-κB dahil olmak üzere temel inflamatuar ve onkojenik yolları önemli ölçüde regüle etti. Bu sonuçlar, HCC'de regorafenib direncinin aşılması için α7 nAChR'yi hedef almanın terapötik potansiyelini vurgulamakta ve ileri evre HCC hastaları için klinik sonuçları iyileştirebilecek yeni bir kombinasyon stratejisi önermektedir.Conference Object Viability Analysis of Drug-Treated Tumor Spheroids Using Machine Learning(IEEE, 2024) Oguz, Kaya; Aslan, Arda; Evcin, Emre; Ozogul, Emre; Sonmez, Mehmet Eren; Karabacak, Yaren; Karagonlar, Zeynep Firtina3D spheroids that are able to mimic the microenvironment of tumors effectively have emerged as significant structures in cancer biology and drug development. This study aims to help cancer researchers monitor the changes in human liver cancer spheroids in response to drug treatment by offering a software tool for evaluating cell viability within 3D spheroids. A dataset of spheroid images are collected, processed, and classified using alternative machine learning models constructed with Random Forest, Logistic Regression, Support Vector Machine and Extreme Gradient Boosting methods. The classification performances of the models are evaluated in terms of the prediction accuracy, precision, recall, and F1-score values. Based on the test experiments conducted, Extreme Gradient Boosting model achieved the highest ratios for all of the performance metrics. Furthermore, a standalone desktop application is implemented to perform analyses of the images with the help of its user-friendly interface.Article Citation - WoS: 7Citation - Scopus: 8Ag-Intercalation of Tm3+/Er3+ Co-Doped Layered Perovskites and Their Exfoliated 2d Nanosheets With an Enhanced Antibiofilm and Antibacterial Activity(Elsevier, 2022) Gunay, Bensu; Doger, Hilal; Karagonlar, Zeynep Firtina; Saglam, OzgeThere is a significant demand for antibiofilm and antimicrobial materials in the medical device industry. It is well established that Ag-based compounds have a high antimicrobial efficiency. Without being in a lattice, silver's antimicrobial action is mainly mediated by the release of Ag+ ions from the compound. These ions at high levels are toxic to most bacterial species. However, rapidly released Ag+ ions tend to aggregate and lose their anti-bacterial effect over time. Thus, utilizing a new approach for using silver as an antimicrobial agent based on imparting the antimicrobial action through contact, rather than releasing Ag+ ions could be beneficial. Here we report that Ag+ ions intercalation of Tm/Er co-doped layered perovskites and their 2D nanosheets exhibit antibacterial and antibiofilm activities against the human opportunistic pathogens Escherichia coli and Bacillus subtilis. Specifically, flocculation of nanosheets with Ag+ ions had efficient antibacterial and antibiofilm activity at 100 mu g/mL. In addition, the flocculated product demonstrated low in vitro cytotoxicity against the Huh7 hepatocellular carcinoma cell line and HEK 293 embryonic kidney cell line. Our results indicate that Ag-intercalated layered perovskites and the flocculation of the nanosheets hold great promise to be used for anti-microbial and antibiofilm purposes in biomedical engineering applications.Article Citation - WoS: 44Citation - Scopus: 48Changes in Wnt and Tgf-Beta Signaling Mediate the Development of Regorafenib Resistance in Hepatocellular Carcinoma Cell Line Huh7(Frontiers Media Sa, 2021) Karabiçici, Mustafa; Azbazdar, Yagmur; Ozhan, Gunes; Senturk, Serif; Firtina Karagonlar, Zeynep; Erdal, EsraHepatocellular carcinoma (HCC) is an aggressive, chemo resistant neoplasm with poor prognosis and limited treatment options. Exploring activated pathways upon drug treatment can be used to discover more effective anticancer agents to overcome therapy resistance and enhance therapeutic outcomes for patients with advanced HCC. Human tumor-derived cell lines recapitulate HCC diversity and are widely used for studying mechanisms that drive drug resistance in HCC. In this study, we show that regorafenib treatment activates Wnt/beta-catenin signaling only in hepatoblast-like HCC cell lines and induces enrichment of markers associated with hepatic stem/progenitor cells. Moreover, activation of Wnt/beta-catenin signaling via Wnt3a/R-Spo1 treatment protects these cells from regorafenib induced apoptosis. On the other hand, regorafenib resistant cells established by long-term regorafenib treatment demonstrate diminished Wnt/beta-catenin signaling activity while TGF-beta signaling activity of these cells is significantly enhanced. Regorafenib resistant cells (RRCs) also show increased expression of several mesenchymal genes along with an induction of CD24 and CD133 cancer stem cell markers. Moreover, regorafenib resistant cells also exhibit significantly augmented in vitro and in vivo migration capacity which could be reversed by TGF-beta type 1 receptor (TGFb -R1) inhibition. When combined with regorafenib treatment, TGF beta-R1 inhibition also significantly decreased colony formation ability and augmented cell death in resistant spheroids. Importantly, when we knocked down TGF beta-R1 using a lentiviral plasmid, regorafenib resistant cells entered senescence indicating that this pathway is important for their survival. Treatment of RRCs with TGF beta-R1 inhibitor and regorafenib significantly abolished pSTAT3, pSMAD2 and pERK (44/42) expression suggesting the involvement of both canonical and non-canonical pathways. In conclusion, our data suggest that HCC tumors with aberrant activation in the Wnt/beta-catenin pathway, might have higher intrinsic regorafenib resistance and the inhibition of this pathway along with regorafenib administration might increase regorafenib-induced cell death in combinational therapies. However, to resolve acquired regorafenib resistance developed in HCC patients, the combined use of TGF-beta pathway inhibitors and Regorafenib constitute a promising approach that can increase regorafenib sensitization and prevent tumor recurrence.
