Browsing by Author "Firtina Karagonlar, Zeynep"

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Citation - WoS: 24
Citation - Scopus: 22
Lgr5/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, Zeynep
Leucine-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.
Citation - WoS: 2
Citation - Scopus: 2
Liraglutide 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, Zeynep
Liraglutide, 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.
Citation - WoS: 10
Citation - Scopus: 11
Upconversion 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, Zeynep
The 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.