Publications by authors named "Huseyin Aktug"

52 Publications

Spectroscopic and microscopic comparisons of cell topology and chemistry analysis of mouse embryonic stem cell, somatic cell and cancer cell.

Acta Histochem 2021 Sep 29;123(6):151763. Epub 2021 Jul 29.

Ege University, Faculty of Medicine, Department of Histology and Embryology, 35100 Izmir, Turkey. Electronic address:

While embryonic stem cells and cancer cells are known to have many similarities in signalling pathways, healthy somatic cells are known to be different in many ways. Characterization of embryonic stem cell is crucial for cancer development and cancer recurrence due to the shared signalling pathways and life course with cancer initiator and cancer stem cells. Since embryonic stem cells are the sources of the somatic and cancer cells, it is necessary to reveal the relevance between them. The past decade has seen the importance of interdisciplinary studies and it is obvious that the reflection of the physical/chemical phenomena occurring on the cell biology has attracted much more attention. For this reason, the aim of this study is to elementally and topologically characterize the mouse embryonic stem cells, mouse lung squamous cancer cells, and mouse skin fibroblast cells by using Atomic Force Microscopy (AFM), X-ray Photoelectron Spectroscopy (XPS) and Scanning Electron Microscopy (SEM) supported with Electron Dispersive Spectroscopy (EDS) techniques in a complementary way. Our AFM findings revealed that roughness data of the mouse embryonic stem cells and cancer cells were similar and somatic cells were found to be statistically different from these two cell types. However, based on both XPS and SEM-EDS results, surface elemental ratios vary in mouse embryonic stem cells, cancer cells and somatic cells. Our results showed that these complementary spectroscopic and microscopic techniques used in this work are very effective in cancer and stem cell characterization and have the potential to gather more detailed information on relevant biological samples.
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http://dx.doi.org/10.1016/j.acthis.2021.151763DOI Listing
September 2021

Effects of ranibizumab and zoledronic acid on endometriosis in a rat model.

Arch Gynecol Obstet 2021 Jun 3. Epub 2021 Jun 3.

Gynecology and Obstetrics, Balikesir University, Balikesir, Turkey.

Purpose: To investigate the histological efficacy of ranibizumab and zoledronic acid in an experimentally induced endometriosis model as compared with danazol, buserelin acetate and dienogest.

Methods: Endometrial implants were introduced in 52 female Wistar albino rats, which were then randomly divided into six groups. The animals were, respectively, given dienogest, danazol, buserelin acetate, zoledronic acid, ranibizumab and 0.9% NaCl. After 4 weeks, the volumes and histopathological properties of the implants were evaluated and the implants were excised completely at the third laparotomy. A histopathological scoring system was used to evaluate the preservation of epithelia. Endometrial explants were evaluated immunohistochemically.

Results: Among the groups, the histological score was significantly lower in the zoledronic acid and ranibizumab groups compared with the controls (p < 0.001). There were no significant differences regarding ellipsoidal volume levels between groups (p > 0.05). However, there was a statistically significant difference regarding cell numbers according to the degree of Bcl-2, NF-κB, and CD31 staining (p < 0.001). There was no statistically significant difference in Bcl-2, CD31, or NF-κB staining in the binary comparisons between the other groups (p > 0.05). For Bcl-2 staining, the staining rate of the group treated with zoledronic acid was significantly lower compared with the dienogest and danazol groups (p < 0.05). The staining rates of CD31 and NF-κB were significantly lower in the zoledronic acid and ranibizumab groups compared with the controls (p < 0.05).

Conclusion: According to these results, zoledronic acid and ranibizumab may be putative candidates for the treatment of endometriosis.
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http://dx.doi.org/10.1007/s00404-021-06104-9DOI Listing
June 2021

The effects of PIKfyve inhibitor YM201636 on claudins and malignancy potential of nonsmall cell cancer cells.

Turk J Biol 2021 9;45(1):26-34. Epub 2021 Feb 9.

Department of Medical Biology, Faculty of Medicine, Ege University, İzmir Turkey.

PIKfyve is an evolutionarily conserved lipid and protein kinase enzyme that has pleiotropic cellular functions. The aim of the present study was to investigate the effects of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) inhibitor, YM201636, on nonsmall cell lung cancer (NSCLC) cells growth, tumorigenicity, and claudin (CLDN) expressions. Three NSCLC cell lines (Calu-1, H1299 and HCC827) were used to compare the effects of YM201636. Cytotoxic effects of YM201636 were analysed using XTT assay. Malignancy potential of cells assesses with wound healing and soft agar colony-forming assays. mRNA and protein expressions of claudins were analysed by qRT-PCR and immunofluorescence staining. Our results revealed that YM201636 inhibited the proliferation and malignancy potential of Calu-1, H1299, and HCC827 cells in a dose-dependent manner. After YM201636 treatment CLDN1, -3 and -5 expressions increased significantly in HCC827 cells. CLDN3 and -5 expressions also significantly increased in Calu1 cell line. YM201636 treatment significantly reduced the CLDN1 and increased the CLDN5 expression in H1299 cells. Immunofluorescence staining of CLDN1, -3 and -5 proteins showed a significant increase after YM201636 treatment. Besides, YM201636 induced EGFR mRNA expression in all NSCLC cell lines. Our results have shown that YM201636 inhibits tumorigenicity of NSCLC cells. Furthermore, estimated glomerular filtration rate (EGFR) pathway is important signalling involved in the regulation of claudins. Understanding the mechanisms of PIKfyve inhibitors may improve cancer treatment particularly for EGFR overactivated NSCLC.
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http://dx.doi.org/10.3906/biy-2010-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877718PMC
February 2021

Holistic Approach to Cell Characteristics and Behavioral Analysis.

Crit Rev Oncog 2019 ;24(1):21-26

Department of Histology and Embryology, Ege University, Izmir, Turkey; Department of Histology and Embryology, Yüzüncü Yil University, Van, Turkey.

Cancer is a group of diseases of our era that affects not only medical status but also lowers the tone of social and emotional well-being. It also has severe impacts on economies. Cancer cells are linked to the somatic cells and stem cells, with their characteristic similarities and differences. Variations in cell-signaling pathways, such as cell death and proliferation balances, kinetic behavior of the cells, and their differentiation potentials, are the featured parameters for therapeutic targeting. The detection of target points should be based not only on the molecular biology methods but also on the physical and topological analyses from the aspect of "geography is fate". In this review, we focus on the importance of the holistic analyses of intracellular and extracellular dynamics and multidisciplinary cooperation.
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http://dx.doi.org/10.1615/CritRevOncog.2019029527DOI Listing
July 2020

The effect of extracellular matrix on the differentiation of mouse embryonic stem cells.

J Cell Biochem 2020 01 6;121(1):269-283. Epub 2019 Jun 6.

Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.

Embryonic stem cells (ESCs) are promising research materials to investigate cell fate determination since they have the capability to differentiate. Stem cell differentiation has been extensively studied with various microenvironment mimicking structures to modify cellular dynamics associated with the cell-extracellular matrix (ECM) interactions and cell-cell communications. In the current study, our aim was to determine the effect of microenvironmental proteins with different concentrations on the capacity and differentiation capability of mouse ESCs (mESCs), combining the biochemical assays, imaging techniques, Fourier transform infrared (FTIR) spectroscopy, and unsupervised multivariate analysis. Based on our data, coating the surface of mESCs with Matrigel, used as an acellular matrix substrate, resulted in morphological and biochemical changes. mESCs exhibited alterations in their phenotype after growing on the Matrigel-coated surfaces, including their differentiation capacity, cell cycle phase pattern, membrane fluidity, and metabolic activities. In conclusion, mESCs can be stimulated physiologically, chemically, or mechanically to convert them a new phenotype. Thus, identification of ESCs' behavior in the acellular microenvironment could be vital to elucidate the mechanism of diseases. It might also be promising to control the cell fate in the field of tissue engineering.
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http://dx.doi.org/10.1002/jcb.29159DOI Listing
January 2020

Autophagy and mTOR pathways in mouse embryonic stem cell, lung cancer and somatic fibroblast cell lines.

J Cell Biochem 2019 10 30;120(10):18066-18076. Epub 2019 May 30.

Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.

Embryonic developmental stages and regulations have always been one of the most intriguing aspects of science. Since the cancer stem cell discovery, striking for cancer development and recurrence, embryonic stem cells and control mechanisms, as well as cancer cells and cancer stem cell control mechanisms become important research materials. It is necessary to reveal the similarities and differences between somatic and cancer cells which are formed of embryonic stem cells divisions and determinations. For this purpose, mouse embryonic stem cells (mESCs), mouse skin fibroblast cells (MSFs) and mouse lung squamous cancer cells (SqLCCs) were grown in vitro and the differences between these three cell lines signalling regulations of mechanistic target of rapamycin (mTOR) and autophagic pathways were demonstrated by immunofluorescence and real-time polymerase chain reaction. Expressional differences were clearly shown between embryonic, cancer and somatic cells that mESCs displayed higher expressional level of Atg10, Hdac1 and Cln3 which are related with autophagic regulation and Hsp4, Prkca, Rhoa and ribosomal S6 genes related with mTOR activity. LC3 and mTOR protein levels were lower in mESCs than MSFs. Thus, the mechanisms of embryonic stem cell regulation results in the formation of somatic tissues whereas that these cells may be the causative agents of cancer in any deterioration.
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http://dx.doi.org/10.1002/jcb.29110DOI Listing
October 2019

The effect of topical voriconazole on conjunctiva in rats as revealed by histopathology and immunohistochemistry.

J Chemother 2019 Sep 29;31(5):267-273. Epub 2019 May 29.

Department of Ophthalmology, Ege University School of Medicine , Bornova , Izmir.

The aim of this study was to evaluate the effects of topical voriconazole with histopathological and immunohistochemical analysis of the conjunctiva in rats. Twenty-eight Sprague Dawley rats were divided into four groups as two study (S1, S2) and two control (C1, C2). Voriconazole was instilled four times daily to S1, S2 rats. Physiologic saline (0.9%) was instilled four times daily in C1 and C2 rats. S1 and C1 were followed in a dark room; S2 and C2 were held in a room with sunlight. Impression cytology was performed at 0, 15, 30, 45 and 60th d after instillations. After 2 months of treatment conjunctival tissue was removed for histological and immunohistochemical analysis. In impression cytology evaluation, there was no difference between S1 and S2. At 60 d the difference between S1 and C1 was significant. In other comparisons, there was no difference between S1 and C1, C2. The scores of S2 was higher than C1 and C2 for all comparisons except 15th day scores of S2 and C2. In study groups, epithelial and gland degeneration were higher in S2, but inflammation scores were similar. The comparison of immunreactivity of ERK, TGFβ and E-cadherin were different in the study groups than the control groups for all comparisons. In conclusion, voriconazole has side effects due to phototoxicity including squamous cell carcinoma. Clinicians should particularly be careful with the long-term use of topical voriconazole and should follow-up patients strictly in terms of ocular surface alterations.
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http://dx.doi.org/10.1080/1120009X.2019.1603798DOI Listing
September 2019

The Preventive Effect of Oxytocin on Retinopathy in Streptozotocin-Induced Diabetic Rats

Turk J Ophthalmol 2019 Apr;49(2):68-72

Ege University Faculty of Medicine, Department of Physiology, İzmir, Turkey

Objectives: The aim of this study was to investigate the impact of intravitreal and intraperitoneal use of oxytocin (OT) on retinopathy in streptozotocin-induced diabetic rats.

Materials And Methods: Twenty-four 6–8-week-old adult male and female Sprague Dawley rats were used in the study. Diabetes was induced in the rats with a single injection of intraperitoneal streptozotocin. Diabetes was verified after 48 hours by measuring blood glucose levels of 260 mg/dl (14.4 mmol/L) or higher in diabetic rats. The rats were divided into 4 groups and treated as follows: intravitreal physiological saline group (0.01 mL saline weekly), intravitreal OT group (10 μU/μL OT weekly), intraperitoneal physiological saline group (1 mL daily), and intraperitoneal OT group (100 IU/kg OT daily). Hamilton syringes fitted with 27-gauge needles were used for intraperitoneal injections while 31-gauge needles were used for intravitreal injection. After 4 weeks of treatment the rats were euthanized to evaluate outer nuclear layer (ONL) thickness, vascular endothelial growth factor (VEGF) immunoexpression, and plasma VEGF levels from blood samples obtained by cardiac puncture.

Results: Morphometric analysis of retinal cross-sections showed that intravitreal and intraperitoneal OT significantly increased ONL thickness compared to physiological saline-treated groups. Also, OT treatment significantly decreased VEGF protein expression compared with the physiological saline groups. Plasma VEGF level was significantly higher in the physiological saline treatment group compared to the OT treatment group.

Conclusion: OT reduces diabetic retinopathy progression, particularly when administered intravitreally. To our knowledge, this is the first attempt to investigate the impact of OT on diabetic retinopathy and may provide a new area for further research.
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http://dx.doi.org/10.4274/tjo.galenos.2018.47897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517859PMC
April 2019

Effects of Glycogen Synthase Kinase Inhibitor on Glioblastoma Multiforme Cell Line via Apoptosis and Cell Signaling Pathways.

Turk Neurosurg 2019 ;29(4):513-521

University of Health Sciences, Tepecik Training and Research Hospital, Department of Neurosurgery, Izmir, Turkey.

Aim: To investigate the apoptotic and molecular effects of glycogen synthase kinase-3 (GSK-3) in glioblastoma multiforme (GBM).

Material And Methods: Human primary glioblastoma cell line (U-87 MG) and the human fetal glial cell line (SVGp12) were used. The cells were exposed to the different doses of GSK inhibitor for 24, 48 and 72 hours. Induction of apoptosis was assessed by DNA fragmentation (TUNEL) assay. EGFR and NF-kB expression was evaluated by immunofluorescence analyses.

Results: GSK-3 inhibitor IX induced cytotoxicity and apoptosis in dose-dependent manner in GBM cells. Our results indicated that GSK-3 inhibitor IX induces apoptosis, resulting in a significant decrease in the expression of NF-kB and EGF.

Conclusion: Inhibition through GSK-3 has been found promising in creating therapeutic management of GBM cells. Proliferation, differentiation, cell cycle regulation, and apoptosis are mechanisms that must be interpreted as a whole. Components associated with EGFR, NF-kB, and apoptosis affect the mechanism solely and collectively. Our collective data suggest that GSK-3 inhibitor IX inhibited cellular proliferation and induced apoptotic events by modulating EGFR and NF-kB expression in GBM cells. GSK-3 inhibition holds promise for the development of new approaches for the therapeutic management of GBM cells.
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http://dx.doi.org/10.5137/1019-5149.JTN.23987-18.2DOI Listing
October 2019

Glycogen synthase kinase-3 inhibition in glioblastoma multiforme cells induces apoptosis, cell cycle arrest and changing biomolecular structure.

Spectrochim Acta A Mol Biomol Spectrosc 2019 Feb 24;209:150-164. Epub 2018 Oct 24.

Department of Histology and Embryology, Faculty of Medicine, Ege University, 35100 Izmir, Turkey.

Glioblastoma multiforme (GBM) is the most malignant and aggressive primary human brain tumors. The regulatory pathways of apoptosis are altered in GBMs, leading to a survival advantage of the tumor cells. Thus, identification of target molecules, which are effective in triggering of the cell death mechanisms in GBM, is an essential strategy for therapeutic purposes. Glycogen synthase kinase-3 (GSK-3) plays an important role in apoptosis, proliferation and cell cycle. This study focused on the effect of GSK-3 inhibitor IX in the GBM cells. Apoptosis induction was determined by Annexin-V assay, multicaspase activity and immunofluorescence analyses. Concentration-dependent effects of GSK-3 inhibitor IX on the cell cycle were also evaluated. Moreover, the effect of GSK inhibitor on the cellular biomolecules was assessed by using ATR-FTIR spectroscopy. Our assay results indicated that GSK-3 inhibitor IX induces apoptosis, resulting in a significant increase in the expression of caspase-3 and caspase-8 proteins. Cell cycle analyses revealed that GSK-3 inhibitor IX leads to dose-dependent G2/M-phase cell cycle arrest. Based on the FTIR data, treatment of GBM cells causes dysregulation in the carbohydrate metabolism and induces apoptotic cell death which was characterized by the spectral alterations in nucleic acids, an increment in the lipid amount with disordering state and compositional changes in the cellular proteins. These findings suggest that GSK-3 inhibitor IX exhibits anti-cancer effects by inducing apoptosis and changing biomolecular structure of membrane lipids, carbohydrates, nucleic acids and proteins, and thus, may be further evaluated as a potential effective candidate agent for the GBM combination therapies.
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http://dx.doi.org/10.1016/j.saa.2018.10.036DOI Listing
February 2019

Deciphering the biochemical similarities and differences among mouse embryonic stem cells, somatic and cancer cells using ATR-FTIR spectroscopy.

Analyst 2018 Mar;143(7):1624-1634

Center for Drug Research & Development and Pharmacokinetic Applications (ARGEFAR), Ege University, 35100, Izmir, Turkey.

Cellular macromolecules play important roles in cellular behaviors and biological processes. In the current work, cancer (KLN205), normal (MSFs) and mouse embryonic stem cells (mESCs) are compared using ATR-FTIR spectroscopy. Modifications in the composition, concentration, structure and function-related changes in the cellular components were deciphered using the infrared spectra. Our results revealed that cancer and embryonic stem cells are very similar but highly different from the normal cells based on the spectral variations in the protein, lipid, carbohydrate and nucleic acid components. The longest lipid acyl chains exist in mESCs, while cancer cells harbor the lowest lipid amount, short lipid acyl chains, a high content of branched fatty acids and thin cell membranes. The highest cellular growth rate and accelerated cell divisions were observed in the cancer cells. However, the normal cells harbor low nucleic acid and glycogen amounts but have a higher lipid composition. Any defect in the signaling pathways and/or biosynthesis of these cellular parameters during the embryonic-to-somatic cell transition may lead to physiological and molecular events that promote cancer initiation, progression and drug resistance. We conclude that an improved understanding of both similarities and differences in the cellular mechanisms among the cancer, normal and mESCs is crucial to develop a potential clinical relevance, and ATR-FITR can be successfully used as a novel approach to gain new insights into the stem cell and cancer research. We suggest that targeting the cellular metabolisms (glycogen and lipid) can provide new strategies for cancer treatment.
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http://dx.doi.org/10.1039/c8an00017dDOI Listing
March 2018

Repression of the Notch pathway prevents liver damage in streptozotocin-induced diabetic mice.

Folia Histochem Cytobiol 2017 10;55(3):140-148. Epub 2017 Oct 10.

1Yuzuncu Yil University, Faculty of Medicine, Department of Histology and Embryology, Van, Turkey. 2Ege University, Faculty of Medicine, Department of Histology and Embryology, Izmir, Turkey..

Introduction: Sunitinib is an oral inhibitor of vascular endothelial growth factor that is used to treat a variety of cancer. There are limited data regarding the effect of sunitinib on diabetes. In the liver, Notch signaling plays an important role in liver tissue development and homeostasis and its dysfunction is associated with liver pathol-ogies. The aim of the present study is to investigate the effects of sunitinib on streptozotocin (STZ)-induced diabetic liver in mice models.

Material And Methods: An experimental diabetes mellitus (DM) model was created in 28 male CD-1 mice. Twenty-eight male CD-1 mice divided in four groups (n = 7 each) were used; control mice (C), control mice treated with sunitinib (C + S), diabetic mice (DM), and diabetic mice treated with sunitinib (DM + S) for four weeks. The histopathological changes in the liver were examined by histochemistry and immunohistochemistry. Immunoreactivity of Notch1, Jagged1, DLL-1 and VEGF were evaluated in control and diabetic mice after sunitinib treatment.

Results: The significant morphological changes in the liver were mostly seen in hepatocytes that were hyper-trophied in the DM mice, with an increased amount of eosinophilic granules; moreover, some hepatocytes contained empty vacuole-like structures. The livers of the DM mice revealed increased deposition of collagen fibers. After sunitinib treatment the hepatocytes and hepatic lobules had almost similar morphology to control mice. The immunoreactivities of Notch1, Jagged1, DLL-1 and VEGF in hepatocytes were significantly lower in the DM group when compared with the C, DM + S and C + S group treated with sunitinib.

Conclusions: These results suggest that sunitinib effectively protects the liver from diabetes-induced damage through the inhibition of the Notch pathway.
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http://dx.doi.org/10.5603/FHC.a2017.0014DOI Listing
November 2018

Accumulation of -Synuclein in Cerebellar Purkinje Cells of Diabetic Rats and Its Potential Relationship with Inflammation and Oxidative Stress Markers.

Neurol Res Int 2017 4;2017:5952149. Epub 2017 Jan 4.

Department of Physiology, Ege University Faculty of Medicine, Izmir, Turkey.

The present study was conducted to evaluate the relationship between plasma oxidative stress markers such as malondialdehyde (MDA) and glutathione (GSH), inflammatory marker pentraxin-3 (PTX3), and cerebellar accumulation of -synuclein in streptozotocin- (STZ-) induced diabetes model in rats. Twelve rats were included in the study. Diabetes ( = 6) was induced with a single intraperitoneal injection of streptozotocin (STZ, 60 mg/kg). Diabetes was verified after 48 h by measuring blood glucose levels. Six rats served as controls. Following 8 weeks, rats were sacrificed for biochemical and immunohistochemical evaluation. Plasma MDA levels were significantly higher in diabetic rats when compared with the control rats ( < 0.01), while plasma GSH levels were lower in the diabetic group than in the control group ( < 0.01). Also, plasma pentraxin-3 levels were statistically higher in diabetic rats than in the control rats ( < 0.01). The analysis of cerebellar -synuclein immunohistochemistry showed a significant increase in -synuclein immunoexpression in the diabetic group compared to the control group ( < 0.01). Due to increased inflammation and oxidative stress in the chronic period of hyperglycemia linked to diabetes, there may be -synuclein accumulation in the cerebellum and the plasma PTX3 levels may be assessed as an important biomarker of this situation.
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http://dx.doi.org/10.1155/2017/5952149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241473PMC
January 2017

Effects of flavopiridol on critical regulation pathways of CD133high/CD44high lung cancer stem cells.

Medicine (Baltimore) 2016 Oct;95(43):e5150

Department of Medical Biology, Ege University Faculty of Medicine, Izmir Department of Histology and Embryology, Yuzuncu Yil University Faculty of Medicine, Van Department of Histology and Embryology, Ege University Faculty of Medicine, Izmir, Turkey.

Background: Flavopiridol a semisynthetic flavone that inhibits cyclin-dependent kinases (CDKs) and has growth-inhibitory activity and induces a blockade of cell-cycle progression at G1-phase and apoptosis in numerous human tumor cell lines and is currently under investigation in phase II clinical trials. Cancer stem cells (CSCs) are comprised of subpopulation of cells in tumors that have been proposed to be responsible for recurrence and resistance to chemotherapy. The aim of the present study was to investigate the effects of flavopiridol in cancer stem cell cytoskeleton, cell adhesion, and epithelial to mesenchymal transition in CSCs.

Methods: The cells were treated with flavopiridol to determine the inhibitory effect. Cell viability and proliferation were determined by using the WST-1 assay. Caspase activity and immunofluorescence analyses were performed for the evaluation of apoptosis, cell cytoskeleton, and epithelial-mesenchymal transition (EMT) markers. The effects of flavopiridol on the cell cycle were also evaluated. Flow cytometric analysis was used to detect the percentages of CSCs subpopulation. We analyzed the gene expression patterns to predict cell cycle and cell cytoskeleton in CSCs by RT-PCR.

Results: Flavopiridol-induced cytotoxicity and apoptosis at the IC50 dose, resulting in a significant increase expression of caspases activity. Cell cycle analyses revealed that flavopiridol induces G1 phase cell cycle arrest. Flavopiridol significantly decreased the mRNA expressions of the genes that regulate the cell cytoskeleton and cell cycle components and cell motility in CSCs.

Conclusion: Our results suggest that Flavopiridol has activity against lung CSCs and may be effective chemotherapeutic molecule for lung cancer treatment.
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http://dx.doi.org/10.1097/MD.0000000000005150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089099PMC
October 2016

Comparison of cell cycle components, apoptosis and cytoskeleton-related molecules and therapeutic effects of flavopiridol and geldanamycin on the mouse fibroblast, lung cancer and embryonic stem cells.

Tumour Biol 2016 Sep 21;37(9):12423-12440. Epub 2016 Jun 21.

Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey.

Similarities and differences in the cell cycle components, apoptosis and cytoskeleton-related molecules among mouse skin fibroblast cells (MSFs), mouse squamous cell lung carcinomas (SqCLCs) and mouse embryonic stem cells (mESCs) are important determinants of the behaviour and differentiation capacity of these cells. To reveal apoptotic pathways and to examine the distribution and the role of cell cycle-cell skeleton comparatively would necessitate tumour biology and stem cell biology to be assessed together in terms of oncogenesis and embryogenesis. The primary objectives of this study are to investigate the effects of flavopiridol, a cell cycle inhibitor, and geldanamycin, a heat shock protein inhibitor on mouse somatic, tumour and embryonic stem cells, by specifically focusing on alterations in cytoskeletal proteins, cell polarity and motility as well as cell cycle regulators. To meet these objectives, expression of several genes, cell cycle analysis and immunofluorescence staining of intracellular cytoskeletal molecules were performed in untreated and flavopiridol- or geldanamycin-treated cell lines. Cytotoxicity assays showed that SqCLCs are more sensitive to flavopiridol than MSFs and mESCs. Keratin-9 and keratin-2 expressions increased dramatically whereas cell cycle regulatory genes decreased significantly in the flavopiridol-treated MSFs. Flavopiridol-treated SqCLCs displayed a slight increase in several cell cytoskeleton regulatory genes as well as cell cycle regulatory genes. However, gene expression profiles of mESCs were not affected after flavopiridol treatment except the Cdc2a. Cytotoxic concentrations of geldanamycin were close to each other for all cell lines. Cdkn1a was the most increased gene in the geldanamycin-treated MSFs. However, expression levels of cell cytoskeleton-associated genes were increased dramatically in the geldanamycin-treated SqCLCs. Our results revealing differences in molecular mechanisms between embryogenesis and carcinogenesis may prove crucial in developing novel therapeutics that specifically target cancer cells.
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http://dx.doi.org/10.1007/s13277-016-5108-9DOI Listing
September 2016

JAK/STAT pathway interacts with intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) while prostate cancer stem cells form tumor spheroids.

J BUON 2015 Sep-Oct;20(5):1250-7

Department of Stem Cell, Institute of Health Sciences, Ege University, Izmir, Turkey.

Purpose: JAK/STAT is an evolutionarily conserved pathway and very important for second messenger system. This pathway is important in malignant transformation and accumulated evidence indicates that this pathway is involved in tumorigenesis and progression of several cancers. It was possible to assume that activation of JAK/STAT pathway is associated with increase in the expressions of ICAM/1 and VCAM-1. In this study we hypothesized that when cells were maintained as spheroids or monolayers, the structure of cancer stem cells (CSCs) could show differentiation when compared with non-CSCs.

Methods: DU-145 human prostate cancer cells were cultured using the Ege University molecular embryology laboratory medium supplemented wıth 10% fetal bovine serum. Clusters of differentiation 133 (CD133)(+high)/CD44(+high) prostate CSCs were isolated from the DU145 cell line by using BD FACSAria. CD133//CD44+ CSCs were cultured until confluent with 3% noble agar. The expression of these proteins in CSCs and non-CSCs was analyzed by immunohistochemistry.

Results: Different expression profiles were observed in the conventional two-dimensional (2D) and three-dimensional (3D) experimental model system when CSCs and non-CSCs were compared. Human prostate CSCs exhibited intense ICAM-1 and VCAM-1 immunoreaction when compared with non-CSCs. These findings were supported by the fact that VCAM-1 on the surface of cancer cells binds to its counterreceptor, the α4β1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1-mediated activation of the phosphoinositide 3-kinase growth and survival pathway in cancer cells.

Conclusions: The results of this study showed that changes in JAK/STAT pathway are related with adhesion molecules and could affect cancer progression.
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January 2016

miR-15a enhances the anticancer effects of cisplatin in the resistant non-small cell lung cancer cells.

Tumour Biol 2016 Feb 28;37(2):1739-51. Epub 2015 Aug 28.

Department of Medical Biology, Ege University School of Medicine, Izmir, Turkey.

Platinum-based chemotherapies have long been used as a standard treatment in non-small cell lung cancer. However, cisplatin resistance is a major problem that restricts the use of cisplatin. Deregulated cell death mechanisms including apoptosis and autophagy could be responsible for the development of cisplatin resistance and miRNAs are the key regulators of these mechanisms. We aimed to analyse the effects of selected miRNAs in the development of cisplatin resistance and found that hsa-miR-15a-3p was one of the most significantly downregulated miRNAs conferring resistance to cisplatin in Calu1 epidermoid lung carcinoma cells. Only hsa-miR-15a-3p mimic transfection did not affect cell proliferation or cell death, though decreased cell viability was found when combined with cisplatin. We found that induced expression of hsa-miR-15a-3p via mimic transfection sensitised cisplatin-resistant cells to apoptosis and autophagy. Our results demonstrated that the apoptosis- and autophagy-inducing effects of hsa-miR-15a-3p might be due to suppression of BCL2, which exhibits a major connection with cell death mechanisms. This study provides new insights into the mechanism of cisplatin resistance due to silencing of the tumour suppressor hsa-miR-15a-3p and its possible contribution to apoptosis, autophagy and cisplatin resistance, which are the devil's triangle in determining cancer cell fate.
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http://dx.doi.org/10.1007/s13277-015-3950-9DOI Listing
February 2016

Therapeutic effect of sunitinib on diabetes mellitus related ovarian injury: an experimental rat model study.

Gynecol Endocrinol 2015 May 23;31(5):388-91. Epub 2015 Feb 23.

Physiology Department, Istanbul Bilim University School of Medicine , Istanbul , Turkey .

The aim of our study is to investigate the effect of sunitinib on diabetes mellitus related-ovarian injury and fibrosis in rat models. An experimental diabetes mellitus model was created in 16 rats, and eight rats with normal blood glucose levels were included in control group (Group-1). The diabetic rats were divided into two groups:diabetic control group (water given) - Group-2 and sunitinib treatment group - Group-3. After four weeks, bilateral oophorectomy was performed and ovaries were examined histologically. The groups were compared by Student's t-test, analysis of variance (ANOVA) and Mann-Whitney's U-test. There was a significant increase in no-medication (water given) diabetic rat's ovary (Group-2) in terms of follicular degeneration, stromal degeneration, stromal fibrosis and NF-kappaB immune-expression compared with control group normal rats' ovary (Group-1) (p < 0.0001). Stromal degeneration (p = 0.04), stromal fibrosis (p = 0.01), follicular degeneration (p = 0.02), NF-kappaB immune-expression (p = 0.001) significantly decreased in sunitinib-treated diabetic rat's ovary (Group-3) when compared with no-medication (water given) diabetic rat's ovary (Group-2) (p < 0.05). When we used sunitinib in the treatment of diabetic rats, ovarian injury, fibrosis and NF-kappaB immunoexpression decreased significantly. The effects of sunitinib in rat models give hope to the improved treatment of premature ovarian failure due to diabetes mellitus in humans.
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http://dx.doi.org/10.3109/09513590.2015.1005593DOI Listing
May 2015

Comparison of montelukast and cabergoline for prevention of ovarian hyperstimulation syndrome: in an experimental rat model.

Gynecol Endocrinol 2015 May 20;31(5):369-73. Epub 2015 Jan 20.

Department of Obstetrics and Gynecology, Ege University Medical School , Izmir , Turkey .

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication that can occur during assisted reproductive techniques. The aim of this study is to investigate the effects of the leukotriene receptor antagonist (montelukast) treatment in prevention of OHSS and compare to cabergoline treatment. Twenty-four immature female Wistar rats were assigned to four groups. Group 1 was the control group. In the remaining three groups, OHSS was induced through ovarian stimulation with gonadotropins. No treatment was given to Group 2. Group 3 was administered a low-dose 100 mg/kg cabergoline treatment and Group 4 was received 20 mg/kg montelukast. Body weight, ovarian weight, vasculary permability (VP), peritoneal fluid vascular endothelial growth factor (VEGF) values and VEGF immune-expression were compared between the groups. Both cabergoline and montelukast prevented progression of OHSS compared to the OHSS group. Body weight, ovarian weight, VP, peritoneal fluid VEGF values and VEGF expression were significantly lower in both cabergoline- and montelukast-treated rats than in those not treated OHSS group. In conclusion, montelukast is an effective option for prevention of OHSS, as well as cabergoline. Montelukast may be a new treatment option to prevent and control the OHSS.
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http://dx.doi.org/10.3109/09513590.2014.1000849DOI Listing
May 2015

The effects of mesenchymal stem cells on lymphoblastic leukemia cell proliferation.

J BUON 2014 Oct-Dec;19(4):1006-17

Department of Medical Biology, Ege University School of Medicine, Izmir, Turkey.

Purpose: Mesenchymal stem cells (MSCs) represent a new approach to the treatment of several neoplastic or non-neoplastic disorders. Their potential to repair damaged tissues through trans differentiation in conjunction with their immunomodulatory ability made them promising candidates for cell-based immunotherapy and regenerative medicine. In the present study, we aimed to determine the effects of MSCs on proliferation, apoptosis and gene expression profile of the acute lymphoblastic leukemia (ALL) cell line CCRF-CEM.

Methods: The experiments were performed after MSCs and CCRF-CEM cells were co-cultured for 72 hrs. We analyzed the gene expression patterns to predict oncogenic pathway dysregulation in the cell groups by quantitative RT-PCR and immunohistochemical staining.

Results: Cell proliferation was significantly inhibited in co-cultured CCRF-CEM cells compared to the control. Furthermore, growth factors, p53, Bax and Caspase-9 expressions were increased and cell-signaling gene expressions decreased significantly. Despite increased levels of growth factors (CTGF, VEGF, FGF, EGFR), the increased apoptosis level was triggered by p53/ Bax.

Conclusion: In this study we have shown that human MSCs have inhibitory effect on their neighboring malignant leukemia cells.
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June 2018

Ovarian failure in diabetic rat model: nuclear factor-kappaB, oxidative stress, and pentraxin-3.

Taiwan J Obstet Gynecol 2014 Dec;53(4):498-503

Physiology Department, School of Medicine, Ege University, Izmir, Turkey.

Objective: The aim of the present study was to investigate the effects of diabetes mellitus (DM) on ovarian reserve and injury by considering laboratory and histopathological parameters in rat models.

Materials And Methods: An experimental DM model was created in 16 rats. Eight rats with normal blood glucose levels were included in the control group. Diabetic rats were divided randomly into two groups: nontreated and resveratrol-treated groups. Histopathological examination and nuclear factor (NF)-κB immunoexpression level determination were performed. Plasma malondialdehyde, glutathione, pentraxin-3, and anti-Müllerian hormone levels were measured. Relations between the variables were compared by Student t test, analysis of variance, and Mann-Whitney U and χ(2) tests.

Results: We found statistically significantly lower glutathione and anti-Müllerian hormone levels, and higher malondialdehyde and pentraxin-3 levels in nontreated diabetic group when compared with the control and resveratrol-treated diabetic groups. Stromal degeneration, follicle degeneration, stromal fibrosis scores, and NF-κB immunoexpression levels were significantly higher in nontreated diabetic rats. Primordial and primary follicle counts were significantly lower in the nontreated diabetic group when compared with the control and resveratrol-treated groups. There was no statistically significant difference in secondary and tertiary follicles between these groups.

Conclusion: These findings provide strong evidence that the ovarian follicle pool in nontreated diabetic rats is affected in the early stages of the follicle development process. We precluded negative effects of DM on ovaries by inhibiting the NF-κB pathway with resveratrol. We thought that the NF-κB pathway plays a role in the pathophysiology of ovarian failure in diabetic rats. Further studies should evaluate this precise mechanism that leads to a decline in the anti-Müllerian hormone levels. In addition, the relationship between this abnormality and reproductive function in diabetic patients should be analyzed further.
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http://dx.doi.org/10.1016/j.tjog.2013.11.008DOI Listing
December 2014

Low-grade chronic inflammation induces behavioral stereotypy in rats.

Metab Brain Dis 2015 Jun 21;30(3):739-46. Epub 2014 Nov 21.

Department of Physiology, Gaziosmanpaşa University, School of Medicine, Tokat, Turkey.

Schizophrenia is known to be associated with metabolic disturbances including diabetes mellitus, obesity and cardiovascular diseases. A growing body of evidence has suggested abnormal cytokine levels in schizophrenia. In the present study, we explored the effects of low-grade chronic inflammation on behavioral stereotypy in a rat model of non-alcoholic fatty liver disease (NAFLD). In order to induce NAFLD, rats were fed with either water enriched with 30 % fructose or plain tap water for 8 weeks. Following feeding period, behavioral stereotypy was evaluated with apomorphine-induced stereotypy test. Also, levels of tumor necrosis factor alpha (TNF-α), interleukin 2 (IL-2) and nuclear factor kappa B (NF-κB) in the liver and brain tissues were assessed biochemically. Brain homovanilic acid (HVA) was measured to evaluate the dopamine turnover. NAFLD rats showed significantly higher stereotypy score compared to controls (p = 0.016). TNF-α, IL-2, and NF-κB levels were significantly increased in NAFLD rats compared to control group. Brain HVA levels were elevated in NAFLD rats as well (p = 0.008). Moreover, NAFLD group prompted a considerable increase in brain IL-2 immunoexpression (p = 0.005). In conclusion, the present study demonstrates that low-grade chronic inflammation such as NAFLD may enhance apomorphine-induced stereotypic behavior via increasing dopaminergic activity in rats.
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http://dx.doi.org/10.1007/s11011-014-9630-4DOI Listing
June 2015

Fatty liver-induced changes in stereotypic behavior in rats and effects of glucagon-like peptide-1 analog on stereotypy.

Kaohsiung J Med Sci 2014 Sep 25;30(9):447-52. Epub 2014 Jun 25.

Department of Physiology, School of Medicine, Ege University, Izmir, Turkey.

Although understanding the relation between psychotic behavior and immune abnormalities has been the focus of research for many years, it remains to be elucidated whether the changes in cytokine levels are part of etiology or a result of the stress associated with the disorder. In accordance with previous studies on changes in cytokine levels due to metabolic changes and psychosis, we hypothesized that fatty liver may potentiate apomorphine-induced stereotypy in a rodent model and that a synthetic glucagon-like peptide-1 analog exenatide would ameliorate this effect. In this study, 18 male Sprague Dawley albino mature rats were used. We induced hepatosteatosis in these rats by feeding them with 30% fructose dissolved in drinking water for 8 weeks. The animals were divided into three groups, namely, the normal group, the intracerebroventricular (ICV) exenatide group, and the ICV NaCl group. Apomorphine-induced stereotypic behavior test was performed in all groups and the liver was removed for histopathological examination after all the rats were euthanized. In the nonalcoholic fatty liver (NAFL) group, stereotypy scores were significantly increased compared with the control group rats (p < 0.00001). A significant decrease in stereotypy scores were observed in the ICV exenatide group with NAFL when compared with the ICV saline group with NAFL (p < 0.005). In addition, brain malondialdehyde and tumor necrosis factor-α levels decreased in the ICV exenatide group. The results of this study showed that fatty liver enhances the effect of apomorphine on stereotypy, which was reversed by exenatide possibly by antioxidant and anti-inflammatory effects.
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http://dx.doi.org/10.1016/j.kjms.2014.05.007DOI Listing
September 2014

Induced growth inhibition, cell cycle arrest and apoptosis in CD133+/CD44+ prostate cancer stem cells by flavopiridol.

Int J Mol Med 2014 Nov 11;34(5):1249-56. Epub 2014 Sep 11.

Ege University Faculty of Medicine, Department of Histology and Embryology, Bornova 35100, Izmir, Turkey.

Flavopiridol is a flavone that inhibits several cyclin‑dependent kinases and exhibits potent growth‑inhibitory activity, apoptosis and G1‑phase arrest in a number of human tumor cell lines. Flavopiridol is currently undergoing investigation in human clinical trials. The present study focused on the effect of flavopiridol in cell proliferation, cell cycle progression and apoptosis in prostate cancer stem cells (CSCs). Therefore, cluster of differentiation 133 (CD133)(+high)/CD44(+high) prostate CSCs were isolated from the DU145 human prostate cancer cell line. The cells were treated with flavopiridol in a dose‑ and time‑dependent manner to determine the inhibitory effect. Cell viability and proliferation were analyzed and the efficiency of flavopiridol was assessed using the sphere‑forming assay. Flavopiridol was applied to monolayer cultures of CD133(high)/CD44(high) human prostate CSCs at the following final concentrations: 100, 300, 500 and 1000 nM . The cultures were incubated for 24, 48 and 72 h. The half maximal inhibitory concentration (IC(50)) value of the drug was determined as 500 nM for monolayer cells. Dead cells were analyzed prior and subsequent to exposure to increasing flavopiridol doses. Annexin‑V and immunofluorescence analyses were performed for the evaluation of apoptotic pathways. According to the results, flavopiridol treatment caused significant growth inhibition at 500 and 1000 nM when compared to the control at 24 h. G(0)/G(1) analysis showed a statistically significant difference between 100 and 500 nM (P<0.005), 100 and 1000 nM (P<0.001), 300 and 1000 nM (P<0.001), and 500 and 1000 nM (P<0.001). Flavopiridol also significantly influenced the cells in the G(2)/M phase, particularly at high‑dose treatments. Flavopiridol induced growth inhibition and apoptosis at the IC(50) dose (500 nM), resulting in a significant increase in immunofluorescence staining of caspase‑3, caspase‑8 and p53. In conclusion, the present results indicated that flavopiridol could be a useful therapeutic agent for prostate CSCs by inhibiting tumor growth and malignant progression, and inducing apoptosis.
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http://dx.doi.org/10.3892/ijmm.2014.1930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199402PMC
November 2014

The protective effect of granulocyte colony-stimulating factor on endometrium and ovary in a rat model of diabetes mellitus.

Gynecol Obstet Invest 2014 15;78(2):94-100. Epub 2014 Jul 15.

Department of Obstetrics and Gynecology-Perinatology, Celal Bayar University School of Medicine, Manisa, Turkey.

Aims: To evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on the endometrium and ovaries in an experimental diabetes mellitus (DM) rat model.

Methods: A total of 18 female Sprague-Dawley albino mature rats (8 weeks, 200-220 g) were used in this study. Diabetes was induced by intraperitoneal (i.p.) injection of streptozocin randomly in 12 rats. No drug was administered to the remainder of the rats (control group, group 1, n = 6). The other 12 rats were randomly divided into 2 groups; 1 ml/kg i.p. saline was given as vehicle to group 2 (diabetic nontreated control group, n = 6) and 100 µg/kg/day of i.p. G-CSF was given to group 3 (G-CSF-treated group, n = 6) for 4 weeks. After 4 weeks, blood samples were collected and hysterectomy with bilateral oophorectomy was performed for histopathological examination.

Results: The mean endometrial gland degeneration and stromal fibrosis scores were significantly higher in group 2 compared with groups 1 and 3. Ovarian follicle degeneration, stromal degeneration and stromal fibrosis scores were significantly higher in group 2 compared with groups 1 and 3. Plasma TGF-β and malondialdehyde levels were significantly lower in groups 1 and 3 compared with group 2. Antimüllerian hormone levels were significantly lower in group 2 compared with groups 1 and 3.

Conclusion: Glucose toxicity occurred severely in the ovaries and endometrium of the DM rats. After G-CSF treatment, ovarian and endometrial injury and fibrosis scores decreased significantly. The effects of G-CSF in rat models give hope to improved treatment of human DM complications such as premature ovarian failure and endometrial dysfunction.
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http://dx.doi.org/10.1159/000363239DOI Listing
May 2015

High-dose atorvastatin ameliorates the uterine microenvironment in streptozotocin-induced diabetic rats.

Gynecol Endocrinol 2014 Nov 3;30(11):789-93. Epub 2014 Jul 3.

Department of Obstetrics and Gynecology .

Abstract The aim of this study was to investigate whether atorvastatin can ameliorate the uterine microenvironment in diabetes mellitus. Six non-diabetic (control) and 12 diabetic mature female Sprague-Dawley albino rats were used in this study. Diabetes was induced by intraperitoneal injections of 60 mg/kg streptozotocin, and 10 mg/kg/day of oral atorvastatin was administered for 4 weeks via orogastric tubes. The animals were euthanized, and blood samples were collected via cardiac puncture for biochemical analysis. Bilateral hysterectomy was performed for the histopathologic examination. Endometrial gland degeneration and stromal fibrosis scores concomitant with epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) immunoexpressions were analyzed. The endometrial gland degeneration scores, stromal fibrosis scores and VEGF immunoexpression was significantly lower, and the EGFR immunoexpression was significantly higher in the atorvastatin-treated diabetic rats when compared to the non-treated diabetic group, suggesting that atorvastatin ameliorates the uterine microenvironment in diabetes mellitus.
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http://dx.doi.org/10.3109/09513590.2014.929657DOI Listing
November 2014

Detection of impaired cognitive function in rat with hepatosteatosis model and improving effect of GLP-1 analogs (exenatide) on cognitive function in hepatosteatosis.

ScientificWorldJournal 2014 11;2014:946265. Epub 2014 Mar 11.

Department of Physiology, School of Medicine, Ege University, Izmir, Turkey.

The aims of the study were to evaluate (1) detection of cognitive function changing in rat with hepatosteatosis model and (2) evaluate the effect of GLP-1 analog (exenatide) on cognitive function in hepatosteatosis. In the study group, 30% fructose was given in nutrition water to perform hepatosteatosis for 8 weeks to 18 male rats. Six male rats were chosen as control group and had normal nutrition. Fructose nutrition group were stratified into 3 groups. In first group (n = 6), intracerebroventricular (ICV) infusion of exenatide (n = 6) was given. ICV infusion of NaCl (n = 6) was given to second group. And also, the third group had no treatment. And also, rats were evaluated for passive avoidance learning (PAL) and liver histopathology. Mean levels of latency time were statistically significantly decreased in rats with hepatosteatosis than those of normal rats (P < 0.00001). However, mean level of latency time in rats with hepatosteatosis treated with ICV exenatide was statistically significantly increased than that of rats treated with ICV NaCl (P < 0.001). Memory performance falls off in rats with hepatosteatosis feeding on fructose (decreased latency time). However, GLP-1 ameliorates cognitive functions (increased latency time) in rats with hepatosteatosis and releated metabolic syndrome.
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http://dx.doi.org/10.1155/2014/946265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967460PMC
December 2014

Capsaicin induced apoptosis and gene expression dysregulation of human acute lymphoblastic leukemia CCRF-CEM cells.

J BUON 2014 Jan-Mar;19(1):183-90

Department of Medical Biology, Ege University School of Medicine, Izmir, Turkey.

Purpose: Capsaicin, an ingredient of red chili pepper, has possible tumorigenicity/genotoxicity properties. We aimed to determine the effects of capsaicin on the proliferation and gene expression profiles of acute lymphoblastic leukemia (ALL) CCRF-CEM cell line.

Methods: Cell viability and IC50 dose was determined by WST cytotoxicity assay. qRT-PCR, immunohistochemical staining and western blot methods were used to determine target genes' expression levels. Apoptosis was evaluated by measuring the caspase-3 activity.

Results: Capsaicin inhibited the proliferation of CCRFCEM cells in a dose-dependent manner. Increased mRNA expressions of caspase gene family members, activated caspase-3 and decreased mRNA and protein expression of BCL-2 gene indicated apoptotic response to capsaicin. Moreover capsaicin treatment suppressed significantly the expression of the key cell signaling pathways of KRAS, AKT, GAB2, PTPN11, BRAF, INPP5D, MAPK7.

Conclusion: Capsaicin induces apoptosis in CCRF-CEM cells and this response is associated with downregulation of cell signaling pathways.
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May 2014

Comparison of skin effects of immediate treatment modalities in experimentally induced hydrofluoric acid skin burns.

Int Wound J 2015 Dec 29;12(6):716-23. Epub 2014 Jan 29.

Department of Plastic Surgery, Ege University, Izmir, Turkey.

Hydrofluoric acid (HF) burns cause immediate damage and painful long-term sequellae. Traditionally, chelating agents have been used as the initial treatment for such burns. We have introduced epidermal growth factor (EGF) into an HF model to compare EGF with Ca(2+) and Mg(2+) treatments; 40 Sprague Dawley rats were divided into five groups. Each rat suffered a 6 × 4 cm(2) burn induced by 40% HF. Group 1 had no treatment, group 2 had saline injected beneath the burn, group 3 received magnesium sulphate injections, group 4 received calcium gluconate and group 5 received EGF. Specimens were evaluated via planimetry and biopsy at intervals of 4, 8, 24 and 72 hours. Fluid losses were significantly less in the Mg(2+) and EGF groups. The EGF group had the smallest burn area, least oedema, least polymorphonuclear granulocyte (PMN) infiltration, most angiogenesis and highest fibroblast proliferation of any group (P < 0·005). EGF limited HF damage morphologically and histologically more effectively than Ca(2+) or Mg(2+). This finding indicates that HF treatment via growth factors may be an improvement over chelation therapy.
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http://dx.doi.org/10.1111/iwj.12214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950442PMC
December 2015

Effect of oxytocin treatment on explant size, plasma and peritoneal levels of MCP-1, VEGF, TNF-α and histopathological parameters in a rat endometriosis model.

Eur J Obstet Gynecol Reprod Biol 2014 Apr 3;175:134-9. Epub 2014 Jan 3.

Department of Obstetrics and Gynecology, Ege University, Bornova, Izmir, Turkey.

Objective: To determine the effects of oxytocin (OT) on surgically induced endometriosis in a rat model.

Study Design: Twelve female Sprague-Dawley rats were included. After the implantation and establishment of autologous endometrium onto the abdominal wall peritoneum, the rats were randomly divided into two groups, treated with intramuscular oxytocin (OT group, 160μgkg/day, n=6) or isotonic NaCl solution (control group, 1mLkg/day, n=6) for 28 days. To evaluate the therapeutic effects of OT, the explant volumes were calculated and the levels of vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1, and TNF-α were measured in plasma and peritoneal fluid. Endometriotic explants were examined histologically by semiquantitative analysis.

Results: After treatment, the mean endometriotic explant volume was decreased in the OT group (p=0.016). The histopathological score and VEGF immunoexpression of endometriotic explants were significantly lower in the OT group (p=0.007) than in controls (p=0.000). Inflammatory cytokine levels in plasma and peritoneal fluid were considerably decreased in the OT group. Moreover, TUNEL immunohistochemistry clearly demonstrated more apoptotic changes in the mononuclear cells of the OT group compared with controls.

Conclusion: We suggest that oxytocin might be considered as a potential candidate therapeutic agent for endometriosis.
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http://dx.doi.org/10.1016/j.ejogrb.2013.12.034DOI Listing
April 2014
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