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Article Citation - WoS: 3Citation - Scopus: 5Investigation of the Effect of Hyperthyroidism on Endoplasmic Reticulum Stress and Transient Receptor Potential Canonical 1 Channel in the Kidney(Tubitak Scientific & Technological Research Council Turkey, 2021) Aykanat, Nuriye Ezgi Bektur; Şahin, Erhan; Kaçar, Sedat; Bağcı, Rıdvan; Karakaya, Şerife; Dönmez, Dilek Burukoğlu; Şahintürk, Varol; Bektur Aykanat, Nuriye Ezgi; Burukoğlu Dönmez, Dilek; Bektur, EzgiBackground/aim: Hyperthyroidism is associated with results in increased glomerular filtration rate as well as increased renin-angiotensin-aldosterone activation. The disturbance of Ca2+ homeostasis in the endoplasmic reticulum (ER) is associated with many diseases, including diabetic nephropathy and hyperthyroidism. Transient receptor potential canonical 1 (TRPC1) channel is the first cloned TRPC family protein. Although it is expressed in many places in the kidney, its function is uncertain. TRPC1 is involved in regulating Ca2+ homeostasis, and its upregulation increases ER Ca2+ level, activates the unfolded protein response, which leads to cellular damage in the kidney. This study investigated the role of TRPC1 in the kidneys of hyperthyroid rats in terms of ER stress markers that are glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), (protein kinase R (PKR)-like endoplasmic reticulum kinase) (PERK), Inositol-requiring enzyme 1 (IRE1). Materials and methods: Twenty male rats were assigned into control and hyperthyroid groups (n = 10). Hyperthyroidism was induced by adding 12 mg/L thyroxine into the drinking water of rats for 4 weeks. The serum-free T3 and T4 (fT3, fT4), TSH, blood urea nitrogen (BUN), and creatinine levels were measured. The histochemical analysis of kidney sections for morphological changes and also immunohistochemical and western blot analysis of kidney sections were performed for GRP78, ATF6, PERK, IRE1, TRPC1 antibodies. Results: TSH, BUN, and creatinine levels decreased while fT3 and fT4 levels increased in the hyperthyroid rat. The morphologic analysis resulted in the capillary basal membrane thickening in glomeruli and also western blot, and immunohistochemical results showed an increase in TRPC1, GRP78, and ATF6 in the hyperthyroid rat (p < 0.05). Conclusion: In conclusion, in our study, we showed for the first time that the relationship between ER stress and TRPC1, and their increased expression caused renal damage in hyperthyroid rats.Key words: Hyperthyroidism, endoplasmic reticulum (ER) stress, transient receptor potential canonical 1 (TRPC1), kidney, ratPublication Article Deneysel Tip 1 Diabetes Mellitusta Aralıklı Hipoksinin Kardiyak Kas Kalsiyum Homeostazisine Etkisi(2019) Dursun, Alı Dogan; Tekin, Demet; Bastug, Metın; Tanyeli, Ayhan; Erdoğan, Derya Güzel; Akat, Fırat; Ficicilar, HakanAmaç Bu çalışmada; Deneysel diyabetik kardiyomiyopatide aralıklı hipoksinin kardiyak fosfolamban ve Ca+2- kalmodulin bağımlı protein kinaz II (CaMKII) düzeylerine etkisiaraştırıldı. ( Sakarya Tıp Dergisi 2019, 9(3):536-543 ) Gereç veYöntemler Wistar albino erkek sıçanlar (n = 34) dört gruba randomize edildi: kontrol (C), aralıklı hipoksi (AH), diabetes mellitus (DM) ve diabetes mellitus + aralıklı hipoksi (DM +AH). Streptozotosin (50 mg/kg, i.p.) uygulandı ve 250 mg/dL ve üzeri kan glukoz seviyeleri diabetes mellitus olarak kabul edildi. AH ve DM+ AH grupları, 3000 m yüksekliğekarşılık gelen bir basınçta 42 gün boyunca 6 saat/ gün hipoksiye tabi tutuldu. Değerlendirmede, Kruskal Wallis testi, çoklu karşılaştırma testleri ve Wilcoxon testleri kullanıldı. Bulgular Diyabetteki kilo kaybını göstermek ve ratların metabolik sağlık durumlarının takibi için rutin olarak ratlar tartıldı. AH grubundaki ağırlık artışı en fazla idi ve DM grubuen azdı. C ve DM (p= 0.003), C- DM + AH (p= 0.024), AH- DM (p= 0.001), AH- DM+ IH (p= 0.006) arasındaki farklar istatistiksel olarak anlamlı bulundu. Fosfolamban/gliseraldehit-3 fosfat dehidrogenaz (PLB/ GAPDH) grupları arasında anlamlı bir fark bulunamamıştır (p= 0.294). CaMKII/ GAPDH açısından, C ve DM; C ve DM+ AH ileAH ve DM+ AH grupları arasında istatistiksel olarak anlamlı bir fark bulundu (p <0.05). Sonuç CaMKII mRNA düzeylerinin DM ve DM+IH gruplarında azaldığı bulundu. Bununla birlikte, fosfolambanda değişiklik tespit edilmemiştir, ancak fosfolambanda meydanagelecek değişiklikler translasyon ve/veya posttranslasyonal seviyelerin etkilerinde ve protein seviyelerinde ve/ veya aktivasyonlarında meydana gelebilecek değişikliklerdeönemlidir.Article Neuron Modeling: Estimating the Parameters of a Neuron Model From Neural Spiking Data(Tubitak Scientific & Technological Research Council Turkey, 2018) Doruk, Resat Ozgur; Doruk, OzgurWe present a modeling study aiming at the estimation of the parameters of a single neuron model from neural spiking data. The model receives a stimulus as input and provides the firing rate of the neuron as output. The neural spiking data will be obtained from point process simulation. The resultant data will be used in parameter estimation based on the inhomogeneous Poisson maximum likelihood method. The model will be stimulated by various forms of stimuli, which are modeled by a Fourier series (FS), exponential functions, and radial basis functions (RBFs). Tabulated results presenting cases with different sample sizes (# of repeated trials), stimulus component sizes (FS and RBF), amplitudes, and frequency ranges (FS) will be presented to validate the approach and provide a means of comparison. The results showed that regardless of the stimulus type, the most effective parameter on the estimation performance appears to be the sample size. In addition, the lowest variance of the estimates is obtained when a Fourier series stimulus is applied in the estimation.Article Fitting a Recurrent Dynamical Neural Network To Neural Spiking Data: Tackling the Sigmoidal Gain Function Issues(Tubitak Scientific & Technological Research Council Turkey, 2019) Doruk, Reşat ÖzgürThis is a continuation of a recent study (Doruk RO, Zhang K. Fitting of dynamic recurrent neural networkmodels to sensory stimulus-response data. J Biol Phys 2018; 44: 449-469), where a continuous time dynamical recurrentneural network is fitted to neural spiking data. In this research, we address the issues arising from the inclusion ofsigmoidal gain function parameters to the estimation algorithm. The neural spiking data will be obtained from the samemodel as that of Doruk and Zhang, but we propose a different model for identification. This will also be a continuoustime recurrent neural network, but with generic sigmoidal gains. The simulation framework and estimation algorithmsare kept similar to that of Doruk and Zhang so that we can have a solid base to compare the results. We evaluatethe estimation performance in two different ways. First, we compare the firing rate responses of the original and theestimated model. We find that responses of both models to the same stimuli are similar. Secondly, we evaluate variationsof the standard deviations of the estimates against a number of samples and stimulus parameters. They show a similarpattern to that of Doruk and Zhang. We thus conclude that our model serves as a reasonable alternative provided thatfiring rate is the response of interest (to any stimulus).Article Romatizmal Mitral Kapak Hastalığında Yeni Yolak: Sitokrom P450 ve Glutatyon S Transferaz İzozim Ekspresyonu(Walter de Gruyter Gmbh, 2020) Şimşek, Erdal; Şimşek, Gülçin; Sayol, Mehmet Fazıl Tolga; Kaygın, Pınar; Oğuztüzün, Serpil; Düzgün, Ali Cemal; Kaplan, Sadi; Sarialtin, Sezen; Soyal, Mehmet Fazil TolgaAmaç: Romatizmal mitral kapak hastalığı ve iskemik mitral kapak yetmezlikli hastalarda Sitokrom P450 (CYP)1A1, glutatyon S-transferaz pi (GSTP1) ve omega (GSTO1) izozimleri karşılaştırılarak, romatizmal mitral kapak hastalığı ile oksidatif stres arasındaki ilişki araştırıldı. Gereç ve Yöntem: Kontrol grubunu, iskemik mitral kapak yetmezliği sebebiyle ameliyat edilen (group I, n:14), çalışma grubunu ise romatizmal mitral kapak hastalığı nedeni ile ameliyat edilen (group II, n:29) hastalar oluşturmuştur. Mitral kapak materyalleri hematoksilen ve eozinle boyandı. CYP1A1, GSTP1, ve GSTO1 immünohistokimyasal belirteçler ile çalışıldı. Bulgular: Çalışma grubunda %20.7 GSTP1 isozim protein ekspresyonu gözlendi; fakat kontrol grubunda ekspresyon izlenmedi. Bu bulgu GSTP1 izozim açısından istatistiksel olarak önemli bulundu. Çalışma ve kontrol grupları arasında GSTO1 ve CYP1A1 protein ekspresyonları açısından istatistiksel anlamlı farklılık görülmedi. Sonuç: Bu çalışmada GSTP1 izozimi romatizmal mitral kapak hastalığı ile ilişkili olabileceği görüldü. Romatizmal mitral kapak hastalığı olan hastalarda oksidatif stresi önleyen strateji, hastalığın ilerleyişini engellemek için çok değerli bir seçim olabilir.Article Alzheimer Hastalığında Kallikrein-6, 7 ve Potasyum Kanal Proteinlerinin Olası Rolü(2021) Bulduk, Erkut Baha; Yıldırım, Zuhal; Yıldırım, FilizObjective: Although the formation mechanism of Alzheimer’s Disease (AD) is not known with certainty, two major proteins, beta amyloid of senile plaques and tau protein of neurofibrillary tangels are responsible for AD. One of the major factors in the development of the disease is the formation of in soluble amyloid deposits, and the other one is the increased tau phosphorylation. Kallikreins (KLK’s) are a sub-family of serine proteases that play a role in the etiology of AD which is characterized by neuronal damage and loss of function.Kallikrein (KLK)-6 and KLK-7 are known to be age-related protease and are found at high levels in the central nervous system (CNS). It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as AD. In this study, we aimed to investigate the possible role of KLK-6 and KLK-7 in the pathogenesis of AD and the relationship between potassium channel proteins. Methods: A total of 35 Alzheimer’s patients over the age 65 years, followed-up by Polatlı Duatepe Government Hospital and 35 healthy individuals (control group) admitted to the neurology clinic for routine screening with cognitive status considered normal were included in this study. After a 12-hour hunger, KLK-6 and KLK-7 were measured with inwardly rectifying potassium channel protein (KCNJ3), and two-pore potassium channel protein (KCNK9) levels were measured by the Enzyme-Linked Immuno Sorbent Assay (ELISA) in the serum of the blood samples which were taken from the antecubital vein after centrifuging for 10 minutes at 2500xg. The differences between the two groups were tested by T- test. A value of p<0.05 was considered statistically significant. Results: All the groups were matched for age and gender, but not statistically significant difference was observed (p>0.05). According to our findings, serum KLK- 6 and KLK-7 levels of Alzheimer’s group were significantly increased (p<0.05). A significant difference was not detected when the levels of serum KCNJ3 and KCNK9 of the Alzheimer’s group compared with the control group (p>0.05). Conclusion: It is thought that the failure in preventing the abnormal protein folding and accumulation leads to AD in the brain. According to the findings of the present study, a positive correlation was detected between the levels of KLK-6 and KLK-7 and AD’s pathology.Article Citation - WoS: 13Citation - Scopus: 13Association between monocyte to high-density lipoprotein cholesterol ratio and bicuspid\raortic valve degeneration(Tubitak Scientific & Technological Research Council Turkey, 2020) Karaduman, Bilge Duran; Ayhan, Hüseyin; Keles, Telat; Bozkurt, Engin; Duran Karaduman, BilgeBackground/aim: From a pathophysiological point of view, inflammation is thought to be more dominant in bicuspid aortic valve\r(BAV) stenosis than tricuspid aortic valve (TAV) stenosis. Our study aimed to determine the association between monocyte to highdensity lipoprotein cholesterol (HDL-C) ratio (MHR), a new inflammatory marker, and the speed of progression of stenosis and\rpathophysiology of BAV stenosis.\rMaterials and methods: A total of 210 severe aortic stenosis patients (70 consecutive BAV patients, 140 matched TAV patients) were\rretrospectively enrolled in the study. Clinical and echocardiographic data and laboratory results related to our research were collected\rretrospectively from the patients’ records. MHR was measured as the ratio of the absolute monocyte count to the HDL-C value.\rResults: Seventy BAV (mean age: 72.0 ± 9.1 years, 42.9% female) and 140 TAV patients (mean age: 77.9 ± 8.3 years, 51.4% female)\rwith severe aortic stenosis were enrolled in this study. There was no difference between the two groups in terms of another baseline\rdemographic or clinic findings except age (P < 0.001). Monocyte count, hemoglobin level, mean platelet volume was significantly\rhigher, and HDL-C level was significantly lower in the BAV group, while other lipid and CBC parameters were found to be similar. In\rthe multivariate analysis, MHR (P = 0.005, 95% CI: 0.90–0.98) and, as expected, age (P = 0.001, 95% CI: 1.02–1.11) were found to be\rsignificant as the independent predictor of BAV, after adjusting for other risk factors.\rConclusion: Our study showed a significant correlation between increased MHR and BAV. MHR was determined as a significant\rindependent predictor for the speed of progression and diagnosis of severe BAV stenosis in multivariate analysis.Article Silimarin Slıt2 Proteinini Aktive Ederek ve Cxcr4 Ekspresyonunu Baskılayarak A549 Hücrelerini İnhibe Etti(2021) Kaçar, Sedat; Aykanat, Nuriye Ezgi Bektur; Bektur, EzgiAkciğer kanseri, dünya çapında hem erkeklerde hem de kadınlarda kansere bağlı önde gelen ölüm nedenlerindendir. SLIT2/ROBO1 sinyali, çeşitli kanser tiplerini inhibe ettiği bildirilen çok önemli bir yolaktır. CXCR4, kanser ilerlemesinde rol oynayan bir kemokin reseptörüdür. Silimarin, başta karaciğer hastalıkları olmak üzere akciğer kanseri de dahil çeşitli kanserlerde anti-kanserojen aktivitesi öne sürülen bir fitokimyasaldır. Ancak silimarinin akciğer kanserinde SLIT2–ROBO1–CXCR4 ekseni üzerindeki etkisini inceleyen çalışma bulunmamaktadır. Burada amacımız silimarinin A549 hücreleri üzerindeki sitotoksik ve morfolojik etkilerini araştırmak ve SLIT2-ROBO1-CXCR4 yolağındaki rolünü ortaya çıkarmaktır. İlk olarak, silimarinin doz analizi için 24, 48 ve 72 saat uzunluğunda sitotoksisite testleri yapıldı. Ardından değişen dozlarda silimarin ile morfolojik değerlendirme için hücreler H-E ile boyandı. Daha sonra SLIT2, ROBO1 ve CXCR4 proteinleri için western blot ve immünositokimya analizleri yapıldı. MTT analizine göre, A549 hücrelerine karşı silimarinin IC50 konsantrasyonları 24, 48 ve 72 saatlik uygulamaları için sırasıyla 930.1, 432.1 ve 99.8 μM olarak saptandı. H-E boyama yapılarak morfolojik olarak incelendiğinde sitoplazmik vakuoller, küçülmüş heterokromatin çekirdek ve bazofilik sitoplazmalı hücreler gözlendi. 750 μM silimarin ile SLIT2, ROBO1 ve CXCR4 proteinleri için Western blot ve immünositokimya analizleri yapıldı. 750 μM silimarin, kontrol grubuna kıyasla SLIT2 ve ROBO1 ekspresyonlarını arttırırken CXCR4'ü azalttı. Sonuç olarak silimarin, SLIT2 ve ROBO1 protein ekspresyonunu aktive ederek ve CXCR4 ekspresyonunu inhibe ederek A549 hücrelerini doza bağlı olarak inhibe etmiştir. Silimarinin akciğer kanseri üzerindeki etkileri literatürde belirtilmiştir. Ancak bu çalışma, A549 hücrelerinde SLIT2–ROBO1–CXCR4 proteinleri ile silimarin arasındaki etkileşimi inceleyen ilk çalışmadır. Çalışmamızın bundan sonraki araştırmalara yeni ufuklar açacağına inanıyoruz.Article Citation - WoS: 1Citation - Scopus: 2Cannabinoid Receptor Ligands Modulate Fibrosis and Inflammation in Idiopathic Pulmonary Fibrosis: a Preliminary Study(Tubitak Scientific & Technological Research Council Turkey, 2024) Kose, Sevil; Onen, Selin; Gizer, Merve; Boduroglu, Esin; Gonullu, Ugur; Korkusuz, PetekBackground/aim: No specific pharmacological treatment regimen for idiopathic pulmonary fibrosis (IPF) exists. Therefore, new antiinflammatory therapeutic strategies are needed. Cannabinoids (CBs), known for their inflammation-modulating and antifibrotic effects, may be potential medication candidates for treating IPF. We aim to evaluate the inflammation-modulating and antifibrotic effects of CB receptor (CBR) agonists and antagonists in lipopolysaccharide-stimulated normal human lung fibroblast, epithelial cells, IPF fibroblast cells, and monocytes. Materials and methods: We detected CBRs in normal human lung fibroblasts (LL24) and IPF fibroblast cells (LL29), epithelial cells (A549) and monocytes (THP-1) by flow cytometry. We determined TGF-(31, IL-8, and TNF-alpha inflammatory cytokines in the LL24, LL29, A549, and THP-1 cell culture supernatants on days 1 and 5 by ELISA. We evaluated the cell viability in LL24, LL29, and A549 cells on days 1, 3, and 5 spectrophotometrically and detected collagen Type I (ColI) production in the LL24 and LL29 cell culture supernatants on days 1, 3, and 5 by ELISA. Results: LL24, LL29, A549, and THP-1 cells exhibited CB1 (CB1R) and CB2 (CB2R) receptors. CB1R and CB2R agonists WIN55,2122 and JWH015 inhibited fibroblastic and epithelial cell proliferation on day 5. TGF-(31 and TNF-alpha release increased, while IL-8 release decreased in LL24, LL29, A549, and THP-1 cells in response to the administration of WIN55,212-2 and JWH015 at a 10-2 mM concentration. CB1R and CB2R antagonists AM251 and AM630 did not block agonistic responses, suggesting a nonclassical CBRmediated pathway. CB2R agonist JWH015 decreased ColI expression in IPF lung fibroblasts LL29 on day 3. Conclusion: These results suggest that CB signaling regulates the progression of pulmonary inflammation and fibrosis via CBR activation. This may offer a potential pharmacological tool for developing antifibrosis therapies.
