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Item Anti-Inflammatory Effects of Melatonin in Rats with Induced Type 2 Diabetes Mellitus(MDPI, 2022-01-01) Yapislar, Hande; Haciosmanoglu, Ebru; Sarioglu, Turkan; Degirmencioglu, Sevgin; Sogut, Ibrahim; Poteser, Michael; Ekmekcioglu, CemIntroduction: Insulin resistance is associated with a pro-inflammatory state increasing the risk for complications in patients with type 2 diabetes mellitus (T2DM). In addition to its chronobiotic effects, the pineal hormone melatonin is known to exert anti-inflammatory and antioxidant effects. Melatonin was also suggested to affect insulin secretion. The aim of this study was therefore to investigate the effect of melatonin on inflammation in diabetic rats and to study the possible involvement of the melatonin receptor, MT2. Materials and Methods: Male Sprague Dawley rats were randomly divided into four experimental groups (n = 10 per group): (1) control, (2) streptozotocin/nicotinamide induced diabetes type 2 (T2DM), (3) T2DM treated with melatonin (500 mu g/kg/day), and (4) T2DM treated with melatonin (500 mu g/kg/day for 6 weeks) and the selective MT2 receptor antagonist luzindole (0.25 g/kg/day for 6 weeks). Blood samples were taken for biochemical parameters and various tissue samples (liver, adipose tissue, brain) were removed for immunohistochemistry (IHC), Western blot (WB), and Q-PCR analyses, respectively. Results: Melatonin significantly reduced increased blood levels of liver transaminases (AST, ALT), blood urea nitrogen (BUN), triglyceride, very low-density lipoprotein (VLDL), and cholesterol in diabetic rats with luzindole treatment partly reversing this effect regarding the lipids. Furthermore, the liver and adipose tissues of T2DM rats treated with melatonin showed lower expression of the inflammatory markers IL-1 beta, IL-6, TNF-alpha, and NF-kappa B as compared to the T2DM group without melatonin. The results also showed that the MT2 receptor is at least partly involved in the protective effects of melatonin. Conclusions: Our results suggest that melatonin exerts relevant anti-inflammatory effects on various tissues in type 2 diabetic rats.Item Evaluation of plasma antimicrobial peptide LL-37 and nuclear factor-kappaB levels in stable chronic obstructive pulmonary disease(DOVE MEDICAL PRESS LTD, 2019-01-01) Uysal, Pelin; Simsek, Gonul; Durmus, Sinem; Sozer, Volkan; Aksan, Hulya; Yurt, Sibel; Cuhadaroglu, Caglar; Kosar, Filiz; Gelisgen, Remise; Uzun, HafizeBackground: Antimicrobial peptides are effectors of host defence against infection and inflammation and can encourage wound repair. Objectives: The objectives of this study were to investigate the plasma antimicrobial peptide LL-37 and nuclear factor-kappaB (NF-kappa B) levels in patients with stable COPD compared with a control group and to highlight their importance in immune inflammation. Methods: One hundred and thirty-eight stable COPD patients and 33 control subjects were enrolled in the study. The COPD patients were classified into four groups based on FEV1 (groups I-IV) and also divided into ``low-risk and high-risk{''} groups (groups A-B {[}low risk], C-D {[}high risk]). Results: Plasma LL-37 levels were significantly lower while plasma NF-kappa B levels of the COPD patients were significantly higher than those of the control subjects (P<0.001, both). LL-37 levels were significantly lower in group IV than in groups I, II, and III (P<0.01, all). NF-kappa B levels were significantly higher in groups III and IV than in groups I and II (P<0.05, both). There was a positive correlation between FEV1 and FEV1/FVC in all COPD patients (r=0.742, P<0.001) and in group D (r=0.741, P<0.001). Furthermore, there was an inverse correlation between LL-37 and NF-kappa B in both the groups C (r=-0.566, P<0.001) and D (r=-0.694, P<0.001) and group C+ D combined (r=-0.593, P<0.001). Furthermore, in group C, LL-37 and FEV1 were positively correlated (r=0.633, P<0.001). Conclusion: Our study indicated that plasma LL-37 and NF-kappa B may play an important role in chronic immune inflammation. Decreased LL-37 levels may be particularly high risk for patients in stage IV disease. The role of LL-37 as a target for treatment of the immune system and COPD must be widely evaluated.Item Inhibition of alveolar Na transport and LPS causes hypoxemia and pulmonary arterial vasoconstriction in ventilated rats(WILEY, 2016-01-01) Davieds, Bodo; Gross, Julian; Berger, Marc M.; Baloglu, Emel; Baertsch, Peter; Mairbaeurl, HeimoOxygen diffusion across the alveolar wall is compromised by low alveolar oxygen but also by pulmonary edema, and leads to hypoxemia and hypoxic pulmonary vasoconstriction (HPV). To test, whether inhibition of alveolar fluid reabsorption results in an increased pulmonary arterial pressure and whether this effect enhances HPV, we established a model, where anesthetized rats were ventilated with normoxic (21\% O-2) and hypoxic (13.5\% O-2) gas received aerosolized amiloride and lipopolisaccharide (LPS) to inhibit alveolar fluid reabsorption. Right ventricular systolic pressure (RVsP) was measured as an indicator of pulmonary arterial pressure. Oxygen pressure (PaO2) and saturation (SaO(2)) in femoral arterial blood served as indicator of oxygen diffusion across the alveolar wall. Aerosolized amiloride and bacterial LPS decreased PaO2 and SaO(2) and increased RVsP even when animals were ventilated with normoxic gas. Ventilation with hypoxic gas decreased PaO2 by 35 mmHg and increased RVsP by 10 mmHg. However, combining hypoxia with amiloride and LPS did not aggravate the decrease in PaO2 and SaO(2) and had no effect on the increase in RVsP relative to hypoxia alone. There was a direct relation between SaO(2) and PaO2 and the RVsP under all experimental conditions. Two hours but not 1 h exposure to aerosolized amiloride and LPS in normoxia as well as hypoxia increased the lung wet-to-dry-weight ratio indicating edema formation. Together these findings indicate that inhibition of alveolar reabsorption causes pulmonary edema, impairs oxygen diffusion across the alveolar wall, and leads to an increased pulmonary arterial pressure.Item Hypoxia Aggravates Inhibition of Alveolar Epithelial Na-Transport by Lipopolysaccharide-Stimulation of Alveolar Macrophages(MDPI, 2022-01-01) Baloglu, Emel; Velineni, Kalpana; Ermis-Kaya, Ezgi; Mairbaeurl, HeimoInflammation and hypoxia impair alveolar barrier tightness, inhibit Na- and fluid reabsorption, and cause edema. We tested whether stimulated alveolar macrophages affect alveolar Na-transport and whether hypoxia aggravates the effects of inflammation, and tested for involved signaling pathways. Primary rat alveolar type II cells (rA2) were co-cultured with rat alveolar macrophages (NR8383) or treated with NR8383-conditioned media after stimulation with lipopolysaccharide (LPSItem The Evaluation of Endothelin-1 and Endothelin Receptor Type A Gene Polymorphisms in Patients with Vitiligo(WOLTERS KLUWER MEDKNOW PUBLICATIONS, 2016-01-01) Bingul, Ilknur; Aydingoz, Ikbal Esen; Vural, Pervin; Dogru-Abbasoglu, Semra; Uysal, MujdatBackground: Endothelin-1 (EDNi) and EDN receptor type A (EDNRA) are implicated in melanocyte functions. Aim and Objectives: This study examines the role of EDN1 (G5665T and T-1370G) and EDNRA (C + 70G and G-231A) polymorphisms as a risk factor for vitiligo, and evaluates the relationship between genotypes and clinical characteristics of vitiligo patients. Materials and Methods: We analyzed genotype/alele distributions of EDN1 and EDNRA polymorphisms in 100 patients with vitiligo and 185 healthy controls by real-time polymerase chain reaction. Results: There was no notable risk for vitiligo afflicted by studied polymorphisms. However, the presence of EDNRA + 70 variant G allele was found to be related with decreased risk for development of generalized type of vitiligo (odds ratio {[}OR]: 0.42, 95\% confidence interval {[}CI] = 0.21-0.86, Por = 0.03) and showed protective effect against associated diseases seen in vitiligo (OR: 0.49, 95\% CI = 0.27-0.88, p(corr) = 0.034). Haplotype analysis demonstrated a strong (disequilibrium coefficient = 0.73, r(2) = 0.405) linkage disequilibrium between EDN1 G5665T and T-1370G polymorphisms. The EDN1 5665/-1330 TT haplotype was over represented significantly in controls than in patients (P = 0.04). Conclusion: The studied polymorphisms do not seem to be a major risk for vitiligo. Haplotype analysis denoting protective effects against vitiligo may indicate an indirect interaction in the course of vitiligo. In addition, EDNRA + 70 polymorphism is protective against generalized type of vitiligo and associated diseases.Item The modulatory action of C-Vx substance on the immune system in COVID-19(TAYLOR \& FRANCIS LTD, 2022-01-01) Tahrali, Ilhan; Akdeniz, Nilgun; Yilmaz, Vuslat; Kucuksezer, Umut C.; Oktelik, Fatma B.; Ozdemir, Ozkan; Cetin-Aktas, Esin; Ogutmen, Yelda; Ergen, Arzu; Abaci, Neslihan; Tuzun, Erdem; Oncul, Oral; Deniz, GunnurThe modulatory effect of C-Vx, a novel therapeutic agent, on the immune system of COVID-19 patients was investigated. The functions of T and NK cells of COVID-19 patients with different disease severity were evaluated by flow cytometry in response to C-Vx stimulation. The levels of pro- and anti-inflammatory cytokines were detected by multiplex assay in supernatants after cell culture with C-Vx. Bradykinin, IRF3, and IFN-alpha levels were also measured by ELISA in the presence or absence of C-Vx stimulation. As a result, increased CD107a expression was observed on NK cells in response to C-Vx addition. The proliferation of T cell subsets was increased by C-Vx, decreasing by disease severity. IL-4 and IL-10 levels were elevated while IFN-gamma and IL-17 levels were reduced in T cells following C-Vx stimulation. However, the levels of pro-inflammatory IL-1 beta, IL-6, IL-8, IFN-gamma and GM-CSF were significantly increased upon C-Vx stimulation. IFN-alpha levels tended to increase after incubation with C-Vx. These findings support an immunomodulatory action of C-Vx on the immune system of patients with a mild and moderate phase of COVID-19.Item VITAMIN D DEFICIENCY DID NOT AUGMENT THE PROGRESSION OF HIGH-FRUCTOSE-INDUCED NONALCOHOLIC FATTY LIVER DISEASE IN RATS(ISTANBUL UNIV, FAC MEDICINE, PUBL OFF, 2021-01-01) Bingul, Ilknur; Kucukgergin, Canan; Aydin, Abdurrahman Fatih; Ekici, Isin Dogan; Abbasoglu, Semra Dogru; Uysal, MujdatObjective: Vitamin D has antioxidant, anti-inflammatory and antiglycation activities, and hepatoprotective potential. There is a relationship between vitamin D deficiency (VDD) and the severity of liver disorders. VDD has been proposed to contribute to the progression of nonalcoholic fatty liver disease (NAFLD). However, experimental results are not clear. Therefore, in this study, the effects of a VDD diet on high fructose (HFr) drinking-induced NAFLD was evaluated. Material and Method: Male Wistar rats were divided into four groups as control, HFr, VDD+HFr, and VDD. Control and HFr groups were fed a control diet, and other groups with a VDD-diet for 12 weeks. HFr (30\%Item Transcriptomics and Proteomics Analyses Reveal JAK Signaling and Inflammatory Phenotypes during Cellular Senescence in Blind Mole Rats: The Reflections of Superior Biology(MDPI, 2022-01-01) Inci, Nurcan; Akyildiz, Erdogan Oguzhan; Bulbul, Abdullah Alper; Turanli, Eda Tahir; Akgun, Emel; Baykal, Ahmet Tarik; Colak, Faruk; Bozaykut, PerinurThe blind mole rat (BMR), a long-living subterranean rodent, is an exceptional model for both aging and cancer research since they do not display age-related phenotypes or tumor formation. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is a cytokine-stimulated pathway that has a crucial role in immune regulation, proliferation, and cytokine production. Therefore, the pathway has recently attracted interest in cellular senescence studies. Here, by using publicly available data, we report that JAK-STAT signaling was suppressed in the BMR in comparison to the mouse. Interestingly, our experimental results showed upregulated Jak1/2 expressions in BMR fibroblasts during the replicative senescence process. The transcriptomic analysis using publicly available data also demonstrated that various cytokines related to JAK-STAT signaling were upregulated in the late passage cells, while some other cytokines such as MMPs and SERPINs were downregulated, representing a possible balance of senescence-associated secretory phenotypes (SASPs) in the BMR. Finally, our proteomics data also confirmed cytokine-mediated signaling activation in senescent BMR fibroblasts. Together, our findings suggest the critical role of JAK-STAT and cytokine-mediated signaling pathways during cellular senescence, pointing to the possible contribution of divergent inflammatory factors to the superior resistance of aging and cancer in BMRs.Item Obstructive Sleep Apnea and Cancer(GALENOS PUBL HOUSE, 2016-01-01) Demir, Ceyda Erel KirisogluObstructive sleep apnea (OSA) is a common disorder which is associated with increased morbidity and mortality. There is growing evidence that patients with OSA have higher incidence of cancer, accelerated progression and cancer mortality. Intermittent hypoxia, oxidative stress and sleep fragmentation are hold responsible for cancer development.Item Inflammation and thrombosis in patients with COVID-19: A prothrombotic and inflammatory disease caused by SARS coronavirus-2(AVES, 2020-01-01) Pamukcu, BurakCoronavirus disease 2019 (COVID-19) caused by ``Severe Acute Respiratory Syndrome Coronavirus-2{''} (SARS-CoV-2) infection emerged in Wuhan, a city of China, and spread to the entire planet in early 2020. The virus enters the respiratory tract cells and other tissues via ACE2 receptors. Approximately 20\% of infected subjects develop severe or critical disease. A cytokine storm leads to over inflammation and thrombotic events. The most common clinical presentation in COVID-19 is pneumonia, typically characterized by bilateral, peripheral, and patchy infiltrations in the lungs. However multi-systemic involvement including peripheral thromboembolic skin lesions, central nervous, gastrointestinal, circulatory, and urinary systems are reported. The disease has a higher mortality compared to other viral agents causing pneumonia and unfortunately, no approved specific therapy, nor vaccine has yet been discovered. Several clinical trials are ongoing with hydroxychloroquine, remdesivir, favipiravir, and low molecular weight heparins. This comprehensive review aimed to summarize coagulation abnormalities reported in COVID-19, discuss the thrombosis, and inflammation-driven background of the disease, emphasize the impact of thrombotic and inflammatory processes on the progression and prognosis of COVID-19, and to provide evidence-based therapeutic guidance, especially from antithrombotic and antiinflammatory perspectives.