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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 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.