Person: BAHAR, ASLI NUR
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BAHAR
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ASLI NUR
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Publication Open Access Signaling pathways in liver fibrosis(2023-01-01) BAHAR, ASLI NUR; BAHAR A. N., AKBULUT K. G.Liver fibrosis is a disease characterized by activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM) components that destroy the physiological structure of the liver. Liver fibrosis contributes to the increasing prevalence and severity of chronic liver diseases. If liver fibrosis, which is of great clinical importance, is not treated, it ends with cirrhosis, which is characterized by fatal and intense complications. Cirrhosis can progress to hepatocellular carcinoma. Although fibrosis was previously thought to be an irreversible process, studies have shown that because of the liver\"s high regenerative ability, regression and return to normal architecture is higher than in other tissues, even in advanced disease.Targeting signaling pathways that cause fibrosis and anti-fibrotic therapies are needed to prevent the progression of liver disease and the development of hepatocellular carcinoma (HCC). Activation of HSCs and transforming growth factor beta (TGF-beta), Wnt/beta-catenin signaling pathways and interactions play an important role in the pathogenesis of the disease. Sirtuins (SIRT) belong to the sirtuin family of Nicotinamide Adenine Dinucleotide, (NAD+) dependent protein deacetylases and are involved in many important cellular biological processes, including the inflammatory response, oxidative stress, and fibrosis. Sirtuin family has been shown to be involved in the regulation of fibrosis signaling pathways and in the cellular and molecular mechanisms of liver fibrosis. In this review, we aimed to summarize current knowledge about the signaling pathways that trigger differentiation, profibrotic activation of myofibroblasts and cause liver fibrosis that can be modulated by sirtuins.Publication Open Access Cerebellum and oxidative stress in natural and accelerated aging model(2023-01-05) BAHAR, ASLI NUR; Kavak H., Bahar A. N., Keskin Aktan A., Akbulut K. G.AIM: Intracerebroventricular administration of galactose causes motor coordination deficiency by decreasing glutathione (GSH) level in the cerebellum. It has been shown that aging increases oxidative stress and Sirtuin 2 (Sirt2) expression in rat cerebellum tissue and Sirt2 inhibition has a protective effect in aging. In our study, we aimed to investigate the effect of AGK-2 administration, a specific Sirt2 inhibitor, on oxidative stress in an accelerated aging model with natural and D-galactose (D-GAL) administration.METHODS: In the study, 7 groups were formed using 48 male rats of Wistar (W) and Sprague-Dawley (SD) species;1) Young-Control (3 months, n=6), 2) Young-AGK-2 (3 months, n=6), 3) Old-Control (22 months, n=6), 4) Old-AGK-2 (22 months, n=6), 5) D-GAL (3 months, n=9), 6) Solvent+D-GAL (3 months, n=8), 7) Solvent+D-GAL+AGK-2 (3 months, n=7). Control groups were given 4% DMSO+PBS, and experimental groups were given AGK-2 (10 μM/bw) subcutaneously (SC). For the accelerated aging model, D-galactose (150 mg/kg/day, SC) was administered for 10 weeks. Malondialdehyde (MDA) and GSH levels in cerebellum tissue were measured by spectrophotometric method.In the statistical analysis, one-way ANOVA (post-hoc LSD) was used to determine the differences between groups. The statistical significance level was set at p<0.05.RESULTS: The D-GAL administration increased the cerebellum MDA level significantly compared to the young control group (p<0.001). In the D-GAL group, AGK-2 administration decreased the MDA levels and increased the GSH levels (p=0.003; p=0.006). D-GAL administration increased MDA levels more and decreased GSH levels significantly compared to aged rats (p=0.006; p<0.001). AGK-2 administration in natural aging was found to be more effective in increasing GSH levels compared to the accelerated aging model (p<0.001).CONCLUSION: Both models compared increased oxidant stress in the cerebellum. AGK-2 application was found to be more effective than D-GAL on oxidant stress in natural aging.Keywords:AGK-2, Accelerated aging, Cerebellum, D-galactose, Natural aging, Oxidative StressPublication Open Access Protective effect of pharmacological SIRT2 inhibition on renal dysfunction, fibrosis, TGF-β1/β-catenin, and klotho signaling in D-galactose-induced aging model(2023-12-01) BAHAR, ASLI NUR; Keskin Aktan A., Bahar A. N., Sonugür F. G., Akarca Dizakar S. Ö., Akbulut K. G.AbstractBackground: Fibrosis induced by transforming growth factor-β1 (TGF-β1) activity and the Wnt/β-catenin pathway is a significant hallmark of progressive kidney disease and kidney aging. We aimed to investigate the effects of pharmacological silent mating type information regulation 2 homolog-2 (SIRT2) inhibition on renal functions, histopathological changes, fibrosis, TGF-β1/β-catenin and klotho signaling, and apoptosis in D-galactose (D-Gal)-induced aging model.Methods: The study was conducted with three months old male rats divided into four groups: control (Saline solution (0.9%, 0.5 mL/day) was administered subcutaneously (sc) for ten weeks) (n = 6), D-Gal (D-galactose saline solution (150 mg/kg/day) was administered sc for ten weeks) (n = 8), D-Gal+DMSO (D-galactose (150 mg/kg/day) and 4% dimethyl sulfoxide (DMSO) in phosphate-buffered saline (PBS) (10 μL/bw/day) were administered sc for ten weeks) (n = 8), and D-Gal+acylglycerol kinase (AGK)-2 (D-galactose (150 mg/kg/day) and AGK-2 in 4% DMSO-PBS (10 μM/bw/day) was administered sc for ten weeks) (n = 8). The kidney index was calculated, renal function markers (sodium (Na+), creatinine (Cr), blood urea nitrogen (BUN)) in plasma and urine samples were analyzed, and fractional excretion of sodium (FeNa%) was calculated. Glomerular diameter, fibrosis, and basement membrane thickness were analyzed with histopathological methods. TGF-β1 and β-catenin mRNA expression were determined with quantitative real-time polymerase chain reaction (qRT-PCR), klotho protein levels were determined with the enzyme linked immunosorbent assay (ELISA) method, and SIRT2 protein expression was determined with western blot. The immunohistochemical method was employed to determine the immunoreactivities of β-catenin, klotho, SIRT2, and fibronectin. Apoptosis was determined with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) method.Results: AGK-2 and D-galactose co-administration increased kidney index and decreased plasma and urine Na+and Cr levels, as well as BUN and FeNa% (p <0.05). AGK-2 improved the histopathological changes induced by D-galactose, reducing fibrosis and basal membrane thickness (p <0.05). Furthermore, AGK-2 administration decreased TGF-β1, β-catenin, SIRT2, and fibronectin in the kidney (p <0.05). AGK-2 and D-galactose co-administration increased klotho protein levels in the kidney; however, the increase was not statistically significant in klotho immunoreactivity (p >0.05). D-galactose induced apoptosis in the kidney (p <0.05); however, AGK-2 did not significantly mitigate apoptosis (p >0.05).Conclusion: Our findings suggested that pharmacological SIRT2 inhibition could ameliorate alterations in functional, histopathological, and fibrosis protein pathway activities in the kidney that are associated with aging.Key wordsD-galactose/fibrosis/kidney/SIRT2 inhibition/TGF-β1