Tuncay Delibasi

Resveratrol and Adipose-Derived Mesenchymal Stem Cells Are Effective in the Prevention and Treatment of Doxorubicin Cardiotoxicity in Rats.

Anthracyclines can cause severe cardiac toxicity leading to heart failure. The aim of this study was to determine the effects of cardioprotective polyphenolic compound resveratrol (RES) and adipose-derived mesenchymal stem cells (ADMSCs) on cardiac tissue of rats treated with doxorubicin (DOX). Forty-two female and three male Wistar–Albino rats were included in the study. The study groups and the control groups were as follows: Group I: DOX; Group II: DOX + RES; Group III: DOX + ADMSCs; Group IV: DOX + RES + ADMSCs; Group V: Sham operation; and Group VI: normal saline. ADMSCs obtained from male rats were defined with stem cell markers [CD11b/c(−), CD45(−), CD90(+), CD44(+), and CD49(+)]. DOX 12 mg/kg intraperitoneally (i.p.) was injected as a single dose in female rats. Resveratrol 100 mg/kg was injected three times i.p. in Groups II and IV. ADMSCs 2 × 106 cells/kg/dose were labeled with bromodeoxyuridine (BrdU) and injected i.p. for a total of three times in Groups III and IV. When the study was terminated after 4 weeks, the beating hearts were connected to a Langendorff setup and records were obtained for 30 minutes. Histopathological, immunhistochemical, and immunofluorescent examination with H&E, Troponin I, and BrdU stains were also performed. Also, ADMSCs were demonstrated in the myocardium of transplanted rats. Left ventricle functions and myocardial histology demonstrated significant impairment in DOX only group compared to groups with ADMSCs (P < .05). We suggest that RES and ADMSCs were successful in the prevention and treatment of the doxorubicin cardiomyopathy in rats. The hypothetical mechanisms of regeneration are multiple, including cell differentiation and autocrine/paracrine effects of ADMSCs.

The effects of oral carvacrol treatment against H2O2 induced injury on isolated pancreas islet cells of rats

Pancreatic islet transplantation is an alternative treatment of insulin replacement therapy in diabetes mellitus, but the islets are exposed to many chemical, mechanical damages, and oxidative stress before transplantation. Carvacrol is a well-known essential oil for its antioxidant, antimicrobial, antifungal and antiinflammatory properties. The aim of this study was to investigate the possible protective effects of carvacrol against H2O2 induced cellular injury on isolated pancreas islets. After carvacrol (20, 40 and 80 mg/kg/day) treatment, the pancreas islets were isolated by enzyme digestion. The isolated islets were incubated within 0, 150 and 300 µM H2O2 containing medium at +4°C for 15 min. Then, the islets were examined with fluorescein diacetate and propidium iodide mixture stains for viability. A number of islets were stored for lipid peroxidation, protein oxidation and DNA fragmentation analysis. The cell viability ratio of Carvacrol 20 mg/kg/day group was increased in comparison to control and vehicle (DMSO) groups. Additionally, carvacrol application protected the cells from lipid peroxidation and protein oxidation induced by H2O2. H2O2 caused tissue injury and DNA fragmentation. There was only one DNA fragmentation band from islet cells of 20 mg/kg/day carvacrol treated group, however there were more than one bands from control and DMSO groups. In conclusion, carvacrol treatment ameliorates islet cell injury induced by H2O2. However, the dose of carvacrol is important and our results suggest that 20 mg/kg/day dose is more effective than doses of 40 or 80 mg/kg/day.

Virus-like nanostructures for tuning immune response.

Synthetic vaccines utilize viral signatures to trigger immune responses. Although the immune responses raised against the biochemical signatures of viruses are well characterized, the mechanism of how they affect immune response in the context of physical signatures is not well studied. In this work, we investigated the ability of zero- and one-dimensional self-assembled peptide nanostructures carrying unmethylated CpG motifs (signature of viral DNA) for tuning immune response. These nanostructures represent the two most common viral shapes, spheres and rods. The nanofibrous structures were found to direct immune response towards Th1 phenotype, which is responsible for acting against intracellular pathogens such as viruses, to a greater extent than nanospheres and CpG ODN alone. In addition, nanofibers exhibited enhanced uptake into dendritic cells compared to nanospheres or the ODN itself. The chemical stability of the ODN against nuclease-mediated degradation was also observed to be enhanced when complexed with the peptide nanostructures. In vivo studies showed that nanofibers promoted antigen-specific IgG production over 10-fold better than CpG ODN alone. To the best of our knowledge, this is the first report showing the modulation of the nature of an immune response through the shape of the carrier system.

Improving pancreatic islet in vitro functionality and transplantation efficiency by using heparin mimetic peptide nanofiber gels.

Pancreatic islet transplantation is a promising treatment for type 1 diabetes. However, viability and functionality of the islets after transplantation are limited due to loss of integrity and destruction of blood vessel networks. Thus, it is important to provide a proper mechanically and biologically supportive environment for enhancing both in vitro islet culture and transplantation efficiency. Here, we demonstrate that heparin mimetic peptide amphiphile (HM-PA) nanofibrous network is a promising platform for these purposes. The islets cultured with peptide nanofiber gel containing growth factors exhibited a similar glucose stimulation index as that of the freshly isolated islets even after 7 days. After transplantation of islets to STZ-induced diabetic rats, 28 day-long monitoring displayed that islets that were transplanted in HM-PA nanofiber gels maintained better blood glucose levels at normal levels compared to the only islet transplantation group. In addition, intraperitoneal glucose tolerance test revealed that animals that were transplanted with islets within peptide gels showed a similar pattern with the healthy control group. Histological assessment showed that islets transplanted within peptide nanofiber gels demonstrated better islet integrity due to increased blood vessel density. This work demonstrates that using the HM-PA nanofiber gel platform enhances the islets function and islet transplantation efficiency both in vitro and in vivo.

Protective Effect of Colchicine on Ovarian Ischemia–Reperfusion Injury An Experimental Study

Objective: The aim of the present study is to investigate the efficiency of colchicine in the experimental rat ovarian torsion model in the light of histological and biochemical data. Study Design: A total of 35 Wistar albino female rats were randomly divided into 5 groups, group 1: (control-sham operated, n = 7); group 2: (torsion/detorsion, n = 7) 2 hours of ischemia and 2 hours of reperfusion; group 3: (torsion/detorsion, n = 7), 2 hours of ischemia and 5 days of reperfusion; group 4: (torsion/detorsion, n = 7) 2 hours of ischemia and 2 hours of reperfusion and a signal dose of oral 1 mL/kg colchicine; and group 5: (torsion/detorsion, n = 7), 2 hours of ischemia and 5 days of reperfusion and 5 days of oral 1 mg/kg colchicine. Histopathologic evaluation was performed by a scoring that assesses congestion, bleeding, edema, and cellular degeneration in the ovarian tissue. Catalase, tissue malondialdehyde (MDA), and protein carbonyl levels were calculated. Results: The histopathologic scores, MDA, and protein carbonyl levels in the control and colchicine groups were significantly lower than groups 2 and 3 (P < .001). Catalase activities were significantly higher in the control and colchicine groups than in groups 2 and 3 (P < .001). The results of the histopathologic parameters and biochemical markers showed that protective effects of colchicine treatment persisted up to 5 days. Conclusion: Our study results revealed that colchicine reduced ovarian ischemia–reperfusion injury in experimental rat ovarian torsion model. As the ovarian detorsion is the first choice of the treatment modality in the early phase, antioxidant and anti-inflammatory treatment modalities like colchicine might be used to reduce ovarian ischemia–reperfusion injury.

The role of BRD7 in embryo development and glucose metabolism

Bromodomain‐containing protein 7 (BRD7) is a member of bromodomain‐containing protein family and its function has been implicated in several diseases. We have previously shown that BRD7 plays a role in metabolic processes. However, the effect of BRD7 deficiency in glucose metabolism and its role in in vivo have not been fully revealed. Here, we report the essential role of BRD7 during embryo development. Mice homozygous for BRD7 led to embryonic lethality at mid‐gestation. Homozygous BRD7 knockout (KO) mice showed retardation in development, and eventually all BRD7 KO embryos died in utero prior to E16.5. Partial knockdown of Brd7 gene displayed mild changes in glucose metabolism.

Secondary Prevention of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus: International Insights From the TECOS Trial (Trial Evaluating Cardiovascular Outcomes With Sitagliptin)

Background: Intensive risk factor modification significantly improves outcomes for patients with diabetes and cardiovascular disease (CVD). However, the degree to which secondary prevention treatment targets are achieved in international clinical practice is unknown. Methods: Attainment of 5 secondary prevention targets—aspirin use, lipid control (low-density lipoprotein cholesterol (LDL-C) Results: Overall, 29.9% of patients with diabetes and CVD had all 5 secondary prevention measures at target. North America had the highest proportion (41.2%), whereas Western Europe, Eastern Europe, and Latin America had proportions of approximately 25%. The likelihood of having individual prevention components at target also varied by region: compared with North America, individuals in all other regions were less likely to have blood pressure at goal, and individuals in Eastern Europe and Latin America were less likely to have LDL-C at target or to be on statin therapy (see Figure). Overall, blood pressure control (57.9%) had the lowest overall attainment while non-smoking status had the highest (89%). Conclusions: On a global scale, significant opportunities exist to improve the quality of cardiovascular secondary prevention care among patients with diabetes and CVD, which in turn could lead to reduced risk of downstream cardiovascular events.Background: Intensive risk factor modification significantly improves outcomes for patients with diabetes mellitus and cardiovascular disease. However, the degree to which secondary prevention treatment goals are achieved in international clinical practice is unknown. Methods: Attainment of 5 secondary prevention parameters—aspirin use, lipid control (low-density lipoprotein cholesterol <70 mg/dL or statin therapy), blood pressure control (<140 mm Hg systolic, <90 mm Hg diastolic), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and nonsmoking status—was evaluated among 13 616 patients from 38 countries with diabetes mellitus and known cardiovascular disease at entry into TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin). Logistic regression was used to evaluate the association between individual and regional factors and secondary prevention achievement at baseline. Cox proportional hazards regression analysis was used to determine the association between baseline secondary prevention achievement and cardiovascular death, myocardial infarction, or stroke. Results: Overall, 29.9% of patients with diabetes mellitus and cardiovascular disease achieved all 5 secondary prevention parameters at baseline, although 71.8% achieved at least 4 parameters. North America had the highest proportion (41.2%), whereas Western Europe, Eastern Europe, and Latin America had proportions of ≈25%. Individually, blood pressure control (57.9%) had the lowest overall attainment, whereas nonsmoking status had the highest (89%). Over a median 3.0 years of follow-up, a higher baseline secondary prevention score was associated with improved outcomes in a step-wise graded relationship (adjusted hazard ratio, 0.60; 95% confidence interval, 0.47–0.77 for those patients achieving all 5 measures versus those achieving ⩽2). Conclusions: In an international trial population, significant opportunities exist to improve the quality of cardiovascular secondary prevention care among patients with diabetes mellitus and cardiovascular disease, which in turn could lead to reduced risk of downstream cardiovascular events. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00790205.

The effects of commonly used intravitreal steroids on proliferation index of ciliary body-derived mesenchymal stem cells: an in vitro study

Abstract Aim: To investigate the effects of commonly used intravitreal steroids on survival and proliferation (namely, proliferation index) of ciliary body-derived mesenchymal stem cells (CB-MSC). Methods: CB-MSCs were isolated from newborn rats’ eye, and they were expanded in the medium. Commonly used intravitreal steroids such as dexamethasone (Dex) and triamcinolone acetonide (TA) were added into the medium at commonly used concentration in clinical practice (0.1 mg/mL) and at lower concentration (0.01 mg/mL). Proliferation indexes of CB-MSCs were analyzed with the xCELLigence system at nine consecutive times (at 3rd, 6th, 21th, 30th, 45th, 60th, 75th, 90th and 100th h). Results: Both TA and Dex at both 0.01 mg/mL and 0.1 mg/mL concentrations had negative effect on proliferation indexes of CB-MSC. Although negative effect of TA on proliferation index of CB-MSC at both concentrations was not statistically significant, statistically significant negative effect of Dex at 0.01 mg/mL concentration started 60th h (p = 0.017) and 0.1 mg/mL concentration started 30th h (p = 0.014). Discussion: Even therapeutic doses of intravitreal corticosteroid agents might have negative effects on limited numbers of stem cells. Especially, Dex caused statistically significant toxic effects on CB-MSCs even at lower concentrations of those used clinically. These novel findings deserve further in vivo investigations.

Effect of lifestyle interventions with or without metformin therapy on serum levels of osteoprotegerin and receptor activator of nuclear factor kappa B ligand in patients with prediabetes

Osteoprotegerin has been shown to be increased in cardiovascular disorders and type 2 diabetes mellitus. Prediabetes represents a high risk condition for diabetes and diabetic complications. Therefore, we aimed to find the relationship between prediabetes and osteoprotegerin with nuclear factor–B ligand, carotid intima media thickness, and metabolic markers. A total of 54 participants with prediabetes including impaired fasting glucose (n = 21), impaired glucose tolerance (n = 8), impaired fasting glucose and impaired glucose tolerance (n = 25), and 60 healthy individuals as a control were admitted to the study. Metabolic and anthropometric parameters, insulin resistance variables, osteoprotegerin, and nuclear factor–B ligand markers, carotid intima media thickness were examined at baseline for all participants. To evaluate the effect of therapy we determined the same parameters after the end of the study. Measurements of waist circumference, body mass index, body fat percentage and levels of fasting blood glucose, fasting insulin, homeostatic model assessment of insulin resistance, triglyceride levels and hsCRP and carotid intima media thickness were significantly higher in patients with prediabetes (p < 0.05). We also found higher osteoprotegerin and lower nuclear factor–B ligand levels in patients than in controls however, the value was non-significant (p > 0.05). Patients with prediabetes were under lifestyle interventions with (group 1, n = 33) or without metformin (group 2, n = 21) therapy. Baseline anthropometric and metabolic characteristics were not found statistically different in group 1 and group 2. Mean follow up period of the patients were 7.9 ± 2.2 month (min-max: 6–12 months). After the follow up period we evaluated the same parameters and found significant differences between waist circumference, body mass index, body fat percentage, fasting insulin, homeostatic model assessment of insulin resistance, and osteoprotegerin levels (p < 0.05). However, carotid intima media thickness, and nuclear factor–B ligand levels significantly different only in the group treated with metformin (p < 0.05). We also compared the variables after the treatment period with the control group and found significantly lower levels in terms of fasting insulin, homeostatic model assessment of insulin resistance, waist circumference, body mass index, body fat percentage, carotid intima media thickness, osteoprotegerin, and nuclear factor–B ligand values (p < 0.05). Correlation analysis revealed a negative relationship between nuclear factor–B ligand and body mass index, and body fat percentage in group 1 (p = 0.05, r = −0.646, p = 0.01, r = −0.585). Therapy of prediabetes was associated with a significant decrease in osteoprotegerin and certain metabolic variables together with an increase in nuclear factor–B ligand levels particularly in patients with under metformin therapy.

Serum vaspin and adiponectin levels in patients with prolactinoma

Abstract Background: Studies investigating serum vaspin and adiponectin levels in patients with prolactinoma are inconclusive. The aim of this study was to evaluate serum vaspin and adiponectin levels in patients with prolactinoma and healthy controls. Methods: A total of 42 prolactinoma patients (Group 1, 21 patients; Group 2, 21 patients) and 30 healthy controls were enrolled in the study. Group 1 consisted of newly diagnosed patients who were never treated or had not received a dopamine agonist (DA) within 6 months prior to screening. Group 2 consisted of prolactinoma patients who were on DA treatment for at least 6 months at the time of screening. The control group (group 3) consisted of healthy controls. Results. Patients with prolactinoma had higher homeostasis model assessment of insulin resistance and lower quantitative insulin sensitivity check index values in comparison to healthy controls (p < 0.001 for both). Serum levels of adiponectin and vaspin were also significantly lower in prolactinoma patients when compared to the control group (p < 0.01 and p < 0.001, respectively). Following adjustment for confounding factors, the respective odds ratios for prolactinoma in patients in the lower subgroup compared with those in the higher subgroup for adiponectin and vaspin were 2.733 (0.621–12.035; p > 0.05) and 5.041 (1.191–21.339; p < 0.05). Conclusion: This is the first study to demonstrate the presence of low vaspin levels in patients with prolactinomas. Further studies are needed to help establish the roles of vaspin and adiponectin in prolactinoma patients.