Is there a connection between inflammation, telomerase activity and the transcriptional status of telomerase reverse transcriptase in renal failure?

Telomerase is involved in the elongation of telomeres. It remains active in very few types of cell in mature organisms. One such cell type is the lymphocytes. In this study, we investigated the activity and expression of telomerase in lymphocytes from renal failure patients and compared it to that for normal controls. Inflammation status was determined at the same time. The enzyme activity was measured using PCR-ELISA with peripheral blood mononuclear cells (PBMCs) from three groups: 53 healthy individuals, 50 patients with chronic kidney disease (CKD) and 50 dialysis patients. In the same cell populations, the expression of the reverse transcriptase of the human telomerase gene (hTERT) was measured via real-time PCR. The inflammationstatus of these individuals was determined by calculating the interleukin 6 (IL-6), IL-10, C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-a) serum concentrations via ELISA. The lowest levels of telomerase activity were detected in CKD, and this group had the highest IL-6 and CRP values and the lowest hTERT expression. The dialysis group showed significant differences in comparison to the normal subjects and to the CKD patients. Further studies are warranted in order to explore the way inflammation influences telomerase activity and hTERT expression. © University of Wrocław, Poland 2015

Myocardial protection provided by chronic skeletal muscle ischemia is not further enhanced by ischemic pre- or postconditioning: Comparative effects on intracellular signaling

Chronic skeletal muscle ischemia protects the ischemic heart by preserving coronary flow and inducing arterioangiogenesis. We sought to determine the effect and the underlying molecular mechanisms of preconditioning (PreC) and postconditioning (PostC), applied in a model of chronic skeletal muscle ischemia. Male rabbits were divided into 3 series. In each series, the animals were subjected either to severe hind limb (HL) ischemia, by excision of the femoral artery, or to sham operation (SHO). After 4 weeks, all the animals underwent 30 minutes of regional heart ischemia and 3 hours reperfusion. The animals of the first series received no further intervention (HL and SHO groups), those of the second series underwent PreC (HL + PreC and SHO + PreC), and of the third series PostC (HL + PostC and SHO + PostC). Infarct size (I) and risk zones (R) were determined, and their ratio was calculated in percentage. Three additional series of experiments were performed with respective interventions up to the 10th minute of reperfusion, where sample tissue was obtained for assessment of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), glycogen synthase kinase 3β (GSK3β), p44/42, signal transducer and activator of transcription (STAT) 3, and STAT5. All groups demonstrated significantly smaller percentage of I/R compared with the SHO group (HL: 14.4% ± 3.7%, HL + PreC: 13.1% ± 1.0%, SHO + PreC: 21.3% ± 1.6%, HL + PostC: 18.0% ± 1.1%, and SHO + PostC: 24.3% ± 1.7%, P <.05 vs 35.7% ± 4.4% in SHO). The PreC and PostC did not further reduce the infarct size in HL groups. The Akt, eNOS, GSK3β, p44/42, and STAT3 were activated in all PreC or PostC groups regardless of the infarct size reduction. The STAT5 was activated only in the HL groups compared with the SHO groups. In conclusion, chronic skeletal muscle ischemia results in effective cardioprotection, which is not further enhanced with application of PreC or PostC. The Akt, eNOS, GSK3β, p44/42, and STAT3 may only be considered as indicators of the intracellular changes taking place during protection. Activation of STAT5 is possibly the end effector, which is responsible for infarct size reduction provided by chronic skeletal muscle ischemia. © The Author(s) 2013

Differential activation of mitogen-activated protein kinases in ischemic and nitroglycerin-induced preconditioning

Previous studies have shown that the cardioprotective effect of ischemic preconditioning (IPC) can be mimicked pharmacologically with clinically relevant agents, including nitric oxide (NO) donors. However, whether pharmacological preconditioning shares the same molecular mechanism with IPC is not fully elucidated. The present study aimed to determine the activation of mitogen-activated protein kinases (MAPKs) (ERK1/2, p38 MAPK and p46/p54 JNKs) during ischemia and at reperfusion in nitroglycerin-induced preconditioning as compared to IPC and to correlate this with the conferred cardioprotection in anesthetized rabbits. Sixty minutes of intravenous administration of nitroglycerin was capable of inducing both early and late phase preconditioning in anesthetized rabbits, as it was expressed by the reduction of infarct size. Despite the cardioprotective effect conferred by both ischemic and nitroglycerin-induced preconditioning, there was a differential phosphorylation of MAPKs between the studied groups. p38 MAPK was activated early in ischemia in both ischemic and the early nitroglycerin-induced preconditioning while JNKs were markedly increased only after IPC. Furthermore, in these groups, ERK1/2 were activated during reperfusion. A different profile was observed in the late preconditioning induced by nitroglycerin with increased p38 MAPK and ERK1/2 phosphorylation during late ischemia. No activation of JNKs was observed at any time point in this group. It seems that activation of individual MAPK subfamilies depends on the nature of preconditioning stimulus. © Steinkopff Verlag Darmstadt 2006

Effect of olmesartan on the level of oral cancer risk factor PAI1

Aim: To study if the angiotensin receptor blocker olmesartan reduces levels of plasminogen activator inhibitor 1 (PAI1), a risk factor for oral cancer, in a mouse model and therefore whether it could be used in the treatment of this malignancy. Materials and Methods: Twelve transgenic PAI1 mice aged 16-20 weeks were divided in two groups each containing six animals. One group was given olmesartan every day for 30 days in drinking water in an amount corresponding to their weight, 0.005 mg/g, while the second group did not receive any medication (control group). Blood samples were obtained from animals of both groups, before and after one month of olmesartan administration and plasma PAI1 levels were measured using enzyme-linked immunosorbent assay. Results: In the olmesartan-treated group, a significant decrease of PAI1 level was found after 1 month of treatment (11.9±8.6 vs. 21.7±7.2 ng/ml, respectively; p=0.028). However, no statistically significant difference was observed in PAI1 levels between the olmesartan-treated and control groups after one month, (p=0.177). Conclusion: Olmesartan did not significantly affect PAI1 levels in this mouse model

Design and synthesis of nitrate esters of aromatic heterocyclic compounds as pharmacological preconditioning agents

Ischemic preconditioning (IPC) constitutes an endogenous protective mechanism in which one or more brief periods of myocardial ischemia and reperfusion render the myocardium resistant to a subsequent more-sustained ischemic insult. Pharmacological preconditioning represents an ideal alternative of IPC. We now describe the design and synthesis of indole, quinoline, and purine systems with an attached pharmacophoric nitrate ester group. The indole and quinoline derivatives 4 and 5 possess structural features of the nitrate containing KATP channel openers. Purine analogues 11 and 12, substituted at the position 6 by a piperidine moiety and at position 9 by an alkyl nitrate, could combine the effects of the nitrate containing KATP channel openers and those of adenosine. Compound 13 bears the nicotinamide moiety of nicorandil instead of nitrate ester. Compounds 4, 5, and 11 reduced infarction and the levels of malondialdehyde (MDA) at reperfusion in anesthetized rabbits. Compounds 12 and 13 did not significantly reduce the infarct size. Analogues 4 and 5 increased cGMP and MDA during ischemia, while combined analogue 4 and mitoKATP blocker 5-hydroxydecanoic acid (5-HD) abrogated this benefit suggesting an action through mitoKATP channel opening. Treatment with derivative 11 combined with 5-HD as well as treatment with 11 and adenosine receptor blocker 8-(p-sulfophenyl)theophylline (SPT) did not abrogate cardioprotection. Compound 11 is a lead molecule for the synthesis of novel analogues possessing a dual mode of action through cGMP-mitoKATP channel opening-free radicals and through adenosine receptors. © 2008 Elsevier Ltd. All rights reserved

Interleukin-15 and Interleukin-12 are elevated in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis

Background: There is evidence that immunological factors may be involved in pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). Interleukin (IL)-15 and IL-12 are proinflammatory cytokines produced by activated blood and glial cells. They promote T cell differentiation and proliferation. Patients and Methods: We measured by ELISA serum and cerebrospinal fluid (CSF) levels of IL-15 and IL-12 in 21 patients with ALS and 19 patients with other noninflammatory neurological disorders (NIND) studied as a control group. IL-15 and IL-12 serum and CSF levels were also correlated with duration of the disease, the disability level determined using the revised ALS Functional Rating Scale and the clinical subtype of the disease onset in patients with ALS. Results: IL-15 and IL-12 serum levels were higher in patients with ALS as compared with patients with NIND (p = 0•014 and p = 0•011, respectively). IL-15 and IL-12 CSF levels were also increased in patients with ALS (p = 0•011 and p = 0•005, respectively). IL-15 and IL-12 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients. Conclusions: Our findings suggest that these molecules may be involved in the pathogenic mechanisms acting as potential markers of immune activation in ALS. Copyright © 2010 S. Karger AG, Basel

Interleukin-17 and interleukin-23 are elevated in serum and cerebrospinal fluid of patients with ALS: A reflection of Th17 cells activation?

Background - There is evidence that immunological factors may involved in pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Th17 cells are characterized by predominant production of IL-17 and are suggested to be crucial in destructive autoimmunity. Interleukin-23 (IL-23) appears to play a supporting role in the continued stimulation and survival of Th17.Patients and methods - We measured by enzyme-like immunosorbent assay (ELISA) serum and cerebrospinal fluid (CSF) levels of IL-17 and IL-23 in 22 patients with ALS and 19 patients with other non-inflammatory neurological disorders (NIND) studied as a control group. IL-17 and IL-23 serum and CSF levels were also correlated with duration of the disease, the disability level and the clinical subtype of the disease onset in patients with ALS.Results - IL-17 and IL-23 serum levels were higher in patients with ALS as compared with patients with NIND (P = 0.015 and P = 0.002 respectively). IL-17 and IL-23 CSF levels were also increased in patients with ALS (P = 0.0006 and P = 0.000001 respectively). IL-17 and IL-23 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients.Conclusions - Our findings suggest that these molecules may be involved in the pathogenetic mechanisms acting as potential markers of Th17 cells activation in ALS. © 2010 The Authors. Journal compilation © 2010 Blackwell Munksgaard