Although statins exert non-lipid cardioprotective effects, their influence on cell death is not fully elucidated. For this purpose, we investigated whether simvastatin treatment (S, 10 mg/kg, 5 days) is capable of mitigating ischemia/reperfusion-induced (IR) apoptosis in the isolated rat hearts, which was examined using immunoblotting analysis. In addition, the content of signal transducer and activator of transcription 3 (STAT3) and its active form, phosphorylated STAT3 (pSTAT3-Thr705), was analyzed. Simvastatin induced neither variations in the plasma lipid levels nor alterations in the baseline content of analysed proteins with the exception of upregulation of cytochrome C. Furthermore, simvastatin significantly increased the baseline levels of pSTAT3 in contrast to the control group. In the IR hearts, simvastatin reduced the expression of Bax and non-cleaved caspase-3. In these hearts, phosphorylation of STAT3 did not differ in comparison to the non-treated IR group, however total STAT3 content was slightly increased. The improved recovery of left ventricular developed pressure co-existed with the increased Bcl- 2/Bax ratio. In conclusion, pleiotropic action of statins may ameliorate viability of cardiomyocytes by favouring the expression of anti-apoptotic Bcl-2 and downregulating the proapoptotic markers; however STAT3 does not seem to be a dominant regulator of this anti-apoptotic action of simvastatin., T. Rajtík, ... [et al.]., and Obsahuje seznam literatury
The activation of metabotropic glutamate receptors subtype 4 (mGluR4) potentiates models of absence seizures in adult rats. These seizures are age-dependent, but data concerning the role of mGluR4 in immature brain is insufficient. N-phenyl-7- (hydroxyimino)cyclopropa[b]chromen-1acarboxamide (PHCCC), which is a positive allosteric modulator of these receptors, was used in three different models of seizures in immature rats: 1) convulsions induced by high doses of pentetrazol (PTZ; a model of generalised tonic-clonic seizures); 2) rhythmic electroencephalographic (EEG) activity induced by low doses of PTZ (a model of absence seizures); and 3) electrically elicited cortical afterdischarges (ADs, a model of myoclonic seizures). We administered four doses of PHCCC (1, 3, 10 and 20 mg/kg) in PTZ-induced convulsions and two doses (3 and 10 mg/kg) in the two electrophysiological models of freely moving rats with implanted electrodes. Every dose and age group consisted from 8 to 10 rats. PTZ-elicited convulsions were not significantly influenced by PHCCC. In contrast, PHCCC potentiated the effect of a subconvulsant dose (60 mg/kg) of PTZ. The 10-mg/kg dose of PHCCC significantly prolonged the duration of PTZ-induced rhythmic activity episodes and shortened the intervals between individual episodes in 25-day-old rats (P25). In contrast, this potentiation was not seen in P18 rats. Cortical ADs were significantly prolonged with repeated stimulations by both doses of PHCCC in P12 and P18 animals. P25 rats exhibited only slightly longer AD durations. In conclusion, we did not find any anticonvulsant effect of PHCCC. On the contrary, proconvulsant action was demonstrated in all three models in immature rats., E. Szczurowska, P. Mareš., and Obsahuje seznam literatury
Exposure to chronic hypoxia results in hypoxic pulmonary hypertension characterized by structural remodeling of peripheral pulmonary vasculature. An important part of this remodeling is an increase of collagen turnover and deposition of newly formed collagen fibrils in the vascular walls. The activity of collagenolytic metalloproteinases in the lung tissue is notably increased in the first days of exposure to hypoxia. The increased collagenolytic activity results in the appearance of collagen cleavages, which may be implied in the triggering of mesenchymal proliferation in peripheral pulmonary arteries. We hypothesize that radical injury to pulmonary vascular walls is involved in collagenolytic metalloproteinase activation., J. Novotná, J. Herget., and Obsahuje bibliografii
Neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are increasing in prevalence. Currently, there are no effective and specific treatments for these disorders. Recently, positive effects of the orexigenic hormone ghrelin on memory and learning were demonstrated in mouse models of AD and PD. In this study, we tested the potential neuroprotective properties of a stable and long-lasting ghrelin analog, Dpr3ghrelin (Dpr3ghr), in SH-SY5Y neuroblastoma cells stressed with 1.2 mM methylglyoxal (MG), a toxic endogenous by-product of glycolysis, and we examined the impact of Dpr3ghr on apoptosis. Pre-treatment with both 10-5 and 10-7 M Dpr3ghr resulted in increased viability in SH-SY5Y cells (determined by MTT staining), as well as reduced cytotoxicity of MG in these cells (determined by LDH assay). Dpr3ghr increased viability by altering pro-apoptotic and viability markers: Bax was decreased, Bcl-2 was increased, and the Bax/Bcl-2 ratio was attenuated. The ghrelin receptor GHS-R1 and Dpr3ghr-induced activation of PBK/Akt were immuno-detected in SH-SY5Y cells to demonstrate the presence of GHS-R1 and GHS-R1 activation, respectively. We demonstrated that Dpr3ghr protected SH-SY5Y cells against MG-induced neurotoxicity and apoptosis. Our data suggest that stable ghrelin analogs may be candidates for the effective treatment of neurodegenerative disorders., A. Popelová, A. Kákonová, L. Hrubá, J. Kuneš, L. Maletínská, B. Železná., and Seznam literatury
Preadipocyte factor-1 (Pref-1) is a member of epidermal growthfactor like family of proteins that regulates adipocyte and osteoblast differentiation. Experimental studies suggest that circulating Pref-1 levels may be also involved in the regulation of lipid and glucose metabolism and energy homeostasis. We hypothesized that alterations in Pref-1 levels may contribute to the ethiopathogenesis of anorexia nervosa or its underlying metabolic abnormalities. We measured Pref-1 concentrations and other hormonal, biochemical and anthropometric parameters in eighteen patients with anorexia nervosa and sixteen healthy women and studied the influence of partial realimentation of anorexia nervosa patients on these parameters. The mean duration of realimentation period was 46±2 days. At baseline, anorexia nervosa patients had significantly decreased body mass index, body weight, body fat content, fasting glucose, serum insulin, TSH, free T4, leptin and total protein. Partial realimentation improved these parameters. Baseline serum Pref-1 levels did not significantly differ between anorexia nervosa and control group (0.26±0.02 vs. 0.32±0.05 ng/ml, p=0.295) but partial realimentation significantly increased circulating Pref-1 levels (0.35±0.04 vs. 0.26±0.02 ng/ml, p<0.05). Postrealimentation Pref-1 levels significantly positively correlated with the change of body mass index after realimentation (r=0.49, p<0.05). We conclude that alterations in Pref-1 are not involved in the ethiopathogenesis of anorexia nervosa but its changes after partial realimentation could be involved in the regulation of adipose tissue expansion after realimentation., P. Kaválková ... [et al.]., and Obsahuje seznam literatury
a1_A new concept of cardioprotection based on the exploitation of endogenous mechanisms is known as ischemic preconditioning (IPC). It has been hypothesized that substances released during brief ischemic stress (e.g. catecholamines) stimulate the receptors and trigger multiple cell signaling cascades. Opening of ATP-sensitive K+ channels [K(ATP)] has been suggested as a possible final step in the mechanisms of protection. In this study, the role of adrenergic activation was tested in Langendorff-perfused rat hearts subjected to test ischemia (TI; 30 min occlusion of LAD coronary artery) by: 1) mimicking IPC (5 min ischemia, 10 min reperfusion) with short-term (5 min) administration of norepinephrine (NE, 1 µM), 15 min prior to TI; 2) blockade with b- or a1-receptor antagonists, propranolol (10 µM) and prazosin (2 µM), respectively, applied 15 min prior to TI during IPC. The role of K(ATP) opening was examined by perfusion with a K(ATP) blocker glibenclamide (10 mM) during IPC. Both IPC and NE-induced PC effectively reduced the incidence of ventricular tachycardia (VT) to 33 % and 37 %, respectively, vs 100 % in the non-PC controls, whereby ventricular fibrillation (VF) was totally abolished by IPC and markedly suppressed by PC with NE (0 % and 10 %, respectively, vs 70 % in the non-PC hearts; P<0.05). The severity of arrhythmias (arrhythmia score, AS) was also markedly attenuated by both interventions (IPC: AS 1.7±0.4; NE-PC: AS 1.8±0.3 vs AS 4.1±0.2 in the controls; P<0.05). Protection was not suppressed by propranolol (VT 28 %; VF 14 %; AS 2.2±0.6), whereas prazosin reversed the protective effect of PC (VT 83 %; VF 67 %; AS 4.0±0.8). Antiarrhythmic protection afforded by NE-PC was abolished by pretreatment of rats with pertussis toxin (25 mg/kg, i.p.) given 48 h prior to the experiments., a2_Glibenclamide did not suppress the IPC-induced protection. In conclusion, the sensitivity of the rat heart to ischemic arrhythmias can be modulated by IPC. Protection is mediated via stimulation of a1-adrenergic receptors coupled with Gi-proteins but glibenclamide-sensitive K(ATP) channels do not appear to be involved in the mechanisms of antiarrhythmic protection in this model., T. Ravingerová, D. Pancza, A. Ziegelhoffer, J. Styk., and Obsahuje bibliografii
Ankylosing spondylarthritis (AS) is associated falsely increased lumbar spine bone mineral density (BMD). New tool for discrimination of subjects at fracture risk is needed. Vertebral fracture (VF) prediction of routine methods for osteoporosis assessment, BMD and trabecular bone score (TBS), in patients with AS. Cross-sectional study of all AS patients regularly followed at the rheumatology outpatient clinics of two centers. All subjects undergone BMD measurement at lumbar spine (LS), total hip (TH) and femoral neck (FN) using Hologic® Horizon device. TBS at L1-4 in all subjects by TBS InSight® software were assessed. Vertebral fracture assessment (VFA) was performed using the lateral spine imaging IVA™ and graded using Genant semi-quantitative approach. 119 AS subjects (90 males/29 females), mean age 47.6 years were included in the study. In 20 patients 34 VFs were detected, from whom 7 patients had multiple fractures. Subjects with VF were older and had lower FN BMD, TBS in comparison to non-VF subjects. No differences in LS BMD, FN BMD or BASDAI between groups were observed. Among patients with VF only 3 had T-score less than -2.5 but 7 has TBS less than 1.23 which means highly degraded microarchitecture. AS patients with VF have lower TBS and FN BMD in comparison to non-VF subjects. In addition, TBS was able to detect 20 % more VFs than BMD. Therefore, TBS seems promising in VF discrimination among patients with AS., Zdenko Killinger, Martin Kužma, Soňa Tomková, Kristína Brázdilová, Peter Jackuliak, Juraj Payer., and Obsahuje bibliografii
Increasing hemodynamic load during early postnatal development leads to rapid growth of the left ventricular (LV) myocardium, which is associated with membrane phospholipid (PL) remodeling characterized by n-3 polyunsaturated fatty acids (PUFA) accumulation. The aim of this study was to examine the influence of additional workload imposed early after birth when ventricular myocytes are still able to proliferate. Male Wistar rats were subjected to abdominal aortic constriction (AC) at postnatal day 2. Concentrations of PL and their fatty acid (FA) profiles in the LV were analyzed in AC, sham-operated (SO) and intact animals on postnatal days 2 (intact only), 5 and 10. AC resulted in LV enlargement by 22 % and 67 % at days 5 and 10, respectively, compared with age-matched SO littermates. Concentrations of phosphatidylcholine, cardiolipin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and sphingomyelin decreased in AC myocardium, albeit with different time course and extent. The main effect of AC on FA remodeling consisted in the accumulation of n-3 PUFA in PL. The most striking effect of AC on FA composition was observed in phosphatidylinositol and cardiolipin. We conclude that excess workload imposed by AC inhibited the normal postnatal increase of PL concentration while further potentiating the accumulation of n-3 PUFA as an adaptive response of the developing myocardium to accelerated growth., F. Novák, ... [et al.]., and Obsahuje seznam literatury