Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve a nd inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They br ought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-α and other proinflammatory cytokines prod uction and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey's inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of va gally-mediated anti-inflammatory pathway in the treatment strategies., I. Zila, D. Mokra, J. Kopincova, M. Kolomaznik, M. Javorka, A. Calkovska., and Obsahuje bibliografii
It is important to determine and clarify the variability of mammary carcinogenesis induction in animal experimental studies particularly in connection with chemoprevention projects. The circannual seasonal rhythms of hormone levels or various parameters within the immune system may involve factors participating in mammary gland carcinogenesis. In our study, 19 experiments were conducted and all of them lasted for about 25 weeks after chemical carcinogen administration (DMBA or NMU) under standard laboratory conditions. Females of two rat strains - a medium susceptible Sprague-Dawley strain and a very low susceptible Wistar:Han were used. We observed not only the effect of seasonal changes but also the effect of age after single or repeated carcinogen administration. The seasonal dependence of mammary carcinogenesis with higher tumor incidence during long days in comparison with winter short days has been demonstrated in Sprague-Dawley rats. In experiments on the Wistar:Han strain, certain features of seasonal character were recorded, although the very low susceptibility of this strain to mammary carcinogenesis might have influenced the results. A limited period of carcinogen administration in early puberty around postnatal days 43-46 (higher susceptibility), when compared to the period after postnatal day 50, is the factor significantly increasing incidence and frequency of mammary carcinogenesis in the Sprague-Dawley strain. Our results indicate the need to consider the effect of season and age of animals at the time of carcinogen administration on rat mammary carcinogenesis induction. However, the application of the results obtained in one strain of experimental animals may only lead to misleading conclusions., P. Kubatka, E. Ahlersová, I. Ahlers, B. Bojková, K. Kalická, E. Adámeková, M. Marková, M. Chamilová, M. Čermáková., and Obsahuje bibliografii
In the process of population screening for apo E gene polymorphism with the PCR and subsequent restriction analysis, we identified a female who demonstrated heterozygosity for an unusual restriction fragment caused by the loss of a CfoI restriction site. Sequence analysis of the apo E gene was performed and a carrier of the mutant allele with C - T substitution at cDNA position 3817 was identified, which caused an Arg136 - Cys change. The first-line relatives have been screened for this rare mutation with PCR and restriction analysis of PCR products. The complete lipoprotein parameters have been determined in the probands family. In the family, only one child had the same mutant allele as his mother had. The proband (7.49 mmol/l) with her siblings had hypercholesterolemia and a high body mass index (BMI 31.6 kg/m2). By contrast, her son had a normal lipid spectrum with normal BMI. We described the mutation apo E2* (Arg136 - Cys) in a family with elevated lipid levels, but there was no confirmation of the connection between this mutation and type III hyperlipoproteinemia or hyperlipoproteinemia at all. In the case of this mutation, other factors (mainly genetic) are important for the development of lipid metabolism disorders., J. A. Hubáček, J. Piťha, P. Stávek, G. Schmitz, R. Poledne., and Obsahuje bibliografii
The aim of the present pilot pharmacogenetic study was to analyse quantitative effects of sulphonylurea treatment in addition to metformin on parameters of glycemic control with respect to CDKAL1 genotypes in patients with type 2 diabetes. Effect of 6-month sulphonylurea therapy on glycemic control according to CDKAL1 genotypes was evaluated in 101 patients with type 2 diabetes who failed to achieve glycemic control on metformin monotherapy. CDKAL1 rs7756992 polymorphism was determined by melting curve analysis of small amplicon following real-time PCR. After sulphonylurea treatment fasting plasma glucose (FPG) levels were significantly different (p=0.045) among three CDKAL1 genotype groups (AA: n=49; AG: n=36; GG: n=16). In a dominant genetic model, carriers of the G-allele (AG+GG, n=52) achieved significantly lower FPG levels in comparison with patients with the AA genotype (6.90±1.08 vs. 7.48±1.12 mmol/l, p=0.013). Consequently, adjusted ΔFPG was significantly higher in the AG+GG compared to the AA group (1.48±1.51 vs. 1.02±1.33 mmol/l, p=0.022). Similar trend was observed for HbA1c levels, but the difference between the genotype groups did not reach the level of statistical significance. Relatively small number of included patients is a limitation of the present study. In conclusion, our results suggest that the magnitude of FPG reduction after 6-month sulphonylurea treatment in patients with type 2 diabetes is related to the variation in CDKAL1., Z. Schroner ... [et al.]., and Obsahuje seznam literatury
The purpose of this study was to determine the role of lipotoxicity in vascular smooth muscle (VSM). C1-BODIPY 500/510 C12 used to assess the ability of VSM A7r5 cells to transport long-chain fatty acids showed that lipid transport did not appear to limit metabolism. Thin layer chromatography revealed that storage of transported fatty acid occurred primarily as mono- and diglycerides and fatty acids but not as triglycerides. We used lipid-induced apoptosis as a measure of lipotoxicity and found that 1.5 mM palmitate (6.8:1) bound to albumin resulted in a 15-fold increase in the number of apoptotic cells compared to the control at 24 hours. This apoptosis did not seem to be due to an increase in reactive oxygen species (ROS) since VSM cells incubated in palmitate showed less ROS production than cells incubated in albumin only. Similar exposure to oleate did not significantly increase the number of apoptotic cells compared to the control. Oleate actually significantly attenuated the apoptosis induced by palmitate, suggesting that unsaturated fatty acids have a protective effect on cells undergoing palmitate-induced apoptosis. These results suggest that vascular smooth muscle is vulnerable to lipotoxicity and that this lipotoxicity may play a role in the development of atherosclerosis., H. M. Mattern, C. D. Hardin., and Obsahuje bibliografii a bibliografické odkazy
Vascular stenosis is often described only by its percentage in both clinical and scientific praxis. Previous studies gave inconclusive results regarding the effect of stenosis eccentricity on its hemodynamic effect. The aim of this experimental study was to investigate and quantify the effect of stenosis severity and eccentricity on the pressure drop. A combination of pressure and flow measurements by Par ticle Imaging Velocimetry (PIV) method was used. Models of the same stenosis significance but with different levels of eccentricity were studied in vitro by PIV. This study has shown that stenosis asymmetry is associated with more profound pressure drop an d flow volume decrease. On the contrary, pressure drop and flow volume decrease were not further significantly influenced by the level of asymmetry. Hemodynamic changes associated with stenosis eccentricity must be taken into account in both clinical and s cientific studies., L. Novakova, J. Kolinsky, J. Adamec, J. Kudlicka, J. Malik., and Obsahuje bibliografii
The effects of transient and sustained hyperthyroidism on vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) levels were studied in the heart atria of developing and adult rats. Newborn rats were divided into 5 groups. Neo-T animals were treated with thyroxine (T4) during postnatal days 1-8 and sacrificed at the age of 60 days. Neo-S rats were treated with T4 during postnatal days 1-60 and sacrificed one day later. Adult-1 and Adult-2 animals received T4 during days 52-60 and were sacrificed 5-6 days and 1 day later, respectively. Control animals were injected with saline. VIP-LI concentrations were determined in extracts from the left and right atria separately. In Neo-S and Adult-2 rats, spontaneous heart rate, the weight of both atria and total T4 serum levels were significantly enhanced, while their body weight was decreased. The ratio atria weight to body weight was significantly increased in all groups except for Adult-1 animals. Hyperthyroidism led to a significant decrease in VIP-LI levels in both atria of Neo-S and Neo-T rats. Hyperthyroidism induced in adult rats also decreased VIP-LI levels in both atria. However, this change was only transient. In conclusion, our data have provided new evidence that hyperthyroidism induced during the early neonatal period interferes with the development of VIP-ergic innervation in rat atria. The period of the first few postnatal days seems to be essential for this effect, since VIP-LI concentrations in 60-day-old animals did not significantly differ between Neo-S and Neo-T atria., J. Kuncová, J. Slavíková., and Obsahuje bibliografii
Pathophysiological mechanisms underlying the development of renal dysfunction and progression of congestive heart failure (CHF) remain poorly understood. Recent studies have revealed striking differences in the rol e of epoxyeicosatrienoic acids (EETs), active products of cytochrome P-450-dependent epoxygenase pathway of arachidonic acid, in the progression of aorto-caval fistula (ACF)-induced CHF between hypertensive Ren-2 renin transgenic rats (TGR) and transgene-negative normotensive Hannover Sprague-Dawley (HanSD) controls. Both ACF TGR and ACF HanSD strains exhibited marked intrarenal EETs deficiency and impairment of renal function, and in both strains chronic pharmacologic inhibition of s oluble epoxide hydrola se (sEH) (which normally degrades EETs) normalized EETs levels. However, the treatment improved the survival rate and attenuated renal function impairment in ACF TGR only. Here we aimed to establish if the reported improved renal function and attenuation o f progression of CHF in ACF TGR observed after sEH blockade depends on increased vasodilatory responsiveness of renal resistance arteries to EETs. Therefore, we examined the responses of interlobar arteries from kidneys of ACF TGR and ACF HanSD rats to EET-A, a new stable 14,15-EET analog. We found that the arteries from ACF HanSD kidneys rats exhibited greater vasodilator responses when compared to the ACF TGR arteries. Hence, reduced renal vasodilatory responsiveness cannot be responsible for the lack of beneficial effects of chronic sEH inhibition on the development of renal dysfunction and progression of CHF in ACF HanSD rats., A. Sporková, Z. Husková, P. Škaroupková, N. Rami Reddy, J. R. Falck, J. Sadowski, L. Červenka., and Obsahuje bibliografii
The aim of this study was to test the hypothesis that vasorelaxing action of vasonatrin peptide (VNP) is due to activation of the large-conductance Ca2+-activated potassium channel (BKCa) via guanylyl cyclase (GC)-coupled natriuretic peptide receptors (NPRs) in vascular smooth muscle cells (VSMCs). Contraction experiments were performed using human radial artery, whereas BKCa current by patch clamp was recorded in cells from rat mesenteric artery. Contractility of rings cut from human radial artery was detected in vitro. As a result, VNP induced a dose-dependent vasorelaxation of human radial artery, which could be mimicked by 8-Br-cGMP, and suppressed by TEA, a blocker of BKCa, HS-142-1, a blocker of GC-coupled NPRs, or methylene blue (MB), a selective inhibitor of guanylyl cyclase. Sequentially, whole-cell K+ currents were recorded using patch clamp techniques. BKCa current of VSMCs isolated from rat mesentery artery was obtained by subtracting the whole cell currents after applications of 10-7 mol/l iberiotoxin (IBX) from before its applications. In accordance with the results of arterial tension detection, BKCa current was significantly magnified by VNP, which could also be mimicked by 8-Br-cGMP, whereas suppressed by HS-142-1, or MB. Taken together, VNP acts as a potent vasodilator, and NPRA/B-cGMP-BKCa is one possible signaling system involved in VNP induced relaxation., J. Yu ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The aim of this study is to define the possible effects of vegetable oils used as vitamin E vehicle on the electrical activity of the rat heart. To test the possible effects of vitamin E vehicles we studied the effect of i.p. injected corn oil, hazelnut oil or peanut oil on the action potential parameters recorded in both papillary and left atrial muscle strips. Four experimental groups were used. The control group was injected (i.p.) with distilled water, while the three remaining groups received injections of corn oil, hazelnut oil, or peanut oil for five weeks (in a dose of 0.4 ml/kg/day - minimum amount of oil in which vitamin E could be dissolved). We used borosilicated (15-20 MΩ) capillary electrodes and intracellular action potentials (AP) were recorded in isolated papillary and left atrium muscle strips. While administration of three different types of vegetable oil had no significant effect on AP parameters of papillary muscle, they significantly prolonged the repolarization phase of AP in atrial strips. These results show that vegetable oils used as vitamin E vehicles may alter the electrical activity of the heart in a tissue-dependent manner. The present data indicate that the possible effect of vegetable oil vehicles should be kept in mind while evaluating the possible effects of in vivo vitamin E administration., S. Ozdemir, M. Ayaz, T. Tuncer, M. Ugur, B. Turan., and Obsahuje bibliografii