Neuroactive steroids represent potential antiepileptic drugs. We tested a newly synthesized analogue of allopregnanolone 3α- hydroxy-21ξ,22-oxido-21-homo-5α-pregnan-20-on (HOHP) against two types of pentylenetetrazol-induced seizures (100 mg/kg s.c.) in 12- and 25-day-old rats. Ganaxolone, a neuroactive steroid in clinical trials, served as a reference drug. Pretreatment with either steroid suppressed generalized tonicclonic seizures in both age groups, their efficacy was comparable. HOHP as well as ganaxolone were more active in 12- than in 25-day-old rats (effective doses were 40 and 60 mg/kg, respectively). Minimal clonic seizures, which can be elicited only in 25-day-old rats, were not influenced by any drug. Very short duration of anticonvulsant action of HPOP demonstrated in 12-day-old animals indicates that this drug might be used only in acute treatment in epileptology., P. Mareš, H. Kubová, A. Kasal., and Obsahuje bibliografii a bibliografické odkazy
GABA-B receptor agonist SKF97541 exhibits age-dependent anticonvulsant and proconvulsant actions in developing rats. It suppressed tonic phase of generalized seizures induced by pentetrazol in 7-, 12- and 18-day-old rats and increased their latency in 7- and 12-day-old animals. Other results in 18-day-old animals are not so clear. SKF 97541 blocked the appearance of minimal clonic seizures, but tended to decrease latencies of both types of seizures. In addition, it significantly decreases latency of generalized seizures in adult rats. The mixed effects of SKF97541 are in agreement with those of baclofen but there are substantial differences between the actions of these two agonists in individual age groups., P. Mareš., and Obsahuje bibliografii a bibliografické odkazy
Diabetes mellitus is characterized by oxidative stress, which in turn determines endothelial dysfunction. Gliclazide is a sulphonylurea antidiabetic drug with antioxidant effects due to its azabicyclo-octyl ring. It has been reported to potentially protect the vasculature through improvements in plasma lipid levels and platelet function. We hypothesized that gliclazide has a beneficial effect on endothelial function in Goto-Kakizaki rats (GK), an animal model of type 2 diabetes fed an atherogenic diet for 4 months. We evaluated the influence of gliclazide on both metabolic and oxidative status and NO-mediated vasodilation. GKAD rats showed increased oxidative stress and impaired endothelium-dependent vasodilation. GKAD rats treated with gliclazide showed increased sensitivity to NO-mediated vasodilation, a significant decrease in fasting glycemia and insulinemia, and a significant decrease in systemic oxidative stress. In conclusion, our results suggest that gliclazide treatment improves NO-mediated vasodilation in diabetic GK rats with dyslipidemia probably due to its antioxidant effects, although we cannot rule out substantial benefits due to a reduction in fasting blood glucose. The availability of a compound that simultaneously decreases hyperglycemia, hyperinsulinemia, and inhibits oxidative stress is a promising therapeutic candidate for the prevention of vascular complications of diabetes., C. M. Sena ... [et al.]., and Obsahuje seznam literatury
Plant-based n-3 polyunsaturated fatty acids (PUFA) possess a prospective antiatherogenic potential. Currant oil from Ribes nigrum L. is one of the few plant oils containing PUFAn-3 (15.3 mol%) in addition to PUFAn-6 (60.5 mol%). This study was aimed at comparing the effects of currant oil with those of lard fat, rich in saturated (43.8 mol%) and monounsaturated (47.0 mol%) fatty acids, on antioxidant parameters, the lipoprotein profile and liver lipids in rats fed on 1 % (w/w) cholesterol diets containing either 10 % of currant oil (COD) or lard fat (LFD). After 3 weeks of feeding, the COD induced a significant decrease in blood glutathione (GSH) and an increase in Cu2+ induced oxidizability of serum lipids, but did not affect liver GSH and t-butyl hydroperoxide-induced lipoperoxidation of liver microsomes. Although the COD did not cause accumulation of liver triacylglycerols as LFD, the lipoprotein profile (VLDL, LDL, HDL) was not significantly improved after COD. The consumption of PUFAn-3 was reflected in LDL as an increase in eicosapentaenoic and docosahexaenoic acid. These results suggest that currant oil affects positively the lipid metabolism in the liver, above all it does not cause the development of a fatty liver. However, adverse effects of currant oil on the antioxidant status in the blood still remain of concern., R. Večeřa, N. Škottová, P. Váňa, L. Kazdová, Z. Chmela, Z. Švagera, D. Walterová, J. Ulrichová, V. Šimánek., and Obsahuje bibliografii
Impaired cerebrovascular reactivity (CVR), an important risk factor for future stroke, is affected by a presence carotid stenosis. However, in some cases CVR can be impaired in the absence of carotid stenosis due to several poorly characterized mechanisms. We hypothesized that arterial stiffening as observed in coronary heart disease (CHD) could be associated with alteration in CVR in CHD patients without carotid stenosis. The study population consisted of patients referred for coronary angiography without significant carotid stenosis (<50 %). CVR was evaluated by breath holding index (BHI) measured with transcranial color code duplex ultrasound. Arterial stiffness was assessed by pulse wave velocity (PWV) measured by the oscillometric method. The extent of coronary atherosclerosis was quantified by Gensini score (GS). Out of 186 subjects, sixty-two patients fulfilled the inclusion and exclusion criteria. BHI decreased with increasing PWV (r = -0.47, p<0.001). Decrease in BHI was significantly inversely associated with GS (r = -0.61, p<0.001). GS was associated with PWV (p<0.001). In conclusion, impaired CVR was associated with increased arterial stiffening in CHD patients in the absence of significant carotid stenosis. Thus, we speculate that increased arterial stiffness may at least partially contribute to the pathophysiology of CVR alteration in coronary artery disease., D. Rucka, J. Marek, Z. Rucklova, J.-C. Lubanda, S. Havranek, J. Skvaril, P. Varejka, M. Chochola, D. Karetova, J. Korinek, A. Linhart., and Obsahuje bibliografii
A predominance of small, dense low-density lipoproteins (LDL) is characteristic of the dyslipidemic state seen in type 2 diabetes. However, no study has investigated the association in gestational diabetes mellitus (GDM), which is pathophysiologically similar to type 2 diabetes. We hypothesized that LDL particle size is reduced in GDM cases compared with controls. Gradient gel electrophoresis was used to characterize LDL subclass phenotypes in non-fasting intrapartum plasma from 105 GDM cases and 96 controls. All participants were free of pre-existing diabetes or hypertension. The authors used logistic regression to estimate odds ratios (OR) and 95 % confidence intervals (CI) adjusted for confounders. Women with this phenotype had a significant 4.9-fold (95 % CI: 1.1-23.2) increased risk of GDM compared with those with the large, buoyant phenotype. The magnitude of this association was attenuated when plasma triglyceride and other confounders were included in the model (OR=4.2, 95 % CI: 0.5-39.5). Mean LDL particle size in GDM cases was smaller compared with controls (270.1 vs. 272.7Å, p=0.003). The OR of GDM risk was 1.8 (95 % CI: 0.9-3.3) for every 10-Å reduction in LDL particle size. Large prospective studies are needed to evaluate the association between smaller LDL particle size in early pregnancy with subsequent GDM risk., C. Qiu, C. Rudra, M. A. Austin, M. A. Williams., and Obsahuje bibliografii a bibliografické odkazy
We assessed association between novel biomarkers of cardiovascular disease and conven tional factors in 40 years old subjects (208 men and 266 women) from the general population of Slovakia. FER HDL (cholesterol esterifi cation rate in HDL plasma), AIP - Atherogenic Index of Plasma [Log(TG/HDL-C)] as markers of lipoprotein particle size, and CILP2, FTO and MLXIPL polymorphisms, were examined in relation to biomarkers and conventional risk factors. Un ivariate analyses confirmed correlation between AIP, FERHDL and the most of measured parameters. Relations between AIP and CILP2, FTO and MLXIPL were not significant. However, CILP2 was significantly related to FERHDL in both genders. In multivariate analysis BMI was the strongest correlate of AIP levels. In multivariate model variability of FER HDL was best explained by AIP (R2 =0.55) in both genders with still significant effect of CILP2 SNP in men. In a model where AIP was omitted, TG leve ls explained 43 % of the FER HDL variability in men, while in women HDL-C was the major determinant (42 %). In conclusions, FERHDL and AIP related to the known markers of cardiovascular risk provide means to express their subtle interactions by one number. Our novel finding of association between CILP2 polymorphism and FERHDL supports its role in lipid metabolism., K. Rašlová ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Level of asymmetric dimethylarginine (ADMA) is elevated and endothelial progenitor cells (EPC) and stem cells (SC) are decreased in patients undergoing renal transplantation (Tx) and may contribute to cardiovascular complications. We tested the hypothesis that ADMA, EPC and SC can be influenced with regular physical exercise early after Tx. Blood samples of ADMA, EPC, SC, adipocytokines and metabolic parameters were randomly obtained from 50 transplant patients before and 6 months after exercise program (Group I). Fifty age, sex HLA typing, duration of dialysis and immunosupression regimen-matched non exercising transplant were examined as controls (Group II). After 6 months, in Group I ADMA decreased (3.50±0.45 vs 2.11±0.35 μmol/l, P<0.01) and was lower comparing to Grou II (P<0.01), SC and EPC also decreased (2816±600 vs 2071±480 cells/ml resp. 194±87 to 125±67 cells/ml, P<0.02). Next changes in Group I: adiponectin (P<0.01), leptin (P<0.01), resistin (P<0.02). Visfatin, blood lipids, HbA1c, insulin and blood pressure were also influenced by training program (P<0.05)., V. Teplan, I. Králová Lesná, J. Piťha, A. Mahrová, J. Racek, I. Valkovský, A. Sekerková, M. Štollová., and Obsahuje bibliografii
Each cell types or tissues contain certain “physiological” levels of R-2-hydroxyglutarate (2HG), as well as enzymes for its synthesis and degradation. 2HG accumulates in certain tumors, possessing heterozygous point mutations of isocitrate dehydrogenases IDH1 (cytosolic) or IDH2 (mitochondrial) and contributes to strengthening their malignancy by inhibiting 2-oxoglutaratedependent dioxygenases. By blocking histone de-methylation and 5-methyl-cytosine hydroxylation, 2HG maintains cancer cells de-differentiated and promotes their proliferation. However, physiological 2HG formation and formation by non-mutant IDH1/2 in cancer cells were neglected. Consequently, low levels of 2HG might play certain physiological roles. We aimed to elucidate this issue and found that compared to highest 2HG levels in hepatocellular carcinoma HepG2 cells and moderate levels in neuroblastoma SH-SY5Y cells, rat primary fibroblast contained low basal 2HG levels at early passages. These levels increased at late passage and likewise 2HG/2OG ratios dropped without growth factors and enormously increased at hypoxia, reaching levels compared to cancer HepG2 cells. Responses in SH-SY5Y cells were opposite. Moreover, external 2HG supplementation enhanced fibroblast growth. Hence, we conclude that low 2HG levels facilitate cell proliferation in primary fibroblasts, acting via hypoxia-induced factor regulations and epigenetic changes., A. Dvořák, J. Zelenka, K. Smolková, L. Vítek, P. Ježek., and Obsahuje bibliografii
During vertebrate evolution, structural changes in red blood cells (RBC) and hemoglobin (Hb), have probably resulted in the importance of blood carbon dioxide transport. The chloride/bicarbonate exchange across the RBC membrane, which is an integral part of the blood CO2 transport process in vertebrates, has been examined on two different species of teleost fish, Euthynnus alletteratus and Thunnus thynnus, at several oxygenation states of erythrocyte HOS (high-oxygenation state, about 90 % of saturation) and LOS (low-oxygenation state, about 15 % of saturation). The results were compared with those observed in human RBC under the same experimental conditions and with the chicken (Gallus gallus) erythrocytes, which have particular modifications at the N-terminus of the band 3 protein (B3). In fish the kinetic measurements have shown a different anion transport in several oxygenation states of erythrocytes, indicating that also at lower levels of vertebrate evolution there exists a modulation of the anionic flow affected by oxygen. The functional correlation of anion transport to changes of parts of the hemoglobin sequence responsible for alterations in the interactions with the cytoplasmic domain of band 3 protein (cdb3) allowed us to suggest a hypothesis about fish physiology. The highest values of kinetic measurements observed in fish have been attributed to the metabolic need of the RBC in response to the removal of CO2 that in teleosts is also of endogenous origin., A. Russo, E. Tellone, S. Ficarra, B. Giardina, E. Bellocco, G. Lagana, U. Leuzzi, A. Kotyk, A. Galtieri., and Obsahuje bibliografii a bibliografické odkazy