Endothelin B (ETB) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ETB receptors stimulation using a highly specific agonist, IRL-1620, to treat CNS disorders. In a rat model of cerebral ischemia intravenous administration IRL-1620 significantly reduced infarct volume and improved neurological and motor functions compared to control. This improvement, in part, is due to an increase in neuroregeneration. We also investigated the role of IRL-1620 in animal models of Alzheimer’s disease (AD). IRL-1620 improved learning and memory, reduced oxidative stress and increased VEGF and NGF in Aβ treated rats. IRL-1620 also improved learning and memory in an aged APP/PS1 transgenic mouse model of AD. These promising findings prompted us to initiate human studies. Successful chemistry, manufacturing and control along with mice, rat and dog toxicological studies led to completion of a human Phase I study in healthy volunteers. We found that a dose of 0.6 μg/kg of IRL-1620 can be safely administered, three times every four hours, without any adverse effect. A Phase II clinical study with IRL-1620 has been initiated in patients with cerebral ischemia and mild to moderate AD., A. Gulati, M. G. Hornick, S. Briyal, M. S. Lavhale., and Seznam literatury
The purpose of the present study was to examine the role of the T-786C endothelial nitric oxide synthase (eNOS) gene polymorphism on changes in renal hemodynamics and blood pressure due to Na+ loading. Twenty-eight older (63±1 years), moderately obese (39±2 % fat) hypertensives had th eir glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure (BP) and plasma nitric oxide (NOx) levels determined after eight days of low (20 mEq) and high (200 mEq) Na+ diets. The two Na+ diets were separated by a 1-week washout period. Subjects were genotyped for the eNOS-786 site and were grouped on whether they were homozygous or heterozygous for the C allele (TC+CC, n=13) or only homozygous for the T allele (TT, n=15). The TC+CC genotype group had a significantly greater increase in diastolic (P=0.021) and mean arterial (P=0.018) BP and a significant decline in both RPF (P=0.007) and GFR (P=0.029) compared to the TT genotype group with Na+ loading. Furthermore, Na+ loading resulted in a significant (P=0.036) increase in plasma NOx in the TT, but not in the TC+CC genotype group as well as a trend (P=0.051) for an increase in urine NOx in TC+CC, but not in the TT genotype group. The increase in BP during Na+ loading in older hypertensives was associated with the eNOS genotype and may be related to changes in renal hemodynamics due to changes in NO metabolism., D. R. Dengel, M. D. Brown, R. E. Ferrell, T. H. Reynolds, M. A. Supiano., and Obsahuje bibliografii a bibliografické odkazy
Parallel glucose measurements in blood and other different tissues give us knowledge about dynamics of glycemia changes, which depend on vascularization, distribution space and local utilization by tissues. Such information is important for the understanding of glucose homeostasis and regulation. The aim of our study was to determine the time-lag between blood, brain, and adipose tissue during rapid glucose changes in a male hHTG rat (n=15). The CGMS sensor Guardian RT (Minimed/Medtronic, USA) was inserted into the brain and into the abdominal subcutaneous tissue. Fixed insulin and variable rate of glucose infusion was used to maintain euglycemia during sensor calibration period. At 0 min, 0.5 g/kg of bolus of glucose was administered, and at 50 min, 5 IU/kg of bolus of insulin was administered. Further glucose and insulin infusion was stopped at this time. The experiment was finished at 130 min and animals were euthanized. The time-shift between glycemia changes in blood, brain, and subcutaneous tissue was calculated by identification of the ideal correlation function. Moreover, the time to achieve 90 % of the maximum glucose excursion after intervention (T90) was measured to compare our data with the literature. The time-lag blood vs. brain and blood vs. subcutaneous tissue was 10 (10; 15) min and 15 (15; 25) min, respectively. The difference was statistically significant (P=0.01). T90 after glucose bolus in brain and subcutaneous tissue was 10 min (8.75; 15) and 15 min (13.75; 21.25), respectively. T90 after insulin bolus in brain and subcutaneous tissue was 10 min (10; 15) and 20 min (20; 27.5), respectively. To the contrary, with literature, our results showed earlier glucose level changes in brain in comparison with subcutaneous tissue after glucose and insulin boluses. Our results suggest that glucose dynamics is different within monitored tissues under rapid changing glucose level and we can expect similar behavior in humans. Improved knowledge about glucose distribution and dynamics is important for avoiding hypoglycemia., M. Žourek, P. Kyselová, D. Čechurová, Z. Rušavý., and Seznam literatury
Advanced glycation end products (AGEs) may play an important adverse role in process of atherosclerosis, diabetes, aging and chronic renal failure. Levels of Ne-carboxymethyllysine and fluorescent AGE values were estimated in two nutritional population groups - alternative group (vegetarians - plant food, milk products, eggs) and traditional group (omnivorous subjects). Vegetarians have a significantly higher carboxymethyllysine content in plasma and fluorescent AGE values. Intake of proteins, lysine and monosaccharides as well as culinary treatment, consumption of food AGEs (mainly from technologically processed products) and the routes of Maillard reaction in organism are the substantial sources of plasma AGEs. Vegetarians consume less proteins and saccharides. Lysine intake is significantly reduced (low content in plant proteins). Subjects on alternative nutrition do not use high temperature for culinary treatment and consume low amount of technologically processed food. Fructation induced AGE fluorescence is greater as compared with that induced by glucose. It is due to higher participation of a more reactive acyclic form of fructose. Intake of vegetables and fruit with predominance of fructose is significantly higher in vegetarians. Comparison of nutrition and plasma AGEs in vegetarian and omnivorous groups shows that the higher intake of fructose in alternative nutrition of healthy subjects may cause an increase of AGE levels., M. Krajčovičová-Kudláčková, K. Šebeková, R. Schinzel., and Obsahuje bibliografii
Accelerated glycoxidation takes part in the development of diabetic complications. We determined advanced glycation end-products (AGEs) and advanced oxidation protein products (AOPP) in the sera of 52 patients with diabetes mellitus (DM) - 18 with DM Type 1 and 34 with DM Type 2 and examined their relationship to the compensation of the disease. AGEs were estimated spectrofluorimetrically (350 nm/440 nm) whereas AOPP were determined spectro-photometrically (340 nm). AGEs were elevated only in DM Type 2 (DM2 5.11±1.15x103 AU/g vs controls 4.08±0.71x103 AU/g, p<0.001, vs DM1 4.14±0.86x103 AU/g, p<0.005, DM1 vs controls were not significant). AOPP were elevated significantly in both types of DM with higher levels in DM Type 2 (DM2 157.50±75.15 mmol/l vs healthy subjects 79.80±23.72 mmol/l, p<0.001, vs DM1 97.50±30.91 mmol/l, p<0.005, DM1 vs controls p<0.05). There was a tight correlation between AGEs and AOPP in both types of DM (DM1 r=0.75, DM2 r=0.47 (p<0.05)) and both AGEs and AOPP correlated with triglycerides. In DM Type 1 only, AGEs correlated with HbA1c r=0.47 (p<0.05) and with blood glucose. Slight but not significant differences in AGEs and AOPP levels were observed in patients with or without diabetic complications. Oxidative stress is increased in both types of DM, more in Type 2 where it contributes to the formation of glycoxidation products., M. Kalousová, J. Škrha, T. Zima., and Obsahuje bibliografii
Because greater Akt substrate of 160 kDa (AS160) phosphorylation has been reported in insulin-stimulated skeletal muscles without improved Akt activation several hours post-exercise, we hypothesized that prior exercise would result in attenuated AS160 dephosphorylation in insulin-stimulated rat skeletal muscle. Epitrochlearis muscles were isolated from rats that were sedentary (SED) or exercised 3 h earlier (3 h postexercise; 3hPEX). Paired muscles were incubated with [3H]-2-deoxyglucose (2-DG) without insulin or with insulin. Lysates from other insulin-stimulated muscles from SED or 3hPEX rats were evaluated using AS160Thr642 and AS160Ser588 dephosphorylation assays. Prior exercise led to greater 2-DG uptake concomitant with greater AS160Thr642 phosphorylation and a non-significant trend (P=0.087) for greater AS160Ser588. Prior exercise also reduced AS160Thr642 and AS160Ser588 dephosphorylation rates. These results support the idea that attenuated AS160 dephosphorylation may favor greater AS160 phosphorylation post-exercise., E. B. Arias, H. Wang, G. D. Cartee., and Seznam literatury
Aldosterone plays a key role in maintaining the homeostasis of the whole organism. Under some circumstances, aldosterone can contribute to the progression of cardiovascular diseases, including coronary artery disease. This study demonstrates that aldosterone associates negatively with some lipidogram parameters and positively with the concentration of homocysteine. These associations are characteristic for coronary artery disease and are not present in control subjects. The findings also indicate that in vitro aldosterone stimulates homocysteine production by rat adrenal glands, which may explain the associations observed with coronary artery disease. Moreover, we have found that aldosterone significantly modulates in vitro platelet reactivity to arachidonate and collagen - aldosterone increases the pro-aggregatory action of collagen, but decreases the pro-aggregatory potential of arachidonate. Therefore, the findings of these in vitro and ex vivo experiments indicate the existence of new pathways by which aldosterone modulates lipid- homocysteine- and platelet-dependent atherogenesis., K. Karolczak, P. Kubalczyk, R. Glowacki, R. Pietruszynski, C. Watala., and Seznam literatury
The polymorphisms of the tumor suppressor gene p53 in exon 4 (p53 BstUI) and in intron 6 (p53 MspI) have been suggested to be associated with the genetically determined susceptibility in diverse types of human cancer. In our hospital-based case-control study, we examined the allele and genotype incidence of these polymorphisms as well as their haplotype combinations in 60 brain tumor patients (27 males and 33 females) and 183 controls without malignancies. The genotype characteristics were determined by the PCR-based RFLP method using DNA extracted from peripheral blood. In this study we show that the p53 BstUI and the p53 MspI polymorphisms are not associated with increased risk of brain tumors. Thus, we conclude that the p53 BstUI and the p53 MspI polymorphic sites within the tumor suppressor gene p53 do not represent genetic determinants of susceptibility to brain tumors., E. Biroš, I. Kalina, A. Kohút, E. Bogyiová, J. Šalagovič, I. Šulla., and Obsahuje bibliografii
Endothelin-1 (ET-1) acts on ETA and ETB receptors and has been implicated in hemorrhagic shock (shock). We determined effect of shock and resuscitation by hypertonic saline (saline) or centhaquin on ETA and ETB receptor expression. Rats were anesthetized, a pressure catheter was placed in the left femoral artery; blood was withdrawn from the right femoral artery to bring mean arterial pressure (MAP) to 35 mm Hg for 30 min, resuscitation was performed and 90 min later sacrificed to collect samples for biochemical estimations. Resuscitation with centhaquin decreased blood lactate and increased MAP. Protein levels of ETA or ETB receptor were unaltered in the brain, heart, lung and liver following shock or resuscitation. In the abdominal aorta, shock produced an increase (140 %) in ETA expression which was attenuated by saline and centhaquin; ETB expression was unaltered following shock but was increased (79 %) by centhaquin. In renal medulla, ETA expression was unaltered following shock, but was decreased (-61 %) by centhaquin; shock produced a decrease (-34 %) in ETB expression which was completely attenuated by centhaquin and not saline. Shock induced changes in ETA and ETB receptors in the aorta and renal medulla are reversed by centhaquin and may be contributing to its efficacy., S. Briyal, R. Gandhakwala, M. Khan, M. S. Lavhale, A. Gulati., and Seznam literatury
Binding of beta2-GP I to anionic phospholipids is thought to be the major antigen required in the reaction of anticardiolipin antibodies to phospholipids. The aim of this study was to investigate the changes of anti-beta2-GP I IgG during the first and second trimester of pregnancy and the relationship between the levels of anti-beta2-GP I and fetoplacental antigens and the correlation between anti-beta2-GP I IgG and antibodies against oxidized low-density lipoprotein IgG (oLAb) in serum of pregnant women. We determined anticardiolipin antibodies (ACA) IgG and maternal serum levels of alpha1-fetoprotein (AFP), human chorionic gonadotrophin (HCG) and trophoblast-specific beta1-glycoprotein (SP1) in 204 pregnant women in the first and second trimester. From this group we selected 52 serum samples positive for ACA IgG and 16 samples negative for ACA IgG. In the samples of selected patients, the levels of anti-b2-GP I IgG and oLAb IgG were determined. Anti-b2-GP I IgG levels significantly decreased in the second trimester (6.2±9.3 U/ml, mean ± S.D.) in comparison with the first trimester (8.3±10.4 U/ml) (p=0.05). Multiple of median (MoM) AFP correlated negatively but not significantly in the first trimester with anti-b2-GP I (r = -0.261, p = 0.12). In the second trimester this correlation was significantly negative (r = -0.278, p = 0.04). The Spearman correlation coefficients for MoM HCG and anti-beta2-GP I were 0.158 for the first trimester and 0.174 for the second trimester. MoM SP1 also did not correlate significantly with anti-beta2-GP I in both trimesters. The correlation between anti-beta2-GP I IgG and oLAb IgG was not significant (r = -0.06). In the first trimester 40 % serum samples were positive for anti-b2-GP I IgG and negative for oLAb IgG or vice versa, while 60 % samples in the second trimester were positive only for one determined autoantibody. We can conclude that the levels of a, L. Fialová, I. Malbohan, L. Mikulíková, O. Benešová, A. Zwinger., and Obsahuje bibliografii