A tumor-targeting drug delivery system consists of a tumor recognition moiety and a directly linked cytotoxic agent or an agent attached to a water-soluble synthetic polymer carrier through a suitable linker. Conjugation of a drug with a polymer carrier can change its solubility, toxicity, biodistribution, blood clearance and therapeutic specificity. Increased therapeutic specificity of a polymer drug can be achieved by the attachment of a targeting moiety (e.g. a lectin, protein, antibody, or peptide) that specifically interacts with receptors on the target cells. A large number of tumor-specific peptides were described in recent years. After a short introduction, some important examples of peptide-targeted conjugates will be described and discussed., E. Böhmová, R. Pola., and Obsahuje bibliografii
The purpose of the present study was to define the indirect central effect of hydrogen sulfide (H2S) on baroreflex control of sympathetic outflow. Perfusing the isolated carotid sinus with sodium hydrosulfide (NaHS), a H2S donor, the effect of H2S was measured by recording changes of renal sympathetic nerve activity (RSNA) in anesthetized male rats. Perfusion of isolated carotid sinus with NaHS (25, 50, 100 μmol/l) dose and timedependently inhibited sympathetic outflow. Preconditioning of glibenclamide (20 μmol/l), a ATP-sensitive K+ channels (KATP) blocker, the above effect of NaHS was removed. With 1, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-[trifluoromethyl] phenyl) pyridine-3-carboxylic acid methyl ester (Bay K8644, 500 nmol/l) pretreatment, which is an agonist of L-calcium channels, the effect of NaHS was eliminated. Perfusion of cystathionine γ-lyase (CSE) inhibitor, DL-propargylglycine (PPG, 200 μmol/l), increased sympathetic outflow. The results show that exogenous H2S in the carotid sinus inhibits sympathetic outflow. The effect of H2S is attributed to opening KATP channels and closing the L-calcium channels., Qi Guo, Yuming Wu, Hongmei Xue, Lin Xiao, Shneg Jin, Ru Wang., and Obsahuje bibliografii
The most dramatic changes in pulmonary circulation occur at the time of birth. We hypothesized that some of the effects of perinatal hypoxia on pulmonary vessels are permanent. We studied the consequences of perinatal exposure to hypoxia (12 % O2 one week before and one week after birth) in isolated lungs of adult male rats (~12 weeks old) perfused with homologous blood. Perfusion pressure-flow relationship was tilted towards lower pressures in the perinatally hypoxic as compared to the control, perinatally normoxic rats. A non-linear, distensible vessel model analysis revealed that this was due to increased vascular distensibility in perinatally hypoxic rats (4.1±0.6 %/mm Hg vs. 2.3±0.4 %/mm Hg in controls, P = 0.03). Vascular occlusion techniques showed that lungs of the perinatally hypoxic rats had lower pressures at both the pre-capillary and post-capillary level. To assess its role, basal vascular tone was eliminated by a high dose of sodium nitroprusside (20 µM). This reduced perfusion pressures only in the lungs of rats born in hypoxia, indicating that perinatal hypoxia leads to a permanent increase in the basal tone of the pulmonary vessels. Pulmonary vasoconstrictor reactivity to angiotensin II (0.1-0.5 µg) was reduced in rats with the history of perinatal hypoxia. These data show that perinatal hypoxia has permanent effects on the pulmonary circulation that may be beneficial and perhaps serve to offset the previously described adverse consequences., V. Hampl, J. Bíbová, J. Herget., and Obsahuje bibliografii
The 24-hour periodicity of supraventricular (SVPB) and ventricular (VEB) extrasystoles in healthy elderly men (age 49-69 years) was studied at two altitudes during 24 h Holter ECG monitoring. At the low altitude (200 m, n = 26), SVPB were more frequent than VEB. The highest occurrence of SVPB was at 17:00 h, the lowest at 01:00 and 02:00 h (P<0.001). The highest occurrence of VEB was at 09:00 h, the lowest one at 04:00 h (P<0.001). At 1350 m (n=9) the incidence of both SVPB and VEB was approximately twofold higher compared to that at the low altitude (P<0.001). The highest occurrence of SVPB was at 13:00 h, the lowest at 06:00 h (P<0.001). VEB were the most frequent at 10:00 h and 13:00 h, while the lowest frequency was observed at 06:00 h (P<0.001). Our results indicate that the incidence of SVPB and VEB in healthy persons at the moderate altitude is twofold and its periodicity is shifted compared to the low altitude. The cause of increased occurrence of extrasystoles is probably due to β-adrenergic activation of the heart at the higher altitude., Š. Kujaník, M. Sninčák, J.Vokáľ, J. Podracký, J. Koval., and Obsahuje bibliografii
Resistance to steroid hormones presents a serious problem with respect to their mass use in therapy. It may be caused genetically by mutation of genes involved in hormonal signaling, not only steroid receptors, but also other players in the signaling cascade as co-regulators and other nuclear factors, mediating the hormone-born signal. Another possibility is acquired resistance which may develop under long-term steroid treatment, of which a particular case is down regulation of the receptors. In the review recent knowledge is summarized on the mechanism of main steroid hormone action, pointing to already proven or potential sites causing steroid resistance. We have attempted to address following questions: 1) What does stay behind differences among patients as to their response to the (anti)steroid treatment? 2) Why do various tissues/cells respond differently to the same steroid hormone though they contain the same receptors? 3) Are such differences genetically dependent? The main attention was devoted to glucocorticoids as the most frequently used steroid therapeutics. Further, androgen insensitivity is discussed with a particular attention to acquired resistance to androgen deprivation therapy of prostate cancer. Finally the potential causes are outlined of breast and related cancer(s) resistance to antiestrogen therapy., R. Hampl, K. Vondra., and Obsahuje bibliografii
Extensive osteolysis adjacent to orthopedic implants is often associated with wear particles of prosthetic material. The activation of the RANKL/RANK/OPG system is considered to be a likely cause of periprosthetic osteolysis leading to implant failure. The aim of this study was to examine the possible correlation between the clinical extent of osteolysis, the number of wear particles and expression of the osteoclastic mediator RANKL (receptor activator of nuclear factor kappa B ligand) in the tissues aro und aseptically loosened cemented and non-cemented total hip replacements. Periprosthetic tissues were harvested from 59 patients undergoing revision of hip replacement for aseptic loosening. We observed RANKL-positive cells in 23 of our 59 patients, their presence was noted predominantly in tissues with a loosened cemented endoprosthesis. We have found that RANKL is present only in tissues with a large amount of wear debris and predominantly in cases involving loosened cemented implants., D. Veigl, J. Niederlová, O. Kryštůfková., and Obsahuje bibliografii a bibliografické odkazy
The purpose of this study was to investigate plasma concentrations of cyclic guanosine monophosphate (cGMP) and atrial natriuretic peptide (ANP) during and after real and simulated space flight. Venous blood was obtained 3 min after the beginning and 2 min after the lower body negative pressure maneuver in two cosmonauts preflight (supine), inflight, and postflight (supine) and in five other subjects before, at the end, and 4 days after a 5-day head-down tilt (-6°) bed rest. In cosmonaut 1 (10 days in space), plasma cGMP fell from preflight 4.3 to 1.4 nM on flight day 6, and was 3.0 nM on the fourth day after landing. In cosmonaut 2 (438 days in space), it fell from preflight 4.9 to 0.5 nM on on flight day 3, and stayed <0.1 nM with 5, 9, and 14 months in space, as well as on the fourth day after landing. Three months after the flight his plasma cGMP was back to normal (6.3 nM). Cosmonaut 2 also displayed relatively low inflight ANP values but returned to preflight level immediately after landing. In a ground-based simulation on five other persons, supine plasma cGMP was reduced by an average of 30 % within 5 days of 6° head-down tilt bed rest. The data consistently demonstrate lowered plasma cGMP with real and simulated weightlessness, and a complete disappearance of cGMP from plasma during, and shortly after long-duration space flight., A. Rössler, V. Noskov, Z. László, V.V. Polyakow, H. G. Hinghofer-Szalkay., and Obsahuje bibliografii
Diabetes mellitus is relatively frequently associated with fatty liver disease. Increased oxidative stress probably plays an important role in the development of this hepatopathy. One of possible sources of reactive oxygen species in liver is peroxisomal system. There are several reports about changes of peroxisomal enzymes in experimental diabetes, mainly enzymes of fatty acid oxidation. The aim of our study was to investigate the possible changes of activities of liver peroxisomal enzymes, other than enzymes of beta-oxidation, in experimental diabetes mellitus type 2. Biochemical changes in liver of experimental animals suggest the presence of liver steatosis. The changes of serum parameters in experimental group are similar to changes in serum of patients with non-alcoholic fatty liver disease. We have shown that diabetes mellitus influenced peroxisomal enzymes by the different way. Despite of well-known induction of peroxisomal beta-oxidation, the activities of catalase, aminoacid oxidase and NADH-cytochrome b5 reductase were not significantly changed and the activities of glycolate oxidase and NADP-isocitrate dehydrogenase were significantly decreased. The effect of diabetes on liver peroxisomes is probably due to the increased supply of fatty acids to liver in diabetic state and also due to increased oxidative stress. The changes of metabolic activity of peroxisomal compartment may participate on the development of diabetic hepatopathy., L. Turecký, V. Kupčová, E. Uhlíková, V. Mojto., and Obsahuje bibliografii
The objective of the current study was to search for genetic determinants associated with antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitor captopril. Linkage and correlation analyses of captopril-induced effects on blood pressure (BP) with renal transc riptome were performed in the BXH/HXB recombinant inbred (RI) strains derived from spontaneously hypertensive rat (SHR) and Brown Norway (BN-Lx) progenitors. Variability of blood pressure lowering effects of captopril among RI strains was continuous suggesting a polygenic mode of inheritance. Linkage analysis of captopril- induced BP effects revealed a significant quantitative trait locus (QTL) on chromosome 15. This QTL colocalized with cis regulated expression QTL (eQTL) for the Ednrb (endothelin receptor type B) gene in the kidney (SHR allele was associated with increased renal expression) and renal expression of Ednrb correlated with captopril-induced BP effects. These results suggest that blood pressure lowering effects of ACE inhibitor captopril may be modulated by the variants at the Ednrb locus., J. Zicha ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy