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
Nucleoside diphosphate kinases (NDPK) are key enzymes involved in the intracellular nucleotide maintenance in all living organisms, especially in trypanosomatids which are unable to synthesise purines de novo. Four putative NDPK isoforms were identified in the Trypanosoma cruzi Chagas, 1909 genome but only two of them were characterised so far. In this work, we studied a novel isoform from T. cruzi called TcNDPK3. This enzyme presents an atypical N-terminal extension similar to the DM10 domains. In T. cruzi, DM10 sequences targeted other NDPK isoform (TcNDPK2) to the cytoskeleton, but TcNDPK3 was localised in glycosomes despite lacking a typical peroxisomal targeting signal. In addition, TcNDPK3 was found only in the bloodstream trypomastigotes where glycolytic enzymes are very abundant. However, TcNDPK3 mRNA was also detected at lower levels in amastigotes suggesting regulation at protein and mRNA level. Finally, 33 TcNDPK3 gene orthologs were identified in the available kinetoplastid genomes. The characterisation of new glycosomal enzymes provides novel targets for drug development to use in therapies of trypanosomatid associated diseases., María de los Milagros Cámara, León Bouvier, Chantal Reigada, Fabio A. Digirolamo, Melisa Sayé, Claudio A. Pereira., and Obsahuje bibliografii
Autologous vein grafts used as aortocoronary bypasses are often prone to intimal hyperplasia, which results in stenosis and occlusion of the vein. The aim of this study was to prevent intimal hyperplasia using a newly developed perivascular system with sustained release of sirolimus. This system of controlled drug release consists of a polyester mesh coated with a copolymer of L-lactic acid and ε -caprolactone that releases sirolimus. The mesh is intended for wrapping around the vein graft during surgery. The mesh releasing sirolimus was implanted in periadventitial position onto arteria carotis communis of rabbits, and neointimal hyperplasia was then assessed. We found that implanted sirolimus-releasing meshes reduced intima thickness by 47±10 % compared to a vein graft after 3 weeks. The pure polyester mesh decreased vein intima thickness by 35±9 %. Thus, our periadventitial system for controlled release of sirolimus prevented the develo pment of intimal hyperplasia in autologous vein grafts in vivo in rabbits. A perivascularly applied mesh releasing sirolimus is a promising device for preventing stenosis of autologous vein grafts., I. Skalský ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
We have assessed the phylogenetic status of the Leishmania genome project Friedlin reference strain by MLEE and multiprimer RAPD including a set of 9 stocks representative of the main Leishmania species and of the whole genetic diversity of the Leishmania genus. To our knowledge, the detailed genetic characterization of the Friedlin strain has never been published before. As previously recorded (Tibayrenc et al. 1993), MLEE and RAPD data gave congruent phylogenetic results. The Friedlin reference strain was definitely attributed to Leishmania (Leishmania) major Yakimoff et Schokhor, 1914. Five specific RAPD patterns made it possible to distinguish between the Friedlin strain and the 2 other L. (L.) major stocks included in the study. Various specific MLEE and RAPD characters permitted to distinguish between the Leishmania species included in the study. All these characters are usable to detect accidental laboratory mix-ups involving the Friedlin reference strain. In confirmation with previous studies involving a more limited set of genetic markers, the general genetic diversity of the Leishmania genus proved to be considerable. It must be made clear that only one strain cannot be considered as representative of the whole genetic variability of the genus Leishmania. In the future, it is therefore advisable to complement the results obtained in the framework of the Leishmania genome project with data from other strains that should be selected on a criterion of important genetic differences with the Friedlin strain.
Diabetic nephropathy (DN), the most serious complication of Type 1 diabetes (DM1), has a strong genetic component. Cyclooxygenase-2 (COX-2), an in ducible enzyme by a number of stimuli, has been implicated in pathophysiology of cardiovascular and renal disease, including DN. The allele -765C, of the -765G>C polymorphism (rs20417) in the COX-2 promoter has lower promoter activity compared with the -765G allele and protective effects in cardiovascular disease. This polymorphism was not investigated in patients with DM1 and nephropathy. The study was conducted in 779 Caucasian patients with DM1 and compared to a representative sample of healthy Czech population. The patients demonstr ated lower frequencies of the CC genotype (P=0.005). From th e DM1 cohort, 153 patients met the criteria for low risk of the development of DN (LRDN, duration of DM1>10 years, normoalbuminuria, normotension) and 139 patients had manifest DN. There were no differences in -765G>C polymorphisms between LRDN and DN patients. Moreover, the C/G allele frequenc ies did not also differ between the groups. In conclusion, patients with DM1 display lower freqencies of the protective CC genotype as compared to healthy subjects. However, the study did not reveal associations of -765G>C polymorphism with the risk of DN., J. A. Hubáček ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
PAM (pulse amplitude modulation) fluorometers can be used to estimate the electron transport rate (ETR) [μmol(e-) m-2 s-1] from photosynthetic yield determinations, provided the absorptance (Abtλ) of the photoorganism is known. The standard assumed value used for absorptance is 0.84 (leaf absorptance factor, AbtF). We described a reflectance-absorptancetransmittance (RAT) meter for routine experimental measurements of the actual absorptance of leaves. The RAT uses a red-green-blue (RGB) LED diode light source to measure absorptances at wavelengths suitable for use with PAM fluorometers and infrared gas analysers. Results using the RAT were compared to Abtλ spectra using a Taylor integrating sphere on bird’s nest fern (Asplenium nidus), banana, Doryanthes excelsa, Kalanchoe daigremontiana, and sugarcane. Parallel venation had no significant effect upon Abt465 in banana, Doryanthes, a Dendrobium orchid, pineapple, and sugarcane, but there was a slight difference in the case of the fern A. nidus. The average Abt465 (approximately 0.96) and Abt625 (approximately 0.89) were approximately 14% and 6% higher than the standard value (AbtF = 0.84). The PAR-range Abt400-700 was only approximately 5% higher than the standard value (approximately 0.88) based on averaged absorptance from the blue, green, and red light data and from where the RGB-diode was used as a ‘white’ light source. In some species, absorptances at blue and red wavelengths are quite different (e.g. water lily). Reflectance measurements of leaves using the RAT would also be useful for remote sensing studies., R. J. Ritchie, J. W. Runcie., and Obsahuje bibliografii
Chronic sojourn in hypoxic environment results in the structural remodeling of peripheral pulmonary arteries and pulmonary hypertension. We hypothesize that the pathogenesis of changes in pulmonary vascular structure is related to the increase of radical production induced by lung tissue hypoxia. Hypoxia primes alveolar macrophages to produce more hydrogen peroxide. Furthermore, the increased release of oxygen radicals by other hypoxic lung cells cannot be excluded. Several recent reports demonstrate the oxidant damage of lungs exposed to chronic hypoxia. The production of nitric oxide is high in animals with hypoxic pulmonary hypertension and the serum concentration of nitrotyrosine (radical product of nitric oxide and superoxide interaction) is also increased in chronically hypoxic rats. Antioxidants were shown to be effective in the prevention of hypoxia induced pulmonary hypertension. We suppose that the mechanism by which the radicals stimulate of the vascular remodeling is due to their effect on the metabolism of vascular wall matrix proteins. Non-enzymatic protein alterations and/or activation of collagenolytic matrix metalloproteinases may also participate. The presence of low-molecular weight cleavage products of matrix proteins stimulates the mesenchymal proliferation in the wall of distal pulmonary arteries. Thickened and less compliant peripheral pulmonary vasculature is then more resistant to the blood flow and the hypoxic pulmonary hypertension is developed., J. Herget, J. Wilhelm, J. Novotná, A. Eckhardt, R. Vytášek, L. Mrázková, M. Ošťádal., and Obsahuje bibliografii
Tzv. teorie optimality patří к nejnovějším směrům současného lingvistického bádání. Nejdříve nalezla uplatnění ve fonologii, později v syntaxi a nejnověji i v sémantice. Naše stať naznačuje možnosti a meze uplatnění tohoto pohledu na oblast aktuálního členění věty.
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