Baroreflex sensitivity (BRS) is abnormal in the prediabetic state. This study was conducted to determine effects of chronic rosiglitazone (RSG), an insulin sensitizer, on BRS in prediabetic hyperglycemic (PDH) rats induced by nicotinamide and streptozotocin. The fasting and postprandial blood glucose levels were 5.6–6.9 and 7.8–11.0 mmol/l, respectively. Rats were treated with RSG or saline for 12 weeks. BRS response to phenylephrine (PE-BRS) or sodium nitroprusside (NP-BRS) was determined by linear regression method. Cardiac sympathetic and parasympathetic influences were determined by autonomic blockades. In the saline-treated PDH rats, PE-BRS was enhanced early at week 4 and became greater at week 12. Abnormalities in NP-BRS and cardiac autonomic influences were found only after week 12. Four weeks of RSG treatment normalized blood glucose levels but not PE-BRS. All altered cardiovascular variables were completely restored by 12 weeks of RSG treatment. The correlation between BRS and blood glucose levels in salinetreated PDH rats was significant at week 12, but no correlation was found in RSG-treated rats. In conclusion, hyperglycemia, even in the prediabetic state, may play a role in BRS abnormalities. RSG treatment early in the prediabetic state may normalize BRS via cardiac autonomic modulation, besides its antihyperglycemic action., L.-Z. Hong ... [et al.]., and Obsahuje seznam literatury
Previous data suggest that type 1 diabetes mellitus leads to the deterioration of myocardial intercellular communication mediated by connexin-43 (Cx43) channels. We therefore aimed to explore Cx43, PKC signaling and ultrastructure in non -treated and omega-3 fatty acid (omega-3) treated spontaneously diabetic Goto-Kakizaki (GK) rats considered as type 2 diabetes model. Four-week-old GK and non-diabetic Wistar-Clea rats were fed omega -3 (200 mg/kg/day) for 2 months and compared with untreated rats. Realtime PCR and immunoblotting were performed to determine Cx43, PKC- epsilon and PKC-delta expression. In situ Cx43 was examined by immunohistochemistry and subcellular alterations by electr on microscopy. Omega-3 intake reduced blood glucose, triglycerides, and cholesterol in diabetic rats and this was associated with improved integrity of cardiomyocytes and capillaries in the heart. Myocardial Cx43 mRNA and protein levels were higher in diab etic versus non- diabetic rats and were further enhanced by omega-3. The ratio of phosphorylated (functional) to non-phosphorylated Cx43 was lower in diabetic compared to non- diabetic rats but was increased by omega-3, in part due to up -regulation of PKC-epsilon. In addition, proapoptotic PKC-delta expression was decreased. In conclusion, spontaneously diabetic rats at an early stage of disease benefit from omega-3 intake due to its hypoglycemic effect, upregulation of myocardial Cx43, and preservation of cardiovascular ultrastructure. These findings indicates that supplementation of omega-3 may be beneficial also in the management of diabetes in humans., J. Radosinska, L. H. Kurahara, K. Hiraishi, C. Viczenczova, T. Egan Benova, B. Szeiffova Bacova, V: Dosenko, J. Navarova, B. Obsitnik, I. Imanaga, T. Soukup, N. Tribulova., and Obsahuje bibliografii
Acute promyelocytic leukemia is characterized by a block of myeloid differentiation. The incubation of cells with 1 μmol/l all-trans retinoic acid (ATRA) for 72 h induced differentiation of HL-60 cells and increased the number of CD11b positive cells. Morphological and functional changes were accompanied by a loss of proliferative capacity. Differentiation caused by preincubation of leukemic cells HL-60 with ATRA is accompanied by loss of clonogenicity (control cells: 870 colonies/103 cells, cells preincubated with ATRA: 150 colonies/103 cells). D0 for undifferentiated cells was 2.35 Gy, for ATRA differentiated cells 2.46 Gy. Statistical comparison of clonogenity curves indicated that in the whole range 0.5-10 Gy the curves are not significantly different, however, in the range 0.5-3 Gy ATRA differentiated cells were significantly more radioresistant than non-differentiated cells. When HL-60 cells preincubated with 1 μmol/l ATRA were irradiated by a sublethal dose of 6 Gy, more marked increase of apoptotic cells number was observed 24 h after irradiation and the surviving cells were mainly in the G1 phase of the cell cycle, while only irradiated cells were accumulated in G2 phase. Our results imply that preincubation of cells with ATRA accelerates apoptosis occurrence (24 h) after irradiation by high sublethal dose of 6 Gy. Forty-eight hours after 6 Gy irradiation, late apoptotic cells were found in the group of ATRA pretreated cells, as determined by APO2.7 positivity. This test showed an increased effect (considering cell death induction) in comparison to ATRA or irradiation itself., M. Mareková, J. Vávrová, D. Vokurková, J. Psutka., and Obsahuje bibliografii
Urocortin 2 (UCN2) is a peptide related to corticotropin-releasing factor, capable of activating CRF-R2. Among its multisystemic effects, it has actions in all 3 muscle subtypes. This study’s aim was to determine its potential role in two of the intrinsic eye muscle kinetics. Strips of iris sphincter (rabbit) and ciliary (bovine) muscles were dissected and mounted in isometric forcetransducer systems filled with aerated-solutions. Contraction was elicited using carbachol (10-6 M for iris sphincter, 10-5 M for ciliary muscle), prior adding to all testing substances. UCN2 induced relaxation in iris sphincter muscle, being the effect maximal at 10-7 M concentrations (-12.2 % variation vs. control). This effect was abolished with incubation of indomethacin, antisauvagine-30, chelerytrine and SQ22536, but preserved with L-nitro-L-arginine. In carbachol pre-stimulated ciliary muscle, UCN2 (10-5 M) enhanced contraction (maximal effect of 18.2 % increase vs. control). UCN2 is a new modulator of iris sphincter relaxation, dependent of CRF-R2 activation, synthesis of prostaglandins (COX pathway) and both adenylate cyclase and PKC signaling pathways, but independent of nitric oxide production. Regarding ciliary muscle, UCN2 enhances carbachol-induced contraction, in higher doses., M. Tavares-Silva, D. Ferreira, S. Cardoso, A. R. Raimundo, J. Barbosa-Breda, A. Leite-Moreira, A. Rocha-Sousa., and Obsahuje bibliografii
The acute effects of β-adrenergic stimulation on myocardial stiffness were evaluated. New-Ze aland white rabbits were treated with saline (control group) or do xorubicin to induce heart failure (HF) (DOXO-HF group). Effects of isoprenaline (10-10-10-5 M), a non-selective β-adrenergic agonist, were tested in papillary muscles from both groups. In the control group, the effects of isoprenaline were also evaluate d in the presence of a damaged endocardial endothelium, atenolol (β1-adrenoceptor antagonist), ICI-118551 (β2-adrenoceptor antagonist), KT-5720 (PKA inhibitor), L-NNA (NO-synthase inhibitor), or indomethacin (cyclooxygenase inhibitor). Passive length-tension relations were constructed before and after adding isoprenaline (10-5 M). In the control group, isoprenaline increased resting muscle length up to 1.017±0.006 L/Lmax. Correction of resting muscle length to its initial value resulted in a 28.5±3.1 % decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the isoprenaline-induced right-downwa rd shift of the passive length- tension relation. These effects were modulated by β1- and β2-adrenoceptors and PKA. In DOXO-HF group, the effect on myocardial stiffness was significantly decreased. We conclude that β -adrenergic stimulation is a relevant mechanism of acute neurohumoral modulation of the diastolic function. Furthermore, this study clarifies the mechanisms by which myocardial stiffness is decreased., I. Falcão-Pires ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
We aimed to explore the effects of melatonin and n-3 polyunsaturated fatty acids (PUFA) supplementation on plasma and aortic nitric oxide (NO) levels in isoproterenol (Iso) affected spontaneously hypertensive (SHR) and Wistar rats. Untreated control rats were compared with Iso injected (118 mg/kg, s.c.) rats, and Iso injected plus supplemented with melatonin (10 mg/kg, p.o.) or PUFA (1.68 g/kg, p.o.) for two months. Plasma and aortic basal, L-NAME inhibited, adrenaline and acetylcholine stimulated NO were determined using Griess method. Plasma NO levels were lower in SHR versus Wistar rats. Iso decreased NO in Wistar while not in SHR. PUFA but not melatonin intake of Iso treated SHR increased plasma NO along with a decrease in systolic blood pressure. Basal aortic NO level was higher in SHR than Wistar rats and not altered by Iso. Intake of melatonin increased but PUFA decreased basal NO levels in Wistar+Iso and did not affect in SHR+Iso rats. Acetylcholine and adrenaline induced aortic NO release was significantly increased in Wistar+Iso but not SHR+Iso group. Melatonin intake increased Ach induced aortic NO in Wistar+Iso and SHR+Iso groups, whereas there was no effect of PUFA intake. Findings suggest that PUFA modulates plasma and melatonin aortic NO levels of isoproterenol affected rats in a strain-dependent manner., K. K. Chaudagar, C. Viczenczova, B. Szeiffova Bacova, T. Egan Benova, M. Barancik, N. Tribulova., and Obsahuje bibliografii
Hypericin is a photosensitizing plant pigment from Hypericum perforatum with multiple modes of light-induced biological activities due to production of singlet oxygen and/or excited-state proton transfer with consequent pH drop in the hypericin environment. In the present work, we studied the effects of three inhibitors of crucial mechanisms responsible for intracellular pH (pHi) regulation on hypericin phototoxicity: N-ethylmaleimide (NEM), an inhibitor of H+-ATPase, 5'-(N,N-dimethyl)-amiloride (DMA), an inhibitor of Na+/H+ exchanger, and omeprazole (OME), an inhibitor of H+K+-ATPase. Our experiments show that the effect of hypericin at 1x10-5 and 1x10-6 mol.l-1 was significantly potentiated by NEM (1x10-7-1x10-9 mol.l-1) and DMA (1x10-6 and 1x10-7 mol.l-1) in leukemic CEM cell line. On the other hand, OME had no significant effect on hypericin cytotoxicity. Our results support the hypothesis that the excited-state proton transfer and the consequent acidification of hypericin environment could play a role in the biological activity of hypericin., A. Miroššay, L. Mirossay, M. Šarišský, P. Papp, J. Mojžiš., and Obsahuje bibliografii
Adipose tissue is an important target for thyroid hormones (TH). However, the metabolism of TH in white adipose tissue is poorly characterized. Our objective was to describe possible changes in activities of TH-metabolizing enzymes in white adipose tissue, and the role of TH metabolism in the tissue during obesogenic treatment, caloric restriction and in response to leptin in mice. Activity of type I iodothyronine 5’-deiodinase (D1) in white fat was stimulated by a high-fat diet, which also increased plasma leptin levels, while brown adipose tissue D1 activity did not change. Caloric restriction decreased the activity of D1 in white fat (but not in the liver), reduced leptin levels, and increased the expression of stearoyl CoA desaturase 1 (SCD-1), a marker and mediator of the effect of leptin on tissue metabolism. Leptin injections increased D1 activity and down-regulated SCD-1 in white fat. Our results demonstrate changes in D1 activity in white adipose tissue under the conditions of changing adiposity, and a stimulatory effect of leptin on D1 activity in the tissue. These results suggest a functional role for D1 in white adipose tissue, with D1 possibly being involved in the control of adipose tissue metabolism and/or accumulation of the tissue., Z. Macek Jílková ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Transient receptor potential A1 (TRPA1) is an excitatory ion channel that functions as a cellular sensor, detecting a wide range of proalgesic agents such as environmental irritants an d endogenous products of inflammation and oxidative stress. Topical application of TRPA1 agonists produces an acute nociceptive response through peripheral release of neuropeptides, purines and other transmitters from activated sensory nerve endings. This, in turn, further regulates TRPA1 activity downstream of G-protein and phospholipase C -coupled signaling cascades. Despite the important physiological relevance of such regulation leading to nociceptor sensitization and consequent pain hypersensitivity, th e specific domains through which TRPA1 undergoes post -translational modifications that affect its activation properties are yet to be determined at a molecular level. This review aims at providing an account of our current knowledge on molecular basis of r egulation by neuronal inflammatory signaling pathways that converge on the TRPA1 channel protein and through modification of its specific residues influence the extent to which this channel may contribute to pain., A. Kádková, V. Synytsya, J. Krusek, L. Zímová, V. Vlachová., and Obsahuje bibliografii
Autosomal dominant hypercholesterolemia (ADH), more known as familial hypercholesterolemia (FH), is a lipid metabolism disorder characterized by an elevation in low-density lipoprotein cholesterol (LDL-C) and increased risk for cardiovascular disea se. In this study, we assessed a spectrum of mutations causing ADH in 3914 unrelated Czech patients with clinical diagnosis of hypercholesterolemia. Samples have been collected within the framework of the MedPed project running in the Czech Republic since 1998. So far we have found 432 patients (11.0 %) with the APOB gene mutation p.(Arg3527Gln) and 864 patients (22.1 %) with the LDLR gene mutation. In 864 probands carrying the LDLR gene mutation, 182 unique allelic variants were detected. We have identified 14 patients homozygous for mutations in the LDLR or APOB genes. We performed function analyses of p.(Leu15Pro) and p.(Gly20Arg) sequence variations., L. Tichý, L. Fajkusová, P. Zapletalová, L. Schwarzová, M. Vrablík, T. Freiberger., and Obsahuje bibliografii