Glucocorticoid (GC) therapy is one of the methods of choices for treatment of autoimmune diseases (ADs). In addition, adrenal androgens are known as immunoprotective GC-antagonists. Adrenal steroids preferentially influence the Th1-components over the Th2 ones. We investigated steroid metabolome (using gas chromatography-mass spectrometry) in healthy controls (H), GC-untreated patients with ADs different from IgA nephropathy (U), GC-treated patients with ADs different from IgA nephropathy (T) and in patients with IgA nephropathy (IgAN), which were monitored on the beginning (N0), after one week (N1) and after one month (N2) of prednisolone therapy (60 mg of prednisolone/day/m2 of body surface). Between-group differences were assessed by one-way ANOVA, while the changes during the therapy were evaluated by repeated measures ANOVA. The ANOVA testing was followed by Duncan’s multiple comparisons. IgAN patients and patients with other ADs exhibited lack of adrenal androgens due to attenuated activity of adrenal zona reticularis (ZR). Androgen levels including their 7α-, 7β-, and 16α-hydroxy-metabolites were further restrained by GC-therapy. Based on these results and data from the literature, we addressed the question, whether a combination of GCs with Δ5-steroids or their more stable synthetic derivatives may be optimal for the treatment of antibodies-mediated ADs., I. Šterzl, M. Hill, L. Stárka, M. Velíková, R. Kančeva, J. Jemelková, L. Czerneková, P. Kosztyu, J. Zadražil, K. Matoušovic, K. Vondrák, M. Raška., 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
Nitric oxide (NO) is an important endogenous neurotransmitter and mediator. It participates in regulation of physiological processes in different organ systems including airways. Therefore, it is important to clarify its role in the regulation of both airway and vascular smooth muscle, neurotransmission and neurotoxicity, mucus transport, lung development and in the surfactant production. The bioactivity of NO is highly variable and depends on many factors: the presence and activity of NO-producing enzymes, activity of competitive enzymes (e.g. arginase), the amount of substrate for the NO production, the presence of reactive oxygen species and others. All of these can change NO primary physiological role into potentially harmful. The borderline between them is very fragile and in many cases not entirely clear. For this reason, the research focuses on a comprehensive understanding of NO synthesis and its metabolic pathways, genetic polymorphisms of NO synthesizing enzymes and related effects. Research is also motivated by frequent use of exhaled NO monitoring in the clinical manifestations of respiratory diseases. The review focuses on the latest knowledge about the production and function of this mediator and understanding the basic physiological processes in the airways., M. Antosova, D. Mokra, L. Pepucha, J. Plevkova, T. Buday, M. Sterusky, A. Bencova., and Obsahuje bibliografii
Emerging evidence indicates that polychlorinated biphenyls (PCBs) are involved in the development of diabetes mellitus in the obese. The purpose of this study was to determine mechanisms by which PCB 153 (2,2′,4,4′,5,5′-hexachlorobiphenyl) could influence diet-induced obesity and insulin resistance during adipogenesis. Lineage of h-ADMSCs was differentiated either as control (differentiation medium only), or with lipid vehicle modeling high fat nutrition (NuTRIflex) or lipid free vehicle (dimethylsulfoxide) for 28 days with or without PCB 153 daily co-exposure (in three concentrations 0.1, 1, and 10 μM). Gene expression analyses were performed using RT-qPCR at days 4, 10, 21, 24, 28; p rotein l evels A kt a nd phosphorylated Akt (Phospho-Akt) by Western blot at days 4, and 21. PCB 153 treatment of h-ADMSCs only in lipid vehicle was associated with down regulation of key master genes of adipogenesis: PPARγ, SREBP-1, PPARGC1B, and PLIN2 during the whole process of differentiation; and with increased Akt and decreased Phospho-Akt protein level at day 21. We have shown that PCB 153, in concentration 0.1 μM, has a potential in lipid rich environment to modulate differentiation of adipocytes. Because European and U.S. adults have been exposed to PCB 153, this particular nutrient-toxicant interaction potentially impacts human obesity and insulin sensitivity., D. Mullerova, M. Pesta, J. Dvorakova, M. Cedikova, V. Kulda, P. Dvorak, V. Bouchalová, M. Kralickova, V. Babuska, J. Kuncova, J. Langmajerova, L. Muller., and Obsahuje bibliografii
Idiopathic pes equinovarus (clubfoot) is a congenital deformity of the foot and lower leg defined as a fixation of the foot in plantar flexion, adduction, supination and varus. The deformity does not affect only the foot position, which is usually investigated by radiography, CT, micro-CT, MRI or ultrasound but logically influence the whole gait biomechanics. It is supposed, that clubfoot belongs to a group of fibroproliferative disorders whose origin and multi- hierarchical effect remain unknown. It has been suggested that fibroblasts and growth factors may be involved. To gain a more global view, direct analysis of the protein composition of extra cellular matrix, a proteomic approach was used. At present two principle methods are mostly used for the treatment of clubfoot: physiotherapy and the Ponseti method. The determination of the general biological and biomechanical parameters for various regio ns of the clubfoot can potentially help in the understanding of the mechanisms participating on this serious anomaly and thus contribute to the development of the more efficient therapeutic approach. This review summarizes the present knowledge on the poss ible pathogenetic mechanisms participating in the development of the clubfoot and their possible relation to the new therapeutic approaches., M. Ošťádal, J. Lišková, D. Hadraba, A. Eckhardt., and Obsahuje bibliografii
In the central nervous system (CNS), monocarboxylate transporter 1 (MCT1) is expressed in astrocytes and endothelial cells but also in oligodendroglia. Oligodendroglia support neurons and axons through lactate transportation by MCT1. Limited information is available on the MCT1 expression changes in candidate cells in the developing rat brain, especially in corpus callosum which is the most vulnerable area in demyelinating diseases. In the present study, we investigated the expression pattern of MCT1 during postnatal development in the rat corpus callosum using immunofluorescene staining, Western blotting analysis and RT-PCR. We reported that MCT1 gene and protein were consistently expressed in the rat corpus callosum from birth to adult. MCT1/CNPase and MCT1/GFAP immunofluorescence staining demonstrated that most of MCT1 positive cells were co-labeled with cyclic nucleotide 3′ phosphodiesterase (CNPase) in rat corpus callosum from P7 to adult, whereas MCT1+/GFAP+ cells preserve the dominate position before P7. Moreover, there were significant associations between the expression of MCT1 protein and the expression of myelin basic protein (MBP) (correlation coefficient: r=0.962, P=0.009) from P7 to adult. Similarly, the MCT1 mRNA expression was also significantly associated with MBP mRNA expression (r=0.976, P=0.005). Our results are proposing that in the developing brain white matter, MCT1 is predominately expressed in oligodendrocyte though it mainly expressed in astrocyte in early postnatal, which indicate that MCT1 may involve in the oligodendrocyte development and myelination., F. Dong, Y. Liu, Z. Zhang, R. Guo, L. Ma, X. Qu, H. Yu, H. Fan, R. Yao., and Obsahuje bibliografii
n previous studies, one of the systolic time intervals - preejection period (PEP) - was used as an index of sympathetic activity reflecting the cardiac contractility. However, PEP could be also influenced by several other cardiovascular variables including preload, afterload and diastolic blood pressure (DBP). The aim of this study was to assess the behavior of the PEP together with other potentially confounding cardiovascular system characteristics in healthy humans during mental and orthostatic stress (head-up tilt test - HUT). Forty-nine healthy volunteers (28 females, 21 males, mean age 18.6 years (SD=1.8 years)) participated in the study. We recorded finger arterial blood pressure by volume-clamp method (Finome ter Pro, FMS, Netherlands), PEP, thoracic fluid content (TFC) - a measure of preload, and cardiac output (CO) by impedance cardiography (CardioScreen ®2000, Medis, Germany). Systemic vascular resistance (SVR) - a measure of afterload - was calculated as a ratio of mean arterial pressure and CO. We observed that during HUT, an expected decrease in TFC was accompanied by an increase of PEP, an increase of SVR and no significant change in DBP. During mental stress, we observed a decrease of PEP and an increase of TFC, SVR and DBP. Correlating a change in assessed measures (delta values) between mental stress and previous supinerest, we found that ΔPEP correlated negatively with ΔCO and positively with ΔSVR. In orthostasis, no significant correlation between ΔPEP and ΔDBP, ΔTFC, ΔCO, ΔMBP or ΔSVR was found. We conclude that despite an expected increase of sympathetic activity during both challenges, PEP behaved differently indicating an effect of other confounding factors. To interpret PEP values properly, we recommend simultaneously to measure other variables influencing this cardiovascular measure., J. Krohova, B. Czippelova, Z. Turianikova, Z. Lazarova, I. Tonhajzerova, M. Javorka., and Obsahuje bibliografii
In modern societies, living organisms are exposed daily to multiform pollution from industrial chemical products. Some of these substances have been shown to affect the endocrine system, and have been termed endocrine disruptors (EDs). Bisphenol A (BPA), which can leach from plastics, and parabens, used in cosmetic products, are among the most well-studied. Prenatal development is a vulnerable phase of human life, and disruptions during this period may have lifelong consequences. Since EDs are known to cross the placental barrier and BPA may accumulate in the fetus, "BPA-free" products have been introduced to the market. However, such products often contain alternative bisphenols (e.g. BPS, BPF) that have not yet been extensively examined or regulated. Moreover, alternative bisphenols often occur together with BPA. The human organism is thus exposed to a mixture of EDs, some of which can have additive or synergic effects. Recent findings have also shown that paraben exposure can alter bisphenol pharmacokinetics. Taking into account the widespread occurrence of various EDs and the potential multiplicity of their effects, doses of EDs currently considered safe may not actually be as safe as they appear, especially during pregnancy., L. Kolatorova, M. Duskova, J. Vitku, L. Starka., and Obsahuje bibliografii
Inflammatory changes, both in the arterial wall and adipose tissue, play a crucial role in the development of atherosclerosis. We measured the gene expression of tumor necrosis factor-alpha (TNFα), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6) in adipose tissue (AT) of living kidney donors (LKD) and patients with peripheral arterial disease (PAD). Quantitative polymerase chain reaction (qPCR) and flow cytometry analyses were performed in subcutaneous (SAT), visceral (VAT), and perivascular adipose tissue (PVAT). Data of PAD patients showed significantly higher expression in VAT in all three genes (TNFα 5-fold, p<0.05; MCP-1 3.6-fold, p<0.05; IL-6 18.8-fold, p<0.001). The differences in PVAT and SAT were less significant. Total body pro-inflammatory status was documented by higher TNFα concentration in patients (4.86± 1.4 pg/ml) compared to LKDs (2.14±0.9 pg/ml; p<0.001), as was hsCRP (11.8±7.0 in PAD; 1.5±0.48 in LKDs; p=0.017). We found no age-dependent relationship between gene expression vs. TNFα and hsCRP concentrations in both compared groups. No effect of the atherosclerosis score on gene expression and circulating inflammatory markers within the PAD group was observed. Our results suggest that the AT of PAD patients infiltrated with macrophages produces more cytokines involved in the development of inflammation and atherosclerosis., S. Čejková, I. Králová Lesná, J. Froněk, L. Janoušek, A. Králová, J. Ždychová, R. Poledne., and Obsahuje bibliografii
Recently, we have established a model of severe stepwise normovolemic hemodilution to a hematocrit of 10 % in rats employing three different colloidal volume replacement solutions (Voluven, Volulyte and Gelafundin) that are routinely used in clinical practice at present. We did not see severe dilutional acidosis as to be expected, but a decline in urinary pH. We here looked on further mechanisms of renal acid excretion during normovolemic hemodilution. Bicarbonate, which had been removed during normovolemic hemodilution, was calculated with the help of the Henderson-Hasselbalch equation. The urinary amount of ammonium as well as phosphate was determined in residual probes. The absolute amount of free protons in urine was obtained from the pH of the respective samples. The amount of protons generated during normovolemic hemodilution was approximately 0.6 mmol. During experimental time (5.5 h), distinct urinary ammonium excretion occurred (Voluven 0.52 mmol, Volulyte 0.39 mmol and Gelafundin 0.77 mmol). Proton excretion via the phosphate buffer constituted 0.04 mmol in every experimental group. Excretion of free protons was in the range of 10-6 mmol. The present data prove that the prompt rise in urinary ammonium excretion is also valid for acute metabolic acidosis originating from severe normovolemic hemodilution., J. K. Teloh, I. N. Waack, H. de Groot., and Obsahuje bibliografii