Alzheimer’s disease (AD) is a primary cause of dementia in the middle-aged and elderly worldwide. Animal models for AD are widely used to study the disease mechanisms as well as to test potential therapeutic agents for disease modification. Among the non-genetically manipulated neuroinflammation models for AD, lipopolysaccharide (LPS)-induced animal model is commonly used. This review paper aims to discuss the possible factors that influence rats’ response following LPS injection. Factors such as dose of LPS, route of administration, nature and duration of exposure as well as age and gender of animal used should be taken into account when designing a study using LPS-induced memory impairment as model for AD., R. Zakaria, W. M. H. Wan Yaacob, Z. Othman, I. Long, A. H. Ahmad, B. Al-Rahbi., and Obsahuje bibliografii
Over activation of the endothelin-1 (ET-1) system in disease states contributes to endothelial dysfunction. On the other hand, ET-1 promotes proliferation and survival of endothelial cells. Regulation of programmed cell death (PCD) pathways is critical for cell survival. Recently discovered necroptosis (regulated necrosis) is a pathological PCD mechanism mediated by the activation of toll like receptor 4 (TLR4), which also happens to stimulate ET-1 production in dendritic cells. To establish the effect of ET-1 on PCD and survival of human brain microvascular endothelial cells (BMVECs) under control and inflammatory conditions, BMVECs were treated with ET-1 (10 nM, 100 nM and 1 μM) or lipopolysaccharide (LPS, 100 ng/ml). ET receptors were blocked with bosentan (10 μM). Under normal growth conditions, exogenous ET-1 reduced BMVEC viability and migration at a relatively high concentration (1 μM). This was accompanied with activation of necroptosis and apoptosis marker genes. LPS decreased endogenous ET-1 secretion, increased ETB receptor expression and activated necroptosis. Even though ET-1 levels were low (less than 10 nM levels used under normal growth conditions), blocking of ET receptors with bosentan inhibited the necroptosis pathway and improved the cell migration ability of BMVECs, suggesting that under inflammatory conditions, ET-1 activates PCD pathways in BMVECs even at physiological levels., Y. Abdul, R. Ward, G. Dong, A. Ergul., and Seznam literatury
Hypokalemia as a typical feature of primary aldosteronism (PA) is associated with muscle weakness and could contribute to lower cardio pulmonary fitness. The aim of this study was to describe cardiopulmonary fitness and exercise blood pressure and their determinants during a symptom-limited exercise stress test in patients with PA. We performed a cross-sectional study of patients with confirmed PA who were included before adrenal vein sampling on whom a symptom-limited exercise stress test with expired gas analysis was performed. Patients were switched to the treatment with doxazosin and verapamil at least tw o weeks befor e the study. In 27 patients (17 male) the VO 2peak was 25.4± 6.0 ml/k g/min which corresponds to 80.8 ±18.9 % of Czech national norm. Linear regression analysis shows that VO 2peak de pends on doxazosin dose (DX) (p=0.001) and kal emia (p= 0.02): VO 2peak = 4.2 - 1.0 * DX + 7.6 * Ka lemia. Patients with higher doxazosin doses had a longer history of hypertension and had used more antihypertensives before examination, thus indicating that VO 2peak also depends on the severity of hypertension. In patients with PA, lower cardiopulmonary fitness depends inversely on the severity of hypertension and o n lower plasma potassium level., V. Tuka, M. Matoulek, T. Zelinka, J. Rosa, O. Petrák, O. Mikeš, Z. Krátká, B. Štrauch, R. Holaj, J. Widimský Jr., and Obsahuje bibliografii
Vaccines have helped considerably in eliminating some lifethreatening infectious diseases in past two hundred years. Recently, human medicine has focused on vaccination against some of the world’s most common infectious diseases (AIDS, malaria, tuberculosis, etc.), and vaccination is also gaining popularity in the treatment of cancer or autoimmune diseases. The major limitation of current vaccines lies in their poor ability to generate a sufficient level of protective antibodies and T cell responses against diseases such as HIV, malaria, tuberculosis and cancers. Among the promising vaccination systems that could improve the potency of weakly immunogenic vaccines belong macromolecular carriers (water soluble polymers, polymer particels, micelles, gels etc.) conjugated with antigens and immunistumulatory molecules. The size, architecture, and the composition of the high molecular-weight carrier can significantly improve the vaccine efficiency. This review includes the most recently developed (bio)polymer-based vaccines reported in the literature., G. Mužíková, R. Laga., and Obsahuje bibliografii
Atherosclerosis pathology is the interplay between high intrav ascular LDL particle concentration and monocyte/ macrophage presence within the sub -endothelial space of the artery. In this project, phenotypes of macrophages connected with subclinical inflammation in adipose tissue of living kidney donors were studied. Samples of subcutaneous adipose tissue of living kidney donors (n=36) were exposed to collagenase. Stromal vascular fraction (SVF) was eluted from the samples, then labeled with monoclonal antibodies (anti- CD14 and anti -calprotectin), conjugated with fluo rochromes and analy zed by flow cytometry. The positive correlation between the number of total macrophages and calprotectin- positive macrophages with BMI in the subcutaneous adipose tissue of postmenopausal women was demonstrated (p<0.05; R=0.43 and p<0.01 ; R=0.60), whereas no positive correlation in premenopausal women and men was shown. In conclusion, we documented a significant effect of BMI increase on the presence of total macrophages in adipose tissue of postmenopausal women, in contrast to premenopausal women. This difference was much more pronounced when proinflammatory macrophages with membrane- bound calprotectin were analyzed., A. Králová, I. Králová Lesná, J. Froněk, S. Čejková, A. Sekerková, L. Janoušek, F. Thieme, I. Stříž, J. Ždychová, R. Poledne., and Obsahuje bibliografii
The aim of our study was to evaluate possible effect of ABCB1, and OPRM1 polymorphisms on the efficacy and safety of remifentanil in women undergoing elective cesarean section under general anesthesia. Women received remifentanil (1 μg/kg i.v.) 30 s prior to the induction to standardized general anesthesia. The ABCB1 (rs2032582, rs1045642) and OPRM1 (rs1799971) polymorphisms were analyzed from maternal peripheral blood. The basal hemodynamic and demographic parameters in the study population (n=54) were similar in all the subgroups. The median ± SD increase of systolic blood pressure at 5 min from the baseline was practically completely abolished in homozygous carriers of ABCB1 variants in comparison with wildtype subjects -2.67±25.0 vs. 16.57±15.7 mm Hg, p<0.05 for rs2032582, and 2.00±23.9 vs. 22.13±16.8 mm Hg, p<0.05, for rs1045642, respectively. While no neonate belonging to ABCB1 wild-type homozygous or OPRM1 variant carrying mothers needed any resuscitative measure, 10.5 % of the neonates belonging to OPRM1 wild-type homozygous mothers received resuscitative support similarly as 11.1 %, and 12.5 % of neonates of mothers carrying variants of rs2032582, and rs1045642, respectively. Decreased stabilizing effects of remifentanil on maternal hemodynamics has been observed in ABCB1 wild type mothers, while the adaptation of the neonates was clinically worse in OPRM1 wild type, and ABCB1 variant allele carriers., H. Bakhouche, P. Noskova, S. Svetlik, O. Bartosova, J. Ulrichova, J. Kubatova, P. Marusicova, A. Parizek, J. Blaha, O. Slanar., and Obsahuje bibliografii
Intrahepatic cholestasis of pregnancy (ICP) is a frequent liver disorder, mostly occurring in the third trimester. ICP is not harmful to the mothers but threatens the fetus. The authors evaluated steroid alterations in maternal and mixed umbilical blood to elucidate their role in the ICP development. Ten women with ICP were included in the study. Steroids in the maternal blood were measured by Gas Chromatography-Mass Spectrometry (GC-MS) (n=58) and RIA (n=5) at the diagnosis of ICP, labor, day 5 postpartum, week 3 postpartum and week 6 postpartum. The results were evaluated by ANOVA consisting of the subject factor, between subject factors ICP, gestational age at the diagnosis of ICP and gestational age at labor, withinsubject factor Stage and ICP × Stage interaction. The 17 controls were firstly examined in the week 36 of gestation. ICP patients showed reduced CYP17A1 activity in the C17,20 lyase step thus shifting the balance between the toxic conjugated pregnanediols and harmless sulfated 5α/β-reduced-17-oxo C19 steroids. Hence, more toxic metabolites originating in maternal liver from the placental pregnanes may penetrate backward to the fetal circulation. As these alterations persist in puerperium, the circulating steroids could be potentially used for predicting the predisposition to ICP even before next pregnancy., P. Šimják, M. Hill, A. Pařízek, L. Vítek, M. Velíková, M. Dušková, R. Kancheva, J. Bulant, M. Koucký, Z. Kokrdová, K. Adamcová, A. Černý, Z. Hájek, L. Stárka., and Obsahuje bibliografii
Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved., Vojtěch Hainer, Irena Aldhoon Hainerová, Marie Kunešová, Radka Taxová Braunerová, Hana Zamrazilová, Běla Bendlová., and Obsahuje bibliografii
The aim of this study was to investigate the effects of melatonin on oxidative stress, the expression of transient receptor potential melastatin-2 (TRPM2) in guinea pig brains, and the influence of melatonin on oxidative stress in lungs and airway inflammation induced by particulate matter 2.5 (PM2.5). A particle suspension (0.1 g/ml) was nasally administered to the guinea pigs to prepare a PM2.5 exposure model. Cough frequency and cough incubation period were determined through RM6240B biological signal collection and disposal system. Oxidative stress markers, including malondialdehyde (MDA), total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px), in the medulla oblongata were examined through spectrophotometer. Reactive oxygen species (ROS) were detected in the hypoglossal nucleus, cuneate nucleus, Botzinger complex, dorsal vagal complex, and airway through dihydroethidium fluorescence. Hematoxylin-eosin (HE) staining and substance P expression via immunohistochemistry revealed the inflammatory levels in the airway. TRPM2 was observed in the medulla oblongata through immunofluorescence and Western blot. The ultrastructure of the blood-brain barrier and neuronal mitochondria was determined by using a transmission electron microscope. Our study suggests that melatonin treatment decreased PM2.5-induced oxidative stress level in the brains and lungs and relieved airway inflammation and chronic cough. TRPM2 might participate in oxidative stress in the cough center by regulating cough., Z. Ji, Z. Wang, Z. Chen, H. Jin, C. Chen, S. Chai, H. Lv, L. Yang, Y. Hu, R. Dong, K. Lai., and Seznam literatury
Although the mutations in MC4R gene became known as the most common genetic cause of human obesity, the effect of rs12970134 A/G near MC4R gene on insulin resistance has been described. The aim of this study was to determine the effect of rs12970134 on obesity, hormone levels, and glucose metabolism in a cohort of women varying in glucose tolerance: 850 normoglycemic women, 423 diagnosed with polycystic ovary syndrome (PCOS), 402 gestational diabetics (GDM), and 250 type 2 diabetic (T2D) women. We did not confirm the explicit effect of rs12970134 on obesity. However, the influence of the A-allele on body adiposity index was observed in a cohort of women diagnosed with PCOS. In normoglycemic women, the A-allele carriership was associated with lower fasting levels of glucose, insulin, C-peptide, and index of insulin resistance. Furthermore, higher levels of growth hormone, leptin and SHBG, and lower levels of fT3, testosterone, and androstenedione were recorded in normoglycemic A-allele carriers. In conclusion, the study presents the evidence of the impact of rs12970134 on complex hypothalamic regulations., O. Bradnová, D. Vejražková, M. Vaňková, P. Lukášová, J. Včelák, S. stanická, K. Dvořáková, B. Bendlová., and Obsahuje bibliografii