Nearly 60 years has elapsed since the first isolation and identification of 7α-hydroxy-dehydroepiandrosterone, and in that time much information has been gained on its occurrence, metabolism, ontogeny, immunomodulatory activity, cell proliferation, cortisol control in local tissues and neuroactivity. Additional knowledge about this steroid may elucidate its role in obesity, neurodegenerative disturbances such as Alzheimer’s disease, or psychiatric disorders such as schizophrenia or depression. This review aims to provide a comprehensive summary of the available literature on 7α-hydroxydehydroepiandrosterone., L. Stárka., and Obsahuje bibliografii
Cytarabine is one of the most efficient drugs in the treatment of hematological malignancies. In this work, we describe the synthesis and characterization of two different polymer conjugates of cytarabine that were designed for the controlled release of cytarabine within the leukemia cells. Reactive copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) and 3-(3-methacrylamidopropanoyl)thiazolidine-2-thione) or 3-(Nmethacryloylglycyl- phenylalanylleucylglycyl)thiazolidine-2-thione were used in the study as reactive polymer precursors for reaction with cytarabine. The enzymatic release of cytarabine from the conjugate containing a GFLG spacer utilizing cathepsin B was verified. In addition to enzymolysis, the pH-dependent hydrolysis of cytarabine from both copolymers was also confirmed. Approximately 40 % and 20 % of the drug was released by spontaneous hydrolysis at pH 7.4 within 72 h from the polymer conjugates with the GFLG and β-Ala spacers, respectively. At pH 6.0, the spontaneous hydrolysis slowed down, and less than 10 % of the drug was liberated within 72 h. The results of the cytotoxicity evaluation of the polymer conjugates in vitro against various cell lines showed that the cytotoxicity of the polymer conjugates is approximately three times lower in comparison to free cytarabine., R. Pola, O. Janoušková, T. Etrych., and Obsahuje bibliografii
The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel contains 12 transmembrane (TM) regions that are presumed to form the channel pore. However, t here is no direct evidence clearly illustrating the involvement of these transmembr ane regions in the actual CFTR pore structure. To obtain insight into the architecture of the CFTR channel pore, we used patch clamp recording techniques and a strategy of comutagenesis of two potential pore-forming transmembrane regions (TM1 and TM6) to investigate the collaboration of these two TM regions. We performed a range of specific functional assays comparing the single channel conductance, anion binding, and anion selectivity properties of the co -mutated CFTR variants, and the results indicated that TM1 and TM6 play vital roles in forming the channel pore and, thus, determine the functional properties of the channel. Furthermore, we provide d functional evidence that the amino acid threonine (T338) in TM6 has synergic effects with lysine (K95) in TM1. Therefore, we propose that these two residues have functional collaboration in the CFTR channel pore and may collectively form a selective filter ., F. Qian, L. Liu, Z. Liu, C. Lu., and Obsahuje bibliografii
We explored the effect of chronically elevated circulating levels of growth hormone (GH)/insulin -like -growth- factor-1 (IGF-1) on mRNA expression of GH/IGF-1/insulin axis components and p85alpha subunit of phosphoinositide -3-kinase (p85alpha) in subcutaneous adipose tissue (SCAT) of patients with active acromegaly and compared these findings with healthy control subjects in order to find its possible relationships with insulin resistance and body composition changes. Acromegaly group had significantly decreased percenta ge of truncal and whole body fat and increased homeostasis model assessment-insulin resistance (HOMA -IR). In SCAT, patients with acromegaly had significantly increased IGF-1 and IGF -binding protein-3 (IGFBP-3) expression that both positively correlated wit h serum GH. P85alpha expression in SCAT did not differ from control group. IGF-1 and IGFBP-3 expression in SCAT were not independently associated with percentage of truncal and whole body fat or with HOMA -IR while IGFBP -3 expression in SCAT was an independ ent predictor of insulin receptor as well as of p85alpha expression in SCAT. Our data suggest that GH overproduction in acromegaly group increases IGF-1 and IGFBP-3 expression in SCAT while it does not affect SCAT p85alpha expression. Increased IGF-1 or IGFBP-3 in SCAT of acromegaly group do not appear to contribute to systemic differences in insulin sensitivity but may have local regulatory effects in SCAT of patients with acromegaly., V. Touskova, J. Klouckova, V. Durovcova, Z. Lacinova, P. Kavalkova, P. Trachta, M. Kosak, M. Mraz, D. Haluzikova, V. Hana, J. Marek, M. Krsek, M. Haluzik., and Obsahuje bibliografii
7β-hydroxy-epiandrosterone (7β-OH-EpiA) is an endogenous androgen metabolite that has been shown to exert neuroprotective, anti-inflammatory and anti-estrogenic effects. However, to the best of our knowledge no information is available about this androgen steroid in relation to sperm quality. We analyzed 7β-OH-EpiA in plasma and seminal plasma using a newly developed isotope dilution ultra-high performance liquid chromatography - mass spectrometry method. Validation met the requirements of FDA guidelines. Levels of 7β-OH-EpiA were measured in 191 men with different degrees of infertility. One-way analysis of variance followed by multiple comparison and correlation analysis adjusted for age, BMI and abstinence time were performed to evaluate the relationships between this steroid and sperm quality. Concentrations of 7β-OH-EpiA in seminal plasma were significantly higher in severely infertile men in comparison with healthy men and slightly infertile men. The same trend was found when blood plasma was evaluated. Furthermore, plasma 7β-OH-EpiA negatively correlated with sperm concentration (-0.215; p<0.01) and total count (-0.15; p<0.05). Seminal 7β-OH-EpiA was negatively associated with motility (-0.26; p<0.01), progressively motile spermatozoa (-0.233; p<0.01) and nonprogressively motile spermatozoa (-0.188; p<0.05). 7β-OH-EpiA is associated with lower sperm quality and deserves more research in that respect., J. Vitku, L. Kolatorova, C. Ricco, C. Ferroud, O. Hennebert, T. Skodova, J. Heracek, L. Starka., and Obsahuje bibliografii
Autophagy is implicated in the maintenance of cardiac homeostasis. Autophagy is activated in heart failure, in which reactive oxygen species (ROS) are increased. Exogenous ROS have been shown to induce cardiomyocyte autophagy alterations. However, little is known about the influences of physiological levels of endogenous ROS on cardiomyocyte autophagy. In the present study, we tested the hypothesis that endogenous ROS in cardiomyocytes play an important role in inducing autophagy. Cultured H9C2 cardiomyocytes or Sprague-Dawley rats were treated with the antioxidant N-acetyl-cysteine (NAC) or the superoxide dismutase mimic tempol under the basal or nutrient deprivation conditions. The autophagic flux was assessed by the lysosomal inhibitor chloroquine. In H9C2 cardiomyocytes, under a basal condition, NAC or tempol increased the ratio of LC3 II/I proteins and reduced LC3 II autophagic flux. Under nutrient deprivation, NAC increased the LC3 II/I ratio and reduced LC3 II autophagic flux. In vivo studies in rats, NAC treatment increased the LC3 II/I ratio and p-Akt protein expression in myocardium. We concluded that the antioxidants reduced autophagic flux in cardiomyocytes under the basal or nutrient deprivation conditions, suggesting that endogenous ROS promote autophagy flux under physiological conditions, and this effect is mediated, at least in part, through Akt inhibition., J.-P. Wang, R.-F. Chi, J. Liu, Y.-Z. Deng, X.-B. Han, F.-Z. Qin, B. Li., and Seznam literatury
Recent studies focused on epicardial fat, formerly relatively neglected component of the heart, have elucidated some of its key roles. It possesses several properties that can distinguish it from other adipose tissue depots. Its unique anatomical location in the heart predisposes the epicardial fat to be an important player in the physiological and biochemical regulation o f cardiac homeostasis. Obesity is associated with an increase in epicardial fat mass. Excess of cardiac fat can contribute to greater left ventricular mass and work, diastolic dysfunction and attenuated septal wall thickening. Imbalance in adipokines levels secreted in autocrine or paracrine fashion by epicardial fat can contribute to the activation of the key atherogenic pathways in the setting of metabolic syndrome. Epicardial fat has also been identified as an important source of pro-inflammatory mediato rs worsening endothelial dysfunction, eventually leading to coronary artery disease. Increased production of pro-inflammatory factors by epicardial fat can also contribute to systemic insulin resistance in patients undergoing cardiac surgery. Here we revie w the most important roles of epicardial fat with respect to heart disease in the context of other underlying pathologies such as obesity and type 2 diabetes mellitus., Z. Matloch, T. Kotulák, M. Haluzík., and Obsahuje bibliografii
Protease-activated receptors (PARs) belong to the G-proteincoupled receptor family, that are expressed in many body tissues especially in different epithelial cells, mast cells and also in neurons and astrocytes. PARs play different physiological roles according to the location of their expression. Increased evidence supports the importance of PARs activation during nociceptive signaling and in the development of chronic pain states. This short review focuses on the role of PAR2 receptors in nociceptive transmission with the emphasis on the modulation at the spinal cord level. PAR2 are cleaved and subsequently activated by endogenous proteases such as tryptase and trypsin. In vivo, peripheral and intrathecal administration of PAR2 agonists induces thermal and mechanical hypersensitivity that is thought to be mediated by PAR2-induced release of pronociceptive neuropeptides and modulation of different receptors. PAR2 activation leads also to sensitization of transient receptor potential channels (TRP) that are crucial for nociceptive signaling and modulation. PAR2 receptors may play an important modulatory role in the development and maintenance of different pathological pain states and could represent a potential target for new analgesic treatments., P. Mrozkova, J. Palecek, D. Spicarova., and Obsahuje bibliografii
Deformability of red blood cells (RBC) is the ability of RBC to change their shape in order to pass through narrow capillaries in circulation. Deterioration in deformability of RBC contributes to alterations in microcirculatory blood flow and delivery of oxygen to tissues. Several factors are responsible for maintenance of RBC deformability. One of them is the Na,K-ATPase known as crucial enzyme in maintenance of intracellular ionic homeostasis affecting thus regulation of cellular volume and consequently RBC deformability. Decreased deformability of RBC has been found to be the marker of adverse outcomes in cardiovascular diseases (CVD) and the presence of cardiovascular risk factors influences rheological properties of the blood. This review summarizes knowledge concerning the RBC deformability in connection with selected risk factors of CVD, including hypertension, hyperlipidemia, and diabetes mellitus, based exclusively on papers from human studies. We attempted to provide an update on important issues regarding the role of Na,K-ATPase in RBC deformability. In patients suffering from hypertension as well as diabetes mellitus the Na,K-ATPase appears to be responsible for the changes leading to alterations in RBC deformability. The triggering factor for changes of RBC deformability during hypercholesterolemia seems to be the increased content of cholesterol in erythrocyte membranes., J. Radosinska, N. Vrbjar., and Obsahuje bibliografii
Intrahepatic cholestasis of pregnancy (ICP) is a disorder of liver function, commonly occurring in the third trimester but sometimes also as soon as the end of the second trimester of pregnancy. Symptoms of this disorder include pruritus, plus abnormal values of bile acids and hepatic transaminases. After birth, symptoms disappear and liver function returns to normal. Though ICP is relatively non-complicated and often symptomatically mild from the point-of-view of the mother, it presents a serious risk to the fetus, making this disease the subject of great interest. The etiology and pathogenesis of ICP is multifactorial and as yet not fully elucidated. Hormonal factors likely play a significant role, along with genetic as well as exogenous factors. Here we summarize the knowledge of changes in steroid hormones and their role in the development of intrahepatic cholestasis of pregnancy. In addition, we consider the role of exogenous factors as possible triggers of steroid hormone changes, the relationship between metabolic steroids and bile acids, as well as the combination of these factors in the development of ICP in predisposed pregnant women., A. Pařízek, M. Dušková, L. Vítek, M. Šrámková, M. Hill, K. Adamcová, P. Šimják, A. Černý, Z. Kordová, H. Vráblíková, B. Boudová, M. Koucký, K. Malíčková, L. Stárka., and Obsahuje bibliografii