Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the reninangiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation., L. Hošková, I. Málek, L. Kopkan, J. Kautzner., and Obsahuje bibliografii
Extreme or unaccustomed eccentric exercise can cause exerciseinduced muscle damage, characterized by structural changes involving sarcomere, cytoskeletal, and membrane damage, with an increased permeability of sarcolemma for proteins. From a functional point of view, disrupted force transmission, altered calcium homeostasis, disruption of excitation-contraction coupling, as well as metabolic changes bring about loss of strength. Importantly, the trauma also invokes an inflammatory response and clinically presents itself by swelling, decreased range of motion, increased passive tension, soreness, and a transient decrease in insulin sensitivity. While being damaging and influencing heavily the ability to perform repeated bouts of exercise, changes produced by exercise-induced muscle damage seem to play a crucial role in myofibrillar adaptation. Additionally, eccentric exercise yields greater hypertrophy than isometric or concentric contractions and requires less in terms of metabolic energy and cardiovascular stress, making it especially suitable for the elderly and people with chronic diseases. This review focuses on our current knowledge of the mechanisms underlying exerciseinduced muscle damage, their dependence on genetic background, as well as their consequences at the structural, functional, metabolic, and clinical level. A comprehensive understanding of these is a prerequisite for proper inclusion of eccentric training in health promotion, rehabilitation, and performance enhancement., Andraž Stožer, Peter Vodopivc, Lidija Križančić Bombek., and Obsahuje bibliografii
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
A tumor-targeting drug delivery system consists of a tumor recognition moiety and a directly linked cytotoxic agent or an agent attached to a water-soluble synthetic polymer carrier through a suitable linker. Conjugation of a drug with a polymer carrier can change its solubility, toxicity, biodistribution, blood clearance and therapeutic specificity. Increased therapeutic specificity of a polymer drug can be achieved by the attachment of a targeting moiety (e.g. a lectin, protein, antibody, or peptide) that specifically interacts with receptors on the target cells. A large number of tumor-specific peptides were described in recent years. After a short introduction, some important examples of peptide-targeted conjugates will be described and discussed., E. Böhmová, R. Pola., and Obsahuje bibliografii
The purpose of the present study was to define the indirect central effect of hydrogen sulfide (H2S) on baroreflex control of sympathetic outflow. Perfusing the isolated carotid sinus with sodium hydrosulfide (NaHS), a H2S donor, the effect of H2S was measured by recording changes of renal sympathetic nerve activity (RSNA) in anesthetized male rats. Perfusion of isolated carotid sinus with NaHS (25, 50, 100 μmol/l) dose and timedependently inhibited sympathetic outflow. Preconditioning of glibenclamide (20 μmol/l), a ATP-sensitive K+ channels (KATP) blocker, the above effect of NaHS was removed. With 1, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-[trifluoromethyl] phenyl) pyridine-3-carboxylic acid methyl ester (Bay K8644, 500 nmol/l) pretreatment, which is an agonist of L-calcium channels, the effect of NaHS was eliminated. Perfusion of cystathionine γ-lyase (CSE) inhibitor, DL-propargylglycine (PPG, 200 μmol/l), increased sympathetic outflow. The results show that exogenous H2S in the carotid sinus inhibits sympathetic outflow. The effect of H2S is attributed to opening KATP channels and closing the L-calcium channels., Qi Guo, Yuming Wu, Hongmei Xue, Lin Xiao, Shneg Jin, Ru Wang., 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
In as early as 1997, the World Health Organization officially recognized obesity as a chronic disease. The current epidemic of obesity and overweightness has aroused great interest in the study of adipose tissue formation. The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) binds to the target gene promoter regulatory sequences, acting as a key factor in regulating the differentiation of preadipocytes in the adipose tissue, and plays an important role in regulating the adipocyte metabolism. A further understanding of the structure and expression characteristics of PPARγ, in addition to its mechanisms of action in adipocyte differentiation, may be applied to control obesity and prevent obesity-related diseases. In this article, recent studies investigating the effect of regulating PPARγ on adipocyte differentiation are reviewed. In particular, the structural characteristics, expression patterns, and molecular mechanisms of PPARγ function in adipocyte differentiation are considered., Hui Wu, Xiaohua Li, Chunyan Shen., and Obsahuje bibliografii
Pharmacokinetics of leptin in mammals has received limited attention and only one study has examined more than two time points and this was in ob/ob mice. This study is the first to observe the distribution of leptin over a time course in female mice. A physiologic dose (12 ng) of radiolabelled leptin was injected in adult female mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course up to two hours. Major targets for administered leptin included the liver, kidneys, gastrointestinal tract and the skin while the lungs had high concentrations of administered leptin per gram of tissue. Leptin was also found to enter the lumen of the digestive tract intact from the plasma. Very little of the dose (<1 %) was recovered from the brain at any time. Consequently we confirm that the brain is not a major target for leptin from the periphery, although it may be very sensitive to leptin that does get to the hypothalamus. Several of the major targets (GI tract, skin and lungs) for leptin form the interface for the body with the environment, and given the ability of leptin to modulate immune function, this may represent a priming effect for tissues to respond to damage and infection., R. A. Hart, R. C. Dobos, L. L. Agnew, R. L. Tellam, J. R. McFarlane., and Obsahuje bibliografii