Hormones exert many actions in the brain. Their access and effects in the brain are regulated by the blood-brain barrier (BBB). Hormones as other substances may enter the brain and vice versa either by paracellular way requiring breaching tight junctions stitching the endothelial cells composing the BBB, or by passage through the cells (transcellular way). Hormones influence both ways through their receptors, both membrane and intracellular, present on/in the BBB. In the review the main examples are outlined how hormones influence the expression and function of proteins forming the tight junctions, as well as how they regulate expression and function of major protein transporters mediating transport of various substances including hormone themselves., R. Hampl, M. Bičíková, L. Sosvorová., and Obsahuje bibliografii
In this paper, we describe the synthesis, physicochemical characterization, drug release kinetics and preliminary biological evaluation of several N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer-retinoid conjugates designed for solid tumor immunotherapy. The conjugates are supposed to inhibit the immunosuppressive activity of myeloid-derived suppressor cells (MDSC) accumulated in the solid tumor microenvironment. All-trans retinoic acid (ATRA) was derivatized to hydrazide (AtrHy) and then attached to the polymer backbone via a spacer that is stable at the normal pH of blood (7.4) and hydrolytically degradable in mildly acidic environments (e.g. in endosomes or lysosomes, pH~5.0-6.5). Polymer-AtrHy conjugates were designed to achieve prolonged blood circulation and release of the immunomodulator intracellularly or extracellularly in solid tumor tissue. Three types of polymer precursors, differing in the structure of the keto acid-containing side chains, were synthesized. A linkage susceptible to hydrolytic cleavage was formed by the conjugation reaction of the carbonyl groupterminated side chains of the polymer precursors with the hydrazide group of a drug derivative. In vitro incubation of the conjugates in buffers resulted in much faster release of the drugs or their derivatives from the polymer at pH 5.0 than at pH 7.4, with the rate depending on the detailed structure of the spacer. Both the AtrHy derivative and its polymer conjugates showed the ability to induce the differentiation of retinoid-responsive HL-60 cells, thus demonstrating the required biological activity., O. Lidický, M. Šírová, T. Etrych., and Obsahuje bibliografii
We studied hsBAFF activity in in vitro mouse splenic B cells. hsBAFF effects on intracellular free Ca 2+ concentration ([Ca 2+ ] i ) were assayed, using a laser scanning confocal microscope with fluorescent probe, Fluo-3/AM. We showed that treatment of B cells with 0.5-5 μ g/ml hsBAFF resulted in significantly higher [Ca 2+ ] i levels in a dose-dependent fashion at 12 and 24 h, respectively (p<0.05 or p<0.01 vs. control). Furthermore, we noticed that 2.5 μ g/ml hsBAFF-treated cells were significantly resistant to decrease of cellular viability induced by thapsigargin (Tg), an endoplasmic reticulum (ER) Ca 2+ -ATPase inhibitor (p<0.05 hsBAFF plus Tg group vs. Tg group). Thus hsBAFF may promote B cell survival by direct upregulation of [Ca 2+ ] i physiological homeostasis contri buting to prevention of [Ca 2+ ] i dysfunction. Using immunocytochemistry and Western blot analysis, we found that the activation of ERK1/2 due to hsBAFF was triggered by a [Ca 2+ ] i -dependent pathway, leading to elevation of B cell proliferation. This is supported by the findings that intracellular Ca 2+ chelator BAPTA/AM attenuated phosphorylated ERK1/2 expression and cell proliferation in hsBAFF-stimulated B cells. hsBAFF-stimulated B cell proliferation was obviously reduced by mitogen extracellular kinase 1/2 (MEK1/2, upstream of ERK1/2) inhibitor U0126. Taken together, the main finding of this study is that hsBAFF elicits higher but homeostatic [Ca 2+ ] i levels, which regulates ERK1/2 activity and cell proliferation in in vitro B cells., J. Q. Liang, W. Zhang, L. Wen, W. Gao, S. Q. Zhang, L. Chen., and Obsahuje bibliografii
We analyzed human postural responses to muscle vibration applied at four different frequencies to lower leg muscles, the lateral gastrocnemius (GA) or tibialis anterior (TA) muscles. The muscle vibrations induced changes in postural orientation characterized by the center of pressure (CoP) on the force platform surface on which the subjects were standing. Unilateral vibratory stimulation of TA induced body leaning forward and in the direction of the stimulated leg. Unilateral vibration of GA muscles induced body tilting backwards and in the opposite direction of the stimulated leg. The time course of postural responses was similar and started within 1 s after the onset of vibration by a gradual body tilt. When a new slope of the body position was reached, oscillations of body alignment occurred. When the vibrations were discontinued, this was followed by rapid recovery of the initial body position. The relationship between the magnitude of the postural response and frequency of vibration differed between TA and GA. While the magnitude of postural responses to TA vibration increased approximately linearly in the 60-100 Hz range of vibration frequency, the magnitude of response to GA vibration increased linearly only at lower frequencies of 40-60 Hz. The direction of body tilt induced by muscle vibration did not depend on the vibration frequency., A. Polónyová, F. Hlavačka., and Obsahuje bibliografii
We analyzed the immune response to gliadin in suckling rats and rats hand-fed with an artificial milk formula, an animal model of gluten enteropathy. Animals of both groups were intragastrically given either gliadin or albumin (control animals) or gliadin from birth till day 55. When compared to the controls, spleen lymphocytes from both groups of gliadin-treated rats cultivated in vitro exhibited a significant increase of spontaneous 3H-thymidine incorporation. Moreover, the proliferation of spleen and mesenteric lymph node (MLN) lymhocytes from both groups of gliadin-treated suckling and hand-fed rats was specifically increased by the in vitro gliadin challenge. Spleen B cells from gliadin-treated rats spontaneously produced higher amounts of gliadin-specific antibodies than those from the controls, however, in vitro stimulation by gliadin caused no further increase in antibody production. Apoptotic DNA fragmentation in MLN cells was higher in gliadin-treated rats than in albumin-treated ones, independently of the milk diet during the suckling period., H. Kozáková, R. Štěpánková, L. Tučková, M. Šinkora, L. Jelínková, H. Tlaskalová-Hogenová., and Obsahuje bibliografii
Hypoxic exposure triggers a generation of reactive oxygen species that initiate free radical damage to the lung. Hydrogen peroxide is the product of alveolar macrophages detectable in the expired breath. We evaluated the significance of breath H2O2 concentration for the assessment of lung damage after hypoxic exposure and during posthypoxic period. Adult male rats were exposed to normobaric hypoxia (10 % O2) for 3 hours or 5 days. Immediately after the hypoxic exposure and then after 7 days or 14 days of air breathing, H2O2 was determined in the breath condensate and in isolated lung macrophages. Lipid peroxidation was measured in lung homogenates. Three-hour hypoxia did not cause immediate increase in the breath H2O2; 5-day hypoxia increased breath H2O2 level to 458 %. After 7 days of subsequent air breathing H2O2 was elevated in both groups exposed to hypoxia. Increased production of H2O2 by macrophages was observed after 5 days of hypoxia and during the 7 days of subsequent air breathing. Lipid peroxidation increased in the periods of enhanced H2O2 generation by macrophages. As the major increase (1040 %) in the breath H2O2 concentration found 7 days after 3 hours of hypoxia was not accompanied by lipid peroxidation, it can be concluded that the breath H2O2 is not a reliable indicator of lung oxidative damage., J. Wilhelm, M. Vaňková, H. Maxová, A. Šišková., and Obsahuje bibliografii
As a novel gasotrans mitter, h ydrogen sulfide (H 2 S) has vasodilating and antihypertensive effects in cardiovascular system. Thus, we hypothesized that H 2 S might have beneficial effects on thoracic endothelial function in two -kidney one -clip (2K1C) rats, a model of renovascular hypertension. Sodium hydrosulfide (NaHS , 56 μmol/kg /day ) was administrated intra - peritoneally from the third day after the 2K1C operation. Along with the development of hypertension, t he systolic blood pressure (SBP) was measured before the operation and each week thereafter. The oxidative stress wa s determined by measurement of malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity and protein expression of oxidative stress -related proteins (AT 1 R, NADPH oxidase subunits). Acetylcholine (ACh) -induced vasorelaxation and angiotensin I I (Ang II) -induced vasocontraction were performed on isolated thoracic aorta. The SBP w as significantly increased from the first week after operation , and was lowered by NaHS. NaHS supplementation ameliorated endothelial dysfunction. The protein expression of oxidative stress -related proteins were downregulated, while SOD activity upregulated. In conclusion, improvement of endothelial function is involved in the antihypertensive mechanism of H 2 S. The protective effect of H 2 S is attributable to suppression o f vascular oxidative stress that involves inhibition of Ang II -AT 1 R action, downregulation of oxidases, as well as upregulation of antioxidant enzyme., H. Xue, S. Zhou, L. Xiao, Q. Guo, S. Liu, Y. Wu., and Obsahuje bibliografii
Hyperandrogenic states in pregnancy are almost always the result of a condition that arises during pregnancy. The onset of virilization symptoms is often very fast. The mother is protected against hyperandrogenism by a high level of SHBG, by placental aromatase and a high level of progesterone. The fetus is protected from the mother’s hyperandrogenism partly by the placental aromatase, that transforms the androgens into estrogens, and partly by SHGB. Nevertheless there is a significant ri sk of virilization of the female fetus if the mother’s hyperandrogenic state is serious. The most frequent cause of hyperandrogenic states during pregnancy are pregnancy luteoma and hyperreactio luteinalis. Hormonal production is evident in a third of all luteomas, which corresponds to virilization in 25-35 % of mothers with luteoma. The female fetus is afflicted with virilization with two thirds of virilized mothers. Hyperreactio luteinalis is created in connection with a high level of hCG, e.g. during multi-fetus pregnancies. This condition most frequently arises in the third trimester, virilization of the mother occurs in a third of cases. Virilization of the fetus has not yet been described. The most serious cause of hyperandrogenism is represented by ovarian tumors, which are fortunately rare., N. Kaňová, M. Bičíková., and Obsahuje bibliografii a bibliografické odkazy
There is evidence that a higher serum level of bilirubin (BIL) may be a protective factor for autoimmune diseases. We examined the effect of BIL supplementation in adjuvant-induced arthritis (AIA) where oxidative stress, inflammation and inadequate immune response are present. Male Lewis rats were randomized into groups: CO - control, AIA - untreated adjuvant-induced arthritis, AIA-BIL - adjuvant-induced arthritis administrated BIL (200 mg/kg b.w. daily i.p. during 14 days). Change of hind paw volume in the AIA-BIL group in comparison to the AIA group was significantly decreased after BIL administration. In CO and AIA groups we found almost untraceable levels of BIL. In the AIA-BIL group hyperbilirubinemia was observed. BIL administration significantly decreased plasma levels of C-reactive protein and ceruloplasmin in the AIA-BIL group in comparison to the AIA group. The values of white and red blood cells, hemoglobin and hematocrit were significantly decreased in AIA-BIL after BIL supplementation. Organs like spleen and thymus had a lower weight in AIA-BIL than in AIA. Histological findings showed decreased or even absent damage in hind paw joint of AIA-BIL animals. We observed an immunomodulatory effect of BIL on AIA development, which may also have a novel pharmacological impact., K. Bauerova, F. Drafi, V. Kuncirova, S. Ponist, D. Mihalova, P. Babal, T. Sykora., and Obsahuje bibliografii
The metabolic pathways that contribute to maintain serum calcium concentration in narrow physiological range include the bone remodeling process, intestinal absorption and renal tubule resorption. Dysbalance in t hese regulations may lead to hyper - or hypocalcemia. Hypercalcemia is a potentionally life -threatening and relatively common clinical problem, which is mostly associated with hyperparathyroidism and/or malignant diseases (90 %). Scarce causes of hypercalce mia involve renal failure, kidney transplantation, endocrinopathies, granulomatous diseases, and the long -term treatment with some pharmaceuticals (vitamin D, retinoic acid, lithium). Genetic causes of hypercalcemia involve familial hypocalciuric hypercalc emia associated with an inactivation mutation in the calcium sensing receptor gene and/or a mutation in the CYP24A1 gene. Furthermore, hypercalcemia accompanying primary hyperparathyroidism, which develops as part of multiple endocrine neoplasia (MEN1 and MEN2), is also genetically determined. In this review mechanisms of hypercalcemia are discussed. The objective of this article is a review of hypercalcemia obtained from a Medline bibliographic search., I. Žofková., and Obsahuje bibliografii