DNA repair is an active cellular process to respond to constant DNA damage caused by metabolic processes and environmental factors. Since the outcome of DNA damage is generally adverse and long term effects may contribute to oncogenesis, cells have developed a variety of DNA repair mechanisms, which operate depending on the type of DNA damage inflicted. At least 15 Fanconi anemia (FA) proteins interact in a common pathway involved in homologous recombination. Inherited homozygous mutations in any of these FA genes cause a rare disease, Fanconi anemia, characterized by congenit al abnormalities, progressive bone-marrow failure and cancer susceptibility. Heterozygous germline FA mutations predispose to various types of cancer. In addition, somatic FA mutations ha ve been identified in diverse cancer types. Evidence exists that cells deficient in the FA pathway become dependent on alternative pathways for survival. Additional inhibition of such alternative pathways is thus expected to result in cell death, creating a relationship of synthetic lethality. Identifying these relationships can reveal yet unknown mechanisms of DNA repair and new targets for therapy., T. Hucl, E. Gallmeier., and Obsahuje bibliografii a bibliografické odkazy
Drug abuse of pregnant women is a growing problem. The effect of prenatal drug exposure may have devastating effect on development of the offsprings that may be long-term or even permanent. One of the most common drug abused by pregnant women is methamphetamine (MA), which is also the most frequently abused illicit drug in the Czech Republic. Our previous studies demonstrated that prenatal MA exposure alters behavior, cognition, pain and seizures in adult rats in sex-specific manner. Our most recent studies demonstrate that prenatal MA exposure makes adult rats more sensitive to acute injection of the same or related drugs than their controls. The aim of the present study was to examine the effect of prenatal MA exposure on drugseeking behavior of adult male rats tested in the Conditioned place preference (CPP). Adult male rats were divided to: prenatally MA-exposed (5 mg/kg daily for the entire prenatal period), prenatally saline-exposed (1 ml/kg of physiological saline) and controls (without maternal injections). The following drugs were used in the CPP test in adulthood: MA (5 mg/kg), amphetamine (5 mg/kg), cocaine (5 and 10 mg/kg), morphine (5 mg/kg), MDMA (5 mg/kg) and THC (2 mg/kg). Our data demonstrated that prenatally MA-exposed rats displayed higher amphetamine-seeking behavior than both controls. MA as well as morphine induced drug-seeking behavior of adult male rats, however this effect did not differ based on the prenatal MA exposure. In contrast, prenatal MA exposure induced rather tolerance to cocaine than sensitization after the conditioning in the CPP. MDMA and THC did not induce significant effects. Even though the present data did not fully confirmed our hypotheses, future studies are planned to test the drug-seeking behavior also in self-administration test., R. Šlamberová, ... [et al.]., and Obsahuje seznam literatury
The aim of this study was to ascertain the persistence of heart rate and blood pressure oscillations at the onset of voluntary apnea in humans and to assess the dependence of the fluctuations` parameters on the chemoreceptor activity. In 24 young subjects (10 males, 14 females, mean age 20.4 years) heart rate (represented by its reciprocal value - RR-intervals), systolic blood pressure (SBP) and diastolic blood pressure (DBP) during controlled breathing (CB) of atmospheric air and oxygen followed by apnea were recorded continuously. The cosine functions were then fitted by nonlinear regression analysis to the heart rate, SBP and DBP oscillations during CB and at the onset of apnea. The parameters of oscillations were different during atmospheric air breathing compared to oxygen breathing. During oxygen breathing there was an increase of the RR-interval oscillations - relative bradycardia and enhanced magnitude of respiratory sinus arythmia. During apnea, the base level of the blood pressure oscillations was higher after breathing of atmospheric air compared o oxygen breathing. At least one cosine-like wave oscillation was present at the onset of apnea in the heart rate, SBP and DBP and the second wave was present in all assessed parameters in at least 70 % of recordings. The oscillations in RR-intervals are, to some extent, independent of blood pressure oscillations. No significant gender differences were found either in the duration of breath holding or in the RR and SBP oscillations parameters., M. Javorka, I. Žila, K. Javorka, A. Čalkovská., and Obsahuje bibliografii
The effect of blocking the first and rate-limiting step in renin-angiotensin cascade on the renal function in ischemia reperfusion injury has not been previously in vestigated. We investigated the effect of aliskiren, the first approved direct oral renin inhibitor, on the alterations in renal functional parameters in this condition. Wistar rats underwent left renal ischemia for 40 min. Group-1 received normal saline whereas Group-2 received aliskiren (30 mg/kg/day) by gavage for 6 days commencing one day before IRI. The hemodynamic an d tubular functions and gene expression of neutrophil gelatinase-associated lipocalin (NGAL) and plasminogen activating inhibitor (PAI-1) in the right and left kidneys were measured five days following the IRI. Comparing Group-1 and Group-2, the left renal blood flow was significantly higher in Group-2 (1.28±0.36 vs. 0.39±0.05, P=0.007). Left kidney glomerular filtration rate was also higher in Group-2 but did not reach statistical signif icance (0.18±0.05 vs. 0.10±0.02, P=0.07). The left renal FE Na was significantly lower in Group-2 (29.9±6.4 vs. 49.7±7.8, P=0.03). Aliskiren also caused a significant decrease in the gene expression of both NGAL and PAI-1 in the left ischemic kidney. In conclusions, the administration of aliskiren before and after IRI appears to have ameliorated the IRI effect on the total renal artery blood flow, and fractional excretion of sodium and gene expression of both NGAL and PAI-1 indicating a renoprotective effects in IRI., F. T. Hammad, S. Al-Salam, L. Lubbad., and Obsahuje bibliografii a bibliografické odkazy
Melatonin has been shown to play a role in antioxidative defence. We therefore studied its effect on oxidative damage to the rat cerebral cortex evoked by painful stimulation and immobilization-induced stress. Moreover, the effect of melatonin on chronic pain perception was examined. Rats were injected with either a high dose of melatonin (100 mg/kg i.p.) or a vehicle for five days and were subjected to painful stimulation or immobilization stress 30 min after the treatment. To determine the degree of oxidative stress, the levels of free radicals, thiobarbituric acid reactive substances (TBARS) as indicators of lipid peroxidation and glutathione peroxidase (GSHPx) were estimated in somatosensory cortex. Pain perception was measured by the tail-flick and plantar test. Melatonin reduced the level of TBARS previously increased by painful stimulation. Melatonin also exhibited a slight analgesic effect in those animals exposed to painful stimulation but its role in free radical scavenging did not contribute to this effect., I. Pekárková, S. Parara, V. Holeček, P. Stopka, L. Trefil, J. Racek, R. Rokyta., and Obsahuje bibliografii
The aim was to compare methods of body fat measurement in different BMI groups. An additional aim was to discuss differences reflecting the structural and functional changes of fat tissue. The study group included 130 adult Caucasian women stratified by body mass index (BMI): 18-24.99 (n=30), 25-29.99 (n=26), 30-34.99 (n=33), 35-39.99 (n=30), and BMI ≥ 40 (n=11). Bioelectrical impedance was performed using Tanita TBF 410 GS, Bodystat 1500, and Omron BF 300. A caliper type Best was also applied. Correspondence of four methods with DEXA was assessed using the Bland-Altman and ANOVA analyses. Measurements by BIA were not si gnificantly different from DEXA up to BMI of 30, but DEXA significantly overestimated in the higher BMI subgroup by all three methods. Caliper measurement significantly underestimated DEXA in all BMI subgroups. BIA methods overestimated DEXA for the obese subjects. Tanita did statistically the best. The Caliper test appeared less preferable than the BIA methods, especially in the higher BMI subgroup. DEXA and Caliper measurements seem to be the best estimate of structural (anatomical) fat quantity. We hypothesize that BIA methods could also measure some other physiopathological conditions like inflammation, hydration or cell infiltration of fat., R: Větrovská, Z. Vilikus, J. Klaschka, Z. Stránská, Š. Svačina, Š. Svobodová, M. Matoulek., and Obsahuje bibliografii
The aim of this study was to investigate aldose reductase inhibitory action of setipiprant as a potential additional mechanism contributing to its anti-inflammatory action. Aldose reductase activity was determined by spectrophotometric measuring of NADPH consumption. Setipiprant was found to inhibit aldose reductase/NADPH-mediated reduction of 4-hydroxynonenal, 4-hydroxynonenal glutathione and prostaglandin H2 substrates, all relevant to the process of inflammation. Molecular modeling simulations into the aldose reductase inhibitor binding site revealed an interaction pattern of setipiprant. Considering multifactorial etiology of inflammatory pathologies, it is suggested that, in addition to the antagonizing prostaglandin D2 receptor, inhibition of aldose reductase may contribute to the reported anti-inflammatory action of setipiprant., J. Ballekova, M. Soltesova-Prnova, M. Majekova, M. Stefek., and Obsahuje bibliografii
Microgravity or simulated microgravity induces acute and chronic cardiovascular responses, whose mechanism is pivotal for understanding of physiological adaptation and pathophysiological consequences. We investigated hemodynamic responses of conscious Wistar rats to 45º head-down tilt (HDT) for 7 days. Arterial blood pressure (BP) was recorded by telemetry. Heart rate (HR), spectral properties and the spontaneous baroreflex sensitivity (sBRS) were calculated. Head-up tilt (HUT) was applied for 2 h before and after HDT to assess the degree of any possible cardiovascular deconditio ning. Horizontal control BP and HR were 112.5±2.8 mmHg and 344.7±10 bpm, respectively. HDT elicited an elevation in BP and HR by 8.3 % and 8.8 %, respectively, in less than 1 h. These elevations in BP and HR were maintained for 2 and 3 days, respectively, and then normalized. Heart rate variability was unchanged, while sBRS was permanently reduced from the beginning of HDT (1.01±0.08 vs. 0.74±0.05 ms/mmHg). HUT tests before and after HDT resulted in BP elevations (6.9 vs. 11.6 %) and sBRS reduction (0.44 vs. 0.37 ms/mmHg), respectively. The pressor response during the post-HDT HUT test was accompanied by tachycardia (13.7 %). In conclusion, chronic HDT does not lead to symptoms of cardiovascular deconditioning. However the depressed sBRS and tachycardic response seen during the post-HDT HUT test may indicate disturbances in cardiovascular control., G. Raffai ... [et al.]., and Obsahuje seznam literatury
We investigated the potential role of magnesium (Mg) dysbalance in the pathogenesis of insulin resistance (IR) in patients with mildly-to-moderately decreased renal function (creatinine: 142.8±11.0 mmol/l). The data were compared to those of 8 age- and sex-matched healthy controls (CTRL). The standard oral glucose tolerance test (oGTT) was performed in 61 patients. Twenty-two patients were classified as IR according to their values on fasting and after-load immunoreactive insulin concentrations. Serum and total erythrocyte Mg (tErMg) (atomic absorption spectro-photometry) and free erythrocyte Mg (fErMg) concentrations (31P NMR spectroscopy) were determined prior to and two hours after the glucose load. Ten out of 39 insulin-sensitive (IS) patients, but only one out of 22 insulin-resistant (IR) patients, had a low basal fErMg concentration (<162.2 mmol/l, c2, p<0.01). IR patients had higher serum Mg, total erythrocyte Mg and bound erythrocyte Mg (bErMg) concentrations (both before and after glucose load) when compared with the IS group. Both groups responded to the glucose load with a significant decrease in serum Mg concentration (within the normal range), while the IR group also exhibited a decline in tErMg and bErMg. The mean sum of insulin needed to metabolize the same glucose load correlated positively with tErMg (r=0.545, p<0.01) and bErMg (r=0.560, p<0.01) in the IR patients. It is concluded that, at an early stage of renal dysfunction, IR is not associated with the decline in free erythrocyte Mg concentration, but the magnesium handling in red blood cells is altered., K. Šebeková, K. Štefíková, D. Polakovičová, V. Spustová, R. Dzúrik., and Obsahuje bibliografii