Muscarinc receptor-mediated signaling takes part in many physiological functions ranging from complex higher nervous activity to vegetative responses. Specificity of action of the natural muscarinic agon ist acetylcholine is effected by action on five muscarinic receptor subtypes with particular tissue and cellular localization, and coupling preference with different G-proteins and their signalin g pathways. In addition to physiological roles it is also implicated in pathologic events like promotion of carcinoma cells growth, early pathogenesis of neurodegenerative diseases in th e central nervous system like Alzheimer's disease and Parkinson's disease, schizophrenia, intoxications resulting in drug addiction, or overactive bladder in the periphery. All of these disturbances demonstrate involvement of specific muscarinic receptor subtypes and point to the importance to develop selective pharmacotherapeutic interventions. Because of the high homology of the orthosteric binding site of muscarinic receptor subtypes there is virtually no subtype selective agonist that binds to this site. Activation of specific receptor subtypes may be achieved by developing allosteric modulators of acetylcholine binding, since ectopic binding domains on the receptor are less conserved compared to the orthosteric site. Potentiation of the effects of acetylcholine by allosteric modulators would be beneficial in cases where acetylcholine release is reduced due to pathological conditions. When presynaptic function is severly compromised, the utilization of ectopic agonists can be a thinkable solution., J. Jakubík ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
According to several studies, women with Crohn's disease (CD) had reduced fertility, which is mostly due to voluntary decisions and reduced ovarian reserve. In our study, we aimed to compare reproductive health parameters (RHP), previous pregnancy complications and outcomes, and ovarian reserve (OR) assessed by the anti-Mullerian hormone (AMH) in CD patients with healthy controls. In CD patients, we also compared OR according to disease phenotypes. Consecutive pre-menopausal women with CD from two IBD centers were included. The control group consisted of age and BMI-matched healthy controls. We used a questionnaire that included RHP, CD phenotype, and CD activity. Serum AMH was assessed by the Elecsys AMH plus essay. We enrolled 50 patients and 56 controls with a median age of 31 years. All CD patients were in clinical remission. We observed no difference in RHP or AMH (median 2.6 vs. 2.1 ug/l, p = 0.98), or the proportion of low OR (AMH<1,77, 38 vs. 41.1 %, p=0.84). The slope of age-related decrease did not differ between the groups. The subgroup of CD patients after surgery and those older than 30 years with CD for >5years had a steeper decrease in AMH (slope -0.12 vs. -0.29, p = 0.04 and - 0.31 vs. -0.2, p = 0.029). In a multivariate analysis, age was the single independent predictor of low OR (OR=1.25). In women with Crohn’s disease, once the disease activity is under control, the reproductive health and ovarian reserve do not substantially differ from healthy controls., Tomáš Koller, Jana Kollerová, Tibor Hlavatý, Barbora Kadlečková, Juraj Payer., and Obsahuje bibliografii
Beneficial effects of Sambucus nigra L. (black elder) as a traditional medicine have been associated with the phytoconstituents including polyphenols, terpenes and lectins. Various antioxidant rich natural products have also been implicated with improvement of reproductive health and fertility, however, the effect of Sambucus nigra on the ovarian cell functions has not been investigated yet. The objectives of the present study were to screen the polyphenols in the elderflower and elderberry extracts, and to examine the secretion activity of steroid hormones 17β-estradiol and progesterone by human ovarian granulosa cells HGL5 after supplementation of the extracts at a concentration range of 12.5 to 100 µg.ml-1 . Qualitative as well as quantitative screening of polyphenols by high-performance liquid chromatography with diode-array detector (HPLC-DAD) analysis revealed rutin to be the most abundant polyphenol in both elderflower and elderberry extracts. In culture, neither elderflower nor elderberry extract caused any significant impact (p>0.05) in cell viability as studied by AlamarBlue assay in comparison to control. However, a dosedependent stimulation of 17β-estradiol release was detected by ELISA after supplementation of elderflower (at 50 µg.ml-1 ; p<0.01) and elderberry (at 100 µg.ml-1 ; p<0.05) extracts at higher doses used in the study. On the other hand, both elderflower and elderberry extracts stimulated the secretion of progesterone by HGL5 cells at a lower dose (12.5 µg.ml-1 ; p<0.05), as compared to control. Therefore, elderflower and elderberry extracts may have the potential to regulate steroidogenesis in ovarian cells., Simona Baldovska, Shubhadeep Roychoudhury, Marek Bandik, Michal Mihal, Erika Mnahoncakova, Julius Arvay, Ales Pavlik, Petr Slama, Adriana Kolesarova., and Obsahuje bibliografii
We studied the relationship between blood pressure (BP), body mass index (BMI, kg/m2) and baroreflex sensitivity (BRS, ms/mmHg) in adolescents. We examined 34 subjects aged 16.2±2.4 years who had repeatedly high causal BP (H) and 52 controls (C) aged 16.4±2.2 years. Forty-four C and 22 H were of normal weight (BMI between 19-23.9), and 8 C and 12 H were overweight (BMI between 24-30). Systolic BP was recorded beat-to-beat for 5 min (Finapres, controlled breathing 0.33 Hz). BRS was determined by the cross-spectral method. The predicting power of BMI and BRS for hypertension was evaluated by sensitivity, specificity, and receiver operating curve (ROC - plot of sensitivity versus specificity). H compared with C had lower BRS (p<0.01) and higher BMI (p<0.05). Multiple logistic regression analysis (p<0.001) revealed that a decreased BRS (p<0.05) and an increased BMI (p<0.01) were independently associated with an increased risk of hypertension. No correlation between BMI and BRS was found either in H or in C. Following optimal critical values by ROC, the sensitivity, specificity and area under ROC were determined for: BMI - 22.2 kg/m2, 61.8 %, 69.2 %, 66.0 %; BRS - 7.1 ms/mmHg, 67.7 %, 69.2 %, 70.0 %; BMI and BRS - 0.439 a.u., 73.5 %, 82.7 %, and 77.3 %. Decreased BRS and overweight were found to be independent risk factors for hypertension., K. Krontorádová, N. Honzíková, B. Fišer, Z. Nováková, E. Závodná, H. Hrstková, P. Honzík., and Obsahuje bibliografii a bibliografické odkazy
Oxidative stress is a phenomenon associated with imbalance between production of free radicals and reactive metabolites (e.g. superoxide and hydrogen peroxide) and the antioxidant defences. Oxidative stress in individuals with Down syndrome (DS) has been associated with trisomy of the 21st chromosome resulting in DS phenotype as well as with various morphological abnormalities, immune disorders, intellectual disability, premature aging and other biochemical abnormalities. Trisomy 21 in patients with DS results in increased activity of an important antioxidant enzyme Cu/Zn superoxide dismutase (SOD) which gene is located on the 21st chromosome along with other proteins such as transcription factor Ets-2, stress inducing factors (DSCR1) and precursor of beta-amyloid protein responsible for the formation of amyloid plaques in Alzheimer disease. Mentioned proteins are involved in the management of mitochondrial function, thereby promoting mitochondrial theory of aging also in people with DS. In defence against toxic effects of free radicals and their metabolites organism has built antioxidant defence systems. Their lack and reduced function increases oxidative stress resulting in disruption of the structure of important biomolecules, such as proteins, lipids and nucleic acids. This leads to their dysfunctions affecting pathophysiology of organs and the whole organism. This paper examines the impact of antioxidant interventions as well as positive effect of physical exercise on cognitive and learning disabilities of individuals with DS. Potential terapeutic targets on the molecular level (oxidative stress markers, gene for DYRK1A, neutrophic factor BDNF) after intervention of natural polyphenols are also discussed., J. Muchová, I Žitňanová, Z. Ďuračková., and Obsahuje bibliografii
Long-term effects of renal denervation (DNX) commonly include a decrease in blood pressure (BP), observed in both normotensive animals and various models of hypertension. On the other hand, short term BP re sponses vary. We examined how post-DNX increase in BP observed in this study depends on baseline metabolic and functional status of an imals, with a special interest for the role of oxidative stress. Anesthetized Wistar rats on standard (STD), low-sodium (LS) or high-sodium (HS) diet were used, untreated or pre-treated with tempol, a superoxide scavenger, or N(omeg a)-propyl-L-arginine (L-NPA), an inhibitor of neuronal NOS (nNOS). Early BP and renal hemodynamic responses were examined to right- and then left- side DNX performed using an own relatively non-invasive technique. Left kidney cortical, outer- and inner-medullary blood flows (CBF, OMBF, IMBF) were co ntinuously recorded as laser- Doppler fluxes. Sequential denervat ions significantly increased BP to final 19 %, 12 %, and 6 % above control level in HS, LS, and STD groups, respectively. CBF, a measure of total renal perfusion, increased in LS and STD but not in HS rats. Tempol pretreatment prevented the post-denervation BP increase on each diet. Selective inhibition of nNOS prevented BP increase in STD and HS groups, a modest incr ease persisted in LS rats. We propose that enhanced afferent impulsation from intrarenal chemoreceptors related to oxidative stress in the kidney was the background for acute BP increase after DNX. The response was triggered by a release of brain sympatho-excitatory centers from inhibition by renal afferents, this was followed by widespread sympathetic cardiovascular stimulation., A. Walkowska, J. Sadowski, E. Kompanowska-Jezierska., and Obsahuje seznam literatury
Glutamate is the main excitatory neurotransmitter in the brain and ionotropic glutamate receptors mediate the majority of excitatory neurotransmission (Dingeldine et al. 1999). The high level of glutamatergic excitation allows the neonatal brain (the 2 nd postnatal week in rat) to develop quickly but it also makes it highly prone to age-specific seizures that can cause lifelong neurological and cognit ive disability (Haut et al. 2004). There are three types of ionotropic glutamate receptors (ligand-gated ion channels) named according to their prototypic agonists: N- methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methyl- isoxazol-4-yl) propanoic acid (AMPA) and kainate (KA). During early stages of postnatal development glutamate receptors of NMDA and AMPA type undergo intensive functional changes owing to modifications in their subunit composition (Carter et al. 1988, Watanabe et al. 1992, Monyer et al. 1994, Wenzel et al. 1997, Sun et al. 1998, Lilliu et al. 2001, Kumar et al. 2002, Matsuda et al. 2002, Wee et al. 2008, Henson et al. 2010, Pachernegg et al. 2012, Paoletti et al. 2013). Participation and role of these receptors in mechanisms of seizures and epilepsy became one of the main targets of intensive investigation (De Sarro et al. 2005, Di Maio et al. 2012, Rektor 2013). LiCl/Pilocarpine (LiCl/Pilo) induced status epilepticus is a model of severe seizures resulting in development temporal lobe epilepsy (TLE). This review will consider developmental changes and contribution of NMDA and AMPA receptors in LiCl/Pilo model of status epilepticus in immature rats., J. Folbergrová., and Obsahuje bibliografii a bibliografické odkazy
Malondialdehyde (MDA), Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and selenium-dependent glutathione peroxidase (GSPHx) are currently considered to be basic markers of oxidative stress. MDA is one of the end-products of the peroxidation of membrane lipids, whereas enzymes Cu,Zn-SOD and GSHPx belong to the natural antioxidants. The role of oxygen free radicals in the pathogenesis of many diseases is well documented. The aim of this study was to ascertain the influence of insulin-induced acute hypoglycemia on oxidative stress in the brain tissue. Hypoglycemia was induced in ICR mice by intraperitoneal administration of insulin at a dose 24 IU/kg. There was a correlation between the severity of hypoglycemia and the levels of MDA, Cu,Zn-SOD and GSHPx. The results showed that in severe hypoglycemia (serum glucose concentration below 1.0 mmol/l) the lipoperoxidation in brain tissue expressed as the level of MDA was higher in comparison with normoglycemic controls (glycemia around 3.7 mmol/l) as well as in comparison with the levels of MDA during moderate hypoglycemia (glycemia ranging between 1-2 mmol/l). This indicates the enhancement of lipoperoxidation in the brain tissue during severe hypoglycemia. However, both enzymes - Cu,Zn-SOD or GSHPx - did not show a similar tendency., J. Patočková, P. Marhol, E. Tůmová, M. Kršiak, R. Rokyta, S. Štípek, J. Crkovská, M. Anděl., and Obsahuje bibliografii
An epileptic seizure and postictal period in addition to well-known features are also characterize d by massive consumption of energy. This is thought to lead to oxidative stress and increased generation of free radicals, which is reflected by increased levels of oxidative products. Our previous work described the neuroprotective effects of melatonin in preventing cognitive worsening after a single epileptic seizure. This work was aimed on direct measurement of free radicals in brain tissue using the EPR method 1, 15 and 60 minutes after seizure. The measurement was performed in adult male Wistar rats at the mentioned intervals after a single tonic-clonic seizure induced by flurothyl. In comparison to control animals there was a significant increase in hydroxyl and nitroxyl radicals 60 minutes after the seizure. The levels of hydroxyl radicals were significantly lower in animals that received melatonin 60 minutes before seizure induction compared to animals without preventive treatment. Therefore, melatonin affected th e generation of the measured free radicals differently. An important finding was the delayed increase in free radicals after a single seizure in the later phases of recovery., J. Mareš ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy