Obstructive sleep apnoea syndrome (OSAS) is a common disorder associated with upper airway muscle dysfunction. Agents that improve respiratory muscle performance may have considerable therapeutic value. We examined the effects of acute exposure to sustained and intermittent hypoxia on rat pharyngeal dilator muscle function. Additionally, we sought to test the efficacy of antioxidant treatment in ameliorating or preventing hypoxia-related muscle dysfunction. Isometric contractile and endurance properties of isolated rat sternohyoid muscle bundles were examined at 35 °C in vitro. Muscle bundles were exposed to one of four gas treatments: hyperoxia (control), sustained hypoxia (SH), intermittent hypoxia (IH) or hypoxia/reoxygenation (HR), in the absence or presence of the superoxide scavenger – Tempol (10 mM). Stress-frequency relationship was determined in response to electrical stimulation (10-100 Hz in increments of 10-20 Hz, train duration: 300 ms). Muscle performance was also assessed during repetitive muscle stimulation (40 Hz, 300 ms every 2 s for 2.5 min). Compared to control, IH and HR treatments significantly decreased sternohyoid muscle force. The negative inotropic effect of the two gas protocols was similar, but both were of lesser magnitude than the effects of SH. SH, but not IH and HR, increased muscle fatigue. Tempol significantly increased sensitivity to stimulation in all muscle preparations and caused a leftward shift in the stressfrequency relationship of IH and SH treated muscles. Tempol did not ameliorate sternohyoid muscle fatigue during SH. We conclude that Tempol increases upper airway muscle sensitivity to stimulation but only modestly ameliorates respiratory muscle weakness during intermittent and sustained hypoxic conditions in vitro. Respiratory muscle fatigue during sustained hypoxia appears unrelated to oxidative stress., J. R. Skelly, ... [et al.]., and Obsahuje seznam literatury
It is important to determine and clarify the variability of mammary carcinogenesis induction in animal experimental studies particularly in connection with chemoprevention projects. The circannual seasonal rhythms of hormone levels or various parameters within the immune system may involve factors participating in mammary gland carcinogenesis. In our study, 19 experiments were conducted and all of them lasted for about 25 weeks after chemical carcinogen administration (DMBA or NMU) under standard laboratory conditions. Females of two rat strains - a medium susceptible Sprague-Dawley strain and a very low susceptible Wistar:Han were used. We observed not only the effect of seasonal changes but also the effect of age after single or repeated carcinogen administration. The seasonal dependence of mammary carcinogenesis with higher tumor incidence during long days in comparison with winter short days has been demonstrated in Sprague-Dawley rats. In experiments on the Wistar:Han strain, certain features of seasonal character were recorded, although the very low susceptibility of this strain to mammary carcinogenesis might have influenced the results. A limited period of carcinogen administration in early puberty around postnatal days 43-46 (higher susceptibility), when compared to the period after postnatal day 50, is the factor significantly increasing incidence and frequency of mammary carcinogenesis in the Sprague-Dawley strain. Our results indicate the need to consider the effect of season and age of animals at the time of carcinogen administration on rat mammary carcinogenesis induction. However, the application of the results obtained in one strain of experimental animals may only lead to misleading conclusions., P. Kubatka, E. Ahlersová, I. Ahlers, B. Bojková, K. Kalická, E. Adámeková, M. Marková, M. Chamilová, M. Čermáková., and Obsahuje bibliografii
The aim of the present pilot pharmacogenetic study was to analyse quantitative effects of sulphonylurea treatment in addition to metformin on parameters of glycemic control with respect to CDKAL1 genotypes in patients with type 2 diabetes. Effect of 6-month sulphonylurea therapy on glycemic control according to CDKAL1 genotypes was evaluated in 101 patients with type 2 diabetes who failed to achieve glycemic control on metformin monotherapy. CDKAL1 rs7756992 polymorphism was determined by melting curve analysis of small amplicon following real-time PCR. After sulphonylurea treatment fasting plasma glucose (FPG) levels were significantly different (p=0.045) among three CDKAL1 genotype groups (AA: n=49; AG: n=36; GG: n=16). In a dominant genetic model, carriers of the G-allele (AG+GG, n=52) achieved significantly lower FPG levels in comparison with patients with the AA genotype (6.90±1.08 vs. 7.48±1.12 mmol/l, p=0.013). Consequently, adjusted ΔFPG was significantly higher in the AG+GG compared to the AA group (1.48±1.51 vs. 1.02±1.33 mmol/l, p=0.022). Similar trend was observed for HbA1c levels, but the difference between the genotype groups did not reach the level of statistical significance. Relatively small number of included patients is a limitation of the present study. In conclusion, our results suggest that the magnitude of FPG reduction after 6-month sulphonylurea treatment in patients with type 2 diabetes is related to the variation in CDKAL1., Z. Schroner ... [et al.]., and Obsahuje seznam literatury
Visual cognitive responses (P300) to moving stimuli were tested in 36 subjects with the aim to find the normal range of P300 parameters. Concomitantly, the circadian intra-individual variability of the P300 was studied in a subgroup of 6 subjects. Visual stimuli consisted of either coherent (frequent stimulus) or non-coherent motion (random stimulus). The oddball paradigm was applied for recording cognitive responses. P300 to rare stimuli had an average latency of 447.3±46.6 ms and amplitude of 12.9±6.0 mV. The average reaction time was in the range from 322 to 611 ms and there was no correlation between the reaction time and P300 latency. We did not find any significant circadian changes of the P300 parameters in the 6 subjects tested four times during the same day. Cognitive (event-related) responses (P300) displayed distinctly greater inter-individual variability (S.D. of 50 ms) when compared with pattern-reversal and motion-onset VEPs (S.D. of 6.0 ms and 14 ms, respectively). For this reason, the clinical use of P300 elicited by this kind of visual stimuli seems to be rather restricted and the evaluation of its intra-individual changes is preferable., Z. Kubová, J. Kremláček, J. Szanyi, J. Chlubnová, M. Kuba., and Obsahuje bibliografii
The relationship between vitamin D receptor (VDR) intragenic polymorphisms FokI, BsmI, ApaI and TaqI and bone mineral density (BMD) or biochemical markers of bone remodeling were investigated in 114 Czech postmenopausal women, on the average 62.5±8.9 years of age. Restriction fragment length polymorphisms in the VDR gene were assessed by PCR amplification and digestion with restriction enzymes FokI, BsmI, ApaI, and TaqI recognizing polymorphic sites in the VDR locus. Bone mineral density was measured at the lumbar spine and at the hip by dual-energy X-ray absorptiometry (DEXA, g/cm2). After adjusting for age and the body mass index (BMI), subjects with the ff genotype had 9.4 % lower BMD at the hip than those with the Ff genotype (p=0.0459, Tukey´s test). FF individuals had an intermediate BMD at the hip. A similar pattern of lower lumbar spine BMD was also found in ff individuals, but it did not reach statistical significance. There was no relationship between BsmI, ApaI and TaqI VDR polymorphisms and BMD at any skeletal site. Subjects with Aa (ApaI) genotypes had higher levels of propeptide of type I collagen (PICP) than homozygous AA (p=0.0459, Tukey´s test). In FokI, BsmI and TaqI restriction sites the biochemical markers of bone remodeling did not differ by genotype. In addition, no significant difference was observed in VDR genotypic distribution between osteoporotic women and non-osteoporotic controls in the study group. To conclude, the FokI genotype of the vitamin D receptor gene is related to bone mass at the hip in Czech postmenopausal women, whereas the importance of remaining VDR genotypes was not evident., K. Zajíčková, I. Žofková, R. Bahbouh, A. Křepelová., and Obsahuje bibliografii
We examined the upregulation of ET-1/ETBR/eNOS signaling in renoprotective effect of vitamin D in kidney fibrosis model in mice using unilateral ureteral obstruction (UUO). One group was treated with intraperitoneal injection of 0.125 mg/kg of Calcitriol (UUO+VD). Vascular remodeling was quantified based on lumen area and lumen/wall area ratio (LWAR) of intrarenal arteries using Sirius Red staining. ET-1, ETBR, eNOS, CD31 and VEGF mRNA expressions were quantified using qRT-PCR. Focusing on endothelin-1 (ET-1) signaling in endothelial cells (EC), siRNA of ET-1 was performed in human umbilical vein endothelial cells (HUVEC) for reducing ET-1 expression. Then HUVECs were treated with and without 100 nM Calcitriol treatment in hypoxic and normoxic conditions to elucidate ET-1/eNOS signaling. Our in vivo study revealed vascular remodeling and renal ischemia attenuation after Calcitriol treatment. Vascular remodeling was attenuated in the UUO+VD group as shown by increasing lumen areas and LWAR in intrarenal arteries. These findings were associated with significant higher CD31 and VEGF mRNA expression compared to the UUO group. Vitamin D treatment also increased ET-1, ETBR and eNOS mRNA expressions. Our in vitro study demonstrated Calcitriol induced ET-1 and eNOS mRNA expressions upregulation in HUVEC under normoxic and hypoxic condition. Meanwhile, siRNA for ET-1 inhibited the upregulation of eNOS mRNA expression after Calcitriol treatment. Vitamin D ameliorates kidney fibrosis through attenuating vascular remodeling and ischemia with upregulating ET-1/ETBR and eNOS expression., N. Arfian, M. H. H. Kusuma, N. Anggorowati, D. B. Nugroho, A. Jeffilano, Y. Suzuki, K. Ikeda, N. Emoto., and Seznam literatury
Wnt/β-catenin signaling is involved in virtually every aspect of embryonic development and also controls homeostatic selfrenewal in a number of adult tissues. Recently, emerging evidence from researches of organ fibrosis suggest that sustained Wnt/β-catenin pathway reactivation is linked to the pathogenesis of fibrotic disorders. Here we focus on Wnt/β-catenin-related pathogenic effects in different organs, such as lung fibrosis, liver fibrosis, skin fibrosis and renal fibrosis. Additionally, Wnt/β- catenin signaling works in a combinatorial manner with TGF-β signaling in the process of fibrosis, and TGF-β signaling can induce expression of Wnt/β-catenin superfamily members and vice versa. Moreover, network analysis, based on pathway databases, revealed that key factors in the Wnt pathway were targeted by some differentially expressed microRNAs detected in fibrosis diseases. These findings demonstrated the crosstalks between Wnt/β-catenin pathway and TGF-β signalings, and microRNAs, highlighting the role of Wnts in organ fibrogenesis. Most importantly, nowadays there is a variety of Wnt pathway inhibitors which give us the potential therapeutic feasibility, modulation of the Wnt pathway may, therefore, present as a suitable and promising therapeutic strategy in the future., Y. Guo ... [et al.]., and Obsahuje seznam literatury