Endothelin-1 (ET-1) and Nerve Growth Factor (NGF) are proteins, released from cancer-ridden tissues, which cause spontaneous pain and hypersensitivity to noxious stimuli. Here we examined the electrophysiological and behavioral effects of these two agents for evidence of their interactions. Individual small-medium cultured DRG sensory neurons responded to both ET-1 (50 nM, n=6) and NGF (100 ng/ml, n=4), with increased numbers of action potentials and decreased slow K+ currents; pre-exposure to ET-1 potentiated NGF´s actions, but not vice versa. Behaviorally, single intraplantar (i.pl.) injection of low doses of ET-1 (20 pmol) or NGF (100 ng), did not increase hindpaw tactile or thermal sensitivity, but their simultaneous injections sensitized the paw to both modalities. Daily i.pl. injections of low ET-1 doses in male rats caused tactile sensitization after 21 days, and enabled further tactile and thermal sensitization from low dose NGF, in ipsilateral and contralateral hindpaws. Single injections of 100 ng NGF, without changing the paw’s tactile sensitivity by itself, acutely sensitized the ipsilateral paw to subsequent injections of low ET-1. The sensitization from repeated low ET-1 dosing and the cross-sensitization between NGF and ET-1 were both significantly greater in female than in male rats. These findings reveal a synergistic interaction between cutaneously administered low doses of NGF and ET-1, which could contribute to cancer-related pain., A. Khodorova, Y. Zhang, G. Nicol, G. Strichartz., and Seznam literatury
ntestinal inflammation induced with dextran sodium sulfate (DSS) is used to study acute or chronic ulcerative colitis in animal models. Decreased gut tissue anti-inflammatory cytokine IL-10 concentration and mRNA abundance are associated with the development of chronic bowel inflammation. Twelve piglets of 3 days old were fitted with an intragastric catheter and randomly allocated into control and DSS groups by administrating either sterile saline or 1.25 g of DSS/ kg body weight (BW) in saline per day, respectively, for 10 days. Growth rate and food conversion efficiency were reduced (p<0.05) in the DSS piglets compared with the control group. Quantitative histopathological grading of inflammation in the jejunum and colon collectively showed that the DSS tr eatment resulted in 12 fold greater (p<0.05) inflammation severity scoring in the colon than in the jejunum, indicative of chronic ulcerative colitis in the colon. Upper gut permeability endpoint was 27.4 fold high er (p<0.05) in the DSS group compared with the control group. The DSS group had higher concentrations and mRNA abundances (p<0.05) of TNF - α and IL-6 in the jejunal and colonic tissues compared with the control group. Colonic concentration and mRNA abundanc e of IL-10 were reduced (p<0.05), however, jejunal IL-10 mRNA abundance was increased (p<0.05) in the DSS group compared with the control group. In conclusion , administration of DSS at 1.25 g/kg BW for 10 days respectively induced acute inflammation in th e jejunum and chronic inflammation and ulcerative colitis in the colon with substantially decreased colonic concentration and mRNA abundance of IL-10 in the young pigs, mimicking the IL-10 expression pattern in humans associated with chronic bowel inflamma tion., D. Lackeyram, D. Young, C. J. Kim, C. Yang, T. L. Archbold, Y. Mine, M. Z. Fan., and Obsahuje bibliografii
The aim of this study was to investigate the spectral characteristics of Purkinje cell interspike background activity caused by the occurrence of particular action potentials or by electrically induced enhancement of cerebellar inhibitory and excitatory input drive. Spontaneously active Purkinje neurons were extracellularly recorded in anesthetized rats before and after cessation of stimulation from the inferior olive (IO) or locus coeruleus (LC). After A/D conversion (30 kHz), direct spectral analysis of extracted interspike background activity was done. Our results have shown that, in contrast to simple spikes, the occurrence of complex spikes induces changes in the spectra of interspike background activity. The different spectral changes of interspike background activity induced by LC and IO stimulation also indicated the importance of this extracellularly recorded phenomenon., J. Šaponjic, M. Culic, B. Jankovic, A Jovanovic., and Obsahuje bibliografii
The interval model training has been more recommended to promote aerobic adaptations due to recovery period that enables the execution of elevated intensity and as consequence, higher workload in relation to continuous training. However, the physiological and aerobic capacity adaptations in interval training with identical workload to continuous are still uncertain. The purpose was to characterize the effects of chronic and acute biomarkers adaptations and aerobic capacity in interval and continuous protocols with equivalent load. Fifty Wistar rats were divided in three groups: Continuous training (GTC), interval training (GTI) and control (CG). The running training lasted 8 weeks (wk) and was based at Anaerobic Threshold (AT) velocity. GTI showed glycogen super-compensation (mg/100 mg) 48 h after training session in relation to CG and GTC (GTI red gastrocnemius (RG)=1.41±0.16; GTI white gastrocnemius (WG)=1.78±0.20; GTI soleus (S)=0.26±0.01; GTI liver (L)=2.72±0.36; GTC RG=0.42±0.17; GTC WG=0.54±0.22; GTC S=0.100±0.01; GTC L=1.12±0.24; CG RG=0.32±0.05; CG WG=0.65±0.17; CG S=0.14±0.01; CG L=2.28±0.33). The volume performed by GTI was higher than GTC. The aerobic capacity reduced 11 % after experimental period in GTC when compared to GTI, but this change was insignificant (19.6±5.4 m/min; 17.7±2.5 m/min, effect size = 0.59). Free fatty acids and glucose concentration did not show statistical differences among the groups. Corticosterone concentration increased in acute condition for GTI and GTC. Testosterone concentration reduced 71 % in GTC immediately after the exercise in comparison to CG. The GTI allowed positive adaptations when compared to GTC in relation to: glycogen super-compensation, training volume performed and anabolic condition. However, the GTI not improved the aerobic performance., G. G. de Araujo, C. A: Gobatto, M. Marcos-Pereira, I. G. M. Dos Reis, R: Verlengia., and Obsahuje bibliografii
Nanocarriers bearing anticancer drugs are promising candidates to improve the efficacy of cancer therapy and minimize side effects. The most potent cytostatics used in the treatment of various cancers are anthracyclines, e.g. doxorubicin or pirarubicin. Recently, polymer therapeutics carrying anthracyclines have been intensively studied. The precise characterization of in vitro nanocarrier biological behavior brings a better understanding of the nanocarrier characteristics and enables prediction of the behavior of the nanocarrier during in vivo application. Advanced fluorescence detection methods, e.g. fluorescence lifetime imaging microscopy (FLIM), were successfully exploited to describe the properties of various polymeric nano-systems and contributed to a complex view of anthracyclines’ intracellular transport and DNA intercalation. Here, we report the application of a specific technique for processing FLIM images, called fluorescence pattern decomposition, to evaluate early events after doxorubicin or pirarubicin treatment of cells. Moreover, we characterized changes in the intracellular localization and release of the anthracyclines during the incubation of cells with polymer nanotherapeutics based on poly[N-(2-hydroxypropyl)- methacrylamide] (pHPMA)., J. Panek, E. Koziolova, P. Stepanek, T. Etrych, O. Janouskova., and Obsahuje bibliografii
The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT 1 ) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/ Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) ra ts served as controls. Both TGR and HanSD rats responded to two weeks' exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT 1 receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of su ppression of ACE/ANG II/AT 1 receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats., V. Hampl, J. Herget, J. Bíbová, A. Baňasová, Z. Husková, Z. Vaňourková, Š. Jíchová, P. Kujal, Z. Vernerová, J. Sadowski, L. Červenka., and Obsahuje bibliografii
It is believed that atherogenesis is a multifactorial process, which could already start in utero. Development of atherosclerosis progresses over decades and leads to the cardiovascular morbidity and mortality in adulthood. At present, we have no exact explanation for all the risk factors acting in the pathogenesis of atherosclerosis. This review should provide an overview about the possible role of intrauterine undernutrition in the development of risk factors for cardiovascular disease. Intrauterine undernutrition leads to changes in fetal growth and metabolism and programs later development of some of these risk factors. A number of experimental and human studies indicates that hypertension as well as impaired cholesterol and glucose metabolism are affected by intrauterine growth. Intrauterine undernutrition plays an important role and acts synergistically with numerous genetic and environmental factors in the development of atherosclerosis. There is evidence that undernutrition of the fetus has permanent effects on the health status of human individuals., P. Szitányi, J. Janda, R. Poledne., and Obsahuje bibliografii
Lipoprotein (a) [Lp(a)] is an LDL-like particle that contains an apolipoprotein B100 molecule covalently bound to a plasminogen-like glycoprotein, apolipoprotein (a) [apo(a)]. Epidemiological evidence supports a direct and causal association between Lp(a) levels and coronary risk. On the contrary, a few prospective findings demonstrate inverse association of Lp(a) levels with risk of type 2 diabetes (T2DM). The aim of our study was to evaluate the association of Lp(a) with indicators of insulin resistance (IR) and metabolic syndrome (MS), which precede development of T2DM. We enrolled 607 asymptomatic dyslipidemic subjects (295 men and 312 women, mea n age 45.6±14.0 years) into our cross-sectional study. Lp(a) concentrations correlated inversely with TG, AIP, insulin, HOMA, C-peptide, BMI, waist circumference, and number of MS components (p<0.01 for all). Subjects with MS had significantly lower Lp(a) concentrations in comparison with those without the presence of this phenotype (p<0.0001). Serum concentrations of Lp(a) in the lower (1th 3rd) quartiles of insulin and HOMA were significantly higher than in the 4 th quartile of these insulin resistance markers (p<0.001). Odds ratios of having increased markers of IR (TG, HOMA) and MS in top quartile of Lp(a) also indicate inverse association of Lp(a) with IR. The results of our study support an inverse association of Lp(a) levels with IR and MS that precedes overt T2DM diagnosis., H. Vaverková, D. Karásek, M. Halenka, L. Cibíčková, V. Kubíčková., and Obsahuje bibliografii
Distension is a regular mechanical stimulus in gastrointestinal (GI) tract. This study was designed to investigate the effect of hypotonic stress on pacemaking activity and determine whether actin microfilament is involved in its mechanism in cultured murine intestinal interstitial cells of Cajal (ICCs) by using whole-cell patch-clamp and calcium imaging techniques. Hypotonic stress induced sustained inward holding current from the baseline to -650±110 pA and significantly decreased amplitudes of pacemaker current. Hypotonic stress increased the intensity of basal fluorescence ratio (F/F0) from baseline to 1.09±0.03 and significantly increased Ca2+ oscillation amplitude. Cytochalasin-B (20 μM), a disruptor of actin microfilaments, significantly suppressed the amplitudes of pacemaker currents and calcium oscillations, respectively. Cytochalasin-B also blocked hypotonic stress-induced sustained inward holding current and hypotonic stress-induced increase of calcium oscillations. Phalloidin (20 μM), a stabilizer of actin microfilaments, significantly enhanced the amplitudes of pacemaker currents and calcium oscillations, respectively. Despite the presence of phalloidin, hypotonic stress was still able to induce an inward holding current and increased the basal fluorescence intensity. These results suggest that hypotonic stress induces sustained inward holding current via actin microfilaments and the process is mediated by alteration of intracellular basal calcium concentration and calcium oscillation in cultured intestinal ICCs., Z. Y. Wang, X. Huang, D. H. Liu, H. L. Lu, Y. C. Kim, W. X. Xu., and Obsahuje bibliografii