AIMS: Inflammatory bowel diseases and colorectal cancer are serious intestinal disorders with continuously increasing incidence. Many aspects of etiopathogenesis still remain unclear. There is an urgent need to improve early diagnostics and markers indicating the progression of the disease. The aim of our study was to analyze the expression of matrix metalloproteinase-19 (MMP-19), and the receptor for advanced glycation end-products (RAGE) in different cell subpopulations in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) compared to the tissue in the vicinity of pathological processes. METHODS: Expression of both markers in epithelium, macrophages and vessels were evaluated in IBD and CRC groups. They were detected using immunohistochemistry in paraffin sections. RESULTS: There were significant differences between the expression of MMP-19 on macrophages and vessels among healthy and cancer tissues. In both, macrophages and vessels were significantly lower levels in cancer tissues. The expression of MMP-19 on vessels was also significantly different between peritumoral and cancer tissues (higher levels in peritumoral tissue). RAGE expression in macrophages was significantly different between healthy and cancer tissues and between peritumoral and cancer tissues. There was significantly lower expression in cancer tissues than in healthy and peritumoral tissues. Expression of RAGE in vessels was significantly different just in the comparison of healthy and peritumoral tissues (higher levels in healthy tissues). CONCLUSION: Both markers seem to be promising potential auxiliary markers in IBD and CRC diagnostics. They can also improve evaluation of disease progression.
- MeSH
- biologické markery metabolismus MeSH
- idiopatické střevní záněty * diagnóza metabolismus patologie MeSH
- kolorektální nádory * diagnóza metabolismus patologie MeSH
- lidé MeSH
- metaloproteinasy secernované do matrix MeSH
- receptor pro konečné produkty pokročilé glykace metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Intra-amniotic infections (IAI) are one of the reasons for preterm birth. High mobility group box 1 (HMGB1) is a nuclear protein with various physiological functions, including tissue healing. Its excessive extracellular release potentiates inflammatory reaction and can revert its action from beneficial to detrimental. We infected the amniotic fluid of a pig on the 80th day of gestation with 1 × 104 colony forming units (CFUs) of E. coli O55 for 10 h, and evaluated the appearance of HMGB1, receptor for glycation endproducts (RAGE), and Toll-like receptor (TLR) 4 in the amniotic membrane and fluid. Sham-infected amniotic fluid served as a control. The expression and release of HMGB1 were evaluated by Real-Time PCR, immunofluorescence, immunohistochemistry, and ELISA. The infection downregulated HMGB1 mRNA expression in the amniotic membrane, changed the distribution of HMGB1 protein in the amniotic membrane, and increased its level in amniotic fluid. All RAGE mRNA, protein expression in the amniotic membrane, and soluble RAGE level in the amniotic fluid were downregulated. TLR4 mRNA and protein expression and soluble TLR4 were all upregulated. HMGB1 is a potential target for therapy to suppress the exaggerated inflammatory response. This controlled expression and release can, in some cases, prevent the preterm birth of vulnerable infants. Studies on suitable animal models can contribute to the development of appropriate therapy.
- MeSH
- amnion imunologie mikrobiologie patologie MeSH
- Escherichia coli růst a vývoj patogenita MeSH
- infekce vyvolané Escherichia coli genetika imunologie mikrobiologie veterinární MeSH
- infekční komplikace v těhotenství genetika imunologie mikrobiologie veterinární MeSH
- interakce hostitele a patogenu genetika imunologie MeSH
- lidé MeSH
- messenger RNA genetika imunologie MeSH
- modely nemocí na zvířatech MeSH
- plodová voda imunologie mikrobiologie MeSH
- prasata MeSH
- předčasný porod prevence a kontrola MeSH
- protein HMGB1 genetika imunologie MeSH
- receptor pro konečné produkty pokročilé glykace genetika imunologie MeSH
- regulace genové exprese MeSH
- signální transdukce MeSH
- těhotenství MeSH
- toll-like receptor 4 genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Advanced glycation end products (AGEs) are involved in several pathophysiologic processes in vascular diseases, including progressive loss of elasticity of the vessel wall (arterial stiffness). Circulating soluble receptors for AGEs (sRAGE) act as a decoy and counterbalanced the harmful properties of AGEs as the natural protective factor. We compared the role of circulating or skin-deposed AGEs and sRAGE regarding the natural course of arterial stiffening. In a prospective cohort study, we longitudinally followed 536 general population-based subjects (subsample of Czech post-MONICA study). Aortic pulse-wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE and carboxymethyl lysine (circulating AGEs) were assessed at the follow-up visit by ELISA, while skin AGEs were measured using the autofluorescence-based device AGE Reader. Using multiple regressions, we found significant association between ∆PWV/year as a dependent variable, and both, sRAGE and skin AGEs as independent ones (each on its own model). However, the closest associations to ∆PWV/year were found for the ratio of these two factors (skin AGEs/sRAGE) [β coeff = 0.0747 (SE 0.0189), p < 0.0001]. In a categorized manner, subjects with skin AGEs/sRAGE ratio ≥ 3.3 showed about twofold higher risk having ΔPWV/year ≥ 0.2 m/s [adjusted odds ratio was 2.09 (95% CI: 1.35-3.22), p = 0.001]. In contrast, neither circulating AGEs nor circulating AGEs/sRAGE showed any significant relation to ΔPWV/year. In conclusion, skin AGEs/sRAGE ratio seems to be a more sensitive biomarker of vascular aging than these single factors themselves or circulation status of AGEs.
Purpose: Advanced glycation end products (AGEs) are a heterogeneous group of highly oxidant compounds which can potentiate microvascular and macrovascular complications through the formation of irreversible cross-links between molecules in the basal membrane and also by engaging the receptor for AGEs (RAGE). Soluble receptor for AGEs (sRAGE) is suggested to have a protective role neutralizing the toxic action of AGEs. We aimed to investigate differences in plasma levels of sRAGE alongside with classic cardiovascular risk factors between offspring of patients with early onset of coronary heart disease (CHD) and healthy controls.Materials and methods: In a cross-sectional design, we examined 114 adult offspring of patients with premature CHD and 194 controls. Concentrations of soluble RAGE were quantified by ELISA methods. Aortic PWV was measured using Sphygmocor device. Multivariate logistic regressions were used to compare differences between the offspring and controls.Results: In the offspring group there were more men (p = 0.023), both groups had similar age (28.5 vs. 28.9 years; p = 0.51). After adjustment for covariates, we observed significantly higher aPWV (6.17 vs. 5.82 m s-1; p = 0.001) and lower sRAGE (1308.11 vs. 1475.59; p = 0.009) in the offspring group compared to controls. The significant determinants of the intergroup difference were sRAGE (p = 0.0017), aPWV (p = 0.011) and current smoking (p = 0.0053).Conclusion: Offspring of patients with early onset of CHD compared to age-matched healthy controls had significantly lower sRAGE levels suggesting a shift in the oxidative balance between stressors and defence mechanisms that may influence a higher cardiovascular risk in the future. The measurement of sRAGE might be a valuable predictor for more precise stratification of cardiovascular risk.
- MeSH
- biologické markery krev MeSH
- dítě postižených rodičů * MeSH
- dospělé děti * MeSH
- dospělí MeSH
- hodnocení rizik MeSH
- koronární nemoc * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- průřezové studie MeSH
- receptor pro konečné produkty pokročilé glykace krev MeSH
- rizikové faktory kardiovaskulárních chorob MeSH
- studie případů a kontrol MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Circulating levels of soluble receptor for advanced glycation end-products (sRAGE) have been suggested to have a protective role in neutralizing advanced glycation end-products (AGEs) and their pathological effects on vessel walls. We aimed to investigate the association between the circulating concentration of sRAGE and the dynamics of arterial wall stiffening as a manifestation of vascular aging in the general population. In a prospective cohort study, we longitudinally followed 530 general-population-based subjects (subsample of Czech post-MONICA study). Aortic pulse wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE were assessed at baseline by ELISA (R&D Systems). The average ∆PWV/year significantly decreased across the sRAGE quintiles (p = 0.048), and a drop by one sRAGE quintile was associated with an ~21% increase in the relative risk of accelerated age-dependent stiffening (∆PWV/year ≥ 0.2 m/s). Subjects in the bottom quintile of sRAGE (<889.74 pg/mL) had a fully adjusted odds ratio of accelerated stiffening of 1.72 (95% CI: 1.06-2.79), p = 0.028, while those with high sRAGE concentrations (≥1695.2 pg/mL) showed the opposite effect [odds ratio 0.55 (95% CI: 0.33-0.90), p = 0.017]. In conclusion, the circulating status of sRAGE independently influenced the individual progression of arterial stiffness over time. This finding strongly supports the hypothesis that high sRAGE has a protective role against vascular aging.
- MeSH
- analýza pulzové vlny MeSH
- dospělí MeSH
- krevní tlak fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- prospektivní studie MeSH
- receptor pro konečné produkty pokročilé glykace krev MeSH
- senioři MeSH
- stárnutí metabolismus MeSH
- tuhost cévní stěny fyziologie MeSH
- věkové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The receptor for the advanced glycation end products (RAGE) is a multiligand transmembrane receptor involved in chronic inflammation whose specific polymorphisms of the promoter gene were found to increase its transcriptional activity. We investigated the association of both allelic and genotypic -374T/A and -429T/C polymorphisms with inflammatory bowel disease. The STREGA guidelines were applied for planning and reporting. We enrolled 133 patients with Crohn's disease (CD), 149 with ulcerative colitis (UC), and 128 blood donors. Genomic DNA was extracted from peripheral blood leukocytes collected from each patient and control. RAGE polymorphisms were analyzed by PCR-restriction fragment length polymorphism assay. The Hardy-Weinberg equilibrium was first assessed, and then, the Kruskal-Wallis test and the Fisher exact test were used for etiologic group comparisons. Distribution of patients' characteristics across genotypes was evaluated by the Fisher exact test, while that across alleles was analyzed with a probit model. A 2-sided value of p < 0.05 was considered significant. Following the evidence of the Hardy-Weinberg equilibrium, we found a higher prevalence of the allele A of the -374T/A haplotype in UC (p = 0.043), and of the allele C of the -429T/C haplotype in CD (p < 0.001) with respect to the other groups. Moreover, the homozygous AA genotype of the -374T/A polymorphism resulted associated with late onset of CD, while its TT genotype with early onset (p = 0.049). The allele C of the 429T/C haplotype was associated with early onset of UC (p = 0.03), while a higher frequency of the heterozygous TC haplotype was found in those with pancolitis (p = 0.026). The differing distribution of these polymorphisms in healthy donors and CD/UC patients suggests a role in the development and outcome of these pathological conditions.
- MeSH
- dospělí MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci * MeSH
- genotyp MeSH
- genotypizační techniky MeSH
- idiopatické střevní záněty genetika MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- polymorfismus délky restrikčních fragmentů MeSH
- prevalence MeSH
- promotorové oblasti (genetika) * MeSH
- receptor pro konečné produkty pokročilé glykace genetika MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE OF REVIEW: The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. RECENT FINDINGS: Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.
- MeSH
- adipogeneze MeSH
- buněčná diferenciace MeSH
- buňky kostní dřeně metabolismus MeSH
- glukagonu podobný peptid 1 metabolismus MeSH
- glukosa metabolismus MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- inzulin metabolismus MeSH
- inzulinová rezistence MeSH
- kosti a kostní tkáň metabolismus MeSH
- kostní dřeň metabolismus MeSH
- lidé MeSH
- metabolické nemoci kostí metabolismus MeSH
- mezenchymální kmenové buňky metabolismus MeSH
- obezita metabolismus MeSH
- parathormon metabolismus MeSH
- protein 4 vázající insulinu podobné růstové faktory metabolismus MeSH
- proteiny insulinového receptorového substrátu metabolismus MeSH
- receptor inzulinu metabolismus MeSH
- receptor pro konečné produkty pokročilé glykace metabolismus MeSH
- stárnutí buněk * MeSH
- tuková tkáň metabolismus MeSH
- tukové buňky metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND/AIMS: Chronic heart failure (HF) disrupts normal kidney function and leads to cardiorenal syndrome that further promotes HF progression. To identify potential participants in HF-related injury, we analyzed kidney proteome in an established HF model. METHODS: HF was induced by chronic volume overload in male HanSD rats using aorto-caval fistula. After 21 weeks, cardiac and renal functions (in-situ kidney study) and renal proteomics were studied in sham-operated (controls) and HF rats, using iTRAQ labeling and LC-MS with Orbitrap Fusion, leading to identification and quantification of almost 4000 proteins. RESULTS: Compared to controls, HF rats had cardiac hypertrophy, systemic and pulmonary congestion. Kidneys of HF rats had reduced renal blood flow, sodium excretion and urine production. While glomerular filtration rate, serum cystatin C and creatinine were still normal compared to controls, HF kidneys showed albuminuria and markedly increased tissue angiotensin-II levels (5-fold). HF kidneys (versus controls) displayed differential expression (˃1.5-fold) of 67 proteins. The most upregulated were angiotensin-converting enzyme (ACE, ˃20-fold), advanced glycosylation product-specific receptor (RAGE, 14-fold), periostin (6.8-fold), caveolin-1 (4.5-fold) and other proteins implicated in endothelial function (vWF, cavins 1-3, T-kininogen 2), proinflammatory ECM activation (MFAP4, collagen-VI, galectin-3, FHL-1, calponin) and proteins involved in glomerular filtration membrane integrity (CLIC5, ZO-1). Carboxylesterase-1D (CES1D), an enzyme that converts ACE inhibitors or sacubitril into active drugs, was also upregulated in HF kidneys. CONCLUSION: Chronic HF leads to latent kidney injury, associated with deep changes in kidney protein composition. These alterations may act in concert with intrarenal renin-angiotensin system activation and may serve as markers and/or targets to tackle cardiorenal syndrome.
- MeSH
- albuminurie etiologie MeSH
- angiotensin konvertující enzym metabolismus MeSH
- endotel metabolismus MeSH
- extracelulární matrix - proteiny metabolismus MeSH
- kardiomegalie patofyziologie MeSH
- kardiorenální syndrom etiologie metabolismus MeSH
- krysa rodu rattus MeSH
- ledviny chemie zranění patofyziologie MeSH
- proteom analýza metabolismus MeSH
- proteomika metody MeSH
- receptor pro konečné produkty pokročilé glykace metabolismus MeSH
- renin-angiotensin systém MeSH
- srdeční selhání komplikace MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury. METHODS: We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume. RESULTS: Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01-1.38; P = 0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02-1.07; P = 0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07-3.64; P = 0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher VT. CONCLUSIONS: Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).
- MeSH
- APACHE MeSH
- biologické markery metabolismus MeSH
- dechová práce MeSH
- dechový objem fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- pozorovací studie jako téma MeSH
- randomizované kontrolované studie jako téma MeSH
- receptor pro konečné produkty pokročilé glykace metabolismus MeSH
- rizikové faktory MeSH
- syndrom dechové tísně krev mortalita MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
The binding of high-mobility group box-1 (HMGB-1) to the membrane receptor for advanced glycation end-products (mRAGE) is a key early mediator of non-infectious inflammation and its triggers include ischaemia/hypoxia. The effects of acute hypoxia on soluble RAGE (sRAGE) are unknown. Fourteen healthy adults (50 % women; 26.6+/-3.8 years) were assessed at baseline normoxia (T0), followed by four time-points (T90, 95, 100 and 180 min) over three hours of continuous normobaric hypoxia (NH, 4,450 m equivalent) and again 60 min after return to normoxia (T240). A 5-min exercise step test was performed during NH at T90. Plasma concentrations of HMGB-1, sRAGE VCAM-1, ICAM-1, VEGF IL-8 and IL-13 were measured using venous blood. Arterial and tissue oxygen saturations were measured using pulse oximetry (SpO(2)) and near-infrared spectroscopy (StO(2)), respectively. NH led to a significant reduction in SpO(2), StO(2), sRAGE and VEGF, which was compounded by exercise, before increasing to baseline values with normoxic restoration (T240). NH-exercise led to a paired increase in HMGB-1. sRAGE inversely correlated with HMGB-1 (r=-0.32; p=0.006), heart rate (r=-0.43; p=0.004) but was not linked to SpO(2) or StO(2). In conclusion, short-term NH leads to a fall in sRAGE and VEGF concentrations with a transient rise post NH-exercise in HMGB-1.
- MeSH
- alarminy krev MeSH
- biologické markery krev MeSH
- dospělí MeSH
- hypoxie krev diagnóza MeSH
- lidé MeSH
- mediátory zánětu krev MeSH
- mladý dospělý MeSH
- prospektivní studie MeSH
- protein HMGB1 krev MeSH
- receptor pro konečné produkty pokročilé glykace krev MeSH
- spotřeba kyslíku fyziologie MeSH
- vaskulární endoteliální růstový faktor A krev MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
