Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Therefore, understanding the molecular regulatory mechanisms underlying the pathogenesis of DKD is imperative. In this study, we aimed to explore the molecular mechanisms of tubule region endothelial dysfunction in early DKD. Early-stage DKD model was established in 16-week-old female db/db mice for 16 weeks. Body weight, glucose level, and urine albumin-to-creatinine ratio (UACR) were measured. Hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were performed to evaluate pathological lesions. RNA sequencing data of the kidneys and integrated publicly available single-cell and spatial transcriptome datasets were used to investigate the mechanism of endothelial dysfunction. There was a significant increase in body weight (p = 0.001), glucose levels (p=0.0008), and UACR (p=0.006) in db/db mice compared with db/m mice. H&E and PAS staining showed that vacuolar lesions and protein casts of tubules were the major histopathological changes observed in early-stage DKD mice. The apoptotic pathway in endothelial cells was notably activated in DKD, and Thbs1 was identified as the central gene involved in this apoptotic process. Deconvolution of the cell composition in the RNA sequencing data showed a decrease in the proportion of endothelial cells in the DKD mice. Further analysis of the activity and regulatory network of transcription factors showed that Creb1 was activated in both mouse and human early-stage DKD, suggesting that Creb1 activation may be involved in early kidney injury. The endothelial cell apoptotic pathway is activated in DKD, and the proportion of endothelial cells was reduced in the DKD mice, which is significantly associated with Thbs1. Keywords: Diabetic kidney disease, Endothelial dysfunction, RNA sequencing,Thbs1, Creb1.

• MeSH
• apoptóza MeSH
• diabetické nefropatie * patologie   metabolismus   patofyziologie   genetika   MeSH
• endoteliální buňky metabolismus   patologie   MeSH
• ledvinové kanálky patologie   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• progrese nemoci * MeSH
• protein vázající cAMP responzivní element metabolismus   genetika   MeSH
• thrombospondin 1 metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Acral fibrochondromyxoid tumor (AFCMT) is a recently described likely benign mesenchymal neoplasm arising in the distal extremities with distinctive histologic features and a recurrent THBS1::ADGRF5 fusion. We studied an additional 37 cases of AFCMT and expanded on the so-far reported clinicopathologic and molecular findings. Tumors occurred in 21 females and 16 males, ranging in age from 17 to 78 years (median age: 47), and solely involved the hands (24/37, 65%) or feet (13/37, 35%). Histologic examination revealed well-delineated uni- or multinodular tumors with prominent vasculature-rich septa and bland, chondrocyte-like tumor cells set within abundant chondromyxoid stroma. Immunohistochemical studies showed that tumor cells were positive for CD34 (25/27; 93%) and ERG (27/27; 100%), whereas negative for S100 protein (0/31). Molecular analysis revealed evidence of a THBS1::ADGRF5 fusion in 17 of 19 (89%) successfully tested tumors. Clinical follow-up was available in 8 cases (median: 97 months), with multiple local recurrences in 1 case at 276, 312, and 360 months. We conclude that AFCMT is a distinct entity with reproducible morphologic, immunohistochemical, and molecular genetic features that should be differentiated from other similar appearing acral mesenchymal neoplasms.

• MeSH
• dospělí MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádory měkkých tkání genetika   patologie   MeSH
• noha (od hlezna dolů) patologie   MeSH
• ruka patologie   MeSH
• senioři MeSH
• thrombospondin 1 genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The development of immunoassays enables more sophisticated studies of the associations between protein concentrations and pregnancy outcomes, allowing early biomarker identification that can improve neonatal outcomes. The aim of this study was to explore associations between selected mid-trimester amniotic fluid proteins and (1) overall gestational duration and (2) spontaneous preterm delivery. A prospective cohort study, including women undergoing mid-trimester transabdominal genetic amniocentesis, was performed in Gothenburg, Sweden, 2008-2016 (n = 1072). A panel of 27 proteins related to inflammation was analyzed using Meso-Scale multiplex technology. Concentrations were adjusted for gestational age at sampling, experimental factors, year of sampling, and covariates (maternal age at sampling, parity (nulliparous/multiparous), smoking at first prenatal visit, and in vitro fertilization). Cox regression analysis of the entire cohort was performed to explore possible associations between protein concentrations and gestational duration. This was followed by Cox regression analysis censored at 259 days or longer, to investigate whether associations were detectable in women with spontaneous preterm delivery (n = 47). Finally, linear regression models were performed to analyze associations between protein concentrations and gestational duration in women with spontaneous onset of labor at term (n = 784). HMG-1, IGFBP-1, IL-18, MIP-1α, MIP-1β, S100A8, and thrombospondin-1 were significantly associated with gestational duration at term, but not preterm. Increased concentrations of thrombospondin-1, MIP-1β, and S100A8, respectively, were significantly associated with decreased gestational duration after the Holm-Bonferroni correction in women with spontaneous onset of labor at term. This adds to the concept of a pregnancy clock, where our findings suggest that such a clock is also reflected in the amniotic fluid at early mid-trimester, but further research is needed to confirm this.

• MeSH
• amniocentéza MeSH
• chemokin CCL4 analýza   MeSH
• dospělí MeSH
• gestační stáří MeSH
• kalgranulin A analýza   MeSH
• lidé MeSH
• nástup porodu MeSH
• plodová voda chemie   MeSH
• prospektivní studie MeSH
• těhotenství metabolismus   MeSH
• thrombospondin 1 analýza   MeSH
• trimestry těhotenství * MeSH
• výsledek těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství metabolismus   MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Thrombospondins (TSPs) are matricellular glycoproteins expressed in response to vascular injury. TSP-1 and TSP-2 are promotors of arterial remodeling while TSP-5 is believed to be protective. The current study assessed the differential effect of TSPs on protein expression in vascular smooth muscle cells (VSMCs). We hypothesized that TSP-1, TSP-2 and TSP-5 would regulate VSMC proteins involved in arterial remodeling. Human VSMCs were exposed to TSP-1, -2, -5 or serum free media (24 hours). Cell lysates were used to assess the targets TSP-1, TSP-2, TSP-5 and CD44), while the culture media was used to detect TGF-ß1, PDGF-BB, ANGPTL-4 and IL-8. Statistical analysis was performed by t-test and p< 0.05 was considered significant. All TSPs increased their own expression and TSP-5 increased TSP-2. TSP-1 and TSP-2 increased production of ANGPTL-4 and PDGF-BB, while TSP-5 only increased ANGPTL-4. TSP-1 increased exclusively TGF-ß1 and CD44 production. TSP-2 increased TSP-1 expression. All TSPs decreased IL-8. The findings suggest that TSP-1 and TSP-2 may promote vascular remodeling, in part, by increasing ANGPTL-4, PDGF-BB and their own expression. TSP-5 did not upregulate the inflammatory mediators TSP-1, PDGF-BB or TGF-ß1, but upregulated its own expression, which could be a protective mechanism against the response to vascular injury.

• MeSH
• arterie metabolismus   MeSH
• chrupavkový oligomerní matrixový protein biosyntéza   MeSH
• kultivované buňky MeSH
• lidé MeSH
• myocyty hladké svaloviny metabolismus   MeSH
• remodelace cév fyziologie   MeSH
• svaly hladké cévní metabolismus   MeSH
• thrombospondin 1 biosyntéza   MeSH
• thrombospondiny biosyntéza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• biologické markery MeSH
• dospělí MeSH
• exprese genu * MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• hodnocení rizik MeSH
• hypoxie genetika   metabolismus   MeSH
• incidence MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorový supresorový protein VHL genetika   MeSH
• následné studie MeSH
• polycytemie komplikace   genetika   metabolismus   MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• thrombospondin 1 genetika   MeSH
• trombóza krev   diagnóza   epidemiologie   etiologie   MeSH
• zárodečné mutace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Nárůst prevalence metabolického syndromu, souhrnně označující rizika pro vznik chorob kardiovaskulárního systému, vedl k hlubšímu zkoumání jeho příčin i důsledků. Zvýšený zájem je věnován hlavním rizikovým faktorům, obesitě, dyslipidemii, hypertensi a diabetu mellitu II. typu. Zájem o významnou roli genetické predispozice přispěl k objevu membránového glykoproteinu CD36. Souvislost proteinu CD36 s metabolickým syndromem je podmíněna zvláště jeho zapojením do metabolismu sacharidů i lipidů. Mezi jeho rozličné funkce můžeme zařadit: úlohu jako transportéru mastných kyselin s dlouhým řetězcem, podíl na vzniku atherosklerosy a též roli v nespecifické imunitě. Pozornost je u proteinu CD36 věnována i regulační schopnosti v procesu angiogenese.

Increasing prevalence of metabolic syndrome, summarizing risks of cardiovascular disease development, gave rise to intense research of its impact, cause and effect. Increased demand is given for the main risk factors, obesity, dyslipidemia, hypertension and diabetes mellitus type II. The interest in significant role of genetic predisposition contributed to location of membrane glycoprotein CD36. Relation of protein CD36 to metabolic syndrome is conditioned especially with its involvement in saccharide and lipid metabolism. Among his various functions can be included: the role as long chain fatty acid transporter, atherosclerosis development and also the role in nonspecific immunity. Attention is paid to regulatory skills of CD36 in angiogenesis process.

• MeSH
• antigeny CD36 fyziologie   chemie   metabolismus   MeSH
• ateroskleróza patofyziologie   MeSH
• buněčná imunita fyziologie   MeSH
• látky modulující angiogenezi MeSH
• lidé MeSH
• malárie MeSH
• membránové transportní proteiny fyziologie   MeSH
• metabolický syndrom patofyziologie   MeSH
• thrombospondin 1 fyziologie   MeSH
• transportní proteiny mastných kyselin fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Restoration of transcriptionally silenced genes by means of methyltransferases inhibitors plays a crucial role in the current therapy of myelodysplastic syndromes and certain types of leukemias. A comparative study of hypomethylating activities of a series of 5-azacytidine nucleosides: 5-azacytidine (AC), 2'-deoxy-5-azacytidine (DAC) and its α-anomer (α-DAC), 5,6-dihydro-5-azacytidine (DHAC), 2'-deoxy-5,6-dihydro-5-azacytidine (DHDAC, KP-1212) and its α-anomer (α-DHDAC), and of a 2-pyrimidone ribonucleoside (zebularine) was conducted. Methylation-specific PCR was employed to detect the efficiency of individual agents on cyclin-dependent kinase inhibitor 2B and thrombospondin-1 hypermethylated gene loci. Overall changes in DNA methylation level were quantified by direct estimation of 5-methyl-2'-deoxycytidine-5'-monophosphate by HPLC using digested genomic DNA. Flow cytometric analysis of cell cycle progression and apoptotic markers was used to determine cytotoxicity of the compounds. mRNA expression was measured using qRT-PCR. 2'-deoxy-5,6-dihydro-5-azacytidine was found to be less cytotoxic and more stable than 2'-deoxy-5-azacytidine at the doses that induce comparable DNA hypomethylation and gene reactivation. This makes it a valuable tool for epigenetic research and worth further investigations to elucidate its possible therapeutic potential.

• MeSH
• apoptóza účinky léků   MeSH
• azacytidin analogy a deriváty   chemie   farmakologie   MeSH
• genetické lokusy MeSH
• genom lidský MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• metylace DNA účinky léků   MeSH
• molekulární struktura MeSH
• regulace genové exprese MeSH
• thrombospondin 1 genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Our aim was to establish whether the pretreatment levels of angiogenesis activators and inhibitors can be used to predict clinical responses to treatment that included high-dose chemotherapy with peripheral stem cell support.
We analyzed samples and treatment outcomes of 96 patients with MM enrolled in the CMG 2002 randomized clinical trial and treated with induction chemotherapy and high-dose chemotherapy with stem cell support. Concentrations of vascular endothelial growth factor (VEGF), hepatocytar growth factor (HGF), basic fibroblastic growth factor (bFGF), thrombospondin-1 (TSP-1), endostatin, and angiostatin were measured in the peripheral blood plasma and in the bone marrow plasma at diagnosis.
Pretreatment HGF concentrations in the peripheral blood plasma as well as in the bone marrow plasma of patients who achieved complete or very good partial response were significantly lower than those in patients who had partial or worse response. Patients with complete or very good partial response had higher TSP-1 levels in the bone marrow plasma than the partial or insufficient response subgroups. There were no correlations between the pretreatment levels of VEGF, bFGF, endostatin, or angiostatin and the treatment response.
Pretreatment concentrations of HGF and TSP-1 were predictive factors for treatment response. Patients with low angiogenesis rate as determined by the relative HGF and TSP-1 concentrations were more likely to achieve complete or very good partial response after high-dose chemotherapy. Keywords: Angiogenesis, cytokines, high-dose chemotherapy, multiple myeloma, therapeutic response.

• MeSH
• angiostatiny krev   MeSH
• dospělí MeSH
• fibroblastový růstový faktor 2 krev   MeSH
• fyziologická neovaskularizace MeSH
• hepatocytární růstový faktor krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom krev   farmakoterapie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• thrombospondin 1 krev   MeSH
• vaskulární endoteliální růstový faktor A krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Angiogenesis plays a significant role in the pathogenesis of multiple myeloma (MM). We have measured concentrations of angiogenesis activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hepatocyte growth factor (HGF), and inhibitors, including endostatin, thrombospondin-1 (TSP-1), and angiostatin in the peripheral and bone marrow blood of MM patients at diagnosis and after high-dose chemotherapy. We have analyzed 96 patients with secretory MM. Serial measurements of angiogenesis factors/inhibitors were analyzed in the plasma by subgroups based on the best treatment response. Concentrations of angiogenic factors were determined in the peripheral blood and bone marrow plasma. There were significant decreases of VEGF and HGF levels and a significant increase in TSP-1 concentrations in the bone marrow plasma of patients who achieved complete or very good partial response in contrast to those who had partial or no response. VEGF and HGF levels decrease but those of TSP-1 increase after successful treatment for MM, indicating a reduction in the rate of angiogenesis.

• MeSH
• angiostatiny krev   MeSH
• dospělí MeSH
• hepatocytární růstový faktor krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom diagnóza   farmakoterapie   krev   MeSH
• protinádorové látky aplikace a dávkování   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• thrombospondin 1 krev   MeSH
• vaskulární endoteliální růstový faktor A krev   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH