BACKGROUND
: Primary hyperparathyroidism (PHPT), one of the most common endocrine pathologies, is associated with a higher incidence of cardiovascular diseases, in particular, those caused by ...endothelial dysfunction. Evaluation of endothelial dysfunction in patients with PHPT will predict the development of cardiovascular pathology and determine the optimal tactics for PHPT management.
AIM
: To evaluate the concentration of soluble endoglin and photoplethysmographic parameters as potential markers of endothelial dysfunction in patients with PHPT.
MATERIALS AND METHODS
: A single-center interventional single-stage study was carried out. 2 groups were formed. The first group included 50 patients with verified PHPT who did not have cardiovascular or other concomitant somatic pathologies in anamnesis. The comparison group included 21 healthy volunteers comparable in sex and age. All participants underwent a biochemical blood test (total calcium, ionized, albumin, lipidogram, urea, uricacid, glucose, creatinine, alkaline phosphatase), parathyroid hormone, 25 (OH) D and endoglin concentrations were evaluated. In addition, echocardiography, ultrasound of the brachiocephalic arteries and arteries of the lower extremities, as well as photoplethysmography were performed.
RESULTS
: The groups differed in mineral parameters associated with PHPT; no differences were found in parameters of lipid, uric acid and carbohydrate metabolism. Serum levels of endoglin were lower in PHPT patients (p=0.002). We found a negative correlation between the concentration of albumin-corrected calcium and PTH with endoglin (r
1
=-0.370, p
1
=0.003 and r
2
=-0.475, p
2
<0.001, respectively) and a positive correlation between the concentration of endoglin and phosphorus (r=0.363, p=0.003). These associations s were accompanied by changes in photoplethysmographic parameters that indicate an increase in the vascular wall stiffness.
CONCLUSION
: The serum level of soluble endoglin is lower in patients with PHPT than in healthy volunteers, negatively correlates with calcium and PTH concentrations and positively with serum phosphorus concentrations. Further studies will make it possible to establish the pathogenetic mechanism of the identified relationships and evaluate the role of endoglin as a potential predictor of cardiovascular pathology in PHPT population.
The airway epithelium is a dynamic tissue that undergoes slow but constant renewal. Dysregulation of airway epithelial function related to cigarette smoke exposure plays an important role in the ...pathophysiology of COPD. Oct4 is a transcription factor responsible for maintaining cellular self-renewal and regeneration, and CD146 and CD105/Endoglin are adhesion molecules involved in cell proliferation, differentiation, epithelial-mesenchymal-transition and tissue remodeling. Bronchial biopsy specimens (BBs) were obtained from 7 healthy controls (HC) and 10 COPD and subjected to paraffin embedding; BBs from HC were also used for epithelial cell expansion and pHBEC/ALI (air-liquid interface) culture. pHBEC/ALI were exposed to cigarette smoke extract (CSE) for 7, 14 and 21 days. In BBs, Oct4, CD146 and CD105 were evaluated by immunohistochemistry. In pHBEC/ALI, the expression of Oct4, CD146, CD105 and acetyl-αtubulin was evaluated by Western Blot, MUC5AC and IL-8 measurements by ELISA.
The Oct4 epithelial immunoreactivity was lower in COPD than in HC, whilst CD146 and CD105 expression was higher in COPD than in HC. In pHBEC/ALI, Transepithelial Electrical Resistance values, measured over 7 to 21 days of differentiation, decreased by 18% (2.5% CSE) and 29% (5% CSE) compared to untreated samples. Oct4 and acetyl-αtubulin were induced after one-week differentiation and downregulated by CSE in reconstituted epithelium; CD146, CD105, MUC5AC and IL-8 were increased by CSE.
Oct4 de-regulation and CD146 and CD105 overexpression, induced by cigarette smoke exposure, might play a role in airway epithelial dysfunction by causing changes in self-renewal and mesenchymal transition mechanisms, leading to alteration of epithelium homeostasis and abnormal tissue remodeling involved in progression of COPD.
•Oxidative-stress mediated mechanisms induce de-regulation of Oct4 protein expression.•De-regulation of Oct4, might play a role in reorientation of lung epithelium self-renewal process.•Overexpressio of CD146 and CD105 mesenchimal markers is associated with de-differentiation and EMT.•Altered Oct4 regulation and CD146 and CD105 expression are potentially involved in lack of lung epithelium homeostasis and abnormal tissue remodeling in COPD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Loss-of-function variants generating premature termination codons associate with bleeds; RNA levels differ between replicate cell cultures.•No PTC-truncated proteins were detected; ENG Q436X (but ...not R93X) induced cell stress and had pathogenic AlphaMissense readthrough scores.
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For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P < .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of near-invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.
Angiogenesis is a highly coordinated, extremely complex process orchestrated by multiple signaling molecules and blood flow conditions. While sprouting mode of angiogenesis is very well investigated, ...the molecular mechanisms underlying intussusception, the second mode of angiogenesis, remain largely unclear. In the current study two molecules involved in vascular growth and differentiation, namely endoglin (ENG/CD105) and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) were examined to unravel their specific roles in angiogenesis. Down- respectively up-regulation of both molecules tightly correlates with intussusceptive microvascular growth. Upon ENG inhibition in chicken embryo model, formation of irregular capillary meshwork accompanied by increased expression of COUP-TFII could be observed. This dynamic expression pattern of ENG and COUP-TFII during vascular development and remodeling correlated with formation of pillars and progression of intussusceptive angiogenesis. Similar findings could be observed in mammalian model of acute rat Thy1.1 glomerulonephritis, which was induced by intravenous injection of anti-Thy1 antibody and has shown upregulation of COUP-TFII in initial phase of intussusception, while ENG expression was not disturbed compared to the controls but decreased over the time of pillar formation. In this study, we have shown that ENG inhibition and at the same time up-regulation of COUP-TFII expression promotes intussusceptive angiogenesis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Herein we demonstrate that nanographene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e., endoglin), a vascular marker for tumor angiogenesis. The ...covalently functionalized nanographene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial noninvasive positron emission tomography imaging and biodistribution studies, which were validated by in vitro, in vivo, and ex vivo experiments. The incorporation of an active targeting ligand (TRC105, a monoclonal antibody that binds to CD105) led to significantly improved tumor uptake of functionalized GO, which was specific for the neovasculature with little extravasation, warranting future investigation of these GO conjugates for cancer-targeted drug delivery and/or photothermal therapy to enhance therapeutic efficacy. Since poor extravasation is a major hurdle for nanomaterial-based tumor targeting in vivo, this study also establishes CD105 as a promising vascular target for future cancer nanomedicine.
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IJS, KILJ, NUK, PNG, UL, UM
After endothelial injury, the transcription factor Krüppel-like factor 6 (KLF6) translocates into the cell nucleus to regulate a variety of target genes involved in angiogenesis, vascular repair and ...remodeling, including components of the membrane transforming growth factor beta (TGF-β) receptor complex such as endoglin and activin receptor-like kinase 1. The membrane metalloproteinase 14 (MMP14 or MT1-MMP) targets endoglin to release soluble endoglin and is involved in vascular inflammation and endothelial tubulogenesis. However, little is known about the regulation of MMP14 expression during vascular wounding. In vitro denudation of monolayers of human endothelial cell monolayers leads to an increase in the KLF6 gene transcriptional rate, followed by an upregulation of MMP14 and release of soluble endoglin. Concomitant with this process, MMP14 co-localizes with endoglin in the sprouting endothelial cells surrounding the wound border. MMP14 expression at mRNA and protein levels is increased by ectopic KLF6 and downregulated by KLF6 suppression in cultured endothelial cells. Moreover, after wire-induced endothelial denudation,
Klf6
+/−
mice show lower levels of MMP14 in their vasculature compared with their wild-type siblings. Ectopic cellular expression of KLF6 results in an increased transcription rate of MMP14, and chromatin immunoprecipitation assays show that KLF6 interacts with MMP14 promoter in ECs, this interaction being enhanced during wound healing. Furthermore, KLF6 markedly increases the transcriptional activity of different reporter constructs of MMP14 gene promoter. These results suggest that KLF6 regulates MMP14 transcription and is a critical player of the gene expression network triggered during endothelial repair.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Autophagy regulation in preeclampsia: Pros and cons Nakashima, Akitoshi; Aoki, Aiko; Kusabiraki, Tae ...
Journal of reproductive immunology,
September 2017, 2017-09-00, 20170901, Volume:
123
Journal Article
Peer reviewed
•Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis against stress.•Autophagy activation is observed in EVTs during early pregnant period in vivo, ...suggesting that EVTs use autophagy for adjusting to hypoxic and low-nutrient conditions. On the other hand, soluble endoglin inhibits autophagy in vitro, resulting in suppression of EVT functions.•There are some opposing reports in which autophagy activation was more frequently observed in preeclamptic or FGR placentas than in normal pregnancy.•It is still unknown how autophagy contributes to pathophysiology of preeclampsia.•This review introduces the role of autophagy for maintaining pregnancy and its correlation with preeclampsia.
Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis against stress. This process has two main functions: producing energy and quality control of intracellular proteins. During early pregnancy, extravillous trophoblasts (EVTs) invade the uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions. Autophagy activation is observed in EVTs under these conditions, suggesting that EVTs use autophagy for adjusting to such harsh conditions. On the other hand, soluble endoglin, which is increased in sera in preeclamptic cases, inhibits autophagy in vitro, resulting in suppression of EVT functions, invasion and vascular remodeling. In addition, p62/SQSTM1, a substrate degraded by autophagy, accumulates in EVTs in preeclamptic placental biopsy samples, exhibiting impaired autophagy in vivo. There are, however, some opposing reports in which autophagy activation, an increase of autophagy vacuoles or LC3 dots, was more frequently observed in preeclamptic or FGR placentas than in normal pregnancy. Thus, changes in autophagy status are seen in preeclamptic placentas, but the mechanism by which autophagy modulates biological changes in the placentas is still unknown. Recently, there is increasing evidence that autophagy is involved in maintaining pregnancy. This review introduces the role of autophagy for maintaining pregnancy and its correlation with preeclampsia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
TGFβ regulates cellular processes by binding to type I and type II TGFβ receptors (TβRI and TβRII, respectively). In addition to these signaling receptors, endoglin is an accessory TGFβ receptor that ...regulates TGFβ signaling. Although there are two different alternatively spliced isoforms of endoglin, L-endoglin (L, long) and S-endoglin (S, short), little is known about the effects of S-endoglin isoform on TGFβ signaling. Here, we have analyzed the TGFβ1 signaling pathways and the effects of L- and S-endoglin in endoglin-deficient L₆E₉ cells. We found that TGFβ activates two distinct TβRI-Smad signaling pathways: ALK1-Smad1-Id1 and ALK5-Smad2-PAI1, in these cells. Interestingly, L-endoglin enhanced the ALK1-Id1 pathway, while S-endoglin promoted the ALK5-PAI1 route. These effects on signaling are supported by biological effects on TGFβ1-induced collagen I expression and inhibition of cell proliferation. Thus, while L-endoglin decreased TGFβ1-induced collagen I and CTGF expression and increased TGFβ1-induced proliferation, S-endoglin strongly increased TGFβ1-induced collagen I and CTGF expression, and reduced TGFβ1-induced cell proliferation.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Care delivery for HHT patients is impeded by the need for laborious, repeated phenotyping and gaps in ...knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address this, we analyzed DNA samples from 183 previously uncharacterized, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 127 rare variants across 168 heterozygous genotypes. Applying modified American College of Medical Genetics and Genomics Guidelines, 106 variants were classified as pathogenic/likely pathogenic and 21 as nonpathogenic (variant of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using 2 approaches: subjective clinical predictions and statistical predictions based on 8 Human Phenotype Ontology terms. Both approaches had some predictive power, but they were insufficiently accurate to be used clinically, without genetic testing. The distributions of red cell indices differed by causal gene but not sufficiently for clinical use in isolation from genetic data. We conclude that parallel sequencing of the 4 known HHT genes, multidisciplinary team review of variant calls in the context of detailed clinical information, and statistical and structural modeling improve the prognostication and treatment of HHT.
•HHT genotypes are clinically relevant but poorly predicted even by analysis of extensive physical and hematological phenotypic data.•High-throughput DNA sequencing, detailed phenotyping, and statistical and structural modeling contribute to a framework to better prognosticate and treat HHT.
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•Soluble endoglin and GDF-15 levels were elevated in late-stage endometriosis.•These molecules were positively correlated with clinical scores for pelvic adhesion and endometriosis.•Serum GDF-15 ...could discriminate the early and late-stage endometriosis.•Peripheral neutrophil profile correlated with soluble endoglin level.
Chronic inflammation and pelvic adhesion play a critical role in endometriosis-related infertility. Research studies suggest that TGF-β superfamily members, such as soluble endoglin (sEng), growth differentiation factor 15 (GDF-15) and tumor growth factor-beta (TGF-β1) contribute to the regulation of inflammation, angiogenesis and cell adhesion. The objective of this study is to investigate the association between the concentrations of these TGF-β-related members and the clinical parameters of infertile women with endometriosis.
Sixty-five infertile women who underwent laparoscopy were divided into two groups in this study: those who had endometriosis (n = 33) and control subjects with benign gynecologic disorders (n = 32). The levels of TGF-β- related members in peritoneal fluid and serum were evaluated by the enzyme-linked immunosorbent assay (ELISA). Clinical and hematological parameters were documented and analyzed.
Endometriosis cases had significantly higher levels of sEng, GDF-15 and TGF-β1 in peritoneal fluid (p<0.0005) compared to control subjects, but not in serum. Moreover, serum GDF-15 level was significantly elevated in the late-stage endometriosis compared to the early-stage group. The levels of three TGF-β related molecules in peritoneal fluid showed positive correlations with rASRM score. Blood neutrophil counts have correlation with the peritoneal sEng concentration.
Our novel evidence on the elevated concentration of peritoneal sEng and GDF-15 in endometriosis, specifically in the late-stage, may indicate the essential role of TGF-β-dependent signaling in endometriosis. Serum GDF-15 might serve as a candidate biomarker for endometriosis severity. Further studies are warranted to investigate the role and regulation of these molecules in endometriosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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