- The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells. [Journal Article]
- BPBiol Psychiatry 2019 Mar 30
- CONCLUSIONS: We provide an extensive neurobiological characterization of the psychiatric risk gene NT5C2, describing its previously unknown role in the regulation of AMPK signaling and protein translation in neural stem cells and its association with Drosophila melanogaster motility behavior.
- Impaired L-arginine metabolism marks endothelial dysfunction in CD73-deficient mice. [Journal Article]
- MCMol Cell Biochem 2019 May 15
- Changes in the ecto-5'-nucleotidase activity-an extracellular nucleotide catabolic enzyme may lead to the inflammation and endothelial dysfunction. We investigated the effect of CD73 deletion on the …
Changes in the ecto-5'-nucleotidase activity-an extracellular nucleotide catabolic enzyme may lead to the inflammation and endothelial dysfunction. We investigated the effect of CD73 deletion on the endothelial function and L-arginine metabolism in various age groups of mice. 1-,3-,6-, and 12-month-old, male C57BL/6 J wild type (WT) and C57BL/6 J CD73-/- (CD73-/-) mice were used. Blood samples were used for the analysis of adenine nucleotide concentrations. Serum samples were analyzed for the concentration of amino acids, Interleukin 6 (IL-6), Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), and endothelial nitric oxide synthase (eNOS) level. Serum and aortic nitrate/nitrite, as well as aortic arginase and NOS activity in endothelial cells (EC) were evaluated. CD73 deletion led to age-dependent increase in IL-6, ICAM-1, and VCAM-1 concentration compared to WT. All CD73-/- mice age groups were characterized by reduced L-Arginine concentration and eNOS level. Significantly lower NOS activity was noticed in EC isolated from CD73-/- mice lungs in comparison to EC isolated from WT lungs. The L-Arginine/ADMA ratio in the CD73-/- decreased in age-dependent manner in comparison to WT. The nitrate/nitrite ratio was reduced in serum and in aortas of 6-month-old CD73-/- mice as compared to WT. The ornithine/arginine and ornithine/citrulline ratios were increased in CD73-/- compared to controls. Blood (erythrocyte) Adenosine-5'-triphosphate and Adenosine-5'-diphosphate levels were reduced in favor to higher blood Adenosine-5'-monophosphate concentration in CD73-/- mice in comparison to WT. The CD73 deletion leads to the development of age-dependent endothelial dysfunction in mice, associated with impaired L-arginine metabolism. CD73 activity seems to protect endothelium.
- Anti-NT5c1A Autoantibodies as Biomarkers in Inclusion Body Myositis. [Journal Article]
- FIFront Immunol 2019; 10:745
- CONCLUSIONS: Anti-NT5c1A has moderate sensitivity and high specificity for sIBM using ALBIA. The presence of anti-NT5c1A antibodies may be associated with muscle weakness. Anti-NT5c1A antibodies were not associated with a specific IIF staining pattern, hence screening using HEp-2 substrate is unlikely to be a useful predictor for presence of these autoantibodies.
- In Vivo Immunological Effects of CD73 Deficiency. [Journal Article]
- CPCell Physiol Biochem 2019; 52(5):1192-1202
- CONCLUSIONS: This in vivo study clear demonstrated certain immunological changes in the CD73-deficient mice and thus immunoregulatory potential of CD73 molecule. This makes this extracellular enzyme to a real immune check point molecule, attractive for further investigations and clinical studies.
- CD73 a novel marker for the diagnosis of benign and malignant salivary gland tumors. [Journal Article]
- JCJ Clin Exp Dent 2019; 11(3):e213-e218
- CONCLUSIONS: The findings suggest that CD73 can be an independent and useful biomarker for predicting the clinical behavior of salivary gland tumors. Key words:Ecto-5'-nucleotidase, immunohistochemistry, salivary gland tumors.
- NT5E is associated with unfavorable prognosis and regulates cell proliferation and motility in gastric cancer. [Journal Article]
- BRBiosci Rep 2019 May 31; 39(5)
- Ecto-5'-nucleotidase (NT5E) is a glycosylphosphatidylinositol anchored cell surface protein, and has been suggested to be dysregulated in most types of human cancer including gastric cancer. The aim …
Ecto-5'-nucleotidase (NT5E) is a glycosylphosphatidylinositol anchored cell surface protein, and has been suggested to be dysregulated in most types of human cancer including gastric cancer. The aim of the present study was to present more evidence about the clinical and prognostic value of Ecto-5'-nucleotidase in gastric cancer patients, and preliminarily explore the biological function of Ecto-5'-nucleotidase in gastric cancer cells. In our study, high Ecto-5'-nucleotidase expression was observed in gastric cancer tissues and cell lines, respectively, compared with normal gastric mucosa tissues cells. Meanwhile, TCGA database also indicated that Ecto-5'-nucleotidase expression levels were notably elevated in gastric cancer tissues compared with normal gastric mucosa tissues. Furthermore, high-expression of Ecto-5'-nucleotidase was obviously associated with advanced clinical stage, deep tumor invasion, lymph node metastasis and distant metastasis in gastric cancer patients. The survival analyses of TCGA database and our study consistent suggested high Ecto-5'-nucleotidase expression was negatively correlated with overall survival time in gastric cancer patients. The univariate and multivariate Cox proportional hazards regression model showed high Ecto-5'-nucleotidase expression was an independent poor prognostic factor for gastric cancer patients. Moreover, silencing of Ecto-5'-nucleotidase expression suppressed cell proliferation, migration and invasion in vitro in gastric cancer. In conclusion, Ecto-5'-nucleotidase is a credible prognostic biomarker, and serves as a potential therapeutic target in gastric cancer.
- Genetic variants in cardiac calcification in Northern Sweden. [Journal Article]
- MMedicine (Baltimore) 2019; 98(15):e15065
- Extensive coronary calcification without significant stenosis, described as calcific coronary artery disease (CCAD) may cause abnormal myocardial perfusion and hence generalized ischemia. There is a …
Extensive coronary calcification without significant stenosis, described as calcific coronary artery disease (CCAD) may cause abnormal myocardial perfusion and hence generalized ischemia. There is a discrepancy in the expression pattern of CCAD compared to the well-known atherosclerotic disease which raises questions about the exact pathophysiology of coronary calcification and whether there is a genetic etiology for it.In this pilot study we studied 3 candidate genes, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), ATP Binding Cassette Subfamily C Member 6 (ABCC6), and 5'-Nucleotidase Ecto (NT5E) involved in pyrophosphate (PPi) and inorganic phosphate (Pi) metabolism, which may predispose to coronary arterial or valvular calcification. We studied 70 patients with calcific cardiac disease; 65 with CCAD (age 43-83 years) and 5 with calcific aortic valve disease (CAVD) (age 76-82 years).Five DNA variants potentially affecting protein function were found in 6 patients. One variant is a known disease-causing mutation in the ABCC6 gene. Our findings support that disturbances in the PPi and Pi metabolism might influence the development of CCAD and CAVD. However, segregation in the families must first be performed to ascertain any damaging effect of these variants we have found.We report 4 new genetic variants potentially related to coronary calcification, through the disturbed Pi and PPi metabolism. The search for direct causative genetic variants in coronary artery and aortic valve calcification must be broadened with other genes particularly those involved with Pi and PPi metabolism.
- NT5DC2 promotes tumorigenicity of glioma stem-like cells by upregulating fyn. [Journal Article]
- CLCancer Lett 2019 Jul 10; 454:98-107
- Glioblastoma (GBM) is an incurable primary brain tumor that is highly resistant to current treatments. Glioma stem-like cells (GSCs) are an aggressive population of glioma cells that not only initiat…
Glioblastoma (GBM) is an incurable primary brain tumor that is highly resistant to current treatments. Glioma stem-like cells (GSCs) are an aggressive population of glioma cells that not only initiate malignant growth, but also promote therapeutic resistance. Thus, targeting GSCs is critical for improving GBM treatment and ensuring complete eradication of the tumor. Here, we show that NT5DC2 (5'-Nucleotidase Domain Containing 2), a functionally unknown protein, plays a crucial role in GSC tumor initiation via upregulating Fyn expression. NT5DC2 is preferentially expressed in GSCs relative to the non-stem tumor cells. Knockdown of NT5DC2 significantly inhibits the GSC tumorsphere formation and cell viability in vitro, and tumorigenesis in vivo, thus, prolonging animal survival. Moreover, disruption of NT5DC2 in GSCs markedly reduces the expression of Fyn, a Src family proto-oncogene that has been implicated in the regulation of GBM progression. Importantly, the expression of NT5DC2 strongly correlated with increased aggression of human gliomas, but not that of other brain tumors. Taken together, our results uncover the function of NT5DC2 in GSC maintenance and highlight NT5DC2 as a promising therapeutic target for GBM.
- Lead Poisoning in Opium-Addicted Subjects, Its Correlation with Pyrimidine 5'-Nucleotidase Activity and Liver Function Tests. [Journal Article]
- IJInt J Prev Med 2019; 10:36
- CONCLUSIONS: Opium-addicted patients in Tehran, Iran, are at high risk of lead poisoning which may result in hematologic problems and possibly hepatic damage.
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- Major glucuronide metabolites of testosterone are primarily transported by MRP2 and MRP3 in human liver, intestine and kidney. [Journal Article]
- JSJ Steroid Biochem Mol Biol 2019 Apr 05; 191:105350
- Testosterone glucuronide (TG), androsterone glucuronide (AG), etiocholanolone glucuronide (EtioG) and dihydrotestosterone glucuronide (DHTG) are the major metabolites of testosterone (T), which are e…
Testosterone glucuronide (TG), androsterone glucuronide (AG), etiocholanolone glucuronide (EtioG) and dihydrotestosterone glucuronide (DHTG) are the major metabolites of testosterone (T), which are excreted in urine and bile. Glucuronides can be deconjugated to active androgen in gut lumen after biliary excretion, which in turn can affect physiological levels of androgens. The goal of this study was to quantitatively characterize the mechanisms by which TG, AG, EtioG and DHTG are eliminated from liver, intestine, and kidney utilizing relative expression factor (REF) approach. Using vesicular transport assay with recombinant human MRP2, MRP3, MRP4, MDR1 and BCRP, we first identified that TG, AG, EtioG, and DHTG were primarily substrates of MRP2 and MRP3, although lower levels of transport were also observed with MDR1 and BCRP vesicles. The transport kinetic analyses revealed higher intrinsic clearances of TG by MRP2 and MRP3 as compared to that of DHTG, AG, and EtioG. MRP3 exhibited higher affinity for the transport of the studied glucuronides than MRP2. We next quantified the protein abundances of these efflux transporters in vesicles and compared the same with pooled total membrane fractions isolated from human tissues by quantitative LC-MS/MS proteomics. The fractional contribution of individual transporters (ft) was estimated by proteomics-based physiological scaling factors, i.e., transporter abundance in whole tissue versus vesicles, and corrected for inside-out vesicles (determined by 5'-nucleotidase assay). The glucuronides of inactive androgens, AG and EtioG were preferentially transported by MRP3, whereas the glucuronides of active androgens, TG and DHTG were mainly transported by MRP2 in liver. Efflux by bile canalicular transport may indicate the potential role of enterohepatic recirculation in regulating the circulating active androgens after deconjugation in the gut. In intestine, MRP3 possibly contributes most to the efflux of these glucuronides. In kidney, all studied glucuronides seemed to be preferentially effluxed by MRP2 and MDR1 (for EtioG). These REF based analysis need to be confirmed with in vivo findings. Overall, characterization of the efflux mechanisms of T glucuronide metabolites is important for predicting the androgen disposition and interindividual variability, including drug-androgen interaction in humans. The mechanistic data can be extrapolated to other androgen relevant organs (e.g. prostate, testis and placenta) by integrating these data with quantitative tissue proteomics data.