ORCID Profile
0000-0001-9546-5561
Current Organisation
University of California Davis
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Publisher: Springer Science and Business Media LLC
Date: 10-2002
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2017
DOI: 10.1161/ATVBAHA.116.308723
Abstract: Sclerostin (SOST) has been identified as an important regulator of bone formation however, it has not been previously implicated in arterial disease. The aim of this study was to assess the role of SOST in aortic aneurysm (AA) and atherosclerosis using human s les, a mouse model, and in vitro investigations. SOST protein was downregulated in human and mouse AA s les compared with controls. Transgenic introduction of human SOST in apolipoprotein E–deficient ( ApoE −/− ) mice ( SOST Tg . ApoE −/− ) and administration of recombinant mouse Sost inhibited angiotensin II–induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOST Tg . ApoE −/− mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOST Tg . ApoE −/− mice showed reduced matrix degradation, reduced elastin breaks, and preserved collagen. Decreased inflammatory cell infiltration and a reduction in the expression of wingless-type mouse mammary virus integration site/β-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas of SOST Tg . ApoE −/− mice. SOST expression was downregulated and the wingless-type mouse mammary virus integration site/β-catenin pathway was activated in human AA s les. The cytosine–phosphate–guanine islands in the SOST gene promoter showed significantly higher methylation in human AA s les compared with controls. Incubation of vascular smooth muscle cells with the demethylating agent 5-azacytidine resulted in upregulation of SOST, suggesting that SOST is epigenetically regulated. This study identifies that SOST is expressed in the aorta and downregulated in human AA possibly because of epigenetic silencing. Upregulating SOST inhibits AA and atherosclerosis development, with potential important implications for treating these vascular diseases.
Publisher: MDPI AG
Date: 09-05-2019
Abstract: This review summarizes recent developments in radiocarbon tracer technology and applications. Technologies covered include accelerator mass spectrometry (AMS), including conversion of s les to graphite, and rapid combustion to carbon dioxide to enable direct liquid s le analysis, coupling to HPLC for real-time AMS analysis, and combined molecular mass spectrometry and AMS for analyte identification and quantitation. Laser-based alternatives, such as cavity ring down spectrometry, are emerging to enable lower cost, higher throughput measurements of biological s les. Applications covered include radiocarbon dating, use of environmental atomic bomb pulse radiocarbon content for cell and protein age determination and turnover studies, and carbon source identification. Low dose toxicology applications reviewed include studies of naphthalene-DNA adduct formation, benzo[a]pyrene pharmacokinetics in humans, and triclocarban exposure and risk assessment. Cancer-related studies covered include the use of radiocarbon-labeled cells for better defining mechanisms of metastasis and the use of drug-DNA adducts as predictive biomarkers of response to chemotherapy.
Publisher: Public Library of Science (PLoS)
Date: 09-08-2017
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.MCE.2015.06.021
Abstract: Sclerostin, the SOST gene product, is a negative regulator of bone formation and a positive regulator of bone resorption. In this study, treatment of human primary osteoblasts, including cells differentiated to an osteocyte-like stage, with 1α,25-dihydroxyvitaminD3 (1,25D) resulted in the dose-dependent increased expression of SOST mRNA. A similar effect was observed in human trabecular bone s les cultured ex vivo, and in osteocyte-like cultures of differentiated SAOS2 cells. Treatment of SAOS2 cells with 1,25D resulted in the production and secretion of sclerostin protein. In silico analysis of the human SOST gene revealed a single putative DR3-type vitamin D response element (VDRE) at position -6216 bp upstream of the transcription start site (TSS). This sequence was confirmed to have strong VDRE activity by luciferase reporter assays and electrophoretic mobility shift analysis (EMSA). Sequence substitution in the VDR/RXR half-sites abolished VDRE reporter activity and binding of nuclear proteins. A 6.3 kb fragment of the human proximal SOST promoter demonstrated responsiveness to 1,25D. The addition of the evolutionary conserved region 5 (ECR5), a known bone specific enhancer region, ahead of the 6.3 kb fragment increased basal promoter activity but did not increase 1,25D responsiveness. Site-specific mutagenesis abolished the responsiveness of the 6.3 kb promoter to 1,25D. We conclude that 1,25D is a direct regulator of human SOST gene and sclerostin protein expression, extending the pathways of control of sclerostin expression. At least some of this responsiveness is mediated by the identified classical VDRE however the nature of the transcriptional regulation by 1,25D warrants further investigation.
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for Gabriela Loots.