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Chen L.,Sun Yat Sen University | Ding M.-L.,Sun Yat Sen University | Wu F.,Sun Yat Sen University | He W.,Sun Yat Sen University | And 6 more authors.
Hypertension | Year: 2016

Although hyperaldosteronemia exerts detrimental impacts on vascular endothelium in addition to elevating blood pressure, the effects and molecular mechanisms of hyperaldosteronemia on early endothelial progenitor cell (EPC)-mediated endothelial repair after arterial damage are yet to be determined. The aim of this study was to investigate the endothelial repair capacity of early EPCs from hypertensive patients with primary hyperaldosteronemia (PHA). In vivo endothelial repair capacity of early EPCs from PHAs (n=20), age-and blood pressure-matched essential hypertension patients (n=20), and age-matched healthy subjects (n=20) was evaluated by transplantation into a nude mouse carotid endothelial denudation model. Endothelial function was evaluated by flow-mediated dilation of brachial artery in human subjects. In vivo endothelial repair capacity of early EPCs and flow-mediated dilation were impaired both in PHAs and in essential hypertension patients when compared with age-matched healthy subjects; however, the early EPC in vivo endothelial repair capacity and flow-mediated dilation of PHAs were impaired more severely than essential hypertension patients. Oral spironolactone improved early EPC in vivo endothelial repair capacity and flow-mediated dilation of PHAs. Increased oxidative stress, oxidative 5,6,7,8-tetrahydrobiopterin degradation, endothelial nitric oxide synthase uncoupling and decreased nitric oxide production were found in early EPCs from PHAs. Nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox knockdown or 5,6,7,8-tetrahydrobiopterin supplementation attenuated endothelial nitric oxide synthase uncoupling and enhanced in vivo endothelial repair capacity of early EPCs from PHAs. In conclusion, PHAs exhibited more impaired endothelial repair capacity of early EPCs than did essential hypertension patients independent of blood pressure, which was associated with mineralocorticoid receptor-dependent oxidative stress and subsequently 5,6,7,8-tetrahydrobiopterin degradation and endothelial nitric oxide synthase uncoupling. © 2015 American Heart Association, Inc. Source


Wu Q.,University of the Chinese | Wu Q.,Zhejiang University | Wang H.,University of the Chinese | Wang H.,Zhejiang University | And 11 more authors.
Antioxidants and Redox Signaling | Year: 2015

Hereditary hemochromatosis (HH) is an iron overload disease that is caused by mutations in HFE, HJV, and several other genes. However, whether HFE-HH and HJV-HH share a common pathway via hepcidin regulation is currently unclear. Recently, some HH patients have been reported to carry concurrent mutations in both the HFE and HJV genes. To dissect the roles and molecular mechanisms of HFE and/or HJV in the pathogenesis of HH, we studied Hfe-/-, Hjv-/-, and Hfe-/-Hjv-/- double-knockout mouse models. Results: Hfe-/-Hjv-/- mice developed iron overload in multiple organs at levels comparable to Hjv-/- mice. After an acute delivery of iron, the expression of hepcidin (i.e., Hamp1 mRNA) was increased in the livers of wild-type and Hfe-/- mice, but not in either Hjv-/- or Hfe-/-Hjv-/- mice. Furthermore, iron-induced phosphorylation of Smad1/5/8 was not detected in the livers of Hjv-/- or Hfe-/-Hjv-/- mice. Innovation: We generated and phenotypically characterized Hfe-/-Hjv-/- double-knockout mice. In addition, because they faithfully phenocopy clinical HH patients, these mouse models are an invaluable tool for mechanistically dissecting how HFE and HJV regulate hepcidin expression. Conclusions: Based on our results, we conclude that HFE may depend on HJV for transferrin-dependent hepcidin regulation. The presence of residual hepcidin in the absence of HFE suggests either the presence of an unknown regulator (e.g., TFR2) that is synergistic with HJV or that HJV is sufficient to maintain basal levels of hepcidin. Antioxid. Redox Signal. 22, 1325-1336. © 2015 Mary Ann Liebert, Inc. Source


Zhang W.-C.,University of the Chinese | Zheng X.-J.,University of the Chinese | Du L.-J.,University of the Chinese | Sun J.-Y.,University of the Chinese | And 20 more authors.
Cell Research | Year: 2015

High salt is positively associated with the risk of many diseases. However, little is known about the mechanisms. Here we showed that high salt increased proinflammatory molecules, while decreased anti-inflammatory and proendocytic molecules in both human and mouse macrophages. High salt also potentiated lipopolysaccharide-induced macrophage activation and suppressed interleukin 4-induced macrophage activation. High salt induced the proinflammatory aspects by activating p38/cFos and/or Erk1/2/cFos pathways, while inhibited the anti-inflammatory and proendocytic aspects by Erk1/2/signal transducer and activator of transcription 6 pathway. Consistent with the in vitro results, high-salt diet increased proinflammatory gene expression of mouse alveolar macrophages. In mouse models of acute lung injury, high-salt diet aggravated lipopolysaccharide-induced pulmonary macrophage activation and inflammation in lungs. These results identify a novel macrophage activation state, M(Na), and high salt as a potential environmental risk factor for lung inflammation through the induction of M(Na). © 2015 IBCB, SIBS, CAS. Source


Zhang D.-Y.,CAS Dalian Institute of Chemical Physics | Zhang D.-Y.,University of the Chinese | Shao L.,CAS Dalian Institute of Chemical Physics | Shao L.,University of the Chinese | And 2 more authors.
ACS Catalysis | Year: 2015

A catalytic asymmetric [3 + 2] cycloaddition of hydrazines to bis-electrophilic C3 synthons generated from propargylic acetates, followed by an intramolecular 1,3-H migration, for the regio- and enantioselective construction of chiral 2-pyrazolines has been reported. By employment of copper catalysis in combination with a structurally rigid tridentate P,N,N-ligand, a variety of chiral 2-pyrazolines were obtained in good yields and with high enantioselectivities (up to 96% ee). A possible transition state has been proposed to explain the origin of the regio- and enantioselectivities. © 2015 American Chemical Society. Source

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