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Fort-de-France, Martinique

Pourhoseini S.,University of South Carolina | Seth R.K.,University of South Carolina | Das S.,University of South Carolina | Dattaroy D.,University of South Carolina | And 6 more authors.
PLoS ONE | Year: 2015

Sinusoidal endothelial dysfunction (SED) has been found to be an early event in nonalcoholic steatohepatitis (NASH) progression but the molecular mechanisms underlying its causation remains elusive. We hypothesized that adipokine leptin worsens sinusoidal injury by decreasing functionally active nitric oxide synthase 3 (NOS)3 via miR21. Using rodent models of NASH, and transgenic mice lacking leptin and leptin receptor, results showed that hyperleptinemia caused a 4-5 fold upregulation of hepatic miR21 as assessed by qRTPCR. The upregulation of miR21 led to a time-dependent repression of its target protein Grhl3 levels as shown by western blot analyses. NOS3-p/NOS3 ratio which is controlled by Grhl3 was significantly decreased in NASH models. SED markers ICAM-1, VEGFR-2, and Eselectin as assessed by immunofluorescence microscopy were significantly up regulated in the progressive phases of NASH. Lack of leptin or its receptor in vivo, reversed the upregulation of miR21 and restored the levels of Grhl3 and NOS3-p/NOS3 ratio coupled with decreased SED dysfunction markers. Interestingly, leptin supplementation in mice lacking leptin, significantly enhanced miR21 levels, decreased Grhl3 repression and NOS3 phosphorylation. Leptin supplementation in isolated primary endothelial cells, Kupffer cells and stellate cells showed increased mir21 expression in stellate cells while sinusoidal injury was significantly higher in all cell types. Finally miR21 KO mice showed increased NOS3-p/ NOS3 ratio and reversed SED markers in the rodent models of NASH. The experimental results described here show a close association of leptin-induced miR21 in aiding sinusoidal injury in NASH. Source


Niu Q.,No. 309 PLA Hospital | Wang W.,No. 309 PLA Hospital | Li Y.,No. 309 PLA Hospital | Ruden D.M.,Institute of Environmental Health science | And 4 more authors.
PLoS ONE | Year: 2012

Cancer side population (SP) cells, which are often referred to as cancer stem cells, are thought to be responsible for lung cancer chemotherapy resistance, and currently no drug can specifically target these cells. We hypothesize low-molecular-weight heparin (LMWH) may affect the biological properties of SP cells and could be used to clinically target these cells. To test this, SP cells were isolated from cisplatin (DDP)-resistant lung adenocarcinoma A549/DDP cells by flow cytometric sorting. Compared to non-SP cells, SP cells formed increased numbers of colonies in vitro, and had a 1000-fold increase in tumorigenicity in vivo. Proliferation and apoptosis assays demonstrated LMWH had no significant effect on lung SP cell proliferation or apoptosis. However, LMWH reduced lung SP cell colony formation ability and protein expression of the multidrug transporter, ABCG2, by FACS and western blot analyses without affecting its mRNA levels by RT-PCR. Consistently, immunohistochemistry stainings of ABCG2 in LMWH-treated tumor tissues were significantly reduced compared with those in controls. Further, we found proteasomal inhibitor MG132, but not lysosomal inhibitors leupeptin and pepstatin A, could restore ABCG2 protein levels in LMWH-treated SP cells. These suggest LMWH ablates lung SP cell chemoresistance by proteasome-mediated reduction of ABCG2 protein levels without affecting its mRNA levels. We also determined LMWH combined with cisplatin could overcome cisplatin-resistance and induced lung SP cells apoptosis both in vitro and in vivo. This study provides an experimental basis for using a combination of LMWH, which targets lung SP cells, with chemotherapy to improve lung cancer survival. © 2012 Niu et al. Source


Senut M.-C.,Institute of Environmental Health science | Senut M.-C.,Wayne State University | Sen A.,Institute of Environmental Health science | Sen A.,Wayne State University | And 9 more authors.
Toxicological Sciences | Year: 2014

Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9μM) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural progenitor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9μM Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina Human Methylation 450 Bead Chip demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. Source


Chia N.,Institute of Environmental Health science | Wang L.,Institute of Environmental Health science | Lu X.,Institute of Environmental Health science | Senut M.-C.,Institute of Environmental Health science | And 2 more authors.
Epigenetics | Year: 2011

Many environmental toxins, such as heavy metals, air particles and ozone, induce oxidative stress and decrease the levels of NADH and NADPH, cofactors that drive anabolic biochemical reactions and provide reducing capacity to combat oxidative stress. Recently, it was found that the Ten-eleven translocation (TET) protein family members, which oxidize 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) in the DNA, were found to be activated under high oxygen conditions by alpha ketoglutarate (α-KG), a cofactor produced by aerobic metabolism in the citric acid cycle. TET, Jumonji-family histone demethylases and prolylhydroxylase, a repressor of HIF1α under high oxygen conditions, all require α-KG as a cofactor for their activation. HIF1α and TET proteins, which appear to have opposing functions, impact several aspects of human life, including cell growth regulation, embryonic stem cell maintenance, cell differentiation and tumorigenesis. The role of metabolism on the regulation of global DNA methylation and chromatin organization has recently gained greater attention from the biomedical research community. This article will discuss the possible role of TET activation and the regulation of 5-hmC and 5-mC levels in response to environmental stress. We will also discuss how 5-hmC and 5-mC levels at the promoters of specific genes might be a useful biomarker for exposure to environmental toxins. © 2011 Landes Bioscience. Source

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