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Indianapolis, IN, United States

Rizzo M.T.,Methodist Research Institute | Rizzo M.T.,Indiana University | Leaver H.A.,University of Edinburgh
Molecular Neurobiology | Year: 2010

Emerging evidence indicates that brain microvascular endothelial cells play a critical role in brain development, maturation, and homeostasis. Acute or chronic insults, including oxidative stress, oxygen-glucose deprivation, trauma, infections, inflammatory cytokines, DNA damaging agents, β-amyloid deposition, and endoplasmic reticulum stress induce brain endothelial cell dysfunction and damage, which can result in cell death. The homeostatic balance between endothelial cell survival and endothelial cell death is critical for brain development, remodeling, and repair. On the other hand, dysregulation of brain endothelial cell death exacerbates, or even initiates, several inflammatory, ischemic, and degenerative disorders of the central nervous system. In here, the morphological, biochemical, and functional characteristics of the brain endothelium and its contribution to brain homeostasis will be reviewed. Recent insights into modalities and regulatory pathways involved in brain endothelial cell death will be described. The effects of regulated and dysregulated endothelial cell death leading to angiogenesis will be outlined. The relevance of brain endothelial cell dysfunction and death to disease processes will be discussed with special reference to recent findings that could help translate current knowledge on brain endothelial cell apoptosis into new therapeutic strategies for the treatment of certain neurological disorders. © 2010 Springer Science+Business Media, LLC. Source


Leaver H.A.,University of Edinburgh | Rizzo M.T.,Methodist Research Institute | Whittle I.R.,University of Edinburgh
Molecular Neurobiology | Year: 2010

The prognosis for patients with malignant gliomas is poor, but improvements may emerge from a better understanding of the pathophysiology of glioma signalling. Recent therapeutic developments have implicated lipid signalling in glioma cell death. Stress signalling in glioma cell death involves mitochondria and endoplasmic reticulum. Lipid mediators also signal via extrinsic pathways in glioma cell proliferation, migration and interaction with endothelial and microglial cells. Glioma cell death and tumour regression have been reported using polyunsaturated fatty acids in animal models, human ex vivo explants, glioma cell preparations and in clinical case reports involving intratumoral infusion. Cell death signalling was associated with generation of reactive oxygen intermediates and mitochondrial and other signalling pathways. In this review, evidence for mitochondrial responses to stress signals, including polyunsaturated fatty acids, peroxidising agents and calcium is presented. Additionally, evidence for interaction of glioma cells with primary brain endothelial cells is described, modulating human glioma peroxidative signalling. Glioma responses to potential therapeutic agents should be analysed in systems reflecting tumour connectivity and CNS structural and functional integrity. Future insights may also be derived from studies of signalling in glioma-derived tumour stem cells. © 2010 Springer Science+Business Media, LLC. Source


Antalis C.J.,Methodist Research Institute | Uchida A.,Purdue University | Buhman K.K.,Purdue University | Siddiqui R.A.,Methodist Research Institute | Siddiqui R.A.,Indiana University
Clinical and Experimental Metastasis | Year: 2011

We previously described a lipid-accumulating phenotype of estrogen receptor negative (ER -) breast cancer cells exemplified by the MDA-MB-231 and MDA-MB-436 cell lines. These cells had more lipid droplets, a higher uptake of oleic acid and LDL, a higher ratio of cholesteryl ester (CE) to triacylglycerol (TAG), and higher expression of acyl-CoA:cholesterol acyltransferase 1 (ACAT1) as compared to ER + MCF-7 breast cancer cells. LDL stimulated proliferation of ER-cells only, and proliferation was reduced by inhibition of ACAT. We hypothesized that storage of exogenous lipids would confer an energetic advantage. We tested this by depriving cells of exogenous lipids and measuring chemotactic migration, an energy-intensive behavior. MDA-MB-231 cells were grown for 48 h in medium with either 5% FBS or 5% lipoprotein-depleted (LD) FBS. Growth in LD medium resulted in visibly reduced lipid droplets and an 85% decrease in cell migration. Addition of LDL to the LD medium dose-dependently restored the ability to migrate in an ACAT-sensitive manner. LDL receptor (LDLR) mRNA was 12-fold higher in MDA-MB-231 cells compared to nontumorigenic ER-MCF-10A breast epithelial cells grown in LD medium. Addition of LDL to the LD medium reduced LDLR mRNA levels in MCF-10A cells only. We asked if ACAT1 activity was associated with the expression of the LDLR in MDA-MB-231 cells. LDLR mRNA in MDA-MB-231 cells was substantially reduced by inhibition of ACAT, demonstrating that high ACAT1 activity permitted higher LDLR expression. This data substantiates the association of lipid accumulation with aggressive behavior in an ER-breast cancer cell line. © 2011 Springer Science+Business Media B.V. Source


Walline C.C.,Methodist Research Institute | Kanakasabai S.,Methodist Research Institute | Bright J.J.,Methodist Research Institute | Bright J.J.,Indiana University
Genes and Immunity | Year: 2011

Multiple sclerosis (MS) is a neurological disorder that causes paralysis in young adults and affects women more frequently than men. The etiology of MS is not known, but it is generally viewed as an autoimmune disease of the central nervous system (CNS), influenced by genetic and environmental factors. Recent studies have identified interleukin-7 receptor α (IL-7Rα) as a risk factor for MS. But the role of IL-7Rα in experimental autoimmune encephalomyelitis (EAE) model of MS is not known. In this study we demonstrate that IL-7Rα-deficient (IL-7Rα -/-) mice remain resistant to MOGp35-55-induced EAE. When compared with C57BL/6 wild-type mice, IL-7Rα -/- mice showed less severe inflammation and demyelination in the CNS. The attenuation of EAE in IL-7Rα -/- mice was associated with a decrease in T-helper (Th) 1 and Th17 responses in the CNS and lymphoid organs. IL-7Rα -/- mice also showed an increase in Th2 response and CD + Foxp3 + regulatory T cells. These findings highlight that IL-7Rα confers susceptibility by influencing autoimmune Th1/Th17 responses in EAE model of MS. © 2011 Macmillan Publishers Limited All rights reserved. Source


Chakraborty S.,Methodist Research Institute | Kanakasabai S.,Methodist Research Institute | Bright J.J.,Methodist Research Institute | Bright J.J.,Indiana University
British Journal of Cancer | Year: 2011

Background: Brain tumours present unique challenges to conventional therapies and pose major health problems around the world. Brain tumour stem cells (BTSCs) represent a small fraction of tumour cells that maintain growth, drug resistance and recurrence properties. Constitutive androstane receptor (CAR) is a nuclear receptor transcription factor that regulates drug metabolism and homoeostasis. In this study, we examined the effect of CAR agonist, 6-(4-chlorophenyl)imidazo2,1-b1,3thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl) oxime (CITCO) on BTSCs. Methods: The expression of CAR in BTSCs was detected by quantitative RT-PCR and western blot. The antiproliferative effect of CITCO on BTSCs was determined by WST-1 and 3 H thymidine uptake assays. The effect of CITCO on CD133 expression, cell cycle progression and apoptosis in BTSCs was analysed by immunostaining and flow cytometry. The in vivo effect of CITCO was studied using subcutaneous (s.c.) BTSC xenograft in nude mice. Results: We show for the first time that BTSCs express altered levels of nuclear receptors compared with glioma cells. The expression of CAR mRNA and protein was low in BTSCs and that increased following treatment with CITCO in culture. CITCO induced a dose-dependent decrease in growth and expansion of CD133 BTSCs as gliospheres in culture. Cell cycle arrest and apoptosis in BTSCs were induced by CITCO, but not in normal astrocytes. Growth of s.c BTSC xenograft in nude mice was also inhibited by CITCO. Conclusion: These findings indicate that CITCO inhibits the growth and expansion of BTSCs, suggesting the use of CAR agonists for the treatment of brain tumour. © 2011 Cancer Research UK All rights reserved. Source

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