Impact of a Prohibitive Versus Restrictive Tobacco Policy on Liver Transplant Candidate Outcomes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150602/1/lt25497_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150602/2/lt25497.pd

Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1beta and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1beta has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway.Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1beta from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1beta was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1beta secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1beta secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization.The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions

APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome

Metabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype

Birth weight and blood lipid levels in Spanish adolescents: Influence of selected APOE, APOC3 and PPARgamma2 gene polymorphisms. The AVENA Study

Background There is increasing evidence indicating that genes involved in certain metabolic processes of cardiovascular diseases may be of particular influence in people with low body weight at birth. We examined whether the apolipoprotein (APO) E, APOC3 and the peroxisome proliferator-activated receptor-γ-2 (PPARγ2) polymorphisms influence the association between low birth weight and blood lipid levels in healthy adolescents aged 13–18.5 years. Methods A cross-sectional study of 502 Spanish adolescents born at term was conducted. Total (TC) and high density lipoprotein cholesterol (HDLc), triglycerides (TG), apolipoprotein (apo) A and B, and lipoprotein(a) [Lp(a)] were measured. Low density lipoprotein cholesterol (LDLc), TC-HDLc, TC/HDLc and apoB/apoA were calculated. Results Low birth weight was associated with higher levels of TC, LDLc, apoB, Lp(a), TC-HDLc, TC/HDLc and apoB/apoA in males with the APOE ε3ε4 genotype, whereas in females, it was associated with lower HDLc and higher TG levels. In males with the APOC3 S1/S2 genotype, low birth weight was associated with lower apoA and higher Lp(a), yet this association was not observed in females. There were no associations between low birth weight and blood lipids in any of the PPARγ2 genotypes. Conclusion The results indicate that low birth weight has a deleterious influence on lipid profile particularly in adolescents with the APOE ε3/ε4 genotype. These findings suggest that intrauterine environment interact with the genetic background affecting the lipid profile in later life.The AVENA study was supported by the Spanish Ministry of Health Instituto de Salud Carlos III (FIS PI021830), the Spanish Ministry of Health, FEDER-FSE funds FIS n° 00/0015, CSD grants 05/UPB32/0, 109/UPB31/03 and 13/UPB20/04, the Spanish Ministry of Education (AP-2004-2745; EX-2007-1124), scholarships from Panrico S.A., Madaus S.A. and Procter and Gamble S.A

Investigational PET tracers for High-grade Gliomas.

High-grade gliomas (HGGs) are the most common primary malignant tumors of the brain, with glioblastoma (GBM) constituting over 50% of all the gliomas in adults. The disease carries very high mortality, and even with optimal treatment, the median survival is 2-5 years for anaplastic tumors and 1-2 years for GBMs. Neuroimaging is critical to managing patients with HGG for diagnosis, treatment planning, response assessment, and detecting recurrent disease. Magnetic resonance imaging (MRI) is the cornerstone of imaging in neuro-oncology, but molecular imaging with positron emission tomography (PET) can overcome some of the inherent limitations of MRI. Additionally, PET has the potential to target metabolic and molecular alterations in HGGs relevant to prognosis and therapy that cannot be assessed with anatomic imaging. Many classes of PET tracers have been evaluated in HGG including agents that target cell membrane biosynthesis, protein synthesis, amino acid transport, DNA synthesis, the tricarboxylic acid (TCA) cycle, hypoxic environments, cell surface receptors, blood flow, vascular endothelial growth factor (VEGF), epidermal growth factor (EGFR), and the 18-kDa translocator protein (TSPO), among others. This chapter will provide an overview of PET tracers for HGG that have been evaluated in human subjects with a focus on tracers that are not yet in widespread use for neuro-oncology

HDL particles for delivery of nucleic acids

Disclosed are high density lipoprotein-nucleic acid particles, wherein the particles include (a) an apolipoprotein; (b) a nucleic acid component comprising a therapeutic nucleic acid segment; and (c) a polypeptide comprising a positively charged region, wherein the positively-charged region of the polypeptide associates with the nucleic acid component. Also disclosed are pharmaceutical compositions that include a) an apolipoprotein; (b) a nucleic acid component comprising a therapeutic nucleic acid segment; and (c) a polypeptide comprising a positively charged region. Methods that concern the particles and pharmaceutical compositions of the present invention are also set forth, as well as kits.Board of Regents, University of Texas Syste