Translational research : the journal of laboratory and clinical medicine
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Lipid rafts are specialized plasma membrane microdomains that serve as platforms for integrating cellular signal transductions. We have recently reported that autoantibodies against cardiac membrane proteins are present in patients with postural orthostatic tachycardia syndrome (POTS). In this study, we examined the presence of autoimmunoreactive IgGs against lipid raft proteins in these patients. ⋯ Multiple pathways were involved including those that regulate caveolae-mediated signaling, oxidative phosphorylation, fatty acid metabolism, protein ubiquitination, and cardiac β-adrenergic signaling. Our results suggest that cardiac lipid raft-associated proteins are targets of autoimmunoreactive IgGs from patients with POTS. Autoimmunity may play a role in the pathogenesis of POTS.
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Chronic kidney disease is associated with premature death from cardiovascular disease, which is, in part, driven by high density lipoprotein deficiency and dysfunction. One of the main causes of high density lipoprotein deficiency in chronic kidney disease is diminished plasma apolipoprotein (Apo)A-I level. Plasma ApoA-I is reduced in dialysis patients and hepatic ApoA-I messenger RNA (mRNA) is decreased in the uremic rats. ⋯ The pre- and postdialysis plasma exerted an equally potent inhibitory effect on ApoA-I mRNA abundance. Uremia lowers ApoA-I production by reducing its RNA stability. The inhibitory effect of uremic milieu on ApoA-I mRNA expression is mediated by non-dialyzable molecule(s) larger than 30 kd.
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Excessive concentrations of oxidized phospholipids (OxPL), the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (PAPC) oxidation have been detected in atherosclerosis, septic inflammation, and acute lung injury (ALI) and have been shown to induce vascular barrier dysfunction. In contrast, oxidized PAPC (OxPAPC) at low concentrations exhibit potent barrier protective effects. The nature of such biphasic effects remains unclear. ⋯ Barrier-disruptive effects of PGPC were abrogated by reactive oxygen species (ROS) inhibitor, N-acetyl cysteine, or Src kinase inhibitor, PP-2. The results of this study show that barrier disruptive effects of fragmented OxPAPC constituents (lyso-PC, POVPC, PGPC) are balanced by barrier enhancing effects of full length oxygenated products (PEIPC). These data strongly suggest that barrier disruptive effects of OxPAPC at higher concentrations are dictated by predominant effects of fragmented phospholipids such as PGPC, which promote ROS-dependent activation of Src kinase and VE-cadherin phosphorylation at Tyr(658) and Tyr(731) leading to disruption of endothelial cell AJs.
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Albuminuria is a sensitive marker to predict future cardiovascular events in patients with type 2 diabetes mellitus. However, current studies only use conventional regression models to discover predictors of albuminuria. We have used 2 different statistical models to predict albuminuria in type 2 diabetes mellitus: a multilayer perception neural network and a conditional logistic regression. ⋯ Using the conditional logistic regression model, glomerular filtration rate, time of onset to diabetes, and sex were significant indicators in the onset of albuminuria. Using a neural network model, we show that high-density lipoprotein is the most important factor in predicting albuminuria in type 2 diabetes mellitus. Our neural network model complements the current risk factor models to improve the care of patients with diabetes.
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Human pluripotent stem cells represent an accessible cell source for novel cell-based clinical research and therapies. With the realization of induced pluripotent stem cells (iPSCs), it is possible to produce almost any desired cell type from any patient's cells. ⋯ This review aims to summarize these recent advances with a focus on iPSC generation techniques, as well as gene modification methods. We will then further discuss some of the main obstacles remaining to be overcome before successful application of human pluripotent stem cell-based therapy arrives in the clinic and what the future of stem cell research may look like.