A portable surface plasmon resonance (SPR) sensor for the detection of immunoglobulin A in plasma.

Background: A life-threatening anaphylactic shock can occur if a patient with undiagnosed immunoglobulin A (IgA) deficiency (i.e., IgA levels <500 ng/mL) receives IgA-containing blood, hence the need for a rapid, point-of-care (POC) method for IgA deficiency screening.

Exercise training remodels inguinal white adipose tissue through adaptations in innervation, vascularization, and the extracellular matrix.

Inguinal white adipose tissue (iWAT) is essential for the beneficial effects of exercise training on metabolic health. The underlying mechanisms for these effects are not fully understood, and here, we test the hypothesis that exercise training results in a more favorable iWAT structural phenotype. Using biochemical, imaging, and multi-omics analyses, we find that 11 days of wheel running in male mice causes profound iWAT remodeling including decreased extracellular matrix (ECM) deposition and increased vascularization and innervation.

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore.

Melanoma is the deadliest form of skin cancer in the US. Although immunotherapeutic checkpoint inhibitors and small-molecule kinase inhibitors have dramatically increased the survival of patients with melanoma, new or optimized therapeutic approaches are still needed to improve outcomes. 15-deoxy-Δ-prostamide J (15d-PMJ) is an investigational small-molecule that induces ER stress-mediated apoptosis selectively in tumor cells.

Monte-Carlo simulation and tissue-phantom model for validation of ocular oximetry.

Ocular oximetry, in which blood oxygen saturation is evaluated in retinal tissues, is a promising technique for the prevention, diagnosis and management of many diseases and conditions. However, the development of new tools for evaluating oxygen saturation in the eye fundus has often been limited by the lack of reference tools or techniques for such measurements. In this study, we describe a two-step validation method.

Prohibitin-1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis.

Background In sepsis, circulating cytokines and lipopolysaccharide elicit mitochondrial dysfunction and cardiomyopathy, a major cause of morbidity and mortality with this condition. Emerging research places the PHB1 (lipid raft protein prohibitin-1) at the nexus of inflammation, metabolism, and oxidative stress. PHB1 has also been reported in circulation, though its function in this compartment is completely unknown.

Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients.

Catecholamine metabolism monoamine oxidase (MAO) contributes to cardiac injury in models of ischemia and diabetes, but the pathogenic mechanisms involved are unclear. MAO deaminates norepinephrine (NE) and dopamine to produce HO and highly reactive "catecholaldehydes," which may be toxic to mitochondria due to the localization of MAO to the outer mitochondrial membrane. We performed a comprehensive analysis of catecholamine metabolism and its impact on mitochondrial energetics in atrial myocardium obtained from patients with and without type 2 diabetes.

Development of a flow standard to enable highly reproducible measurements of deformability of stored red blood cells in a microfluidic device.

Background: Great deformability allows red blood cells (RBCs) to flow through narrow capillaries in tissues. A number of microfluidic devices with capillary-like microchannels have been developed to monitor storage-related impairment of RBC deformability during blood banking operations. This proof-of-concept study describes a new method to standardize and improve reproducibility of the RBC deformability measurements using one of these devices.

Kinin B1 Receptor Blockade Prevents Angiotensin II-induced Neuroinflammation and Oxidative Stress in Primary Hypothalamic Neurons.

Neuroinflammation has become an important underlying factor in many cardiovascular disorders, including hypertension. Previously we showed that elevated angiotensin II (Ang II) and angiotensin II type I receptor (AT1R) expression levels can increase neuroinflammation leading to hypertension. We also found that kinin B1 receptor (B1R) expression increased in the hypothalamic paraventricular neurons resulting in neuroinflammation and oxidative stress in neurogenic hypertension.

Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening.

Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system.

Expression of macrophage genes within skeletal muscle correlates inversely with adiposity and insulin resistance in humans.

Local inflammation in obese adipose tissue has been shown to contribute to insulin resistance; however, the role of macrophage infiltration within skeletal muscle is still debatable. This study aimed to evaluate the association of skeletal muscle macrophage gene expression with adiposity levels and insulin sensitivity in obese patients. Twenty-two nondiabetic obese patients and 23 healthy lean controls were included.

Dyslipidemia management update.

Association of hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) is well established. Reducing low-density lipoprotein-cholesterol (LDL-C) and raising high-density lipoprotein-cholesterol (HDL-C) have been the therapeutic targets to reduce the risk of ASCVD. Cholesterol-lowering medications have been used to provide both primary and secondary prevention of ASCVD for many years by reducing the absorption and reabsorption, promoting excretion, or decreasing the synthesis of cholesterol.

NOX4 NADPH Oxidase-Dependent Mitochondrial Oxidative Stress in Aging-Associated Cardiovascular Disease.

Aims: Increased oxidative stress and vascular inflammation are implicated in increased cardiovascular disease (CVD) incidence with age. We and others demonstrated that NOX1/2 NADPH oxidase inhibition, by genetic deletion of p47phox, in Apoe(-/-) mice decreases vascular reactive oxygen species (ROS) generation and atherosclerosis in young age. The present study examined whether NOX1/2 NADPH oxidases are also pivotal to aging-associated CVD.

A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids.

Preadipocytes are periodically subjected to fatty acid (FA) concentrations that are potentially cytotoxic. We tested the hypothesis that prolonged exposure of preadipocytes of human origin to a physiologically relevant mix of FAs leads to mitochondrial inner membrane (MIM) permeabilization and ultimately to mitochondrial crisis. We found that exposure of preadipocytes to FAs led to progressive cyclosporin A-sensitive MIM permeabilization, which in turn caused a reduction in MIM potential, oxygen consumption, and ATP synthetic capacity and, ultimately, death.

EGF receptor (ERBB1) abundance in adipose tissue is reduced in insulin-resistant and type 2 diabetic women.

Context: Indications of adipose tissue dysfunction correlate with systemic insulin resistance and type 2 diabetes. It has been suggested that a defect in adipose tissue turnover may be involved in the development of these disorders. Whether this dysfunction causes or exacerbates systemic insulin resistance is not fully understood.

Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice.

Vascular dysfunction in response to reactive oxygen species (ROS) plays an important role in the development and progression of atherosclerotic lesions. In most cells, mitochondria are the major source of cellular ROS during aerobic respiration. Under most conditions the rates of ROS formation and elimination are balanced through mechanisms that sense relative ROS levels.

Orphan nuclear receptor NOR-1 enhances 3',5'-cyclic adenosine 5'-monophosphate-dependent uncoupling protein-1 gene transcription.

Prolonged cold exposure induces nonshivering thermogenesis primarily through beta-adrenergic- and cAMP-mediated regulation of uncoupling protein-1 (UCP1) in brown adipose tissue. Molecular mechanisms involved in this induction of Ucp1 gene transcription consists of an intricate interplay between many nuclear receptors in coordination with coactivators/corepressors. Recently, it has been shown that members of the nuclear receptor-4A (NR4A) family of orphan nuclear receptors (Nur77, Nurr1, and NOR-1) are highly responsive to cAMP-second messenger pathways.

Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype.

The adipocyte integrates crucial information about metabolic needs in order to balance energy intake, storage, and expenditure. Whereas white adipose tissue stores energy, brown adipose tissue is a major site of energy dissipation through adaptive thermogenesis mediated by uncoupling protein 1 (UCP1) in mammals. In both white and brown adipose tissue, nuclear receptors and their coregulators, such as peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator 1alpha (PGC-1alpha), play key roles in regulating their development and metabolic functions.

Requirement of vimentin filament assembly for beta3-adrenergic receptor activation of ERK MAP kinase and lipolysis.

Catecholamine stimulation of beta-adrenergic receptors (betaAR) in adipocytes activates the cAMP-dependent protein kinase to promote liberation of fatty acids as a fuel source. The adipocyte beta3AR also activates extracellular signal-regulated kinases (ERK)-1 and -2 through direct recruitment and activation of Src kinase. This pathway together with cAMP-dependent protein kinase contributes to maximal beta3AR-stimulated lipolysis.

p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis.

Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood.

Maximal beta3-adrenergic regulation of lipolysis involves Src and epidermal growth factor receptor-dependent ERK1/2 activation.

Catecholamine-stimulated lipolysis is primarily a beta-adrenergic and cAMP-dependent event. In previous studies we established that the beta(3)-adrenergic receptor (beta(3)AR) in adipocytes utilizes a unique mechanism to stimulate extracellular signal-regulated kinases 1 and 2 (ERK) by direct recruitment and activation of Src kinase. Therefore, we investigated the role of the ERK pathway in adipocyte metabolism and found that the beta(3)AR agonist CL316,243 regulates lipolysis through both cAMP-dependent protein kinase (PKA) and ERK.

p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis.

Hepatic gluconeogenesis is essential for maintaining blood glucose levels during fasting and is the major contributor to postprandial and fasting hyperglycemia in diabetes. Gluconeogenesis is a classic cAMP/protein kinase A-dependent process initiated by glucagon, which is elevated in the blood during fasting and in diabetes. In this study, we have shown that p38 mitogen-activated protein kinase (p38) was activated in liver by fasting and in primary hepatocytes by glucagon or forskolin.

Selective activation of mitogen-activated protein (MAP) kinase kinase 3 and p38alpha MAP kinase is essential for cyclic AMP-dependent UCP1 expression in adipocytes.

The sympathetic nervous system regulates the activity and expression of uncoupling protein 1 (UCP1) through the three beta-adrenergic receptor subtypes and their ability to raise intracellular cyclic AMP (cAMP) levels. Unexpectedly, we recently discovered that the cAMP-dependent regulation of multiple genes in brown adipocytes, including Ucp1, occurred through the p38 mitogen-activated protein kinases (MAPK) (W. Cao, K.

Persistent nuclear factor-kappa B activation in Ucp2-/- mice leads to enhanced nitric oxide and inflammatory cytokine production.

One of the phenotypes of mice with targeted disruption of the uncoupling protein-2 gene (Ucp2-/-) is greater macrophage phagocytic activity and free radical production, resulting in a striking resistance to infectious microorganisms. In this study, the molecular mechanisms of this enhanced immune response were investigated. We found that levels of nitric oxide measured in either plasma or isolated macrophages from Ucp2-/- mice are significantly elevated in response to bacterial lipopolysaccharide challenge compared with similarly treated Ucp2+/+ mice.

Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism.

The three beta AR (beta-adrenergic receptor) subtypes (beta(1)AR, beta(2)AR, and beta(3)AR) are members of the large family of G protein-coupled receptors, each of which is coupled to G alpha s and increases in intracellular cAMP levels. In white adipose tissues, catecholamine activation of the beta ARs leads to the mobilization of stored fatty acids and regulates release of several adipokines, whereas in brown adipose tissue they stimulate the specialized process of adaptive nonshivering thermogenesis. Noteworthy, in most models of obesity the beta AR system is dysfunctional, and its ability to stimulate lipolysis and thermogenesis are both impaired.

Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: physiological and molecular characteristics.

The development of the metabolic syndrome in an increasing percentage of the populations of Western societies, particularly in the United States, requires valid models for establishing basic biochemical changes and performing preclinical studies on potential drug targets. The C57BL/6J mouse has become an important model for understanding the interplay between genetic background and environmental challenges such as high-fat/high-calorie diets that predispose to the development of the metabolic syndrome. This review highlights metabolic and signal transduction features that are altered during the course of disease progression, many of which mirror the human situation.