4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model.

Sandhoff disease (SD), a fatal and rare lysosomal storage disorder (LSD), is caused by a deficiency of the enzyme β-hexosaminidase B and leads to severe accumulation of GM2 gangliosides in lysosomes, primarily within the central nervous system (CNS). This accumulation results in severe neurological impairment, lower motor neuron disease, and death. Currently, there are no effective therapies available for SD.

GDF10 is a negative regulator of vascular calcification.

Cardiovascular mortality is particularly high and increasing in patients with chronic kidney disease, with vascular calcification (VC) as a major pathophysiologic feature. VC is a highly regulated biological process similar to bone formation involving osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). We have previously demonstrated that loss of T-cell death-associated gene 51 (TDAG51) expression leads to an attenuation of medial VC.

Small molecules targeting GRP78 mitigate anti-GRP78 autoantibody-mediated tissue factor procoagulant activity in cultured endothelial cells.

Background: The 78-kDa glucose-regulated protein (GRP78) expressed on the cell surface (csGRP78) has been reported to regulate tissue factor (TF) procoagulant activity (PCA) in lesion-resident endothelial cells (ECs), which is further enhanced by circulating anti-GRP78 autoantibodies that bind to the Leu-Leu epitope in GRP78.

Objectives: Determine the effects of the engagement of the anti-GRP78 autoantibody to csGRP78 on ECs and the underlying mechanisms that impact TF PCA.

Methods: Immunofluorescent staining was used to determine the presence of csGRP78 in tumor necrosis factor α-treated ECs.

Fatal attractions that trigger inflammation and drive atherosclerotic disease.

Background: Atherosclerosis is the salient, underlying cause of cardiovascular diseases, such as arrhythmia, coronary artery disease, cardiomyopathy, pulmonary embolism and myocardial infarction. In recent years, atherosclerosis pathophysiology has evolved from a lipid-based to an inflammation-centric ideology.

Methods: This narrative review is comprised of review and original articles that were found through the PubMed search engine.

Reduced plasma GDF10 levels are positively associated with cholesterol impairment and childhood obesity.

Childhood obesity is a global health concern affecting over 150 million children worldwide, with projections of a rise to 206 million by 2025. Understanding the mechanisms underlying this epidemic is crucial for developing effective interventions. In this study, we investigated circulating levels of Growth Differentiation Factor 10 (GDF10), a novel regulator of adipogenesis.

PCSK7: A novel regulator of apolipoprotein B and a potential target against non-alcoholic fatty liver disease.

Background: Epidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. We associated the known PCSK7 gain-of-function non-coding SNP rs236918 with higher levels of plasma apolipoprotein B (apoB) and the loss-of-function coding variant p.Pro777Leu (SNP rs201598301) with lower apoB and TG.

Repurposing Two Old Friends to Fight Cancer: Caffeine and Statins.

Statins are a class of cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Evidence suggests that certain cancers depend on the mevalonate pathway for growth and survival, and thus blocking the mevalonate pathway with statins may offer a viable therapeutic approach for treating cancer, or at least enhance the efficacy of existing cancer drugs. In this issue of Cancer Research, Tran and colleagues showed that caffeine works jointly with FOXM1 inhibition to enhance the antitumor activity of statins in neuroblastoma cells.

A Metabolic Enhancer Protects against Diet-Induced Obesity and Liver Steatosis and Corrects a Pro-Atherogenic Serum Profile in Mice.

Objective: Metabolic Syndrome (MetS) affects hundreds of millions of individuals and constitutes a major cause of morbidity and mortality worldwide. Obesity is believed to be at the core of metabolic abnormalities associated with MetS, including dyslipidemia, insulin resistance, fatty liver disease and vascular dysfunction. Although previous studies demonstrate a diverse array of naturally occurring antioxidants that attenuate several manifestations of MetS, little is known about the (i) combined effect of these compounds on hepatic health and (ii) molecular mechanisms responsible for their effect.

study of Au nanoparticle formation in a mechanochemical-aging-based method.

As we strive to perform chemical transformations in a more sustainable fashion, enabling solid-state reactions through mechanochemistry has emerged as a highly successful approach. Due to the wide-ranging applications of gold nanoparticles (AuNPs), mechanochemical strategies have already been employed for their synthesis. However, the underlying processes surrounding gold salt reduction, nucleation and growth of AuNPs in the solid state are yet to be understood.

Extensive diet-induced atherosclerosis in scavenger receptor class B type 1-deficient mice is associated with substantial leukocytosis and elevated vascular cell adhesion molecule-1 expression in coronary artery endothelium.

High levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease. Mice that lack genes involved in the clearance of LDL from the bloodstream, such as the LDL receptor and apolipoprotein E, are widely used models of experimental atherosclerosis. Conversely, mice that lack the HDL receptor, scavenger receptor class B type I, and therefore have disrupted HDL functionality, also develop diet-inducible atherosclerosis but are a seldom-used disease model.

The Impact of COVID-19 on Emergency Medicine Rotations.

Introduction The impact of modifications in curriculum and clinical rotations made secondary to the COVID-19 pandemic on medical education has yet to be fully investigated. We observed differences in the types of patients seen by medical students that may have resulted from clinical disruptions due to the COVID-19 pandemic. We then evaluated what impact these disruptions had on the students' clinical competency.

Direct observation by high resolution transmission electron microscopy of gold(III) particle transformation during aging reduction reaction.

We use a gold nanoparticle synthesis as a model system to study the morphological and compositional changes in gold(III) precursor particles, while reduction is taking place during aging after mechanical activation. Scanning transmission electron microscopy coupled with a high-angle annular dark field detector revealed the nanoscale changes in particle morphology, while electron energy loss spectroscopy mapped the changes in the chemical landscape during the reduction process. Tracking a specific region of interest on the sample grid allowed for comparisons to be made of the same particles across a two day monitoring period.

Inhibitory Antibodies against PCSK9 Reduce Surface CD36 and Mitigate Diet-Induced Renal Lipotoxicity.

Background: PCSK9 modulates the uptake of circulating lipids through a range of receptors, including the low-density lipoprotein receptor (LDLR) and CD36. In the kidney, CD36 is known to contribute to renal injury through pro-inflammatory and -fibrotic pathways. In this study, we sought to investigate the role of PCSK9 in modulating renal lipid accumulation and injury through CD36 using a high fat diet (HFD)-induced murine model.

Scratching the Surface-An Overview of the Roles of Cell Surface GRP78 in Cancer.

The 78 kDa glucose-regulated protein (GRP78) is considered an endoplasmic reticulum (ER)-resident molecular chaperone that plays a crucial role in protein folding homeostasis by regulating the unfolded protein response (UPR) and inducing numerous proapoptotic and autophagic pathways within the eukaryotic cell. However, in cancer cells, GRP78 has also been shown to migrate from the ER lumen to the cell surface, playing a role in several cellular pathways that promote tumor growth and cancer cell progression. There is another insidious consequence elicited by cell surface GRP78 (csGRP78) on cancer cells: the accumulation of csGRP78 represents a novel neoantigen leading to the production of anti-GRP78 autoantibodies that can bind csGRP78 and further amplify these cellular pathways to enhance cell growth and mitigate apoptotic cell death.

The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases.

The importance of the proprotein convertase subtilisin/kexin type-9 () gene was quickly recognized by the scientific community as the third locus for familial hypercholesterolemia. By promoting the degradation of the low-density lipoprotein receptor (LDLR), secreted PCSK9 protein plays a vital role in the regulation of circulating cholesterol levels and cardiovascular disease risk. For this reason, the majority of published works have focused on the secreted form of PCSK9 since its initial characterization in 2003.

Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance.

Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR).

TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease.

Chronic kidney disease (CKD) is characterized by the gradual loss of renal function and is a major public health concern. Risk factors for CKD include hypertension and proteinuria, both of which are associated with endoplasmic reticulum (ER) stress. ER stress-induced TDAG51 protein expression is increased at an early time point in mice with CKD.

Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin.

The hepatic carbohydrate-recognizing asialoglycoprotein receptor (ASGR1) mediates the endocytosis/lysosomal degradation of desialylated glycoproteins following binding to terminal galactose/N-acetylgalactosamine. Human heterozygote carriers of ASGR1 deletions exhibit ∼34% lower risk of coronary artery disease and ∼10% to 14% reduction of non-HDL cholesterol. Since the proprotein convertase PCSK9 is a major degrader of the low-density lipoprotein receptor (LDLR), we investigated the degradation and functionality of LDLR and/or PCSK9 by endogenous/overexpressed ASGR1 using Western blot and immunofluorescence in HepG2-naïve and HepG2-PCSK9-knockout cells.

Controlling Liquid Crystal Orientations for Programmable Anisotropic Transformations in Cellular Microstructures.

Geometric reconfigurations in cellular structures have recently been exploited to realize adaptive materials with applications in mechanics, optics, and electronics. However, the achievable symmetry breakings and corresponding types of deformation and related functionalities have remained rather limited, mostly due to the fact that the macroscopic geometry of the structures is generally co-aligned with the molecular anisotropy of the constituent material. To address this limitation, cellular microstructures are fabricated out of liquid crystalline elastomers (LCEs) with an arbitrary, user-defined liquid crystal (LC) mesogen orientation encrypted by a weak magnetic field.