Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.

Infection of lung endothelial cells with pneumococci activates the superoxide-generating enzyme NADPH oxidase 2 (NOX2), involving the pneumococcal virulence factor pneumolysin (PLY). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the α subunit of the epithelial sodium channel (ENaC) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2.

First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma.

Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating β1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown.

Type of correlation between bite force and EMG activity of the temporalis and masseter muscles during maximal and submaximal clenching.

Maximal bite force is an important determinant of masticatory function and is essential for the estimation of dental status. Bite force is usually measured by gnathodynamometry.

Effect of pre-orthodontic trainer treatment on the masticatory and perioral muscles in patients with class II subdivision 1 malocclusion evaluated by surface EMG.

Myofunctional appliances have been shown to have a positive effect on the muscles in the facial area. Surface electromyography (sEMG) is one of the reliable methods used to investigate these effects.

Molecular Insights into the MLCK Activation by CaM.

Calmodulin (CaM) is a universal regulatory protein that modulates numerous cellular processes by using calcium (Ca) as the signal. In smooth muscle cells (SMC), one major target of CaM is myosin light chain kinase (MLCK), a kinase that phosphorylates the myosin regulatory light chain and thereby regulates cell contraction. In the absence of CaM, MLCK remains inhibited by its autoinhibitory domain (AID).

STIM1 ablation impairs exercise-induced physiological cardiac hypertrophy and dysregulates autophagy in mouse hearts.

Cardiac stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca entry (SOCE), is a known determinant of cardiomyocyte pathological growth in hypertrophic cardiomyopathy. We examined the role of STIM1 and SOCE in response to exercise-dependent physiological hypertrophy. Wild-type (WT) mice subjected to exercise training (WT-Ex) showed a significant increase in exercise capacity and heart weight compared with sedentary (WT-Sed) mice.

Potential utility of a multi-component coagulation factor panel to calculate MELD scores and assess the risk of portal vein thrombosis in chronic liver disease.

Background: Current quantitative approaches to assess chronic liver disease (CLD) severity have limitations. Further, portal vein thrombosis (PVT) pre-liver transplant (LT) is a major contributor to morbidity in CLD; the means of detecting and/or predicting PVT are limited. We sought to explore whether plasma coagulation factor activity levels can serve as a substitute for prothrombin time/international normalized ratio (PT/INR) in the Model for End-stage Liver Disease (MELD), and/or help assess the risk of PVT.

NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.

Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels.

Integrin regulation by tissue factor promotes cancer stemness and metastatic dissemination in breast cancer.

Tissue Factor (TF) is the initiator of blood coagulation but also functions as a signal transduction receptor. TF expression in breast cancer is associated with higher tumor grade, metastasis and poor survival. The role of TF signaling on the early phases of metastasis has never been addressed.

SARS-CoV-2, platelets, and endothelium: coexistence in space and time, or a pernicious ménage à trois?

As we enter year 3 of SARS-CoV-2 pandemic, long-term consequences of COVID-19 have become a major public health issue worldwide; however, the molecular and cellular underpinnings of 'long COVID' remain very poorly understood. A paradigm has recently emerged that thrombo-inflammatory consequences of SARS-CoV-2's impact on endothelial cells and platelets likely play a significant role in the development of chronic symptomatology associated with COVID-19. In this brief overview, we discuss the recent findings pertaining to the detection of SARS-CoV-2 virions in vascular cell subtypes, the contribution of the coagulation system to the development of 'long COVID', and the potential role of stem/progenitor cells in the viral and thrombotic dissemination in this disorder.

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia.

Background: Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca homeostasis, impairing luminal Ca regulation of the sarcoplasmic reticulum (SR) Ca release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redox-mediated increase of RyR2 function in cardiac disease remain elusive. We tested whether the oxidoreductase family of proteins that dynamically regulate the oxidative environment within the SR are involved in this process.

Obesity and the Bidirectional Risk of Cancer and Cardiovascular Diseases in African Americans: Disparity vs. Ancestry.

Cardiovascular disease (CVD) and cancer often occur in the same individuals, in part due to the shared risk factors such as obesity. Obesity promotes adipose inflammation, which is pathogenically linked to both cardiovascular disease and cancer. Compared with Caucasians, the prevalence of obesity is significantly higher in African Americans (AA), who exhibit more pronounced inflammation and, in turn, suffer from a higher burden of CVD and cancer-related mortality.

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes.

It is widely assumed that synthesis of membrane proteins, particularly in the heart, follows the classical secretory pathway with mRNA translation occurring in perinuclear regions followed by protein trafficking to sites of deployment. However, this view is based on studies conducted in less-specialized cells, and has not been experimentally addressed in cardiac myocytes. Therefore, we undertook direct experimental investigation of protein synthesis in cardiac tissue and isolated myocytes using single-molecule visualization techniques and a novel proximity-ligated in situ hybridization approach for visualizing ribosome-associated mRNA molecules for a specific protein species, indicative of translation sites.

Functional Characteristics and Regulated Expression of Alternatively Spliced Tissue Factor: An Update.

In human and mouse, alternative splicing of tissue factor's primary transcript yields two mRNA species: one features all six TF exons and encodes full-length tissue factor (flTF), and the other lacks exon 5 and encodes alternatively spliced tissue factor (asTF). flTF, which is oftentimes referred to as "TF", is an integral membrane glycoprotein due to the presence of an alpha-helical domain in its C-terminus, while asTF is soluble due to the frameshift resulting from the joining of exon 4 directly to exon 6. In this review, we focus on asTF-the more recently discovered isoform of TF that appears to significantly contribute to the pathobiology of several solid malignancies.

Acute Detubulation of Ventricular Myocytes Amplifies the Inhibitory Effect of Cholinergic Agonist on Intracellular Ca Transients.

Muscarinic receptors expressed in cardiac myocytes play a critical role in the regulation of heart function by the parasympathetic nervous system. How the structural organization of cardiac myocytes affects the regulation of Ca handling by muscarinic receptors is not well-defined. Using confocal Ca imaging, patch-clamp techniques, and immunocytochemistry, the relationship between t-tubule density and cholinergic regulation of intracellular Ca in normal murine ventricular myocytes and myocytes with acute disruption of the t-tubule system caused by formamide treatment was studied.

A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma.

In 2021, pancreatic ductal adenocarcinoma (PDAC) is the 3 leading cause of cancer deaths in the United States. This is largely due to a lack of symptoms and limited treatment options, which extend survival by only a few weeks. There is thus an urgent need to develop new therapies effective against PDAC.

Enhanced Efficacy of Combination of Gemcitabine and Phosphatidylserine-Targeted Nanovesicles against Pancreatic Cancer.

Phosphatidylserine (PS) is often externalized in viable pancreatic cancer cells and is therapeutically targetable using PS-selective drugs. One of the first-line treatments for advanced pancreatic cancer disease, gemcitabine (GEM), provides only marginal benefit to patients. We therefore investigated the therapeutic benefits of combining GEM and the PS-targeting drug, saposin C-dioleoylphosphatidylserine (SapC-DOPS), for treating pancreatic ductal adenocarcinoma (PDAC).

Alternatively spliced tissue factor levels are elevated in the plasma of patients with chronic liver diseases.

Objectives: In patients with chronic liver diseases, hypercoagulability can contribute to the progression of fibrosis and complications of cirrhosis. Tissue factor (TF) is a transmembrane glycoprotein that initiates the extrinsic pathway of blood coagulation. Recent investigations have established that TF is elevated in patients with pancreatic cancer, blood disorders, diabetes, and cardiovascular disease.

A single high-fat meal provokes pathological erythrocyte remodeling and increases myeloperoxidase levels: implications for acute coronary syndrome.

High-fat meal (HFM) consumption can produce acute lipemia and trigger myocardial infarction in patients with atherosclerosis, but the mechanisms are poorly understood. Erythrocytes (red blood cells, RBCs) intimately interact with inflammatory cells and blood vessels and play a complex role in regulating vascular function. Chronic high-fat feeding in mice induces pathological RBC remodeling, suggesting a novel link between HFM, RBCs, and vascular dysfunction.

Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding.

Objective: Inflammation in adipose tissues in obesity promotes insulin resistance and metabolic disease. The Duffy antigen receptor for chemokines (DARC) is a promiscuous non-signaling receptor expressed on erythrocytes and other cell types that modulates tissue inflammation by binding chemokines such as monocyte chemoattractant protein-1 (MCP-1) and by acting as a chemokine reservoir. DARC allelic variants are common in humans, but the role of DARC in modulating obesity-related metabolic disease is unknown.

Activation of carbonic anhydrase IX by alternatively spliced tissue factor under late-stage tumor conditions.

Molecules of the coagulation pathway predispose patients to cancer-associated thrombosis and also trigger intracellular signaling pathways that promote cancer progression. The primary transcript of tissue factor, the main physiologic trigger of blood clotting, can undergo alternative splicing yielding a secreted variant, termed asTF (alternatively spliced tissue factor). asTF is not required for normal hemostasis, but its expression levels positively correlate with advanced tumor stages in several cancers, including pancreatic adenocarcinoma.

Heterogeneous incidence and propagation of spreading depolarizations.

Spreading depolarizations are implicated in a diverse set of neurologic diseases. They are unusual forms of nervous system activity in that they propagate very slowly and approximately concentrically, apparently not respecting the anatomic, synaptic, functional, or vascular architecture of the brain. However, there is evidence that spreading depolarizations are not truly concentric, isotropic, or homogeneous, either in space or in time.

Antibody-based targeting of alternatively spliced tissue factor: a new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma.

Alternatively spliced Tissue Factor (asTF) is a secreted form of Tissue Factor (TF), the trigger of blood coagulation whose expression levels are heightened in several forms of solid cancer, including pancreatic ductal adenocarcinoma (PDAC). asTF binds to β1 integrins on PDAC cells, whereby it promotes tumor growth, metastatic spread, and monocyte recruitment to the stroma. In this study, we determined if targeting asTF in PDAC would significantly impact tumor progression.

Red Blood Cell Dysfunction Induced by High-Fat Diet: Potential Implications for Obesity-Related Atherosclerosis.

Background: High-fat diet (HFD) promotes endothelial dysfunction and proinflammatory monocyte activation, which contribute to atherosclerosis in obesity. We investigated whether HFD also induces the dysfunction of red blood cells (RBCs), which serve as a reservoir for chemokines via binding to Duffy antigen receptor for chemokines (DARC).

Methods And Results: A 60% HFD for 12 weeks, which produced only minor changes in lipid profile in C57/BL6 mice, markedly augmented the levels of monocyte chemoattractant protein-1 bound to RBCs, which in turn stimulated macrophage migration through an endothelial monolayer.