Soluble vascular endothelial glycocalyx proteoglycans as potential therapeutic targets in inflammatory diseases.

Reducing the activity of cytokines and leukocyte extravasation is an emerging therapeutic strategy to limit tissue-damaging inflammatory responses and restore immune homeostasis in inflammatory diseases. Proteoglycans embedded in the vascular endothelial glycocalyx, which regulate the activity of cytokines to restrict the inflammatory response in physiological conditions, are proteolytically cleaved in inflammatory diseases. Here we critically review the potential of proteolytically shed, soluble vascular endothelial glycocalyx proteoglycans to modulate pathological inflammatory responses.

Biomolecular interactions between the antibacterial ceftolozane and the human inflammatory disease target ADAM17: a drug repurposing study.

Inhibition of a disintegrin and metalloproteinase-17 (ADAM17), a metzincin, is proposed as a novel therapeutic strategy to suppress overproduction of the proinflammatory cytokine TNF-α in rheumatoid arthritis and inflammatory bowel disease. Existing ADAM17 inhibitors generate toxic metabolites or haven't progressed in clinical trials. Previous studies suggest that ligands which bind to ADAM17 active site by interacting with the Zn ion and L-shaped hydrophobic S1'- and S3'-pockets and forming favorable hydrogen bonds could act as potential ADAM17 inhibitors.

Improved method for surgical induction of chronic hypertension in mice.

Chronic hypertension can be induced in mice by one-kidney one-clip (1K1C) or two-kidney one-clip surgery, transgenic overexpression of angiotensinogen and renin, administration of deoxycorticosterone acetate-salt, supplying Nitro-L-arginine methyl-ester in the drinking water and Angiotensin-II infusion. Although each model has its own pros and cons, selection of a model that mimics human hypertensive disease accurately is essential to ensure rigor and reproducibility in hypertension research. 1K1C mice represent an efficient, budget-friendly, and translationally capable model; however, their use in preclinical research has remained largely hindered due to concerns about potential technical complexity and lack of reported information regarding procedure-related mortality rates.

The Neuropeptide α-Calcitonin Gene-Related Peptide as the Mediator of Beneficial Effects of Exercise in the Cardiovascular System.

Regular physical activity exerts cardiovascular protective effects in healthy individuals and those with chronic cardiovascular diseases. Exercise is accompanied by an increased plasma concentration of α-calcitonin gene-related peptide (αCGRP), a 37-amino acid peptide with vasodilatory effects and causative roles in migraine. Moreover, mouse models revealed that loss of αCGRP disrupts physiological adaptation of the cardiovascular system to exercise in normotension and aggravates cardiovascular impairment in primary chronic hypertension, both can be reversed by αCGRP administration.

Novel regulators of airway epithelial barrier function during inflammation: potential targets for drug repurposing.

Introduction: Endogenous inflammatory signaling molecules resulting from deregulated immune responses can impair airway epithelial barrier function and predispose individuals with airway inflammatory diseases to exacerbations and lung infections. Therapeutically targeting the specific endogenous factors disrupting the airway barrier therefore has the potential to prevent disease exacerbations without affecting the protective immune responses.

Areas Covered: Here, we review the endogenous factors and specific mechanisms disrupting airway epithelial barrier during inflammation and reflect on whether these factors can be specifically targeted by repurposing the existing drugs.

Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells.

Downregulation of drug metabolizing enzymes and transporters by proinflammatory mediators in hepatocytes, enterocytes and renal tubular epithelium is an established mechanism affecting pharmacokinetics. Emerging evidences indicate that vascular endothelial cell expression of drug metabolizing enzymes and transporters may regulate pharmacokinetic pathways in heart to modulate local drug bioavailability and toxicity. However, whether inflammation regulates pharmacokinetic pathways in human cardiac vascular endothelial cells remains largely unknown.

CGRP Receptor Antagonism in COVID-19: Potential Cardiopulmonary Adverse Effects.

Recently, the US FDA has authorized a drug repurposing trial with calcitonin gene-related peptide (CGRP) receptor antagonists to reduce lung inflammation in coronavirus 2019 (COVID-19). However, the well-established cardiopulmonary protective effects of CGRP raise concerns about the safety of antagonizing CGRP in COVID-19. Awareness regarding potential cardiopulmonary adverse effects may enable their early detection and prevent illness from worsening.

Blood Pressure Normalization-Independent Cardioprotective Effects of Endogenous, Physical Activity-Induced αCGRP (α Calcitonin Gene-Related Peptide) in Chronically Hypertensive Mice.

Rationale: αCGRP (α calcitonin gene-related peptide), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure.

Objective: However, we hypothesize that endogenous, physical activity-induced αCGRP has blood pressure-independent cardioprotective effects in chronic hypertension.

Methods And Results: Chronically hypertensive (one-kidney-one-clip surgery) wild-type and αCGRP sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37.

RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1.

Background: Endothelial barrier dysfunction characterized by hyperpermeability of the vascular endothelium is a key factor in the pathogenesis of chronic inflammatory diseases and affects clinical outcomes. In states of chronic inflammation, mediators secreted by activated immune cells or vascular endothelium may affect the barrier function and permeability of the vascular endothelium. The matricellular R-spondin family member RSPO3 is produced by inflammatory-activated human monocytes and vascular endothelial cells, but its effects in the regulation of vascular endothelial barrier function remains elusive.

Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis.

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry.

Inflammatory Wnt5A signalling pathways affecting barrier function of human vascular endothelial cells.

Wnt5A is a chemokine secreted by inflammatory-activated human macrophages that sustains their inflammatory response in an autocrine manner. High levels of Wnt5A are found in sera of patients with sepsis and septic shock. Here, we comment on recently reported Wnt5A signalling pathways in human vascular endothelial cells (VEC).

IL-4 Causes Hyperpermeability of Vascular Endothelial Cells through Wnt5A Signaling.

Microvascular leakage due to endothelial barrier dysfunction is a prominent feature of T helper 2 (Th2) cytokine mediated allergic inflammation. Interleukin-4 (IL-4) is a potent Th2 cytokine, known to impair the barrier function of endothelial cells. However, the effectors mediating IL-4 induced cytoskeleton remodeling and consequent endothelial barrier dysfunction remain poorly defined.

Wnt5A/Ryk signaling critically affects barrier function in human vascular endothelial cells.

Satisfactory therapeutic strategies for septic shock are still missing. Previously we found elevated levels of Wnt5A in patients with severe sepsis and septic shock. Wnt5A is released by activated macrophages but knowledge of its effects in the vascular system remains scant.