Ovarian Cancer G protein-coupled receptor-1 signaling bias dictates anti-contractile effect of benzodiazepines on airway smooth muscle.

Background: We recently reported that the ovarian cancer G protein-coupled receptor-1 (OGR1) can be pharmacologically biased with specific benzodiazepines to couple with distinct heterotrimeric G proteins in human airway smooth muscle (ASM) cells. Lorazepam stimulated both G and G signaling via OGR1, whereas sulazepam only stimulated G signaling in ASM cells. The present study sought to determine the effects of sulazepam and lorazepam on contraction of human precision cut lung slices (hPCLS), and detail the biochemical mechanisms mediating these effects.

A-Kinase-Anchoring Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle.

AKAPs (A-kinase-anchoring proteins) act as scaffold proteins that anchor the regulatory subunits of the cAMP-dependent PKA (protein kinase A) to coordinate and compartmentalize signaling elements and signals downstream of Gs-coupled GPCRs (G protein-coupled receptors). The βAR (β-2-adrenoceptor), as well as the Gs-coupled EP2 and EP4 (E-prostanoid) receptor subtypes of the EP receptor subfamily, are effective regulators of multiple airway smooth muscle (ASM) cell functions whose dysregulation contributes to asthma pathobiology. Here, we identify specific roles of the AKAPs Ezrin and Gravin in differentially regulating PKA substrates downstream of the βAR, EP2R (EP2 receptor) and EP4R.

Heated tobacco product IQOS induces unique metabolic signatures in human bronchial epithelial cells.

https://bit.ly/3TkhBox.

Epicutaneous Sensitization to the Phytocannabinoid β-Caryophyllene Induces Pruritic Inflammation.

In recent years, there has been increased accessibility to cannabis for recreational and medicinal use. Incidentally, there has been an increase in reports describing allergic reactions to cannabis including exacerbation of underlying asthma. Recently, multiple protein allergens were discovered in cannabis, yet these fail to explain allergic sensitization in many patients, particularly urticaria and angioedema.

Proteomics-Based Approach for Detailing the Allergenic Profile of Cannabis Chemotypes.

Allergic sensitization to cannabis is an emerging public health concern and is difficult to clinically establish owing to lack of standardized diagnostic approaches. Attempts to develop diagnostic tools were largely hampered by the Schedule I restrictions on cannabis, which limited accessibility for research. Recently, however, hemp was removed from the classified list, and increased accessibility to hemp allows for the evaluation of its practical clinical value for allergy diagnosis.

Immunomodulatory Actions of Cannabinoids: Clinical Correlates and Therapeutic Opportunities for Allergic Inflammation.

Endogenously produced cannabinoids as well as phytocannabinoids broadly exhibit anti-inflammatory actions. Recent emergence of cannabis for multiple medical issues combined with reports on potent immunomodulatory actions of distinct components has underscored the therapeutic potential of cannabis. Although synthetic cannabinoids that are based on structural similarities to the existing class of cannabinoids have been on the rise, their application in therapeutics have been limited owing to toxicity concerns.

Targeted Inhibition of Select Extracellular Signal-regulated Kinases 1 and 2 Functions Mitigates Pathological Features of Asthma in Mice.

ERK1/2 (extracellular signal-regulated kinases 1 and 2) regulate the activity of various transcription factors that contribute to asthma pathogenesis. Although an attractive drug target, broadly inhibiting ERK1/2 is challenging because of unwanted cellular toxicities. We have identified small molecule inhibitors with a benzenesulfonate scaffold that selectively inhibit ERK1/2-mediated activation of AP-1 (activator protein-1).

Impact of cannabis knowledge and attitudes on real-world practice.

Background: Increased cannabis consumption worldwide challenges allergists because of an upsurge in cannabis allergy and need to discuss cannabis with patients.

Objective: To determine the knowledge, attitudes, and practices regarding cannabis among allergists and their approach to recognizing and diagnosing suspected cannabis allergy.

Methods: The International Allergist Canna Knowledge, Attitudes, and Practices Survey was completed by members from 3 International Allergy Societies.

OGR1-dependent regulation of the allergen-induced asthma phenotype.

The proton-sensing receptor, ovarian cancer G protein-coupled receptor (OGR1), has been shown to be expressed in airway smooth muscle (ASM) cells and is capable of promoting ASM contraction in response to decreased extracellular pH. OGR1 knockout (OGR1KO) mice are reported to be resistant to the asthma features induced by inhaled allergen. We recently described certain benzodiazepines as OGR1 activators capable of mediating both procontractile and prorelaxant signaling in ASM cells.

Diacylglycerol Kinase Inhibition Reduces Airway Contraction by Negative Feedback Regulation of Gq-Signaling.

Exaggerated airway smooth muscle (ASM) contraction regulated by the Gq family of G protein-coupled receptors causes airway hyperresponsiveness in asthma. Activation of Gq-coupled G protein-coupled receptors leads to phospholipase C (PLC)-mediated generation of inositol triphosphate (IP) and diacylglycerol (DAG). DAG signaling is terminated by the action of DAG kinase (DGK) that converts DAG into phosphatidic acid (PA).

Cooperativity between β-agonists and c-Abl inhibitors in regulating airway smooth muscle relaxation.

Current therapeutic approaches to avoid or reverse bronchoconstriction rely primarily on β2 adrenoceptor agonists (β-agonists) that regulate pharmacomechanical coupling/cross bridge cycling in airway smooth muscle (ASM). Targeting actin cytoskeleton polymerization in ASM represents an alternative means to regulate ASM contraction. Herein we report the cooperative effects of targeting these distinct pathways with β-agonists and inhibitors of the mammalian Abelson tyrosine kinase (Abl1 or c-Abl).

Occupational Allergies to Cannabis.

Within the last decade there has been a significant expansion in access to cannabis for medicinal and adult nonmedical use in the United States and abroad. This has resulted in a rapidly growing and diverse workforce that is involved with the growth, cultivation, handling, and dispensing of the cannabis plant and its products. The objective of this review was to educate physicians on the complexities associated with the health effects of cannabis exposure, the nature of these exposures, and the future practical challenges of managing these in the context of allergic disease.

Therapeutic potential and challenges of bitter taste receptors on lung cells.

Airway smooth muscle (ASM) hyperresponsiveness and airway remodeling are pathological drivers of disease progression and mortality in asthma. Importantly, approximately 50% of affected individuals are unable to reliably manage disease symptoms using the current standard of care. Recently, T2Rs have been identified as a novel class of G protein-coupled receptors expressed in the airway that on activation can induce ASM relaxation and reduction in airway tone.

The proton-sensing receptor ovarian cancer G-protein coupled receptor 1 (OGR1) in airway physiology and disease.

Numerous G protein-coupled receptors (GPCRs) regulate multiple airway functions and play fundamental roles in normal and aberrant airway and lung physiology. Thus, GPCRs are prime candidates of targeting by disease therapeutics. The intriguing proton-sensing GPCR Ovarian cancer G-protein coupled receptor 1 (OGR1; aka GPR68) has recently been shown capable of regulating airway smooth muscle (ASM) contraction and proliferation.

Cannabis: An Emerging Occupational Allergen?

Cannabis is the most commonly used psychoactive drug. In recent years, Cannabis access has expanded for both medicinal and non-medicinal has grown. This is also marked with an increasing number of individuals gaining employment in this emerging industry.

Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors.

The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors.

Inhalation of Fragments Induces Pulmonary Arterial Remodeling.

is a fungal contaminant within the built environment and a respiratory health concern in the United States. The objective of this study was to characterize the mechanisms influencing pulmonary immune responses to repeatedly inhaled . Groups of B6C3F1/N mice repeatedly inhaled viable trichothecene-producing conidia (strain A or strain B), heat-inactivated conidia, or high-efficiency particulate absolute-filtered air twice per week for 4 and 13 weeks.