British Journal of Pharmacology

BACKGROUND AND PURPOSE: Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil-associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil-associated psoriasiform dermatitis. EXPERIMENTAL APPROACH: The anti-inflammatory effects of palbociclib were determined in activated human neutrophils...

Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age-related brain alterations have been long considered to predispose to neurodegeneration. Although protein misfolding and the accumulation of toxic protein aggregates have been contemplated as causative events in neurodegeneration, several biological pathways affected by brain ageing also contribute to pathogenesis. Here, we discuss the evidence showing the involvement of the mechanisms controlling neuronal structure, gene expression, autophagy, cell metabolism, and neuroinflammation in the onset and progression of neurodegenerative disorders...

The ubiquitin-proteasome system is one of the major pathways for the degradation of cellular proteins. In recent years, methods have been developed to exploit the ubiquitin-proteasome system to artificially degrade target proteins. Targeted protein degraders are extremely useful as biological tools for discovery research. They have also been developed as novel therapeutics with several targeted protein degraders currently in clinical trials. However, almost all targeted protein degrader technologies have been developed for cytosolic proteins...

Background and purpose mitochondrial dysfunction and inflammation contribute to the pathophysiology of a myriad of cardiovascular diseases. Additionally, the deleterious crosstalk of mitochondria and persistent endoplasmic reticulum (ER) stress triggers oxidative stress, which is deeply involved in the development of vascular diseases. The purpose of this work was to determine whether inhibition of mitochondrial stress reduces aneurysm development in angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE-/- ) mice and its effect on ER stress...

G protein-coupled receptors (GPCRs) are the most prominent receptors on the surface of the cell and play a central role in the regulation of cardiac and metabolic functions. GPCRs transmit extracellular stimuli to the interior of the cells by activating one or more heterotrimeric G proteins. The duration and intensity of G protein-mediated signalling are tightly controlled by a large array of intracellular mediators, including regulators of G protein signalling (RGS) proteins. RGS proteins selectively promote the GTPase activity of a subset of Gα subunits, thus serving as negative regulators of G protein signalling in a pathway-dependent manner...

BACKGROUND AND PURPOSE: Vascular smooth muscle cells (SMCs) undergo phenotypic switching during sustained inflammation, contributing to an unfavorable atherosclerotic plaque phenotype. PPARδ plays an important role in regulating SMC functions; however, its role in atherosclerotic plaque vulnerability remains unclear. Here, we aimed to explore the pathological roles of PPARδ in atherosclerotic plaque vulnerability in severe atherosclerosis and elucidate the underlying mechanisms...

BACKGROUND AND PURPOSE: Acute respiratory distress syndrome (ARDS) is a catastrophic pulmonary inflammatory dysfunction with a high mortality rate. Overwhelming neutrophilic immunity is a key feature in infective or sterile ARDS. Formyl peptide receptor 1 (FPR1) is a crucial damage sensation receptor for phlogistic reactions in initiation and progression of neutrophil-mediated ARDS. However, effective targets for controlling dysregulated neutrophilic inflammatory injuries in ARDS are limited...

BACKGROUND AND PURPOSE: Drugs of abuse, including alcohol, increase dopamine (DA) in the mesocorticolimbic system via actions on DA neurons in the ventral tegmental area (VTA). Increased DA transmission can activate inhibitory G protein signaling pathways in VTA DA neurons, including those controlled by GABAB (GABAB R) and D2 DA (D2 R) receptors. Members of the R7 subfamily of Regulator of G protein Signaling (RGS) proteins can regulate inhibitory G protein signaling, but their influence in VTA DA neurons is unclear...

BACKGROUND AND PURPOSE: Itch associates several pathologies and is a common drug-induced side effect. Chloroquine (CQ) was reported to induce itch by activating the Mas-related G protein-coupled receptor MrgprA3 and subsequently TRPA1. In this study we demonstrate that CQ employs at least two MrgprA3-independent mechanisms to activate or sensitize TRPA1 and TRPV1. EXPERIMENTAL APPROACH: Patch Clamp and calcium-imaging were utilized to examine effects of CQ on TRPA1 and TRPV1 expressed in HEK-293T cells...

BACKGROUND AND PURPOSE: Mitochondrial oxidative stress, inflammation and apoptosis primarily underlies gastric mucosal injury by non-steroidal anti-inflammatory drugs (NSAIDs), the most unavoidable and widely used anti-inflammatory medicines. Alternative gastroprotective strategy is therefore warranted. Sirtuin-3 pivotally maintains mitochondrial structural integrity and metabolism while preventing oxidative stress; however never explored in gastric injury. We investigated whether and how Sirtuin-3 stimulation by a phytochemical, 'honokiol' (HKL), rescued NSAID-induced gastric injury...

BACKGROUND AND PURPOSE: Respiratory diseases have become a global health problem and may lead to acute lung injury (ALI) in severe cases. ALI progression is associated with complex pathological changes; however, there are currently no effective therapeutic drugs. Excessive activation and recruitment of immunocytes in the lungs and the release of large amounts of cytokines are considered the primary causes of ALI, but the cellular mechanisms involved remain unknown. Therefore, new therapeutic strategies need to be developed to control the inflammatory response and prevent the further aggravation of ALI...

BACKGROUND AND PURPOSE: Cardiovascular disease (CVD) affects up to half of the patients with chronic obstructive pulmonary disease (COPD), and exerts deleterious impact on health outcomes and survivability. Vascular endothelial dysfunction marks the onset of cardiovascular disease. The present study examined the effect of a potent NADPH Oxidase (NOX) inhibitor and free-radical scavenger, apocynin, on COPD-related CVD. EXPERIMENTAL APPROACH: Male BALB/c mice were exposed to either room air (Sham) or cigarette smoke (CS) generated from 9 cigarettes per day, 5 days a week for up to 24 weeks with or without apocynin treatment (5 mg·kg-1 ·day-1 , intraperitoneal injection)...

BACKGROUND AND PURPOSE: Local blood flow regulation relies mostly on the coordination between neurons and pericyte-containing capillaries. Pericyte relaxation and contraction are influenced by various vasoactive substances and regulated by neurotransmitters. α7 nicotinic acetylcholine receptors (α7-nAChRs), involved in the regulation of vascular function and inhibitory GABA systems, have neuroprotective effects against central nervous system diseases. Although α7-nAChRs are found throughout the retina, their contribution to the retinal capillary tone remains unknown...

No abstract text is available yet for this article.

BACKGROUND AND PURPOSE: Therapies based on apolipoprotein A-I (ApoA-I), classically tested for cardiovascular diseases, were recently proposed for Alzheimer's disease (AD). Based on a drug reprofiling approach, our objective was to explore the use of a natural variant of ApoA-I form, ApoA-I-Milano (M), as a treatment for AD. ApoA-I-M contains the R173C mutation, and confers protection against atherosclerosis development, although ApoA-I-M carriers exhibit low HDL levels. EXPERIMENTAL APPROACH: Middle-aged (12-month-old) and aged (21-month-old) APP23 mice were intraperitoneally treated for 10 weeks with human recombinant ApoA-I-M (hrApoA-I-M) protein or saline...

Human neutrophils belong to the innate immune system and are the most abundant white blood cells in circulation. They are professional phagocytes and express several G protein-coupled receptors (GPCRs) which are essential for proper neutrophil functions. So far, the two formyl peptide receptors (FPR1 and FPR2) have been the most extensively studied group of neutrophil GPCRs, but recently a new group, the free fatty acid sensing receptors (FFARs), has gained growing attention. Neutrophils express GPR84 and FFA2 (sensing medium- and short-chain fatty acids, respectively) which display similar activation profiles...

BACKGROUND AND PURPOSE: The causal relationship between altered host microbiome composition, especially the respiratory tract microbiome, and the occurrence of pulmonary hypertension (PH) has not yet been studied. An increased abundance of airway streptococci is seen in patients with PH compared with healthy individuals. This study aimed to determine the causal link between elevated airway exposure to Streptococcus and PH. EXPERIMENTAL APPROACH: The dose-, time-, and bacterium-specific effects of Streptococcus salivarius (S...

BACKGROUND AND PURPOSE: Despite its contradictory clinical performance, Veklury® (remdesivir) has a pivotal role in COVID-19 therapy. Possible contributions of the vehicle sulfobutylether-β-cyclodextrin (SBECD) to Veklury® effects are neglected and the powder and solution formulations of Veklury® are treated equivalently despite their different vehicle content. Our objective was to study Veklury® effects on initial membrane-coupled events of SARS-CoV-2 infection and highlight the cholesterol depletion-mediated active role of SBECD...

No abstract text is available yet for this article.

Mitochondria and mitochondria-mediated signaling pathways are known to control synaptic signaling as well as long-lasting changes in neuronal structure and function. Mitochondrial impairment is linked to synaptic dysfunction in normal aging and age-associated neurodegenerative ailments including Parkinson's disease (PD) and Alzheimer's disease (AD). Both proteolysis and mitophagy perform a major role in neuroprotection by maintaining a healthy mitochondrial population during aging. Mitophagy, a highly evolutionarily conserved cellular process, helps in the clearance of damaged mitochondria and thereby maintains the mitochondrial and metabolic balance, energy supply, neuronal survival, and neuronal health...