Physiological Features of the Neural Stem Cells Obtained from an Animal Model of Spinal Muscular Atrophy and Their Response to Antioxidant Curcumin.

The most prevalent rare genetic disease affecting young individuals is spinal muscular atrophy (SMA), which is caused by a loss-of-function mutation in the telomeric gene survival motor neuron () . The high heterogeneity of the SMA pathophysiology is determined by the number of copies of , a separate centromeric gene that can transcribe for the same protein, although it is expressed at a slower rate. SMA affects motor neurons.

G protein-coupled receptor (GPCR) pharmacogenomics.

The field of pharmacogenetics, the investigation of the influence of one or more sequence variants on drug response phenotypes, is a special case of pharmacogenomics, a discipline that takes a genome-wide approach. Massively parallel, next generation sequencing (NGS), has allowed pharmacogenetics to be subsumed by pharmacogenomics with respect to the identification of variants associated with responders and non-responders, optimal drug response, and adverse drug reactions. A plethora of rare and common naturally-occurring GPCR variants must be considered in the context of signals from across the genome.

Differential Epigenetic Changes in the Dorsal Hippocampus of Male and Female SAMP8 Mice: A Preliminary Study.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The causes of the disease are not well understood, as it involves a complex interaction between genetic, environmental, and epigenetic factors. SAMP8 mice have been proposed as a model for studying late-onset AD, since they show age-related learning and memory deficits as well as several features of AD pathogenesis.

Cell Surface Platelet Tissue Factor Expression: Regulation by P2Y and Link to Residual Platelet Reactivity.

Background: ADP-induced platelet activation leads to cell surface expression of several proteins, including TF (tissue factor). The role of ADP receptors in platelet TF modulation is still unknown. We aimed to assess the (1) involvement of P2Y and P2Y receptors in ADP-induced TF exposure; (2) modulation of TF-platelets in anti-P2Y-treated patients with coronary artery disease.

Montelukast Inhibits Platelet Activation Induced by Plasma From COVID-19 Patients.

Leukotrienes are important pro-inflammatory lipid mediators derived from the arachidonic acid metabolism. In particular, cysteinyl leukotrienes, namely LTC, LTD, and LTE are involved in many of the principal features of asthma, while more recently they have also been implicated in cardiovascular diseases. COVID-19 is characterized by an overwhelming state of inflammation, sometimes resulting in an acute respiratory distress syndrome.

Antiplatelet Agents Affecting GPCR Signaling Implicated in Tumor Metastasis.

Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different mechanisms. In addition to their direct interaction with cancer cells, thus forming heteroaggregates such as leukocytes, platelets release molecules that are necessary to promote a disseminating phenotype in cancer cells via the induction of an epithelial-mesenchymal-like transition.

Effects of non-steroidal anti-inflammatory drugs and other eicosanoid pathway modifiers on antiviral and allergic responses: EAACI task force on eicosanoids consensus report in times of COVID-19.

Non-steroidal anti-inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti-inflammatory, antipyretic, and analgesic effects are applied against symptoms of respiratory infections, including SARS-CoV-2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID-19 also revealed the gaps in our understanding of their mechanism of action, selectivity, and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs-exacerbated respiratory disease (NERD).

ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen.

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages.

Montelukast Use Decreases Cardiovascular Events in Asthmatics.

Cysteinyl leukotrienes are proinflammatory mediators with a clinically established role in asthma and a human genetic and preclinical role in cardiovascular pathology. Given that cardiovascular disease has a critical inflammatory component, the aim of this work was to conduct an observational study to verify whether the use of a cysteinyl leukotriene antagonist, namely, montelukast, may protect asthmatic patients from a major cardiovascular event and, therefore, represent an innovative adjunct therapy to target an inflammatory component in cardiovascular disease. We performed an observational retrospective 3-year study on eight hundred adult asthmatic patients 18 years or older in Albania, equally distributed into two cohorts, exposed or nonexposed to montelukast usage, matched by age and gender according to information reported in the data collection.

Reciprocal interference between the NRF2 and LPS signaling pathways on the immune-metabolic phenotype of peritoneal macrophages.

The metabolic and immune adaptation to extracellular signals allows macrophages to carry out specialized functions involved in immune protection and tissue homeostasis. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that coordinates cell redox and metabolic responses to stressors. However, the individual and concomitant activation of NRF2 and inflammatory pathways have been poorly investigated in isolated macrophages.

Current perspective on eicosanoids in asthma and allergic diseases: EAACI Task Force consensus report, part I.

Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D receptor antagonists, have been shown to modulate features of asthma and allergic diseases.

Rapid Metabolization of Protectin D1 by β-Oxidation of Its Polar Head Chain.

Protectin D1 [neuroprotectin D1 (), PD1] has been proposed to play a key role in the resolution of inflammation. Aside from its ω-monohydroxylated metabolite, little has been reported on its metabolic fate. Upon incubation in HepG2 cells, liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed the formation of two main metabolites, identified as and by comparison with standards obtained through demanding total chemical syntheses.

Arachidonic Acid and Docosahexaenoic Acid Metabolites in the Airways of Adults With Cystic Fibrosis: Effect of Docosahexaenoic Acid Supplementation.

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by genetic mutations in CF transmembrane conductance regulator protein. Several reports have indicated the presence of specific fatty acid alterations in CF patients, most notably decreased levels of plasmatic and tissue docosahexaenoic acid (DHA), the precursor of specialized pro-resolving mediators. We hypothesized that DHA supplementation could restore the production of DHA-derived products and possibly contribute to a better control of the chronic pulmonary inflammation observed in CF subjects.

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain.

The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo.

Two-pronged approach to anti-inflammatory therapy through the modulation of the arachidonic acid cascade.

Chronic inflammation and pain is a major global health problem, and nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most frequently prescribed drugs and common option for the treatment of inflammatory pain. However, they have the potential to cause serious complications, such as gastrointestinal (GI) lesions, bleeding and cardiovascular (CV) problems. NSAIDs exert their anti-inflammatory, analgesic and anti-pyretic actions by inhibiting the cyclooxygenases (COX)-1 and COX-2, key enzymes of the arachidonic acid (AA) cascade.

Nonsteroidal Anti-Inflammatory Drugs: Exploiting Bivalent COXIB/ TP Antagonists for the Control of Cardiovascular Risk.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely prescribed or dispensed over the counter analgesics and antipyretics that act by inhibiting prostaglandins and thromboxane synthesis. After the identification of a second isoform of COX, the pharmaceutical research focused on developing COX-2- selective drugs (COXIBs) considered as second generation NSAIDs that would retain the anti-inflammatory and analgesic activities of traditional NSAID without blunting the gastrointestinal cytoprotection sustained by COX1-derived products such as PGE2. However, while several clinical trials confirmed a gastrointestinal safer profile of COXIBs vs unselective COX inhibitors, increasing evidence for potential cardiovascular risk associated with COXIBs rapidly emerged.

The leukotriene receptor antagonist montelukast and its possible role in the cardiovascular field.

Background: Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are pro-inflammatory mediators of the 5-lipooxygenase (5-LO) pathway, that play an important role in bronchoconstriction, but can also enhance endothelial cell permeability and myocardial contractility, and are involved in many other inflammatory conditions. In the late 1990s, leukotriene receptor antagonists (LTRAs) were introduced in therapy for asthma and later on, approved for the relief of the symptoms of allergic rhinitis, chronic obstructive pulmonary disease, and urticaria. In addition, it has been shown that LTRAs may have a potential role in preventing atherosclerosis progression.

The DRY motif and the four corners of the cubic ternary complex model.

Recent structural data on GPCRs using a variety of spectroscopic approaches suggest that GPCRs adopt a dynamic conformational landscape, with ligands stabilizing subsets of these states to activate one or more downstream signaling effectors. A key outstanding question posed by this emerging dynamic structural model of GPCRs is what states, active, inactive, or intermediate are captured by the numerous crystal structures of GPCRs complexed with a variety of agonists, partial agonists, and antagonists. In the early nineties the discovery of inverse agonists and constitutive activity led to the idea that the active receptor state (R) is an intrinsic property of the receptor itself rather than of the RG complex, eventually leading to the formulation of the cubic ternary complex model (CTC).

Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions.

Impaired thromboxane receptor dimerization reduces signaling efficiency: A potential mechanism for reduced platelet function in vivo.

Thromboxane A is a potent mediator of inflammation and platelet aggregation exerting its effects through the activation of a G protein-coupled receptor (GPCR), termed TP. Although the existence of dimers/oligomers in Class A GPCRs is widely accepted, their functional significance still remains controversial. Recently, we have shown that TPα and TPβ homo-/hetero-dimers interact through an interface of residues in transmembrane domain 1 (TM1) whose disruption impairs dimer formation.

Design and Characterization of Superpotent Bivalent Ligands Targeting Oxytocin Receptor Dimers via a Channel-Like Structure.

Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface.

In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition.

Purpose: Patients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atherosclerosis) that require effective management of chronic pain may take advantage from new non-steroidal anti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activity and reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with a cardioprotective component involving antagonism of thromboxane A2 prostanoid (TP) receptor.

Methods: New compounds were obtained modulating the structure of the most potent coxib, lumiracoxib, to obtain novel multitarget NSAIDs endowed with balanced coxib and TP receptor antagonist properties. Antagonist activity at TP receptor (pA2) was evaluated for all compounds in human platelets and in an heterologous expression system by measuring prevention of aggregation and Gq-dependent production of intracellular inositol phosphate induced by the stable thromboxane A2 (TXA2) agonist U46619.