Probing non-peptide agonists binding at the human nociceptin/orphanin FQ receptor: a molecular modelling study.

The N/OFQ-NOP receptor is a fascinating peptidergic system with the potential to be exploited for the development of analgesic drugs devoid of side effects associated with classical opioid signalling modulation. To date, up to four X-ray and cryo-EM structures of the NOP receptor in complex with the endogenous peptide agonist N/OFQ and three small molecule antagonists have been solved and released. Despite the available structural information, the details of selective small molecule agonist binding to the NOP receptor in the active state remain elusive.

Pregnancy Entails a Metabolic Rewiring of Maternal Circulating Neutrophils.

Immunometabolism is an emerging growing field that focuses on the role of cellular metabolism in the regulation of immune cell function and fate. Thus, proliferation, differentiation, activation, and function of immune cell populations are modulated by reprogramming their fueling and metabolic pathways. Pregnancy entails a fine immune and metabolic regulation of the maternal-fetal interaction to assist the energetic demands of the fetus where trophoblast cells have a central role.

Paracetamol Use and COVID-19 Clinical Outcomes: A Meta-Analysis.

Background: During the COVID-19 pandemic, paracetamol was widely recommended in different clinical settings, and sometimes advised over non-steroidal anti-inflammatory drugs (NSAIDs). These recommendations sparked a strong debate, with reports suggesting either potential benefits or harms for the individuals infected with SARS-CoV-2. As no systematic review is available, we performed a meta-analysis to estimate the impact of paracetamol on COVID-19 clinical outcomes compared to a placebo, no use, or NSAIDs.

Efficacy of Thiocolchicoside for Musculoskeletal Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

: Despite the fact that thiocolchicoside has been widely used in the treatment of musculoskeletal pain, its efficacy has never been systematically evaluated. We carried out a systematic review and meta-analysis of randomized clinical trials (RCTs) to appraise the existing evidence on the efficacy of thiocolchicoside for musculoskeletal pain management. : The literature search was performed on multiple databases, extracting reports of RCTs evaluating the efficacy of thiocolchicoside compared to placebo or no exposure.

Immunogenicity and Safety of Chikungunya Vaccines: A Systematic Review and Meta-Analysis.

Several vaccines against chikungunya fever have been developed and tested, and one has been recently licensed. We performed a meta-analysis to estimate the immunogenicity and safety of all chikungunya vaccines that have been progressed to clinical trial evaluation (VLA1553; mRNA-1388/VAL-181388; PXVX0317/VRC-CHKVLP059-00-VP; ChAdOx1 Chik; MV-CHIK). We included trials retrieved from MedLine, Scopus, and ClinicalTrials.

Effects of Stress Exposure to Pain Perception in Pre-Clinical Studies: Focus on the Nociceptin/Orphanin FQ-NOP Receptor System.

Exposure to physical and psychological stress modulates pain transmission in a dual manner. Stress-induced analgesia (SIA) refers to the reduction in pain sensitivity that can occur in response to acute stress. On the contrary, chronic stress exposure may lead to a phenomenon named stress-induced hyperalgesia (SIH).

A Multi-Angle Approach to Predict Peptide-GPCR Complexes: The N/OFQ-NOP System as a Successful AlphaFold Application Case Study.

With nearly 700 structures solved and a growing number of customized structure prediction algorithms being developed at a fast pace, G protein-coupled receptors (GPCRs) are an optimal test case for validating new approaches for the prediction of receptor active state and ligand bioactive conformation complexes. In this study, we leveraged the availability of hundreds of peptide GPCRs in the active state and both classical homology and artificial intelligence (AI) based protein modeling combined with docking and AI-based peptide structure prediction approaches to predict the nociceptin/orphanin FQ-NOP receptor active state complex (N/OFQ-NOPa). The generated hypotheses were validated via the design, synthesis, and pharmacological characterization of novel linear N/OFQ(1-13)-NH analogues, leading to the discovery of a novel antagonist (; p = 6.

In vitro pharmacological characterization of growth hormone secretagogue receptor ligands using the dynamic mass redistribution and calcium mobilization assays.

Ghrelin modulates several biological functions via selective activation of the growth hormone secretagogue receptor (GHSR). GHSR agonists may be useful for the treatment of anorexia and cachexia, while antagonists and inverse agonists may represent new drugs for the treatment of metabolic and substance use disorders. Thus, the identification and pharmacodynamic characterization of new GHSR ligands is of high interest.

Immunogenicity, Safety and Efficacy of the Dengue Vaccine TAK-003: A Meta-Analysis.

The TAK-003 dengue vaccine was licensed in Europe in December 2022, and the official recommendations from most EU countries are still under formulation. To support policymakers, we performed a meta-analysis to quantify TAK-003's immunogenicity, efficacy and safety among seronegative and seropositive populations after the administration of one or two vaccine doses. We included trials retrieved from MEDLINE, Scopus and ClinicalTrials.

The tiny giant of the sea, Ostreococcus's unique adaptations.

Ostreococcus spp. are unicellular organisms with one of the simplest cellular organizations. The sequencing of the genomes of different Ostreococcus species has reinforced this status since Ostreococcus tauri has one most compact nuclear genomes among eukaryotic organisms.

Activation of NOP receptor increases vulnerability to stress: role of glucocorticoids and CRF signaling.

Rationale: Recently, we demonstrated that the activation of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) signaling facilitates depressive-like behaviors. Additionally, literature findings support the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal (HPA) axis.

Objectives: Considering that dysfunctional HPA axis is strictly related to stress-induced psychopathologies, we aimed to study the role of the HPA axis in the pro-depressant effects of NOP agonists.

Monocyte immunometabolic reprogramming in human pregnancy: contribution of trophoblast cells.

Immunometabolism research is uncovering the relationship between metabolic features and immune cell functions in physiological and pathological conditions. Normal pregnancy entails a fine immune and metabolic regulation of the maternal-fetal interaction to assist the energetic demands of the fetus with immune homeostasis maintenance. Here, we determined the immunometabolic status of monocytes of pregnant women compared with nonpregnant controls and its impact on monocyte anti-inflammatory functions such as efferocytosis.

pharmacological characterization of standard and new lysophosphatidic acid receptor antagonists using dynamic mass redistribution assay.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that acts as an agonist of six G protein-coupled receptors named LPA receptors (LPA). LPA elicits diverse intracellular events and modulates several biological functions, including cell proliferation, migration, and invasion. Overactivation of the LPA-LPA receptor system is reported to be involved in several pathologies, including cancer, neuropathic pain, fibrotic diseases, atherosclerosis, and type 2 diabetes.

Extracellular Vesicles of Disrupt Trophoblast Cell Interaction with Vascular and Immune Cells in an In Vitro Model of Early Placentation.

Extracellular vesicles released by the primary pathogen of periodontal disease (), referred to as outer membrane vesicles (OMVs), have been associated with the pathogenesis of systemic diseases like cardiovascular disease, rheumatoid arthritis, and Alzheimer's disease. A pathogenic role for by disrupting placental homeostasis was proposed in the association between periodontal disease and adverse pregnancy outcomes. On the basis that trophoblast-derived factors modulate endothelial and immune cell profiles in normal pregnancy and the scarce presence of in placenta, we hypothesized that OMVs from affect trophoblast cell phenotype, impairing trophoblast-endothelium and trophoblast-neutrophil interactions.

Porphyromonas gingivalis outer membrane vesicles shape trophoblast cell metabolism impairing functions associated to adverse pregnancy outcome.

Periodontitis is proposed as a risk factor for preterm delivery, fetal growth restriction, and preeclampsia with severe consequences for maternal and neonatal health, but the biological mechanisms involved are elusive. Porphyromonas gingivalis gain access to the placental bed and impair trophoblast cell function, as assessed in murine and human pregnancy, suggesting a pathogenic role in adverse pregnancy and neonatal outcomes. P.

Nociceptin/Orphanin FQ receptor expression in primary human umbilical vein endothelial cells is not regulated by exposure to breast cancer cell media or angiogenic stimuli.

Background: Opioid receptors are naloxone-sensitive (MOP [mu: μ], DOP [delta: δ], and KOP [kappa: κ]) and naloxone-insensitive Nociceptin/Orphanin FQ (N/OFQ) peptide receptor (NOP). Clinically, most opioid analgesics target MOP. Angiogenesis is the formation of new blood vessels and involves endothelial cell activation, proliferation, and migration.

Presence of SARS-CoV-2 in urban effluents in south-east Buenos Aires, Argentina, May 2020 to March 2022.

Objectives: To implement and evaluate the use of wastewater sampling for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in two coastal districts of Buenos Aires Province, Argentina.

Methods: In General Pueyrredon district, 400 mL of wastewater samples were taken with an automatic sampler for 24 hours, while in Pinamar district, 20 L in total (2.2 L at 20-minute intervals) were taken.

Preclinical effects of cannabidiol in an experimental model of migraine.

Migraine is a disabling disorder characterized by recurrent headaches, accompanied by abnormal sensory sensitivity and anxiety. Despite extensive historical use of cannabis in headache disorders, there is limited research on the nonpsychoactive cannabidiol (CBD) for migraine and there is no scientific evidence to prove that CBD is an effective treatment. The effects of CBD are examined here using a calcitonin gene-related peptide (CGRP)-induced migraine model that provides measures of cephalic allodynia, spontaneous pain, altered light sensitivity (photophobia), and anxiety-like behavior in C57BL/6J mice.

In vitro sepsis up-regulates Nociceptin/Orphanin FQ receptor expression and function on human T- but not B-cells.

Background And Purpose: In animal models of sepsis, increased activation of the Nociceptin/Orphanin FQ (N/OFQ) receptor NOP is associated with mortality and NOP antagonists improved survival. We have explored the role of the N/OFQ-NOP system in freshly isolated volunteer human B- and T-cells incubated with lipopolysaccharide (LPS) and peptidoglycan G (PepG) as a model of in vitro sepsis.

Experimental Approach: B- and T-cell NOP expression was measured using the NOP fluorescent probe N/OFQ , N/OFQ content was measured using immunofluorescence, N/OFQ release was tracked using a CHO biosensor assay and NOP function was measured using transwell migration and cytokine/chemokine release using a 25-plex assay format.

Functional selectivity of EM-2 analogs at the mu-opioid receptor.

The mu opioid receptor agonists are the most efficacious pain controlling agents but their use is accompanied by severe side effects. More recent developments indicate that some ligands can differentially activate receptor downstream pathways, possibly allowing for dissociation of analgesia mediated through the G protein from the opioid-related side effects mediated by β-arrestin pathway. In an effort to identify such biased ligands, here we present a series of thirteen endomorphin-2 (EM-2) analogs with modifications in positions 1, 2, and/or 3.

VPAC1 and VPAC2 receptor deficiencies negatively influence pregnancy outcome through distinct and overlapping modulations of immune, trophoblast and vascular functions.

Pregnancy outcome relies on the maintenance of immune and metabolic homeostasis at the maternal fetal interface. Maternal and perinatal morbidity and mortality is associated with impaired placental development. Multiple regulatory effects of the endogenous-produced vasoactive intestinal peptide (VIP) on vascular, metabolic and immune functions at the maternal-fetal interface have been reported.