Cannabinoid CB2 Receptor Potentiates Obesity-Associated Inflammation, Insulin Resistance and Hepatic Steatosis

BACKGROUND: Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver. METHODOLOGY: Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 -/-). PRINCIPAL FINDINGS: In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 -/- mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 -/- mice. CONCLUSION/SIGNIFICANCE: These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorder

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Etude de l'interaction entre le récepteur nicotinique de l'acetylcholine et la toxine alpha de Naja nigricollis par ingénierie chimique du ligand

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

How do short neurotoxins bind to a muscular-type nicotinic acetylcholine receptor?

International audienceWe investigated the interacting surface between a short curarimimetic toxin and a muscular-type nicotinic acetylcholine receptor, looking for the ability of various biotinylated Naja nigricollis ␣-neurotoxin analogues to bind simultaneously the receptor and streptavidin. All these derivatives, modified at positions 10 (loop I), 27, 30, 33, 35 (loop II), 46, and 47 (loop III) or the N-terminal (erabutoxin numbering), still shared high affinity for the receptor, and in the absence of receptor they all bound soluble streptavidin. However, the proportion of the toxin-receptor complex that bound to streptavidincoated beads, varied both with the location of the modification and with the length of the linker between biotin and the toxin. In the receptor-toxin complex, the concave side of loops II and III was not accessible to streptavidin, unlike the N terminus of the toxin and, to a certain extent, loop I. On the convex face, loop III was the most accessible, whereas the tip of loop II, especially Arg-30, seemed to be closer to the receptor. The present data demonstrate that short toxins neither penetrate deeply into a crevice as proposed earlier nor lie parallel to the receptor extracellular wall. These data also suggest that they may not lie strictly perpendicular to the cylindrical wall of the receptor. These results fit nicely with three-dimensional models of interaction between long neurotoxins and their receptors and support the idea that short and long curarimimetic toxins share a similar overall topology of interaction when bound to nicotinic receptors

A Cysteine-Linkable, Short Cleavable Photoprobe with Dual Functionality To Explore Protein−Protein Interfaces

International audienc

Autophagy: A Multifaceted Partner in Liver Fibrosis

Liver fibrosis is a common wound healing response to chronic liver injury of all causes, and its end-stage cirrhosis is responsible for high morbidity and mortality worldwide. Fibrosis results from prolonged parenchymal cell apoptosis and necrosis associated with an inflammatory reaction that leads to recruitment of immune cells, activation and accumulation of fibrogenic cells, and extracellular matrix accumulation. The fibrogenic process is driven by hepatic myofibroblasts, that mainly derive from hepatic stellate cells undergoing a transdifferentiation from a quiescent, lipid-rich into a fibrogenic myofibroblastic phenotype, in response to paracrine/autocrine signals produced by neighbouring inflammatory and parenchymal cells. Autophagy is an important regulator of liver homeostasis under physiological and pathological conditions. This review focuses on recent findings showing that autophagy is a novel, but complex, regulatory pathway in liver fibrosis, with profibrogenic effects relying on its direct contribution to the process of hepatic stellate cell activation, but with antifibrogenic properties via indirect hepatoprotective and anti-inflammatory properties. Therefore, cell-specific delivery of drugs that exploit autophagic pathways is a prerequisite to further consider autophagy as a potential target for antifibrotic therapy

: Cannabinoïdes et hépatopathies chroniques

(1er paragraphe) Le cannabis (marijuana, Cannabis sativa) est utilisé depuis l'antiquité comme substance psychoactive récréative, mais également en médecine traditionnelle pour ses effets orexigènes et antalgiques (1, 2). Le principal composé actif du cannabis, le Δ9–tetrahydrocannabinol (THC) n'a cependant a été isolé qu'en 1964. La compréhension des mécanismes d'action des phytocannabinoïdes a connu un essor considérable depuis les années quatre-vingt dix, avec le clonage de deux récepteurs spécifiques, CB1 et CB2, suivi de l'identification de ligands endogènes de ces récepteurs, les endocannabinoïdes. Ce système a depuis été progressivement impliqué dans de très nombreux processus physiopathologiques, ouvrant ainsi de nouvelles perspectives thérapeutiques (1, 2). L'hépatologie n'est pas en reste, avec en l'espace de cinq ans, l'identification d'un rôle clef des cannabinoïdes dans la physiopathologie de l'hypertension portale, de la stéatose et de la fibrogenèse hépatique (3)