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Jolanta Weresa, Anna Pędzińska-Betiuk, Rafał Kossakowski, Barbara Malinowska
BACKGROUND: Drugs targeting CB1 and CB2 receptors have been suggested to possess therapeutic benefit in cardiovascular disorders associated with elevated sympathetic tone. Limited data suggest cannabinoid ligands interact with postsynaptic β-adrenoceptors. The aim of this study was to examine the effects of CB1 and CB2 antagonists, AM251 and AM630, respectively, at functional cardiac β-adrenoceptors. METHODS: Experiments were carried out in isolated spontaneously beating right atria and paced left atria where inotropic and chronotropic increases were induced by isoprenaline and selective agonists of β1 and β2 -adrenergic receptors...
September 17, 2018: Pharmacological Reports: PR
Shamsh Pervez, Madhuri Verma, Suresh Tiwari, Rajan K Chakrabarty, John G Watson, Judith C Chow, Abhilash S Panicker, Manas Kanti Deb, Mohammad Nahid Siddiqui, Yasmeen Fatima Pervez
Emission factors (EFs) of PM2.5, carbon fractions, major ionic (K+ , Ca2+ , NH4 + , SO4 2- , NO3 - and Cl- ) and elemental (Al, Cr, Cu and Fe) species from combustion of commonly used household solid fuel were determined in 10 different states in India during cooking practices. The study involved sampling during actual household cooking involving use of a variety of fuels including coal balls (CB), fuel wood (FW), dung cakes (DC), crop residues (CR), mixed fuels (MF: dung cakes + fuel woods). Species-wise highest EFs (g·kg-1 ) were: 34...
November 4, 2018: Science of the Total Environment
Silvia L Cruz, Elizabeth Sánchez-Miranda, Jorge Ivan Castillo-Arellano, Rodolfo Daniel Cervantes-Villagrana, Alfredo Ibarra-Sánchez, Claudia González-Espinosa
Activation of high affinity receptor for IgE (FcεRI) by IgE/antigen complexes in mast cells (MCs) leads to the release of preformed pro-inflammatory mediators stored in granules by a Ca2+ -dependent process known as anaphylactic degranulation. Degranulation inhibition has been proposed as a strategy to control allergies and chronic inflammation conditions. Cannabinoids are important inhibitors of inflammatory reactions but their effects on IgE/Ag-mediated MCs responses are not well described. In this study, we analyzed the effect of the endocannabinoid anandamide (AEA), the selective CB2 receptor agonist HU308, and the GPR55 receptor agonist lysophosphatidylinositol (LPI) on FcεRI-induced activation in murine bone marrow-derived mast cells (BMMCs)...
September 19, 2018: International Immunopharmacology
J T Toguri, E Leishman, A M Szczesniak, R B Laprairie, O Oehler, A J Straiker, M E M Kelly, H B Bradshaw
Uveitis is inflammation of the uvea which consists of the iris, ciliary body and the choroid of the eye. Uveitis can lead to impaired vision and is responsible for 10% of all cases of blindness globally. Using an endotoxin-induced uveitis (EIU) rodent model, our previous data implicated the endogenous cannabinoid system (ECS) in the amelioration of many of the components of the inflammatory response. Here, we test the hypothesis that the reduction in inflammatory mediators in the EIU model by the CB2 agonist, HU308, is associated with changes in ECS endogenous ligands as well as related lipids, prostaglandins (PGs), 2-acyl glycerols, and lipoamines...
September 16, 2018: Prostaglandins & Other Lipid Mediators
Ahmed H E Hassan, Min Chang Cho, Hye In Kim, Ji Seul Yang, Kyung Tae Park, Ji Young Hwang, Choon-Gon Jang, Ki Duk Park, Yong Sup Lee
CRA13; a peripheral dual CB1 R/CB2 R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB1 R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB1 R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB1 R and CB2 R activity revealed the alcohol metabolite 8c as a more potent and more effective CB2 R ligand with attenuated CB1 R affinity relative to CRA13...
September 6, 2018: Bioorganic & Medicinal Chemistry
Xiaojing Jia, Robert M Kelly, Yejun Han
( R )-acetoin is a four-carbon platform compound used as the precursor for synthesizing novel optically active materials. Ethylene glycol (EG) is a large-volume two-carbon commodity chemical used as the anti-freezing agent and building-block molecule for various polymers. Currently established microbial fermentation processes for converting monosaccharides to either ( R )-acetoin or EG are plagued by the formation of undesirable by-products. We show here that a cell-free bioreaction scheme can generate enantiomerically pure acetoin and EG as co-products from biomass-derived D-xylose...
December 2018: Metabolic Engineering Communications
Gemma Navarro, Irene Reyes-Resina, Rafael Rivas-Santisteban, Verónica Sánchez de Medina, Paula Morales, Salvatore Casano, Carlos Ferreiro-Vera, Alejandro Lillo, David Aguinaga, Nadine Jagerovic, Xavier Nadal, Rafael Franco
Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal-regulated kinases (ERK1/2), β-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB1 or CB2 , or CB1 -CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured...
September 6, 2018: Biochemical Pharmacology
Sjoerd W Westra, Stijn P G van Vugt, Sümeyye Sezer, Reinder Evertz, Martin E Hemels, Rypko J Beukema, Carlo de Asmundis, Marc A Brouwer, Gian-Battista Chierchia
PURPOSE: Currently, information on the optimal approach of redo procedures for paroxysmal atrial fibrillation (PAF) is limited. Radiofrequency ablation is the preferred technique, with reported success rates of 50-70% at 1-2 years, whereas only few reports exist on redo cryoballoon (CB) ablations. We describe outcomes on a systematic approach of repeat procedures with a second-generation cryoballoon (CB-2) after a successful index CB ablation. METHODS: Cohort study of 40 consecutive patients with recurrent PAF (55% male), median CHA2 DS2 -VASc score 1 (IQR 0-3)...
August 8, 2018: Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing
Paula Morales, Pilar Goya, Nadine Jagerovic
During these last years, the CB2 cannabinoid receptor has emerged as a potential anti-inflammatory target in diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, ischemic stroke, autoimmune diseases, osteoporosis, and cancer. However, the development of clinically useful CB2 agonists reveals to be very challenging. Allosterism and biased-signaling mechanisms at CB2 receptor may offer new avenues for the development of improved CB2 receptor-targeted therapies. Although there has been some exploration of CB1 receptor activation by new CB1 allosteric or biased-signaling ligands, the CB2 receptor is still at initial stages in this domain...
July 26, 2018: Biochemical Pharmacology
Carmen Del Rio, Irene Cantarero, Belén Palomares, María Gómez-Cañas, Javier Fernández-Ruiz, Carolina Pavicic, Adela García-Martín, Maria Luz Bellido, Rafaela Ortega-Castro, Carlos Pérez-Sánchez, Chary López-Pedrera, Giovanni Appendino, Marco A Calzado, Eduardo Muñoz
BACKGROUND AND PURPOSE: The endocannabinoid system and PPARγ are important targets for the development of novel compounds against fibrotic diseases such as systemic sclerosis (SSc), also called scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and study its anti-inflammatory and anti-fibrotic activities. EXPERIMENTAL APPROACH: The binding of VCE-004.3 to CB1 and CB2 receptors and PPARγ and its effect on their functional activities were studied in vitro and in silico...
October 2018: British Journal of Pharmacology
Francesca Gado, Lorenzo Di Cesare Mannelli, Elena Lucarini, Simone Bertini, Elena Cappelli, Maria Digiacomo, Lesley A Stevenson, Marco Macchia, Tiziano Tuccinardi, Carla Ghelardini, Roger G Pertwee, Clementina Manera
The direct activation of cannabinoid receptors (CBRs) results in several beneficial effects; therefore several CBRs ligands have been synthesized and tested in vitro and in vivo. However, none of them reached an advanced phase of clinical development due mainly to side effects on the CNS. Medicinal chemistry approaches are now engaged to develop allosteric modulators that might offer a novel therapeutic approach to achieve potential therapeutic benefits avoiding inherent side effects of orthosteric ligands...
July 23, 2018: Journal of Medicinal Chemistry
Gemma Navarro, Katia Varani, Irene Reyes-Resina, Verónica Sánchez de Medina, Rafael Rivas-Santisteban, Carolina Sánchez-Carnerero Callado, Fabrizio Vincenzi, Salvatore Casano, Carlos Ferreiro-Vera, Enric I Canela, Pier Andrea Borea, Xavier Nadal, Rafael Franco
Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB1 (CB1 R) and CB2 (CB2 R) receptors and the effects of the compound on agonist activation of those receptors and of CB1 -CB2 heteroreceptor complexes. Using [3 H]-CP-55940, CBG competed with low micromolar K i values the binding to CB1 R and CB2 R...
2018: Frontiers in Pharmacology
Hai-Ying Zhang, Hui Shen, Chloe J Jordan, Qing-Rong Liu, Eliot L Gardner, Antonello Bonci, Zheng-Xiong Xi
Cannabinoid CB1 receptors are highly expressed in the brain and functionally modulate presynaptic neurotransmitter release, while cannabinoid CB2 receptors (CB2 Rs) were initially identified in the spleen and regarded as peripheral cannabinoid receptors. Recently, growing evidence indicates the presence of functional CB2 Rs in the brain. However, this finding is disputed because of the specificity of CB2 R antibody signals. We used two strains of currently available partial CB2 -knockout (CB2 -KO) mice as controls, four anti-rat or anti-mouse CB2 R antibodies, and mRNA quantification to further address this issue...
July 2, 2018: Acta Pharmacologica Sinica
Lirit N Franks, Benjamin M Ford, Toshifumi Fujiwara, Haibo Zhao, Paul L Prather
Selective estrogen receptor modulators (SERMs) target estrogen receptors (ERs) to treat breast cancer and osteoporosis. Several SERMs exhibit anti-cancer activity not related to ERs. To discover novel anti-cancer drugs acting via ER-independent mechanisms, derivatives of the SERM tamoxifen, known as the "ridaifen" compounds, have been developed that exhibit reduced or no ER affinity, while maintaining cytotoxicity. Tamoxifen and other SERMs bind to cannabinoid receptors with moderate affinity. Therefore, ER-independent effects of SERMs might be mediated via cannabinoid receptors...
June 12, 2018: Toxicology and Applied Pharmacology
Irene Reyes-Resina, Gemma Navarro, David Aguinaga, Enric I Canela, Clara T Schoeder, Michał Załuski, Katarzyna Kieć-Kononowicz, Carlos A Saura, Christa E Müller, Rafael Franco
GPR18, still considered an orphan receptor, may respond to endocannabinoids, whose canonical receptors are CB1 and CB2 . GPR18 and CB2 receptors share a role in peripheral immune response regulation and are co-expressed in microglia, which are immunocompetent cells in the central nervous system (CNS). We aimed at identifying heteroreceptor complexes formed by GPR18 and CB1 R or CB2 R in resting and activated microglia. Receptor-receptor interaction was assessed using energy-transfer approaches, and receptor function by determining cAMP levels and ERK1/2 phosphorylation in heterologous cells and primary cultures of microglia...
June 2, 2018: Biochemical Pharmacology
Alicia López, Noelia Aparicio, M Ruth Pazos, M Teresa Grande, M Asunción Barreda-Manso, Irene Benito-Cuesta, Carmen Vázquez, Mario Amores, Gonzalo Ruiz-Pérez, Elena García-García, Margaret Beatka, Rosa M Tolón, Bonnie N Dittel, Cecilia J Hillard, Julián Romero
BACKGROUND: Because of their low levels of expression and the inadequacy of current research tools, CB2 cannabinoid receptors (CB2 R) have been difficult to study, particularly in the brain. This receptor is especially relevant in the context of neuroinflammation, so novel tools are needed to unveil its pathophysiological role(s). METHODS: We have generated a transgenic mouse model in which the expression of enhanced green fluorescent protein (EGFP) is under the control of the cnr2 gene promoter through the insertion of an Internal Ribosomal Entry Site followed by the EGFP coding region immediately 3' of the cnr2 gene and crossed these mice with mice expressing five familial Alzheimer's disease (AD) mutations (5xFAD)...
May 24, 2018: Journal of Neuroinflammation
Mohammed I Khan, Anna A Sobocińska, Klaudia K Brodaczewska, Katarzyna Zielniok, Malgorzata Gajewska, Claudine Kieda, Anna M Czarnecka, Cezary Szczylik
BACKGROUND: The anti-tumor properties of cannabinoids have been investigated in many in vitro and in vivo studies. Many of these anti-tumor effects are mediated via cannabinoid receptor types 1 and 2 (CB1 and CB2 ), comprising the endocannabinoid system (ECS). In this study, we investigated the ECS based on CB 1 and CB 2 receptor gene and protein expression in renal cell carcinoma (RCC) cell lines. In view of their further use for potential treatments, we thus investigated the roles of CB1 and CB2 receptors in the anti-proliferative action and signal transduction triggered by synthetic cannabinoid agonists [such as JWH-133 and WIN 55,212-2 (WIN-55)] in RCC cell lines...
May 23, 2018: BMC Cancer
Mohammad Kurd, Vahid Valipour Dehnou, Seyed A Tavakoli, Daniel E Gahreman
AIMS/INTRODUCTION: To investigate the effect of endurance training on hippocampus DJ-1 and cannabinoid receptor type 2 (CB2 ) protein and blood glucose concentration in diabetic rats. MATERIALS AND METHODS: A total of 32 rats were randomly divided into diabetic (D), diabetic and exercise (DE), exercise (E) and control (C) groups. The endurance training was carried out five times per week for 6 weeks. The hippocampus DJ-1 and CB2 were measured using an enzyme-linked immunosorbent assay method...
May 23, 2018: Journal of Diabetes Investigation
Francisco Espejo-Porras, Laura García-Toscano, Carmen Rodríguez-Cueto, Irene Santos-García, Eva de Lago, Javier Fernandez-Ruiz
BACKGROUND AND PURPOSE: Cannabinoid CB2 receptors are up-regulated in reactive microglia in the spinal cord of TDP-43 (A315T) transgenic mice, an experimental model of amyotrophic lateral sclerosis. To determine whether this up-regulation can be exploited pharmacologically, we investigated the effects of different treatments that affect CB2 receptor function. EXPERIMENTAL APPROACH: We treated TDP-43 (A315T) transgenic mice with the non-selective agonist WIN55,212-2, alone or combined with selective CB1 or CB2 antagonists, as well as with the selective CB2 agonist HU-308, and evaluated their effects on the pathological phenotype...
March 25, 2018: British Journal of Pharmacology
Marjolein Soethoudt, Mark W H Hoorens, Ward Doelman, Andrea Martella, Mario van der Stelt, Laura H Heitman
A decade ago, the drug-target residence time model has been (re-)introduced, which describes the importance of binding kinetics of ligands on their protein targets. Since then, it has been applied successfully for multiple protein targets, including GPCRs, for the development of lead compounds with slow dissociation kinetics (i.e. long target residence time) to increase in vivo efficacy or with short residence time to prevent on-target associated side effects. To date, this model has not been applied in the design and pharmacological evaluation of novel selective ligands for the cannabinoid CB2 receptor (CB2 R), a GPCR with therapeutic potential in the treatment of tissue injury and inflammatory diseases...
June 2018: Biochemical Pharmacology
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