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Endocannabinoids and cannabinoid 1 (CB(1)) receptors have been implicated in cardiac dysfunction, inflammation, and cell death associated with various forms of shock, heart failure, and atherosclerosis, in addition to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB(1) receptors in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), increased expression of CB(1), advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT(1)R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB(1) receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB(1) receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT(1)R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB(1) receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.

ABSTRACT Murine macrophages are activated by interferon-γ (IFN-γ) and/or Toll-like receptor (TLR) agonists such as bacterial endotoxin (lipopolysaccharide [LPS]) to express an inflammatory (M1) phenotype characterized by the expression of nitric oxide synthase-2 (iNOS) and inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-12. In contrast, Th2 cytokines IL-4 and IL-13 activate macrophages by inducing the expression of arginase-1 and the anti-inflammatory cytokine IL-10 in an IL-4 receptor-α (IL-4Rα)-dependent manner. Macrophages activated in this way are designated as “alternatively activated” (M2a) macrophages. We have shown previously that adenosine A 2A receptor (A 2A R) agonists act synergistically with TLR2, TLR4, TLR7, and TLR9 agonists to switch macrophages into an “M2-like” phenotype that we have termed “M2d.” Adenosine signaling suppresses the TLR-dependent expression of TNF-α, IL-12, IFN-γ, and several other inflammatory cytokines by macrophages and induces the expression of vascular endothelial growth factor (VEGF) and IL-10. We show here using mice lacking a functional IL-4Rα gene (IL-4Rα −/− mice) that this adenosine-mediated switch does not require IL-4Rα-dependent signaling. M2d macrophages express high levels of VEGF, IL-10, and iNOS, low levels of TNF-α and IL-12, and mildly elevated levels of arginase-1. In contrast, M2d macrophages do not express Ym1, Fizz1 (RELM-α), or CD206 at levels greater than those induced by LPS, and dectin-1 expression is suppressed. The use of these markers in vivo to identify “M2” macrophages thus provides an incomplete picture of macrophage functional status and should be viewed with caution.

Key Points Several lines of evidence highlight the importance of adenosine as a crucial regulatory autocrine and paracrine factor that accumulates in the neoplastic microenvironment. The concentrations of adenosine, which is physiologically present at low levels in the interstitial fluids of unstressed tissues, can rapidly increase in response to pathological conditions, such as hypoxia, ischaemia, inflammation or trauma. After being released from the intracellular space into the extracellular space, adenosine functions as an 'alarm' or danger signal and, through the activation of specific receptors, it generates various cellular responses that aim to restore tissue homeostasis. The persistence of increased adenosine levels beyond the acute injury phase can become detrimental to tissues because it can activate pathways that promote and maintain an unremitting wound-healing process. These pathways lead to fibrotic remodelling or trigger several immune and tissue reactions that promote neoplastic changes. Extracellular adenosine, which is usually present at high concentrations in cancer tissues, is a crucial mediator in the alteration of immune cell functions in cancer. This is possibly because the tightly regulated adenosine receptor pathways of immune cells undergo substantial alterations in tumours, thereby switching the functions of these cells from immune surveillance and host defence to the promotion of cancer cell transformation and growth. Beyond the task of providing an immune-tolerant tumour microenvironment by helping to determine the activity of immune and inflammatory cells, the adenosine system directly regulates cancer growth and metastatic dissemination through specific receptors that are expressed on cancer cells. Although the strategy of counteracting the growth and progression of malignancies through the pharmacological modulation of adenosine receptors and/or metabolism has been shown to work in vitro and in animal models, the translation of these results into clinical practice will require a better understanding of how adenosine helps to determine the tumour milieu and the onset and progression of tumour growth in humans. Several studies have recently highlighted a crucial role for adenosine signalling in regulating various aspects of the cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses adenosine and its effects on immune, endothelial and cancer cells during the course of neoplastic disease. Cancer is a complex disease that is dictated by both cancer cell-intrinsic and cell-extrinsic processes. Adenosine is an ancient extracellular signalling molecule that can regulate almost all aspects of tissue function. As such, several studies have recently highlighted a crucial role for adenosine signalling in regulating the various aspects of cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses the role of adenosine and its receptors in regulating the complex interplay among immune, inflammatory, endothelial and cancer cells during the course of neoplastic disease.

Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1 R and CB2 R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1 R facilitates the development of cardiometabolic disease, whereas activation of CB2 R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ9 -tetrahydrocannabinol (THC), is an agonist of both CB1 R and CB2 R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1 R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.

Key Points Adenosine is a key endogenous molecule that is released from cells and regulates tissue function via activating four G-protein-coupled adenosine receptors: A 1 , A 2A , A 2B and A 3 . These receptors are abundantly expressed on the surface of immune cells as well as on endothelial, smooth muscle, epithelial cells, fibroblasts and cardiomyocytes. Adenosine serves as an endogenous modulator of inflammatory and immune processes. Its release can be triggered from almost all cell types by ischaemia, hypoxia, inflammation and oxidative/nitrosative stress. Adenosine receptors can be targeted for the treatment of various inflammatory diseases. In asthma and chronic obstructive pulmonary disease, A 2A receptor agonists prevent inflammatory cell infiltration into the lung. A 2B receptor antagonists prevent mast-cell degranulation and the overproduction of pro-inflammatory mediators in the lung. In ischaemia, A 2A receptor agonists potently down-regulate inflammatory cell infiltration into tissues, production of deleterious free radicals and pro-inflammatory cytokines. In arthritis, A 2A receptor agonists have a wide range of anti-inflammatory effects in the inflamed joint. A 3 receptor agonists decrease tumour necrosis factor-a production by monocytes and synoviocytes. In sepsis, A 1 receptor agonists can prevent inflammation-mediated organ injury in animal models. A 2A receptor antagonists are beneficial in sepsis by boosting the eradication of bacteria. In inflammatory bowel disease, A 2A receptor agonists attenuate inflammatory cell sequestration in the gut and increase the activity of regulatory T cells thereby ameliorating the course of disease. A 2B receptor antagonists prevent intestinal epithelial-cell-mediated inflammatory events and thereby prevent mucosal inflammation. Topical administration of A 2A receptor agonists increases the rate of wound healing in part by stimulating angiogenesis in the skin. Thus, A 2A receptor agonists are good candidates for the treatment of diabetic foot ulcer. In the clinic, A 2A receptor agonists are being tested as therapeutic agents in wound healing and asthma. A 2B receptor agonists have shown promise in clinical trials in patients with asthma and A 3 receptor agonists improve symptoms in patients with rheumatoid arthritis. Here, Haskó and colleagues discuss how an increased awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases. Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A 1 , A 2A , A 2B and A 3 . Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.

The liver is a crucial metabolic organ that has a key role in maintaining immune and endocrine homeostasis. Accumulating evidence suggests that chronic liver disease might promote the development of various cardiac disorders (such as arrhythmias and cardiomyopathy) and circulatory complications (including systemic, splanchnic and pulmonary complications), which can eventually culminate in clinical conditions ranging from portal and pulmonary hypertension to pulmonary, cardiac and renal failure, ascites and encephalopathy. Liver diseases can affect cardiovascular function during the early stages of disease progression. The development of cardiovascular diseases in patients with chronic liver failure is associated with increased morbidity and mortality, and cardiovascular complications can in turn affect liver function and liver disease progression. Furthermore, numerous infectious, inflammatory, metabolic and genetic diseases, as well as alcohol abuse can also influence both hepatic and cardiovascular outcomes. In this Review, we highlight how chronic liver diseases and associated cardiovascular effects can influence different organ pathologies. Furthermore, we explore the potential roles of inflammation, oxidative stress, vasoactive mediator imbalance, dysregulated endocannabinoid and autonomic nervous systems and endothelial dysfunction in mediating the complex interplay between the liver and the systemic vasculature that results in the development of the extrahepatic complications of chronic liver disease. The roles of ageing, sex, the gut microbiome and organ transplantation in this complex interplay are also discussed.Chronic liver disease can promote the development of numerous cardiac disorders and circulatory complications. In this Review, Pacher and colleagues describe some of the extrahepatic complications of chronic liver disease and their shared pathophysiological mechanisms, including inflammation and oxidative stress.

The role played by adenosine A2B receptors (A2BRs) in the regulation of enteric glial cell (EGC) functions remains unclear. This study was aimed at investigating the involvement of A2BRs in the control of EGC functions in a model of obesity. C57BL/6 mice were fed with standard diet (SD) or high fat diet (HFD) for eight weeks. Colonic tachykininergic contractions were recorded in the presence of BAY60-6583 (A2BRs agonist), MRS1754 (A2BRs antagonist), and the gliotoxin fluorocitrate. Immunofluorescence distribution of HuC/D, S100β, and A2BRs was assessed in whole mount preparations of colonic myenteric plexus. To mimic HFD, EGCs were incubated in vitro with palmitate (PA) and lipopolysaccharide (LPS), in the absence or in the presence of A2BR ligands. Toll-like receptor 4 (TLR4) expression was assessed by Western blot analysis. Interleukin-1β (IL-1β), substance P (SP), and glial cell derived neurotrophic factor (GDNF) release were determined by enzyme-linked immunosorbent assay (ELISA) assays. MRS1754 enhanced electrically evoked tachykininergic contractions of colonic preparations from HFD mice. BAY60-6583 decreased the evoked tachykininergic contractions, with higher efficacy in HFD mice. Such effects were blunted upon incubation with fluorocitrate. In in vitro experiments on EGCs, PA and LPS increased TLR4 expression as well as IL-1β, GDNF, and SP release. Incubation with BAY60-6583 reduced TLR4 expression as well as IL-1β, GDNF, and SP release. Such effects were blunted by MRS1754. The present results suggest that A2BRs, expressed on EGCs, participate in the modulation of enteric inflammation and altered tachykininergic responses associated with obesity, thus representing a potential therapeutic target.

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.

Cannabidiol (CBD) is a non-psychoactive component of marijuana, which has anti-inflammatory effects. It has also been approved by FDA for various orphan diseases for exploratory trials. Herein, we investigated the effects of CBD on liver injury induced by chronic plus binge alcohol feeding in mice. CBD or vehicle was administered daily throughout the alcohol feeding study. At the conclusion of the feeding protocol, serums samples, livers or isolated neutrophils were utilized for molecular biology, biochemistry and pathology analysis. CBD significantly attenuated the alcohol feeding-induced serum transaminase elevations, hepatic inflammation (mRNA expressions of TNFα, MCP1, IL1β, MIP2 and E-Selectin, and neutrophil accumulation), oxidative/nitrative stress (lipid peroxidation, 3-nitrotyrosine formation, and expression of reactive oxygen species generating enzyme NOX2). CBD treatment also attenuated the respiratory burst of neutrophils isolated from chronic plus binge alcohol fed mice or from human blood, and decreased the alcohol-induced increased liver triglyceride and fat droplet accumulation. Furthermore, CBD improved alcohol-induced hepatic metabolic dysregulation and steatosis by restoring changes in hepatic mRNA or protein expression of ACC-1, FASN, PPARα, MCAD, ADIPOR-1, and mCPT-1. Thus, CBD may have therapeutic potential in the treatment of alcoholic liver diseases associated with inflammation, oxidative stress and steatosis, which deserves exploration in human trials.

Key Points Preclinical studies have highlighted a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of diabetes mellitus Adenosine signalling regulates β-cell homeostasis by controlling the proliferation and regeneration of these cells, as well as by promoting their survival in an inflammatory microenvironment Adenosine modulates insulin secretion mainly via A 1 and A 2A adenosine receptors Signalling through the A 2A adenosine receptor increases proliferation and survival of β cells and promotes β-cell regeneration A 2B adenosine receptors modulate glucose and lipid homeostasis and regulate the activity of resident macrophages in adipose tissue in type 2 diabetes mellitus Adenosine contributes to endothelial dysfunction in endothelial cells from the umbilical veins of patients with gestational diabetes mellitus The adenosine–adenosine receptor system has a key role in regulating glucose homeostasis and in the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). In this Review, the authors discuss the role of the adenosinergic system in regulating both the onset and progression of T1DM and T2DM, and the potential of manipulating this system as an approach to manage T1DM, T2DM and their associated complications. Adenosine is a key extracellular signalling molecule that regulates several aspects of tissue function by activating four G-protein-coupled receptors, A 1 , A 2A , A 2B and A 1 adenosine receptors. Accumulating evidence highlights a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Although adenosine signalling is known to affect insulin secretion, new data indicate that adenosine signalling also contributes to the regulation of β-cell homeostasis and activity by controlling the proliferation and regeneration of these cells as well as the survival of β cells in inflammatory microenvironments. Furthermore, adenosine is emerging as a major regulator of insulin responsiveness by controlling insulin signalling in adipose tissue, muscle and liver; adenosine also indirectly mediates effects on inflammatory and/or immune cells in these tissues. This Review critically discusses the role of the adenosine–adenosine receptor system in regulating both the onset and progression of T1DM and T2DM, and the potential of pharmacological manipulation of the adenosinergic system as an approach to manage T1DM, T2DM and their associated complications.