The discovery of the endocannabinoid system, comprising the G‐protein coupled cannabinoid 1 and 2 receptors (CB1/2), their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing ...enzymes, has triggered an avalanche of experimental studies implicating the endocannabinoid system in a growing number of physiological/pathological functions. These studies have also suggested that modulating the activity of the endocannabinoid system holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders; obesity/metabolic syndrome; cachexia; chemotherapy‐induced nausea and vomiting; and tissue injury and pain, amongst others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally‐restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain, have introduced unexpected complexities, suggesting that a better understanding of the pathophysiological role of the endocannabinoid system is required to devise clinically successful treatment strategies.
Modulating the endocannabinoid system (ECS) holds therapeutic potential in a broad range of diseases affecting humans. However, the successful translation of preclinical findings to clinical practice depends on finding the right balance between desirable and undesirable consequences of targeting this system, and on precise understanding the pathological role of the ECS in various diseases and of endocannabinoid pharmacology.
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.
Role of Macrophages in the Endocrine System Rehman, Abdul; Pacher, Pál; Haskó, György
Trends in endocrinology and metabolism,
April 2021, 2021-04-00, 20210401, Volume:
32, Issue:
4
Journal Article
Peer reviewed
Macrophages are cells of the innate immune system that play myriad roles in the body. Macrophages are known to reside in endocrine glands, and a body of evidence now suggests that these cells ...interact closely with endocrine cells. Immune–endocrine interactions are important in the development of endocrine glands and their functioning during physiological states, and also become key players in pathophysiological states. Through gene expression profiling, diverse subpopulations of tissue macrophages have been discovered within endocrine organs; this has important implications for disease pathogenesis and potential pharmacotherapy. The molecular basis for the crosstalk between macrophages and endocrine cells is being unraveled, and allows the identification of multiple points for pharmacologic intervention. Macrophages in adipose tissue and pancreatic islets are key players in the process of metaflammation (metabolic inflammation) that underlies the development of insulin resistance, metabolic syndrome, diabetes mellitus, and non-alcoholic fatty liver disease. In the ovary, they play important roles in ovarian folliculogenesis and ovulation, whereas in the male reproductive tract they regulate spermatogenesis through the regulation of steroidogenesis by Leydig cells. We summarize the diverse roles played by macrophages in the endocrine system and identify potential targets for pharmacotherapy in endocrine disorders.
Macrophages play important roles in all endocrine tissues of the body during both physiological and pathological states.In the pituitary, macrophage–endocrine cell interactions determine the functioning of other endocrine tissues through hypothalamus–pituitary–adrenal axis, the hypothalamus–pituitary–gonadal axis, and hypothalamus–pituitary–thyroid axis.Macrophages play important roles in reproductive function and are implicated in ovarian folliculogenesis, ovulation, testosterone production, and spermatogenesis.In obesity, macrophage–adipocyte interactions are implicated in adipose tissue remodeling, insulin resistance, adipokine release, and the induction of metaflammation.Pancreatic macrophage–β cell crosstalk influences the onset and severity of β cell dysfunction and pancreatic islet insufficiency.
Following its release into the extracellular space in response to metabolic disturbances, the endogenous nucleoside adenosine exerts a range of immunomodulatory effects and cells of the mononuclear ...phagocyte system are among its major targets. Adenosine governs mononuclear phagocyte functions via 4 G-protein-coupled cell membrane receptors, which are denoted A(1), A(2A), A(2B), and A(3) receptors. Adenosine promotes osteoclast differentiation via A(1) receptors and alters monocyte to dendritic cell differentiation through A(2B) receptors. Adenosine downregulates classical macrophage activation mainly through A(2A) receptors. In contrast A(2B) receptor activation upregulates alternative macrophage activation. Adenosine promotes angiogenesis, which is mediated by inducing the production of vascular endothelial growth factor by mononuclear phagocytes through A(2A), A(2B), and A(3) receptors. By regulating mononuclear phagocyte function adenosine dictates the course of inflammatory and vascular diseases and cancer.
Section on Oxidative Stress Tissue Injury, Laboratory of Physiologic Studies, National Institutes of Health, National Institute of Alcohol Abuse and Alcoholism, Bethesda, Maryland; Linus Pauling ...Institute, Department of Biochemistry and Biophysics, 2011 Agricultural and Life Sciences, Oregon State University, Corvallis, Oregon; and Department of Intensive Care Medicine, University Hospital, Lausanne, Switzerland
The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.
Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent ...cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar), antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics e.g., rosiglitazone (Avandia). Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities.
Cardiovascular disease is the leading cause of death and disability worldwide, which can be largely attributed to atherosclerosis, a chronic inflammation of the arteries characterized by lesions ...containing immune and smooth muscle cells, lipids and extracellular matrix. In recent years, the lipid endocannabinoid system has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the cardiovascular system. The discovery that Δ‐9‐tetrahydrocannabinol (Δ9‐THC), the main active constituent of marijuana, inhibited atherosclerotic plaque progression via a cannabinoid 2 (CB2) receptor‐dependent anti‐inflammatory mechanism, and that certain natural and synthetic cannabinoid ligands could modulate the myocardial or cerebral ischaemia–reperfusion‐induced tissue damage, have stimulated impetus for a growing number of studies investigating the implication of CB2 receptors in atherosclerosis, restenosis, stroke, myocardial infarction and heart failure. The aim of this review is to update on recent findings and controversies on the role of CB2 receptors in cardiovascular disease. Particular emphasis will be placed on novel insights in the potential cellular targets of CB2 stimulation in cardiovascular system (e.g. endothelial and vascular smooth muscle cells, cardiomyocytes, infiltrating and/or resident monocytes/macrophages and leukocytes, etc.), their interplay and intracellular signalling mechanisms identified, as well as on experimental and clinical studies.
Resolution of inflammation requires proresolving molecular pathways triggered as part of the host response during the inflammatory phase. Adenosine and its receptors, which are collectively called ...the adenosine system, shape inflammatory cell activity during the active phase of inflammation, leading these immune cells toward a functional repolarization, thus contributing to the onset of resolution. Strategies based on the resolution of inflammation have shaped a new area of pharmacology referred to as ‘resolution pharmacology’ and in this regard, the adenosine system represents an interesting target to design novel pharmacological tools to ‘resolve’ the inflammatory process. In this review, we outline the role of the adenosine system in driving the events required for an effective transition from the proinflammatory phase to the onset and establishment of resolution.
Inflammation is a self-limiting protective process regulated by a balanced production of pro-and anti-inflammatory mediators.The proresolving mediators regulate key events of the inflammatory process, limiting immune cell recruitment and inducing their apoptosis, spurring the recruitment of non-phlogistic monocytes, and eliciting the activity of immunosuppressive cells, restoring a homeostatic condition.Adenosine is a pro-resolutive mediator accumulating in the microenvironment of damaged tissue which drives the immune responses toward pro-resolutive cellular events.The adenosine system represents an interesting target to design novel pharmacological tools to ‘resolve’ the inflammatory process.
Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. 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.
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