Pharmacoepidemiology in Pharmacogenetics.
Abstract Epidemiologic methods provide rigorous means by which to study the interplay between genetic factors and drug response. In this chapter, we describe the differences between experimental and observational study designs, and illustrate how to implement the highly efficient case-control study design. We discuss analytic approaches to evaluating gene-drug interactions within typical study designs and review sources of bias that must be assessed and accounted for in epidemiologic analyses. PMID: 29801572 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Ahern TP Tags: Adv Pharmacol Source Type: research

Population Diversity in Pharmacogenetics: A Latin American Perspective.
Abstract Pharmacogenetics/pharmacogenomics (PGx) relies on human genetic diversity. In this review we initially examine the PGx implications of human demographic history and genetic diversity, and highlight results from recent studies on the worldwide distribution of common and rare variants in pharmacogenes. The abundance of rare variants implies that a substantial effort will be required to identify their putative functional effects and to develop reliable algorithms for PGx-guided prescription. Furthermore, variants in all pharmacogenes relevant to a drug treatment must be considered. This implies a shift of th...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Suarez-Kurtz G, Parra EJ Tags: Adv Pharmacol Source Type: research

Pharmacogenetics of Adverse Drug Reactions.
Abstract Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Genetic factors predispose to many ADRs, affecting susceptibility to both type A and type B reactions. The overall contribution of genetics will vary according to drug and ADR, and should be considered when attempting to predict and prevent ADRs. Genetic risk factors are considered in detail for a number of type A ADRs, especially those relating to warfarin and thiopurines, and type B ADRs affecting skin, the liver, and the heart. As the availability of whole genome sequencing increases, it is likely that prospective genotype...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Osanlou O, Pirmohamed M, Daly AK Tags: Adv Pharmacol Source Type: research

Pharmacogenetics: Applications to Pediatric Patients.
Abstract Individual genomic differences may affect drug disposition and effects of many drugs, and identification of biomarkers are crucial to personalize dosage and optimize response. In children, developmental changes associated with growth and maturation translate into different relationships between genotype and phenotype and different responses to treatment compared to adults. This review aims to summarize some developmental aspects of pharmacogenetics, based on practical examples. PMID: 29801575 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Adam de Beaumais T, Jacqz-Aigrain E Tags: Adv Pharmacol Source Type: research

Implementation of Pharmacogenomics in Everyday Clinical Settings.
Abstract Currently, germline pharmacogenomics (PGx) is successfully implemented within certain specialties in clinical care. With the integration of PGx in pharmacotherapy multiple stakeholders are involved, which are identified in this chapter. Clinically relevant pharmacogenes with their related PGx test are discussed, along with diagnostic test criteria to guide clinicians and policy makers in PGx test selection. The chapter further reviews the similarities and the differences between the guidelines of the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium which bot...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Bank PCD, Swen JJ, Guchelaar HJ Tags: Adv Pharmacol Source Type: research

Pharmacogenetics in Pain Treatment.
e; AM Abstract Pain is an unpleasant feeling usually resulting from tissue damage that can persist along weeks, months, or even years after the injury, turning into pathological chronic pain, the leading cause of disability. Currently, pharmacology interventions are usually the first-line therapy but there is a highly variable analgesic drug response. Pharmacogenetics (PGx) offers a means to identify genetic biomarkers that can predict individual analgesic response opening doors to precision medicine. PGx analyze the way in which the presence of variations in the DNA sequence (single-nucleotide polymorphisms, SNPs...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Peiró AM Tags: Adv Pharmacol Source Type: research

The Pharmacogenetics of Immune-Modulating Therapy.
Abstract Immunosuppressive drugs are a prerequisite in organ transplantation to prevent rejection and are also widely used in inflammatory diseases such as inflammatory bowel disease (IBD) or also in some hematologic malignancies-depending on the mode of action. For thiopurine analogs the polymorphic thiopurine S-methyltransferase (TPMT) was early detected to be associated with thiopurine-induced leukopenia; recent studies identified also NUDT15 to be related to this severe side effect. For drugs like methotrexate and mycophenolate mofetil a number of ADME genes like UDP-glucuronosyltransferases (UGTs) and ABC eff...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Cascorbi I Tags: Adv Pharmacol Source Type: research

Pharmacogenetics in Psychiatry.
Abstract Mental illness represents a major health issue both at the individual and at the socioeconomical level. This is partly due to the current suboptimal treatment options: existing psychotropic medications, including antidepressants, antipsychotics, and mood stabilizers, are effective only in a subset of patients or produce partial response and they are often associated with debilitating side effects that discourage adherence. Pharmacogenetics is the study of how genetic information impacts on drug response/side effects with the goal to provide tailored treatments, thereby maximizing efficacy and tolerability...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Corponi F, Fabbri C, Serretti A Tags: Adv Pharmacol Source Type: research

Cytochrome P450 in Pharmacogenetics: An Update.
Abstract Interindividual variability in drug disposition is a major cause of lack of efficacy and adverse effects of drug therapies. The majority of hepatically cleared drugs are metabolized by cytochrome P450 (CYP) enzymes, mainly in families CYP1, CYP2, and CYP3. Genes encoding these enzymes are highly variable with allele distribution showing considerable differences between populations. Genetic variability of especially CYP2C9, CYP2C19, CYP2D6, and CYP3A5 is known to have clear clinical impact on drugs that are metabolized by these enzymes. CYP1A2, CYP2A6, CYP2B6, CYP2C8, and CYP3A4 all show variability that a...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Tornio A, Backman JT Tags: Adv Pharmacol Source Type: research

Epigenetics and MicroRNAs in Pharmacogenetics.
Abstract Germline pharmacogenetics has so far mainly studied common variants in "pharmacogenes," i.e., genes encoding drug metabolizing enzymes and transporters (DMET genes), certain auxiliary and regulatory genes, and drug target genes. Despite remarkable progress in understanding genetically determined differences in pharmacokinetics and pharmacodynamics of drugs, currently known common variants even in important pharmacogenes explain genetic variability only partially. This suggests "missing heritability" that may in part be due to rare variants in the classical pharmacogenes, but current ev...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Zanger UM, Klein K, Kugler N, Petrikat T, Ryu CS Tags: Adv Pharmacol Source Type: research

Pharmacogenetics in Cardiovascular Medicine.
Abstract Considerable interindividual variability in response to cardiovascular pharmacotherapy exists with drug responses varying from being efficacious to inadequate to induce severe adverse events. Fueled by advancements and multidisciplinary collaboration across disciplines such as genetics, bioinformatics, and basic research, the vision of personalized medicine, rather than a one-size-fits-all approach, may be within reach. Pharmacogenetics offers the potential to optimize the benefit-risk profile of drugs by tailoring diagnostic and treatment strategies according to the individual patient. To date, a multitu...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Weeke PE Tags: Adv Pharmacol Source Type: research

Pharmacogenetics of Antidiabetic Drugs.
Abstract Pharmacogenetic studies of antidiabetic drugs have so far focused largely on response to metformin, which is the first-line therapy for treatment of type 2 diabetes (T2D). The first studies of metformin pharmacogenetics were focused on candidate genes that were implicated in metformin pharmacokinetics and transport. Since 2011, genome-wide association studies have been conducted in large cohorts of individuals with T2D identifying genes that are associated with glycemic response to metformin. There have been fewer pharmacogenetic studies of other antidiabetic drugs, and those have been largely limited to ...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Srinivasan S, Yee SW, Giacomini KM Tags: Adv Pharmacol Source Type: research

Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics.
Abstract Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. The issue of the clinical utility of CYP2D6 genotype testing is subject to considerable and ongoing academic and clinical controversy. In this chapter, we outline tamoxifen's clinical pharmacology and give an ov...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Cronin-Fenton DP, Damkier P Tags: Adv Pharmacol Source Type: research

Imaging in Pharmacogenetics.
Abstract An increasing collection of imaging technologies makes it possible to differentiate treatment responders from nonresponders based on genetic variation. This chapter will review some of the imaging technologies currently available in nuclear medicine to visualize drug absorption, distribution, metabolism, and elimination. Some of the commonly used techniques to detect radiation-emitting compounds are the two-dimensional scintigraphy and the three-dimensional single-photon emission computed tomography (SPECT) which both detect photons using a gamma camera, and the three-dimensional positron emission tomogra...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Vendelbo MH, Gormsen LC, Jessen N Tags: Adv Pharmacol Source Type: research

Preface.
ier P PMID: 29801586 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Brøsen K, Damkier P Tags: Adv Pharmacol Source Type: research

Multiple Pathways Mediate MicroRNA Degradation: Focus on the Translin/Trax RNase Complex.
Abstract The discovery of the microRNA system has revolutionized our understanding of translational control. Furthermore, growing appreciation of the pivotal role that de novo translation plays in activity-dependent synaptic plasticity has fueled interest among neuroscientists in deciphering how the microRNA system impacts neuronal signaling and the pathophysiology of neuropsychiatric disorders. Although we have a general understanding of how the microRNA system operates, many key questions remain. In particular, the biosynthesis of microRNAs and their role in translational silencing are fairly well understood. Ho...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Baraban JM, Shah A, Fu X Tags: Adv Pharmacol Source Type: research

Regulation of Mitochondrial, Cellular, and Organismal Functions by TSPO.
Abstract In 1999, the enigma of the 18kDa mitochondrial translocator protein (TSPO), also known as the peripheral-type benzodiazepine receptor, was the seeming disparity of the many functions attributed to TSPO, ranging from the potential of TSPO acting as a housekeeping gene at molecular biological levels to adaptations to stress, and even involvement in higher emotional and cognitive functioning, such as anxiety and depression. In the years since then, knowledge regarding the many functions modulated by TSPO has expanded, and understanding has deepened. In addition, new functions could be firmly associated with ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Gavish M, Veenman L Tags: Adv Pharmacol Source Type: research

Unique Effects of Clozapine: A Pharmacological Perspective.
Abstract Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's uniq...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Khokhar JY, Henricks AM, Sullivan EDK, Green AI Tags: Adv Pharmacol Source Type: research

Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia.
Abstract Neuroinflammation has long been considered a potential contributor to neurodegenerative disorders that result in dementia. Accumulation of abnormal protein aggregates in Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies is associated with the activation of microglia and astrocytes into proinflammatory states, and chronic low-level activation of glial cells likely contributes to the pathological changes observed in these and other neurodegenerative diseases. The 18kDa translocator protein (TSPO) is a key biomarker for measuring inflammation in the brain via positron emission tomog...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Kreisl WC, Henter ID, Innis RB Tags: Adv Pharmacol Source Type: research

RNA-Based Fluorescent Biosensors for Detecting Metabolites in vitro and in Living Cells.
We describe the development of this new technology, its uses, and future directions to facilitate the use of this assay technology in mammalian cells and in high-throughput applications. PMID: 29413520 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Jaffrey SR Tags: Adv Pharmacol Source Type: research

Phosphorylation of the Amino Terminus of the Dopamine Transporter: Regulatory Mechanisms and Implications for Amphetamine Action.
Abstract Amphetamines (AMPHs) are potent psychostimulants that are widely used and abused, with profound medical and societal impact. Their actions at dopaminergic neurons are thought to mediate their therapeutic efficacy as well as their liability for abuse and dependence. AMPHs target the dopamine transporter (DAT), the plasmalemmal membrane protein that mediates the inactivation of released dopamine (DA) through its reuptake. AMPHs act as substrates for DAT and are known to cause mobilization of dopamine (DA) to the cell exterior via DAT-mediated reverse transport (efflux). It has become increasingly evident th...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Karam CS, Javitch JA Tags: Adv Pharmacol Source Type: research

Receptor Binding Assays and Drug Discovery.
Abstract Although Solomon Snyder authored hundreds of research reports and several books covering a broad range of topics in the neurosciences, he is best known by many as the person who developed neurotransmitter receptor radioligand binding assays. By demonstrating the utility of this approach for studying transmitter receptors in brain, Dr. Snyder provided the scientific community with a powerful new tool for identifying and characterizing these sites, for defining their relationship to neurological and psychiatric disorders, and their involvement in mediating the actions of psychotherapeutics. Although it was ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Bylund DB, Enna SJ Tags: Adv Pharmacol Source Type: research

Anti-NMDA Receptor Encephalitis: Clinical Features and Basic Mechanisms.
Abstract In slightly more than 10 years, anti-NMDA receptor (NMDAR) encephalitis has changed from a rare paraneoplastic syndrome to the most common cause of nonviral encephalitis. It presents fulminantly with progressive psychosis, seizures, and autonomic dysfunction, leading to death if untreated. However, rapid recognition and treatment can lead to survival and a return to baseline levels of functioning in many patients. While initially associated with ovarian teratomas, it is now associated with other tumors and can reflect a postviral event. The antibodies to the NMDAR made in this syndrome are pathogenic and ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Lynch DR, Rattelle A, Dong YN, Roslin K, Gleichman AJ, Panzer JA Tags: Adv Pharmacol Source Type: research

Mu Opioid Pharmacology: 40 Years to the Promised Land.
Abstract Opioids continue to play a major role in medicine, but not without problems. Side effects limit their utility medically, while the potential of addiction has had a major societal impact. Pharmacologists have been trying to develop opioids lacking side effects since the first derivative, heroin, was synthesized in the 1870s. The identification of opioid receptors about 40 years ago opened up new insights into our understanding of opioid action, fueled by the molecular biology revolution of the 1980s and 1990s. A major result of these studies was the discovery that the mu opioid receptor gene, Oprm1, underg...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Pasternak GW Tags: Adv Pharmacol Source Type: research

Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer's Disease Through Prion Protein and mGluR5.
Abstract Alzheimer's disease (AD) represents an impending global health crisis, yet the complexity of AD pathophysiology has so far precluded the development of any interventions to successfully slow or halt AD progression. It is clear that accumulation of Amyloid-beta (Aβ) peptide triggers progressive synapse loss to cause AD symptoms. Once initiated by Aβ, disease progression is complicated and accelerated by inflammation and by tau pathology. The recognition that Aβ peptide assumes multiple distinct states and that soluble oligomeric species (Aβo) are critical for synaptic damage is central ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Brody AH, Strittmatter SM Tags: Adv Pharmacol Source Type: research

The Neurobiology of d-Serine Signaling.
Abstract d-Serine is a physiological coagonist of NMDA receptors involved in synaptic plasticity, neurodevelopment, and neurodegeneration. d-Serine is synthesized by the enzyme serine racemase, which converts l- to d-serine. Recent studies indicate that the supply of l-serine by astroglia fuels the neuronal synthesis of d-serine. This pathway, named the serine shuttle, highlights the importance of the glia-neuron metabolic crosstalk for regulating NMDA receptor activity. Dysfunction of different components of the serine shuttle pathway leads to neurodevelopmental defects, neurodegeneration, and may be involved in ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Wolosker H Tags: Adv Pharmacol Source Type: research

The Role of Serine Racemase in the Pathophysiology of Brain Disorders.
Abstract The N-methyl-d-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or d-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes d-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of d-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR-/-), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine de...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Coyle JT, Balu DT Tags: Adv Pharmacol Source Type: research

Nitric Oxide Signaling in Neurodegeneration and Cell Death.
Abstract In this tribute to Solomon H. Snyder (Sol) we discuss the mechanisms by which nitric oxide (NO) kills neurons. We provide a historical perspective regarding the discovery that glutamate excitotoxicity is mediated by NO. It also contains a discussion of the discovery that neuronal nitric oxide synthase (nNOS) catalytic activity accounts for NADPH diaphorase activity and its localization in the central nervous system. NADPH diaphorase/nNOS neurons are unique in that they are resistant to toxic effects of excess glutamate and that they are resistant to neurodegeneration in a variety of neurodegenerative dise...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Dawson TM, Dawson VL Tags: Adv Pharmacol Source Type: research

Carboxypeptidase E and the Identification of Novel Neuropeptides as Potential Therapeutic Targets.
Abstract Peptides and small molecules that bind to peptide receptors are important classes of drugs that are used for a wide variety of different applications. The search for novel neuropeptides traditionally involved a time-consuming approach to purify each peptide to homogeneity and determine its amino acid sequence. The discovery in the 1980s of enkephalin convertase/carboxypeptidase E (CPE), and the observation that this enzyme was involved in the production of nearly every known neuropeptide led to the idea for a one-step affinity purification of CPE substrates. This approach was successfully used to isolate ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Fricker LD Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 29413530 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Pasternak GW, Coyle JT, Enna SJ Tags: Adv Pharmacol Source Type: research

Foreword.
PMID: 29413531 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Iversen L Tags: Adv Pharmacol Source Type: research

The Dynamic Actin Cytoskeleton in Smooth Muscle.
Abstract Smooth muscle contraction requires both myosin activation and actin cytoskeletal remodeling. Actin cytoskeletal reorganization facilitates smooth muscle contraction by promoting force transmission between the contractile unit and the extracellular matrix (ECM), and by enhancing intercellular mechanical transduction. Myosin may be viewed to serve as an "engine" for smooth muscle contraction whereas the actin cytoskeleton may function as a "transmission system" in smooth muscle. The actin cytoskeleton in smooth muscle also undergoes restructuring upon activation with growth factors or th...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Tang DD Tags: Adv Pharmacol Source Type: research

Integrins in Vascular Development and Pathology.
Abstract During vascular development, endothelial cells (ECs) and neighboring stromal cells interact and communicate through autocrine and paracrine signaling mechanisms involving extracellular matrix (ECM) proteins and their cell surface integrin adhesion receptors. Integrin-mediated adhesion and signaling pathways are crucial for normal vascular development and physiology, and alterations in integrin expression and/or function drive several vascular-related pathologies including thrombosis, autoimmune disorders, and cancer. The purpose of this chapter is to discuss integrin adhesion and signaling pathways import...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Guerrero PA, McCarty JH Tags: Adv Pharmacol Source Type: research

Mechanotransduction in Blood and Lymphatic Vascular Development and Disease.
Abstract The blood and lymphatic vasculatures are hierarchical networks of vessels, which constantly transport fluids and, therefore, are exposed to a variety of mechanical forces. Considering the role of mechanotransduction is key for fully understanding how these vascular systems develop, function, and how vascular pathologies evolve. During embryonic development, for example, initiation of blood flow is essential for early vascular remodeling, and increased interstitial fluid pressure as well as initiation of lymph flow is needed for proper development and maturation of the lymphatic vasculature. In this review...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Urner S, Kelly-Goss M, Peirce SM, Lammert E Tags: Adv Pharmacol Source Type: research

Extracellular Matrix Macromolecules as Potential Targets of Cardiovascular Pharmacotherapy.
;inen H Abstract The extracellular matrix (ECM) forms the structural basis for the functional properties of different organs and tissues including the vasculature. Consequently, any alteration in the ECM may significantly influence the function of organs and tissues in question. This is also true for the cardiovascular system and its pathologies. Thus, therapies specifically targeting the ECM are likely very potent in the treatment of various diseases. Unfortunately, so far there are no therapies in clinical use primarily targeting the ECM. Nevertheless, most cardiovascular drugs are known to modulate the ECM and ...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Sainio A, Järveläinen H Tags: Adv Pharmacol Source Type: research

Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease.
Abstract Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM), and leukocyt...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Wang X, Khalil RA Tags: Adv Pharmacol Source Type: research

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction.
Abstract Ischemia/reperfusion (I/R) induces leukocyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated dilatory responses (EDD) in upstream arterioles. A large body of evidence has implicated reactive oxygen species, adherent leukocytes, and proteases in postischemic EDD dysfunction in conduit arteries. However, arterioles represent the major site for the regulation of vascular resistance but have received less attention with regard to the mechanisms underlying their reduced responsiveness to EDD stimuli in I/R. Even though leukocytes do not rol...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Korthuis RJ Tags: Adv Pharmacol Source Type: research

The Role of Age-Related Intimal Remodeling and Stiffening in Atherosclerosis.
Abstract Age-related vascular stiffening is closely associated with cardiovascular risk. The clinical measure of arterial stiffness, pulse wave velocity, reflects bulk structural changes in the media observed with age, but does not reflect intimal remodeling that also drives atherosclerosis. Endothelial barrier integrity is disrupted during early atherogenesis and is regulated by the mechanics and composition of the underlying intima, which undergoes significant atherogenic remodeling in response to age and hemodynamics. Here, we first review the best characterized of these changes, including physiological intimal...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: VanderBurgh JA, Reinhart-King CA Tags: Adv Pharmacol Source Type: research

Smoothelins and the Control of Muscle Contractility.
Abstract Smooth muscle cells display distinctive expression and organization of contractile filament proteins, which reflect a unique method of contractile regulation. As the focus of this review, the smoothelin and smoothelin-like family members represent a family of poorly understood muscle proteins that appear to act as structural components of the contractile apparatus. The protein family is characterized by the presence a single C-terminal type-2 calponin homology (CH) domain. Often used as the preferred marker of differentiated contractile smooth muscle cells, smoothelin A and B (SMTN-A and SMTN-B) may influ...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Murali M, MacDonald JA Tags: Adv Pharmacol Source Type: research

The Cytoskeletal Network Regulates Expression of the Profibrotic Genes PAI-1 and CTGF in Vascular Smooth Muscle Cells.
Abstract Vascular smooth muscle cells (VSMCs) are subject to changing hemodynamic stimuli that alter cytoskeletal dynamics, cellular architecture, and structure-associated signal transduction. Tensional stress, force application, and structural perturbations are sensed by VSMCs and impact the physiological as well as pathophysiological responses of the vasculature. Microtubule-targeting drugs provide useful tools to analyze cytoskeletal-associated signaling pathways and their linkages to pathological outcomes. Architecture-based controls on a subset of profibrotic genes commonly expressed in vascular disease are h...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Samarakoon R, Higgins PJ Tags: Adv Pharmacol Source Type: research

Basic Components of Vascular Connective Tissue and Extracellular Matrix.
Abstract Though the composition of the three layers constituting the blood vessel wall varies among the different types of blood vessels, and some layers may even be missing in capillaries, certain basic components, and properties are shared by all blood vessels, though each histologically distinct layer contains a unique complement of extracellular components, growth factors and cytokines, and cell types as well. The structure and composition of vessel layers informs and is informed by the function of the particular blood vessel. The adaptation of the composition and the resulting function of the extracellular ma...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Halper J Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 29310806 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Khalil RA Tags: Adv Pharmacol Source Type: research

Endocannabinoid Analytical Methodologies: Techniques That Drive Discoveries That Drive Techniques.
Abstract Identification of the two major endogenous cannabinoid ligands, known as endocannabinoids, N-arachidonoyl-ethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2-AG), opened the way for the identification and isolation of other lipid congeners, all derivatives of fatty acids and related to the Endocannabinoid System. The nomenclature of this anandamide-type class of lipids is evolving as new species are discovered all the time. However, they each fall under the larger umbrella of lipids that are a conjugation of a fatty acid with an amine through and amide bond, which we will refer to as lipoamines....
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Piscitelli F, Bradshaw HB Tags: Adv Pharmacol Source Type: research

Spicing Up Pharmacology: A Review of Synthetic Cannabinoids From Structure to Adverse Events.
Abstract Recreational use of synthetic cannabinoids (SCB), a class of novel psychoactive substances is an increasing public health problem specifically in Western societies, with teenagers, young adults, and the prison population being the most affected. Some of these SCB are analogs of tetrahydrocannabinol, aminoalkylindoles, and other phytocannabinoid analogs have been detected in herbal preparations generically called "Spice." Spice, "K2" or "fake cannabis" is a general term used for variable herbal mixtures of unknown ingredients or chemical composition. SCB are highly potent CB1 ...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Davidson C, Opacka-Juffry J, Arevalo-Martin A, Garcia-Ovejero D, Molina-Holgado E, Molina-Holgado F Tags: Adv Pharmacol Source Type: research

CB1 and CB2 Receptor Pharmacology.
Abstract The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects....
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Howlett AC, Abood ME Tags: Adv Pharmacol Source Type: research

Functional Selectivity at Cannabinoid Receptors.
Abstract It is now clear that, in contrast to traditional descriptions of G protein-coupled receptor signaling, agonists can activate or inhibit characteristic patterns of downstream effector pathways depending on their structures and the conformational changes induced in the receptor. This is referred to as functional selectivity (also known as agonist-directed trafficking, ligand-induced differential signaling, or biased agonism). It is important because even small structural differences can result in significant variations in overall agonist effects (wanted and unwanted) depending on which postreceptor signalin...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Priestley R, Glass M, Kendall D Tags: Adv Pharmacol Source Type: research

Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors.
Abstract Of the druggable group of G protein-coupled receptors in the human genome, a number remain which have yet to be paired with an endogenous ligand-orphan GPCRs. Among these 100 or so entities, 3 have been linked to the cannabinoid system. GPR18, GPR55, and GPR119 exhibit limited sequence homology with the established CB1 and CB2 cannabinoid receptors. However, the pharmacology of these orphan receptors displays overlap with CB1 and CB2 receptors, particularly for GPR18 and GPR55. The linking of GPR119 to the cannabinoid receptors is less convincing and emanates from structural similarities of endogenous lig...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Irving A, Abdulrazzaq G, Chan SLF, Penman J, Harvey J, Alexander SPH Tags: Adv Pharmacol Source Type: research

Actions and Regulation of Ionotropic Cannabinoid Receptors.
Abstract Almost three decades have passed since the identification of the two specific metabotropic receptors mediating cannabinoid pharmacology. Thereafter, many cannabinoid effects, both at central and peripheral levels, have been well documented and characterized. However, numerous evidences demonstrated that these pharmacological actions could not be attributable solely to the activation of CB1 and CB2 receptors since several important cannabimimetic actions have been found in biological systems lacking CB1 or CB2 gene such as in specific cell lines or transgenic mice. It is now well accepted that, beyond thei...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: De Petrocellis L, Nabissi M, Santoni G, Ligresti A Tags: Adv Pharmacol Source Type: research

The Role of Nuclear Hormone Receptors in Cannabinoid Function.
Abstract Since the early 2000s, evidence has been accumulating that most cannabinoid compounds interact with the nuclear hormone family peroxisome proliferator-activated receptors (PPARs). This can be through direct binding of these compounds to PPARs, metabolism of cannabinoid to other PPAR-activating chemicals, or indirect activation of PPAR through cell signaling pathways. Delivery of cannabinoids to the nucleus may be facilitated by fatty acid-binding proteins and carrier proteins. All PPAR isoforms appear to be activated by cannabinoids, but the majority of evidence is for PPARα and γ. To date, li...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Pistis M, O'Sullivan SE Tags: Adv Pharmacol Source Type: research

Endocannabinoid Turnover.
We describe the enzymes associated with these events and their characterization. We identify the inhibitor profile for these enzymes and the status of therapeutic exploitation, which to date has been limited to clinical trials for fatty acid amide hydrolase inhibitors. To bring the review to a close, we consider whether point block of a single enzyme is likely to be the most successful approach for therapeutic exploitation of the endocannabinoid system. PMID: 28826539 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Fowler CJ, Doherty P, Alexander SPH Tags: Adv Pharmacol Source Type: research