| 1. |
- Amisten, Stefan, et al.
(author)
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An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans
- 2013
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In: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; 139:3, s. 359-391
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Research review (peer-reviewed)abstract
- G-protein coupled receptors (GPCRs) regulate hormone secretion from islets of Langerhans, and recently developed therapies for type-2 diabetes target islet GLP-1 receptors. However, the total number of GPCRs expressed by human islets, as well as their function and interactions with drugs, is poorly understood. In this review we have constructed an atlas of all GPCRs expressed by human islets: the 'islet GPCRome'. We have used this atlas to describe how islet GPCRs interact with their endogenous ligands, regulate islet hormone secretion, and interact with drugs known to target GPCRs, with a focus on drug/receptor interactions that may affect insulin secretion. The islet GPCRome consists of 293 GPCRs, a majority of which have unknown effects on insulin, glucagon and somatostatin secretion. The islet GPCRs are activated by 271 different endogenous ligands, at least 131 of which are present in islet cells. A large signalling redundancy was also found, with 119 ligands activating more than one islet receptor. Islet GPCRs are also the targets of a large number of clinically used drugs, and based on their coupling characteristics and effects on receptor signalling we identified 107 drugs predicted to stimulate and 184 drugs predicted to inhibit insulin secretion. The islet GPCRome highlights knowledge gaps in the current understanding of islet GPCR function, and identifies GPCR/ligand/drug interactions that might affect insulin secretion, which are important for understanding the metabolic side effects of drugs. This approach may aid in the design of new safer therapeutic agents with fewer detrimental effects on islet hormone secretion. (C) 2013 Elsevier Inc. All rights reserved.
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| 2. |
- Edvinsson, Lars, et al.
(author)
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Basic mechanisms of migraine and its acute treatment.
- 2012
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In: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; 136:3, s. 319-333
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Journal article (peer-reviewed)abstract
- Migraine is a neurovascular disorder characterized by recurrent unilateral headaches accompanied by nausea, vomiting, photophobia and phonophobia. Current theories suggest that the initiation of a migraine attack involves a primary event in the central nervous system (CNS), probably involving a combination of genetic changes in ion channels and environmental changes, which renders the individual more sensitive to environmental factors; this may, in turn, result in a wave of cortical spreading depression (CSD) when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Early PET studies have suggested the involvement of a migraine active region in the brainstem. Migraine headache is associated with trigeminal nerve activation and calcitonin gene-related peptide (CGRP) release from the trigeminovascular system. Administration of triptans (5-HT(1B/1D) receptor agonists) causes the headache to subside and the levels of CGRP to normalize. Moreover, administration of CGRP receptor antagonists aborts the headache. Recent immunohistochemical and pharmacological results suggest that the trigeminal system has receptors for CGRP; further, 5-HT(1B/1D) receptors, which inhibit the action of CGRP in pain transmission when activated, have been demonstrated. This offers an explanation for the treatment response. The present review provides an updated analysis of the basic mechanisms involved in the pathophysiology of migraine and the various pharmacological approaches (including 5-HT(1B/1D) receptor agonists, CGRP receptor antagonists and glutamate receptor antagonists) that have shown efficacy for the acute treatment of this disorder.
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| 3. |
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| 4. |
- Johansson, CH, et al.
(author)
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BRAF inhibitors in cancer therapy
- 2014
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In: Pharmacology & therapeutics. - : Elsevier BV. - 1879-016X .- 0163-7258. ; 142:2, s. 176-182
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Journal article (peer-reviewed)
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| 5. |
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| 6. |
- Xu, Cang-Bao, et al.
(author)
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Cardiovascular risk factors regulate the expression of vascular endothelin receptors.
- 2010
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In: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; Jul 1, s. 148-155
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Journal article (peer-reviewed)abstract
- Cardiovascular disease remains as the leading cause of death in the developed world. However, there is limited knowledge about how cardiovascular risk factors actually cause vascular disease. Traditional cardiovascular risk factors include increased circulating levels of low-density lipoproteins, cigarette smoking and hypertension (both strongly related to arterial wall injury), inflammation and atherosclerosis. The vascular endothelin receptors are a protein family that belongs to the larger family of G-protein coupled receptors. They mediate vascular smooth muscle contraction, proliferation and apoptosis, which are important events in the pathogenesis of atherosclerotic vascular disease. Recent investigations into intracellular signaling mechanisms suggest that the above risk factors increase the expression of endothelin receptors in vascular smooth muscle cells by activating intracellular mitogen-activated protein kinase pathways and downstream transcription factors such as nuclear factor-kappaB. Understanding the mechanisms involved in vascular endothelin receptor upregulation during cardiovascular disease may provide novel therapeutic approaches.
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| 7. |
- Yeganeh, Behzad, et al.
(author)
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Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease
- 2014
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In: Pharmacology and Therapeutics. - : Elsevier. - 0163-7258 .- 1879-016X. ; 143:1, s. 87-110
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Research review (peer-reviewed)abstract
- The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA.Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate.The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering.In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer.
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