| 1. |
- ARNER, ESJ, et al.
(författare)
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Mammalian deoxyribonucleoside kinases
- 1995
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Ingår i: Pharmacology & therapeutics. - : Elsevier BV. - 0163-7258. ; 67:2, s. 155-186
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Tidskriftsartikel (refereegranskat)
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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Amisten, Stefan, et al.
(författare)
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An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans
- 2013
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Ingår i: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; 139:3, s. 359-391
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Forskningsöversikt (refereegranskat)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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| 6. |
- Amisten, Stefan, et al.
(författare)
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An atlas of G-protein coupled receptor expression and function in human subcutaneous adipose tissue.
- 2015
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Ingår i: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; 146:Sep 19, s. 61-93
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Forskningsöversikt (refereegranskat)abstract
- G-protein coupled receptors (GPCRs) are involved in the regulation of adipose tissue function, but the total number of GPCRs expressed by human subcutaneous adipose tissue, as well as their function and interactions with drugs, is poorly understood. We have constructed an atlas of all GPCRs expressed by human subcutaneous adipose tissue: the 'adipose tissue GPCRome', to support the exploration of novel control nodes in metabolic and endocrine functions. This atlas describes how adipose tissue GPCRs regulate lipolysis, insulin resistance and adiponectin and leptin secretion. We also discuss how adipose tissue GPCRs interact with their endogenous ligands and with GPCR-targeting drugs, with a focus on how drug/receptor interactions may affect lipolysis, and present a model predicting how GPCRs with unknown effects on lipolysis might modulate cAMP-regulated lipolysis. Subcutaneous adipose tissue expresses 163 GPCRs, a majority of which have unknown effects on lipolysis, insulin resistance and adiponectin and leptin secretion. These GPCRs are activated by 180 different endogenous ligands, and are the targets of a large number of clinically used drugs. We identified 119 drugs, acting on 23 GPCRs, that are predicted to stimulate lipolysis and 173 drugs, acting on 25 GPCRs, that are predicted to inhibit lipolysis. This atlas highlights knowledge gaps in the current understanding of adipose tissue GPCR function, and identifies GPCR/ligand/drug interactions that might affect lipolysis, which is important for understanding and predicting metabolic side effects of drugs. This approach may aid in the design of new, safer therapeutic agents, with fewer undesired effects on lipid homeostasis.
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| 7. |
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| 8. |
- D'Arcy, Padraig, et al.
(författare)
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Deubiquitinase inhibition as a cancer therapeutic strategy
- 2015
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Ingår i: Pharmacology and Therapeutics. - : Elsevier. - 0163-7258 .- 1879-016X. ; 147, s. 32-54
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Forskningsöversikt (refereegranskat)abstract
- The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS has made this an attractive target for development of drugs that show selectivity for tumor cells. Deubiquitinases (DUBs, ubiquitin isopeptidases) are components of the UPS that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. The majority of DUBs are cysteine proteases and are likely to be more "druggable" than E3 ligases. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles. Various compounds containing α,β-unsaturated ketones have indeed been demonstrated to inhibit cellular DUB activity. Inhibition of proteasomal cysteine DUB enzymes (i.e. USP14 and UCHL5) can be predicted to be particularly cytotoxic to cancer cells as it leads to blocking of proteasome function and accumulation of proteasomal substrates. We here provide an overall review of DUBs relevant to cancer and of various small molecules which have been demonstrated to inhibit DUB activity.
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| 9. |
- Edvinsson, Lars, et al.
(författare)
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Basic mechanisms of migraine and its acute treatment.
- 2012
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Ingår i: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; 136:3, s. 319-333
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Tidskriftsartikel (refereegranskat)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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| 10. |
- Gabrielsson, Johan, et al.
(författare)
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In vivo potency revisited - Keep the target in sight
- 2018
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Ingår i: Pharmacology & Therapeutics. - : Elsevier BV. - 0163-7258 .- 1879-016X. ; 184, s. 177-188
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Tidskriftsartikel (refereegranskat)abstract
- Potency is a central parameter in pharmacological and biochemical sciences, as well as in drug discovery and development endeavors. It is however typically defined in terms only of ligand to target binding affinity also in in vivo experimentation, thus in a manner analogous to in in vitro studies. As in vivo potency is in fact a conglomerate of events involving ligand, target, and target-ligand complex processes, overlooking some of the fundamental differences between in vivo and in vitro may result in serious mispredictions of in vivo efficacious dose and exposure. The analysis presented in this paper compares potency measures derived from three model situations. Model A represents the closed in vitro system, defining target binding of a ligand when total target and ligand concentrations remain static and constant. Model B describes an open in vivo system with ligand input and clearance (Cl-(L)),a adding in parallel to the turnover (k(syn), k(deg)) of the target. Model C further adds to the open in vivo system in Model B also the elimination of the target-ligand complex (km) via a first-order process. We formulate corresponding equations of the equilibrium (steady-state) relationships between target and ligand, and complex and ligand for each of the three model systems and graphically illustrate the resulting simulations. These equilibrium relationships demonstrate the relative impact of target and target-ligand complex turnover, and are easier to interpret than the more commonly used ligand-, target- and complex concentration-time courses. A new potency expression, labeled L-50, is then derived. L-50 is the ligand concentration at half-maximal target and complex concentrations and is an amalgamation of target turnover, target-ligand binding and complex elimination parameters estimated from concentration-time data. L-50 is then compared to the dissociation constant K-d (target-ligand binding affinity), the conventional Black & Leff potency estimate EC50, and the derived Michaelis-Menten parameter K-m (target-ligand binding and complex removal) across a set of literature data. It is evident from a comparison between parameters derived from in vitro vs. in vivo experiments that L-50 can be either numerically greater or smaller than the K-d (or K-m,) parameter, primarily depending on the ratio of k(deg)-to-k(e(RL)). Contrasting the limit values of target R and target-ligand complex RL for ligand concentrations approaching infinity demonstrates that the outcome of the three models differs to a great extent. Based on the analysis we propose that a better understanding of in vivo pharmacological potency requires simultaneous assessment of the impact of its underlying determinants in the open system setting. We propose that L-50 will be a useful parameter guiding predictions of the effective concentration range, for translational purposes, and assessment of in vivo target occupancy/suppression by ligand, since it also encompasses target turnover - in turn also subject to influence by pathophysiology and drug treatment. Different compounds may have similar binding affinity for a target in vitro (same K-d), but vastly different potencies in vivo. L-50 points to what parameters need to be taken into account, and particularly that closed-system (in vitro) parameters should not be first choice when ranking compounds in vivo (open system).
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| 11. |
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| 12. |
- Hombach-Klonisch, Sabine, et al.
(författare)
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Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response
- 2018
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Ingår i: Pharmacology and Therapeutics. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0163-7258 .- 1879-016X. ; 184, s. 13-41
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Forskningsöversikt (refereegranskat)abstract
- Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15 months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.
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| 13. |
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| 14. |
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| 15. |
- Jerlhag, Elisabeth, 1978
(författare)
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Gut-brain axis and addictive disorders: A review with focus on alcohol and drugs of abuse
- 2019
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Ingår i: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258 .- 1879-016X. ; 196, s. 1-14
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Forskningsöversikt (refereegranskat)abstract
- © 2018 The Author Due to the limited efficacy of existing medications for addictive disorders including alcohol use disorder (AUD), the need for additional medications is substantial. Potential new medications for addiction can be identified through investigation of the neurochemical substrates mediating the ability of drugs of abuse such as alcohol to activate the mesolimbic dopamine system. Interestingly, recent studies implicate neuropeptides of the gut-brain axis as modulators of reward and addiction processes. The present review therefore summarizes the current studies investigating the ability of the gut-brain peptides ghrelin, glucagon-like peptide-1 (GLP-1), amylin and neuromedin U (NMU) to modulate alcohol- and drug-related behaviors in rodents and humans. Extensive literature demonstrates that ghrelin, the only known orexigenic neuropeptide to date, enhances reward as well as the intake of alcohol, and other drugs of abuse, while ghrelin receptor antagonism has the opposite effects. On the other hand, the anorexigenic peptides GLP-1, amylin and NMU independently inhibits reward from alcohol and drugs of abuse in rodents. Collectively, these rodent and human studies imply that central ghrelin, GLP-1, amylin and NMU signaling may contribute to addiction processes. Therefore, the need for randomized clinical trials investigating the effects of agents targeting these aforementioned systems on drug/alcohol use is substantial.
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| 16. |
- Johansson, CH, et al.
(författare)
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BRAF inhibitors in cancer therapy
- 2014
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Ingår i: Pharmacology & therapeutics. - : Elsevier BV. - 1879-016X .- 0163-7258. ; 142:2, s. 176-182
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Tidskriftsartikel (refereegranskat)
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| 17. |
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| 18. |
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Rådinger, Madeleine, 1967, et al.
(författare)
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Eosinophil progenitors in allergy and asthma - do they matter?
- 2009
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Ingår i: Pharmacology & therapeutics. - : Elsevier BV. - 0163-7258. ; 121:2, s. 174-84
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Tidskriftsartikel (refereegranskat)abstract
- Allergic inflammation is associated with marked infiltration of eosinophils in affected tissues. The eosinophil is believed to be a key effector cells in allergen induced asthma pathogenesis. However, the role of eosinophils in the clinical manifestation of asthma has recently been questioned, since therapies directed against eosinophil infiltration (i.e. anti-interleukin-5) failed to improve clinical symptoms such as airways hyper-responsiveness (AHR) in patients with asthma. Although eosinophils in peripheral blood and the airways were largely depleted after anti-IL-5 treatment, residual eosinophilia in lung tissue persisted, which permits speculation that the remaining eosinophils may be sufficient to drive the asthma symptomatology. Furthermore, recent findings suggest that primitive eosinophil progenitor cells traffic from the bone marrow to sites of inflammation in response to allergen exposure. These progenitors may then differentiate in situ and thus provide an ongoing supply of mature pro-inflammatory cells and secretory mediators that augment the inflammatory response. In the present article, we will review the evidence for these findings, and discuss the rationale for targeting hematopoiesis and their migration pathways in the treatment of allergic diseases. Furthermore, this review will highlight the hypothesis that both IL-5- and CCR3-mediated signaling pathways may need to be targeted in order to control the inflammation and AHR associated with asthma.
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| 23. |
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| 24. |
- Sörhede Winzell, Maria, et al.
(författare)
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G-protein-coupled receptors and islet function-Implications for treatment of type 2 diabetes.
- 2007
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Ingår i: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; 116:3, s. 437-448
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Tidskriftsartikel (refereegranskat)abstract
- Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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| 25. |
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| 26. |
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| 27. |
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| 28. |
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| 29. |
- Wigerup, Caroline, et al.
(författare)
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Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
- 2016
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Ingår i: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; 164, s. 152-169
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Forskningsöversikt (refereegranskat)abstract
- Insufficient tissue oxygenation, or hypoxia, contributes to tumor aggressiveness and has a profound impact on clinical outcomes in cancer patients. At decreased oxygen tensions, hypoxia-inducible factors (HIFs) 1 and 2 are stabilized and mediate a hypoxic response, primarily by acting as transcription factors. HIFs exert differential effects on tumor growth and affect important cancer hallmarks including cell proliferation, apoptosis, differentiation, vascularization/angiogenesis, genetic instability, tumor metabolism, tumor immune responses, and invasion and metastasis. As a consequence, HIFs mediate resistance to chemo- and radiotherapy and are associated with poor prognosis in cancer patients. Intriguingly, perivascular tumor cells can also express HIF-2α, thereby forming a "pseudohypoxic" phenotype that further contributes to tumor aggressiveness. Therefore, therapeutic targeting of HIFs in cancer has the potential to improve treatment efficacy. Different strategies to target hypoxic cancer cells and/or HIFs include hypoxia-activated prodrugs and inhibition of HIF dimerization, mRNA or protein expression, DNA binding capacity, and transcriptional activity. Here we review the functions of HIFs in the progression and treatment of malignant solid tumors. We also highlight how HIFs may be targeted to improve the management of patients with therapy-resistant and metastatic cancer.
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| 30. |
- Xu, Cang-Bao, et al.
(författare)
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Cardiovascular risk factors regulate the expression of vascular endothelin receptors.
- 2010
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Ingår i: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; Jul 1, s. 148-155
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Tidskriftsartikel (refereegranskat)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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| 31. |
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| 32. |
- Yeganeh, Behzad, et al.
(författare)
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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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Ingår i: Pharmacology and Therapeutics. - : Elsevier. - 0163-7258 .- 1879-016X. ; 143:1, s. 87-110
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Forskningsöversikt (refereegranskat)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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| 33. |
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