共查询到20条相似文献,搜索用时 31 毫秒
1.
Chronic inflammation in the kidneys and vascular wall is a major contributor to hypertension. However, the stimuli and cellular mechanisms responsible for such inflammatory responses remain poorly defined. Inflammasomes are crucial initiators of sterile inflammation in other diseases such as rheumatoid arthritis and gout. These pattern recognition receptors detect host-derived danger-associated molecular patterns (DAMPs), such as microcrystals and reactive oxygen species, and respond by inducing activation of caspase-1. Caspase-1 then processes the cytokines pro-IL-1β and pro-IL-18 into their active forms thus triggering inflammation. While IL-1β and IL-18 are known to be elevated in hypertensive patients, no studies have examined whether this occurs downstream of inflammasome activation or whether inhibition of inflammasome and/or IL-1β/IL-18 signalling prevents hypertension. In this review, we will discuss some known actions of IL-1β and IL-18 on leukocyte and vessel wall function that could potentially underlie a prohypertensive role for these cytokines. We will describe the major classes of inflammasome-activating DAMPs and present evidence that at least some of these are elevated in the setting of hypertension. Finally, we will provide information on drugs that are currently used to inhibit inflammasome/IL-1β/IL-18 signalling and how these might ultimately be used as therapeutic agents for the clinical management of hypertension.Tables of Links TARGETS | |
---|
Catalytic receptorsa2013a | Enzymesd2013a | IL-1 receptor | Caspase-1 | IL-1 decoy receptor (IL-1RII) | HMG CoA reductase | IL-18 receptor | Endothelial NOS | GPCRsb2013a | Inducible NOS | Angiotensin AT1 receptor | | CCR2 | | Ligand-gated ion channelsc2013a | | P2X7 receptor | | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,c,d Alexander et al., 2013a,b,c,d , , , ). LIGANDS |
---|
A-438079 | Anakinra | Angiotensin II | Canakinumab | IL-1Ra | IL-18 | IL-33 | Simvastatin | TNF-α | Open in a separate window 相似文献
2.
The universal second messenger cAMP is generated upon stimulation of G s protein-coupled receptors, such as the β 2-adreneoceptor, and leads to the activation of PKA, the major cAMP effector protein. PKA oscillates between an on and off state and thereby regulates a plethora of distinct biological responses. The broad activation pattern of PKA and its contribution to several distinct cellular functions lead to the introduction of the concept of compartmentalization of cAMP. A-kinase anchoring proteins (AKAPs) are of central importance due to their unique ability to directly and/or indirectly interact with proteins that either determine the cellular content of cAMP, such as β 2-adrenoceptors, ACs and PDEs, or are regulated by cAMP such as the exchange protein directly activated by cAMP. We report on lessons learned from neurons indicating that maintenance of cAMP compartmentalization by AKAP5 is linked to neurotransmission, learning and memory. Disturbance of cAMP compartments seem to be linked to neurodegenerative disease including Alzheimer''s disease. We translate this knowledge to compartmentalized cAMP signalling in the lung. Next to AKAP5, we focus here on AKAP12 and Ezrin (AKAP78). These topics will be highlighted in the context of the development of novel pharmacological interventions to tackle AKAP-dependent compartmentalization.Tables of Links TARGETS |
---|
GPCRsa | A2B receptor | β2-adrenoceptor | M3 muscarinic receptor | Ligand gated ion channelsb | AMPA (GluA) receptors | Ionotropic glutamate receptors | NMDA (GluN) receptor | Ion channelsc | Cav1.2 | IP3 receptor | Potassium channels | Enzymesd | AC (adenylyl cyclases) | Epac | ERK1/2 | GRK2 | GSK3β | LKB1 | PDE4B | PDE7 | PDE8 | PKA | PKB (Akt) | PKC | PLCε1 | Other protein targets | CREB binding protein | Open in a separate windowLIGANDS |
---|
ACh | Amyloid β | Calmodulin | cAMP | Fenoterol | H-89 | IL-8 (CXCL8) | Isoprenaline | LPS | Roflumilast | Rolipram | Salbutamol | Tiotropium | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,c,dAlexander et al., 2013a,b,c,d , , , ). 相似文献
3.
Background and PurposeMyeloid differentiation 2 (MD-2) recognizes LPS, which is required for TLR4 activation, and represents an attractive therapeutic target for severe inflammatory disorders. We previously found that a chalcone derivative, L6H21, could inhibit LPS-induced overexpression of TNF-α and IL-6 in macrophages. Here, we performed a series of biochemical experiments to investigate whether L6H21 specifically targets MD-2 and inhibits the interaction and signalling transduction of LPS-TLR4/MD-2. Experimental ApproachThe binding affinity of L6H21 to MD-2 protein was analysed using computer docking, surface plasmon resonance analysis, elisa, fluorescence measurements and flow cytometric analysis. The effects of L6H21 on MAPK and NF-κB signalling were determined using EMSA, fluorescence staining, Western blotting and immunoprecipitation. The anti-inflammatory effects of L6H21 were confirmed using elisa and RT-qPCR in vitro. The anti-inflammatory effects of L6H21 were also evaluated in septic C57BL/6 mice. Key ResultsCompound L6H21 inserted into the hydrophobic region of the MD-2 pocket, forming hydrogen bonds with Arg 90 and Tyr 102 in the MD-2 pocket. In vitro, L6H21 subsequently suppressed MAPK phosphorylation, NF-κB activation and cytokine expression in macrophages stimulated by LPS. In vivo, L6H21 pretreatment improved survival, prevented lung injury, decreased serum and hepatic cytokine levels in mice subjected to LPS. In addition, mice with MD-2 gene knockout were universally protected from the effects of LPS-induced septic shock. Conclusions and ImplicationsOverall, this work demonstrated that the new chalcone derivative, L6H21, is a potential candidate for the treatment of sepsis. More importantly, the data confirmed that MD-2 is an important therapeutic target for inflammatory disorders.Tables of Links TARGETS | | |
---|
Catalytic receptorsa | Enzymesb | | TLR2 | COX-1 | JNK | TLR4 | ERK | JNK2 | | ERK1 | p38 | | IKK-β | | Open in a separate windowLIGANDS | |
---|
Auranofin | IL-6 | Curcumin | IL-10 | E5564 (eritoran) | IL-12 | IFN | LPS | IL-1β | TNF-α | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 a,bAlexander et al., 2013 a, b). 相似文献
4.
Background and PurposePrevious studies have demonstrated that nicotine releases protons from adrenergic nerves via stimulation of nicotinic ACh receptors and activates transient receptor potential vanilloid-1 (TRPV1) receptors located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves, resulting in vasodilatation. The present study investigated whether perivascular nerves release protons, which modulate axon-axonal neurotransmission. Experiment ApproachPerfusion pressure and pH levels of perfusate in rat-perfused mesenteric vascular beds without endothelium were measured with a pressure transducer and a pH meter respectively. Key ResultsPeriarterial nerve stimulation (PNS) initially induced vasoconstriction, which was followed by long-lasting vasodilatation and decreased pH levels in the perfusate. Cold-storage denervation of the preparation abolished the decreased pH and vascular responses to PNS. The adrenergic neuron blocker guanethidine inhibited PNS-induced vasoconstriction and effects on pH, but not PNS-induced vasodilatation. Capsaicin (CGRP depletor), capsazepine and ruthenium red (TRPV1 inhibitors) attenuated the PNS-induced decrease in pH and vasodilatation. In denuded preparations, ACh caused long-lasting vasodilatation and lowered pH; these effects were inhibited by capsaicin pretreatment and atropine, but not by guanethidine or mecamylamine. Capsaicin injection induced vasodilatation and a reduction in pH, which were abolished by ruthenium red. The use of a fluorescent pH indicator demonstrated that application of nicotine, ACh and capsaicin outside small mesenteric arteries reduced perivascular pH levels and these effects were abolished in a Ca 2+-free medium. Conclusion and ImplicationThese results suggest that protons are released from perivascular adrenergic and CGRPergic nerves upon PNS and these protons modulate transmission in CGRPergic nerves.Tables of Links Targets |
---|
GPCRs | α1-adrenoceptor | Muscarinic ACh receptor | CGRP receptor | Ligand-gated ion channels | Nicotinic ACh receptor | Ion channels | TRPV1 channel | Open in a separate windowLIGANDS | |
---|
ACh | Mecamylamine | Atropine | Methoxamine | Capsaicin | Neuropeptide Y | Capsazepine | Nicotine | CGRP | Nitric oxide (NO) | Guanethidine | Noradrenaline | | Ruthenium red | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (Alexander et al., 2013a,b,c , , ). 相似文献
5.
Reorganization of the actin cytoskeleton is essential for cell motility and chemotaxis. Actin-binding proteins (ABPs) and membrane lipids, especially phosphoinositides PI(4,5)P 2 and PI(3,4,5)P 3 are involved in the regulation of this reorganization. At least 15 ABPs have been reported to interact with, or regulated by phosphoinositides (PIPs) whose synthesis is regulated by extracellular signals. Recent studies have uncovered several parallel intracellular signalling pathways that crosstalk in chemotaxing cells. Here, we review the roles of ABPs and phosphoinositides in chemotaxis and cell migration. Linked ArticlesThis article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24Tables of Links TARGETS |
---|
Enzymesa | PI3Kγ | PLCβ2 | PTEN phosphatase | SHIP1, (INPP5D) | GPCRsb | CCR5 | CXCR4 | Ligand-gated ion channelsc | IP3 receptors | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,cAlexander et al., 2013a,b,c , , ). LIGANDS |
---|
C5a, complement component | cAMP | fMLP, formylMet-Leu-Phe | IL-8 | IP3, inositol 1,4,5-triphosphate; | LTB4 | PI(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate, PIP3 | PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; PIP2 | Open in a separate window 相似文献
6.
Background and PurposeSativex® is an oromucosal spray, containing equivalent amounts of Δ 9-tetrahydrocannabinol (Δ 9-THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS). In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler''s murine encephalomyelitis virus-induced demyelinating disease model of MS. Experimental ApproachA Sativex-like combination of phytocannabinoids and each phytocannabinoid alone were administered to mice once they had established MS-like symptoms. Motor activity and the putative targets of these cannabinoids were assessed to evaluate therapeutic efficacy. The accumulation of chondroitin sulfate proteoglycans (CSPGs) and astrogliosis were assessed in the spinal cord and the effect of Sativex on CSPGs production was evaluated in astrocyte cultures. Key ResultsSativex improved motor activity – reduced CNS infiltrates, microglial activity, axonal damage – and restored myelin morphology. Similarly, we found weaker vascular cell adhesion molecule-1 staining and IL-1β gene expression but an up-regulation of arginase-1. The astrogliosis and accumulation of CSPGs in the spinal cord in vehicle-infected animals were decreased by Sativex, as was the synthesis and release of CSPGs by astrocytes in culture. We found that CBD-BDS alone alleviated motor deterioration to a similar extent as Sativex, acting through PPARγ receptors whereas Δ 9-THC-BDS produced weaker effects, acting through CB 2 and primarily CB 1 receptors. Conclusions and ImplicationsThe data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair.Tables of Links TARGETS |
---|
GPCRsa | CB1 receptors | CB2 receptors | Nuclear hormone receptorsb | PPAR-γ | Enzymesc | Arg-1, arginase 1 | Open in a separate window
LIGANDS |
---|
AM251 | AM630 | CBD, cannabidiol | IFN-γ | IL-10 | T0070907 | TNF-α | Δ9-THC, Δ9-tetrahydrocannabinol- | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,cAlexander et al., 2013a, b, c). 相似文献
7.
Cannabinoids and their synthetic analogues affect a broad range of physiological functions, including cardiovascular variables. Although direct evidence is still missing, the relaxation of a vast range of vascular beds induced by cannabinoids is believed to involve a still unidentified non-CB 1, non-CB 2 G i/o protein-coupled receptor located on endothelial cells, the so called endothelial cannabinoid receptor (eCB receptor). Evidence for the presence of an eCB receptor comes mainly from vascular relaxation studies, which commonly employ pertussis toxin as an indicator for GPCR-mediated signalling. In addition, a pharmacological approach is widely used to attribute the relaxation to eCB receptors. Recent findings have indicated a number of GPCR-independent targets for both agonists and antagonists of the presumed eCB receptor, warranting further investigations and cautious interpretation of the vascular relaxation studies. This review will provide a brief historical overview on the proposed novel eCB receptor, drawing attention to the discrepancies between the studies on the pharmacological profile of the eCB receptor and highlighting the G i/o protein-independent actions of the eCB receptor inhibitors widely used as selective compounds. As the eCB receptor represents an attractive pharmacological target for a number of cardiovascular abnormalities, defining its molecular identity and the extent of its regulation of vascular function will have important implications for drug discovery. This review highlights the need to re-evaluate this subject in a thoughtful and rigorous fashion. More studies are needed to differentiate G i/o protein-dependent endothelial cannabinoid signalling from that involving the classical CB 1 and CB 2 receptors as well as its relevance for pathophysiological conditions.Table of Links TARGETS | LIGANDS |
---|
5-HT receptor | Abn-CBD | α1 adrenoceptor | Acetylcholine | Akt | Anandamide (AEA) | AT1 receptor | AM251 | BKCa channels | Apamin | CaV2.2 | Bradykinin | CaV3.1 | Cannabidiol | CaV3.2 | Carbachol | CaV3.3 | Charybdotoxin | CB1 receptor | Forskolin | CB2 receptor | HU-210 | ERK1/2 | Iberiotoxin | Glycine receptors | L-NAME | GPR18 | LPI | GPR55 | NaGly | GPR119 | NO | Ionotropic glutamate receptor | NS1619 | IP3 receptor | O-1602 | KCa channels | Oleamide | M1 muscarinic receptor | Oleoylethanolamide | M2 muscarinic receptor | Rimonabant (SR141716) | MAPK | Ryanodine | Na+/Ca2+ exchanger (NCX) | THC | NaV channel | WIN55212-2 | Nicotinic acetylcholine receptors | | NOS | | Opioid receptors | | PI3K | | PPARγ | | ROCK | | TRP channels | | TRPV channels | | VEGF receptor | | Open in a separate windowThis Table lists key protein targets and ligands in this document, which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (Alexander et al., 2013a,b,c,d,f,g , , , , , ). 相似文献
8.
Background and PurposeIn the aorta of adult spontaneously hypertensive (SHR), but not in that of normotensive Wistar-Kyoto (WKY), rats, previous exposure to phenylephrine inhibits subsequent contractions to PGE 2. The present experiments were designed to examine the mechanism(s) underlying this inhibition. Experimental ApproachIsometric tension was measured in isolated rings of SHR and WKY aortae. Gene expression and protein presence were measured by quantitative real-time PCR and Western blotting respectively. Key ResultsIn aorta of 18 weeks SHR, but not age-matched WKY, pre-exposure to phenylephrine inhibited subsequent contractions to PGE 2 that were mediated by thromboxane prostanoid (TP) receptors. This inhibition was not observed in preparations of pre-hypertensive 5-week-old SHR, and was significantly larger in those of 36- than 18-week-old SHR. Pre-exposure to the PKC activator, phorbol 12,13-dibutyrate, also inhibited subsequent contractions to PGE 2 in SHR aortae. The selective inhibitor of PKC-ε, ε-V1-2, abolished the desensitization caused by pre-exposure to phenylephrine. Two molecular PKC bands were detected and their relative intensities differed in 36-week-old WKY and SHR vascular smooth muscle. The mRNA expressions of PKC-α, PKC-ε, PK-N2 and PKC-ζ and of G protein-coupled kinase (GRK)-2, GRK4 and β-arrestin2 were higher in SHR than WKY aortae. Conclusions and ImplicationsThese experiments suggest that in the SHR but not the WKY aorta, α 1-adrenoceptor activation desensitizes TP receptors through activation of PKC-ε. This heterologous desensitization is a consequence of the chronic exposure to high arterial pressure.Tables of Links TARGETS | |
---|
Enzymesb | PKC ή | COX-1 | PKC ζ | COX-2 | PKN2 | GRK2 | GPCRsa | GRK4 | EP receptors | PKC α | TP receptors | PKC ε | | Open in a separate window
LIGANDS |
---|
Calphostin C | Go6976 | Noradrenaline | PGE2 | Phenoxybenzamine | Phenylephrine | S-18886, terutroban | U46619 | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,bAlexander et al., 2013a, b). 相似文献
9.
Background and Purposeβ 2-adrenoceptor agonists are widely used in the management of obstructive airway diseases. Besides their bronchodilatory effect, several studies suggest inhibitory effects on various aspects of inflammation. The aim of our study was to determine the efficacy of the long-acting β 2-adrenoceptor agonist olodaterol to inhibit pulmonary inflammation and to elucidate mechanism(s) underlying its anti-inflammatory actions. Experimental ApproachOlodaterol was tested in murine and guinea pig models of cigarette smoke- and LPS-induced lung inflammation. Furthermore, effects of olodaterol on the LPS-induced pro-inflammatory mediator release from human parenchymal explants, CD11b adhesion molecule expression on human granulocytes TNF-α release from human whole blood and on the IL-8-induced migration of human peripheral blood neutrophils were investigated. Key ResultsOlodaterol dose-dependently attenuated cell influx and pro-inflammatory mediator release in murine and guinea pig models of pulmonary inflammation. These anti-inflammatory effects were observed at doses relevant to their bronchodilatory efficacy. Mechanistically, olodaterol attenuated pro-inflammatory mediator release from human parenchymal explants and whole blood and reduced expression of CD11b adhesion molecules on granulocytes, but without direct effects on IL-8-induced neutrophil transwell migration. Conclusions and ImplicationsThis is the first evidence for the anti-inflammatory efficacy of a β 2-adrenoceptor agonist in models of lung inflammation induced by cigarette smoke. The long-acting β 2-adrenoceptor agonist olodaterol attenuated pulmonary inflammation through mechanisms that are separate from direct inhibition of bronchoconstriction. Furthermore, the in vivo data suggest that the anti-inflammatory properties of olodaterol are maintained after repeated dosing for 4 days.Tables of Links TARGETS |
---|
GPCRsa | β2-adrenoceptors | β1-adrenoceptors | CXCR2 | Catalytic receptorsb | CD11b | Enzymesc | MMP-9 | Open in a separate window
LIGANDS | |
---|
ACh | IL-8 | CCL2 | KC (mouse orthologue of CXCL1) | CCL4 | LPS | CGP-20712A | M-CSF-1 | CXCL9 | Olodaterol | GM-CSF | TNFα | ICI-118,551 | | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,cAlexander et al., 2013a,b,c , , ). 相似文献
10.
Since the discovery of endothelin (ET)-1 in 1988, the main components of the signalling pathway have become established, comprising three structurally similar endogenous 21-amino acid peptides, ET-1, ET-2 and ET-3, that activate two GPCRs, ET A and ET B. Our aim in this review is to highlight the recent progress in ET research. The ET-like domain peptide, corresponding to prepro-ET-1 93–166, has been proposed to be co-synthesized and released with ET-1, to modulate the actions of the peptide. ET-1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long-lasting action. To date, the major therapeutic strategy to block the unwanted actions of ET in disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for the ET A receptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET-converting enzyme and neutral endopeptidase such as SLV306 (daglutril). A third strategy based on activating the ET B receptor, has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally, we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research.Tables of Links TARGETS |
---|
GPCRsa | AT1 receptors | ETA receptors | ETB receptors | GPR37 | GPR37L | Hydroxycarboxylic acid receptors | μ opioid receptors | Enzymesb | Cathepsin A | Chymase | CYP3A4 | CYP2C19 | Endothelin-converting enzyme 1 | Endothelin-converting enzyme 2 | Neutral endopeptidase | Open in a separate windowThese Tables list protein targets and ligands that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and the Concise Guide to PHARMACOLOGY 2013/14 ( a,bAlexander et al., 2013a,b , ). LIGANDS | |
---|
5-Fluorouracil | Endothelin-3 | Ambrisentan | IRL1620 | Amyloid β-peptide | KC-12615 | Atrial natriuretic peptide (ANP) | Losartan | β-Catenin | Macitentan | Bosentan | NO | BQ123 | Prosaptide | BQ788 | PGI2 | BQ3020 | Sarafotoxin S6b | Captopril | Sarafotoxin S6c | Daglutril | Sitaxentan | Docetaxel | TGFβ1 | Doxorubicin | | Endothelin-1 | | Endothelin-2 | | Open in a separate windowThis article, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittee for the endothelin receptors, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions, and their likely physiological roles in health and disease. More information on these receptor families can be found in the Concise Guide to PHARMACOLOGY ( http://onlinelibrary.wiley.com/doi/10.1111/bph.12445/abstract) and for each member of the family in the corresponding database http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=21&familyType=GPCR. 相似文献
11.
Breast cancer (BC) is the second most common cause of cancer deaths. Triple-negative breast cancer (TNBC) does not show immunohistochemical expression of oestrogen receptors, progesterone receptors or HER2. At present, no suitable treatment option is available for patients with TNBC. This dearth of effective conventional therapies for the treatment of advanced stage breast cancer has provoked the development of novel strategies for the management of patients with TNBC. This review presents recent information associated with different therapeutic options for the treatment of TNBC focusing on promising targets such as the Notch signalling, Wnt/β-catenin and Hedgehog pathways, in addition to EGFR, PARP1, mTOR, TGF-β and angiogenesis inhibitors.Tables of Links TARGETS |
|
---|
GPCRsa | Enzymesc | FZD7 receptor | ADAM | SMO receptor | ADAM17 | Catalytic receptorsb | Akt (PKB) | EGFR | Aspartyl protease | Fas | GSK3β | HER2 | mTOR | TGFBR1 | PARP1 | VEGFR2 | p70S6kinase | | PKCα | | SGK1 | | ULK1 | Open in a separate windowLIGANDS |
|
---|
β-catenin | Lapatinib | Angiopoietin-1 | LY2157299 | Angiopoietin-2 | Neratinib | Cisplatin | Olaparib | Erlotinib | Rapamycin | Everolimus | Rucaparib | Gefitinib | Temsirolimus | IFN-γ | TGFβ | IGF-1 | TNF-α | IL-1α | Veliparib | IL-1β | Wnt | IL-2 | | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 a,b,cAlexander et al., 2013a,b,c , , ). 相似文献
12.
Background and PurposeMatrine is a small molecule drug used in humans for the treatment of chronic viral infections and tumours in the liver with little adverse effects. The present study investigated its therapeutic efficacy for insulin resistance and hepatic steatosis in high-fat-fed mice. Experimental ApproachC57BL/J6 mice were fed a chow or high-fat diet for 10 weeks and then treated with matrine or metformin for 4 weeks. The effects on lipid metabolism and glucose tolerance were evaluated. Key ResultsOur results first showed that matrine reduced glucose intolerance and plasma insulin level, hepatic triglyceride content and adiposity in high-fat-fed mice without affecting caloric intake. This reduction in hepatosteatosis was attributed to suppressed lipid synthesis and increased fatty acid oxidation. In contrast to metformin, matrine neither suppressed mitochondrial respiration nor activated AMPK in the liver. A computational docking simulation revealed HSP90, a negative regulator of HSP72, as a potential binding target of matrine. Consistent with the simulation results, matrine, but not metformin, increased the hepatic protein level of HSP72 and this effect was inversely correlated with both liver triglyceride level and glucose intolerance. Conclusions and ImplicationsTaken together, these results indicate that matrine may be used for the treatment of type 2 diabetes and hepatic steatosis, and the molecular action of this hepatoprotective drug involves the activation of HSP72 in the liver.Tables of Links TARGETS | |
---|
Nuclear hormone receptorsa | Transportersb | PPARα | UCP2 | Enzymesc | | ACC | GSK3β | AMPK | IKKα | AST | IKKβ | ERK1 | JNK | ERK2 | PKCε | FAS | | Other protein targets | | α-tubulin | HSP72 | Open in a separate windowLIGANDS | |
---|
Adiponectin | Leptin | IL-1β | Metformin | IL-6 (HSF1) | Palmitate | Insulin | TNFα | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 a,b,cAlexander et al., 2013a,b,c , , ). 相似文献
13.
Background and PurposeMonoglyceride lipase (MGL) degrades 2-arachidonoyl glycerol (2-AG), an endogenous agonist of cannabinoid receptors (CB 1/2). Because the CB 1 receptor is involved in the control of gut function, we investigated the effects of pharmacological inhibition and genetic deletion of MGL on intestinal motility. Furthermore, we determined whether defective 2-AG degradation affects μ-opioid receptor (μ receptor) signalling, a parallel pathway regulating gut motility. Experimental ApproachGut motility was investigated by monitoring Evans Blue transit and colonic bead propulsion in response to MGL inhibition and CB 1 receptor or μ receptor stimulation. Ileal contractility was investigated by electrical field stimulation. CB 1 receptor expression in ileum and colon was assessed by immunohistochemical analyses. Key ResultsPharmacological inhibition of MGL slowed down whole gut transit in a CB 1 receptor-dependent manner. Conversely, genetic deletion of MGL did not affect gut transit despite increased 2-AG levels. Notably, MGL deficiency caused complete insensitivity to CB 1 receptor agonist-mediated inhibition of whole gut transit and ileal contractility suggesting local desensitization of CB 1 receptors. Accordingly, immunohistochemical analyses of myenteric ganglia of MGL-deficient mice revealed that CB 1 receptors were trapped in endocytic vesicles. Finally, MGL-deficient mice displayed accelerated colonic propulsion and were hypersensitive to μ receptor agonist-mediated inhibition of colonic motility. This phenotype was reproduced by chronic pharmacological inhibition of MGL. Conclusion and ImplicationsConstantly elevated 2-AG levels induce severe desensitization of intestinal CB 1 receptors and increased sensitivity to μ receptor-mediated inhibition of colonic motility. These changes should be considered when cannabinoid-based drugs are used in the therapy of gastrointestinal diseases.Tables of Links TARGETS | |
---|
GPCRsa | Enzymesb | μ receptor | FAAH | CB1 receptor | MGL | CB2 receptor | | Open in a separate windowLIGANDS | |
---|
2-AG | JZL184 | ACh | Loperamide | Arachidonic acid | Salvinorin A | Bethanechol | WIN55,212-2 | CP55,940 | | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 a,bAlexander et al., 2013a,b , ). 相似文献
14.
Background and PurposeIn pigs, ivabradine reduces infarct size even when given only at reperfusion and in the absence of heart rate reduction. The mechanism of this non-heart rate-related cardioprotection is unknown. Hence, in the present study we assessed the pleiotropic action of ivabradine in more detail. Experimental ApproachAnaesthetized mice were pretreated with ivabradine (1.7 mg·kg −1 i.v.) or placebo (control) before a cycle of coronary occlusion/reperfusion (30/120 min ± left atrial pacing). Infarct size was determined. Isolated ventricular cardiomyocytes were exposed to simulated ischaemia/reperfusion (60/5 min) in the absence and presence of ivabradine, viability was then quantified and intra- and extracellular reactive oxygen species (ROS) formation was detected. Mitochondria were isolated from mouse hearts and exposed to simulated ischaemia/reperfusion (6/3 min) in glutamate/malate- and ADP-containing buffer in the absence and presence of ivabradine respectively. Mitochondrial respiration, extramitochondrial ROS, mitochondrial ATP production and calcium retention capacity (CRC) were assessed. Key ResultsIvabradine decreased infarct size even with atrial pacing. Cardiomyocyte viability after simulated ischaemia/reperfusion was better preserved with ivabradin, the accumulation of intra- and extracellular ROS decreased in parallel. Mitochondrial complex I respiration was not different without/with ivabradine, but ivabradine significantly inhibited the accumulation of extramitochondrial ROS, increased mitochondrial ATP production and increased CRC. Conclusion and ImplicationsIvabradine reduces infarct size independently of a reduction in heart rate and improves ventricular cardiomyocyte viability, possibly by reducing mitochondrial ROS formation, increasing ATP production and CRC.Tables of Links TARGETS | |
---|
GPCRsa | Ion channelsb | α-adrenoceptor | HCN2 | β-adrenoceptor | HCN4 | | Enzymesc | | NOS | Open in a separate windowLIGANDS | |
---|
ADP | H2O2 | Ascorbate | Ivabradine | ATP | Malate | Glutamate | | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 a,b,cAlexander et al., 2013 a, b, c). 相似文献
16.
Background and PurposeOpioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling. Experimental ApproachA time-dependent effect of morphine (1 mg·kg −1, i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [ 35S]-GTPγS binding assay. Key ResultsMorphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN. Conclusions and ImplicationsOur data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3β.Tables of Links TARGETS | |
---|
GPCRsa1997 | Enzymesc1997 | δ receptor | Akt (PKB) | κ receptor | Clock | μ receptor | ERK1/2 | Nuclear hormone receptorsb1997 | GSK3β | Rev-Erb-α | | Open in a separate window
LIGANDS | |
---|
Arginine vasopressin | GDP | cAMP | GTPγS | DADLE | Morphine | DAMGO | Neuropeptide Y | Enkephalin | Thiopental | GABA | U-50488 | Gastrin | UTP | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,cAlexander et al., 2013a, b, c). 相似文献
17.
Background and PurposeMost forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research. Experimental ApproachWe first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT 2C and 5-HT 1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT 2C receptors. ResultsCo-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT 2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions. Conclusions and ImplicationsOur study provides evidence that drugs, which activate 5-HT 2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.Tables of Links TARGETS | |
---|
GPCRsa | Catalytic receptorsb | 5-HT1B receptor | Leptin receptor | 5-HT2C receptor | Enzymesc | Melanocortin 4 receptor | JAK2 | Open in a separate window
LIGANDS | |
---|
5-HT | Leptin | Agouti-related peptide | Lorcaserin | Amylin | Meta-chlorophenylpiperazine | Glycine | Neuropeptide Y | H2O2 | POMC | Isoflurane | Sibutramine | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,cAlexander et al., 2013a, b, c). 相似文献
18.
Background and PurposeHydrogen sulphide reduces uterine contractility and is of potential interest as a treatment for uterine disorders. The aim of this study was to explore the mechanism of sodium sulphide (Na 2S)-induced relaxation of rat uterus, investigate the importance of redox effects and ion channel-mediated mechanisms, and any interactions between these two mechanisms. Experimental ApproachOrgan bath studies were employed to assess the pharmacological effects of Na 2S in uterine strips by exposing them to Na 2S with or without Cl − channel blockers (DIDS, NFA, IAA-94, T16Ainh-A01, TA), raised KCl (15 and 75 mM), K + channel inhibitors (glibenclamide, TEA, 4-AP), L-type Ca 2+ channel activator (S-Bay K 8644), propranolol and methylene blue. The activities of antioxidant enzymes were measured in homogenates of treated uteri. The expression of bestrophin channel 1 (BEST-1) was determined by Western blotting and RT-PCR. Key ResultsNa 2S caused concentration-dependent reversible relaxation of spontaneously active and calcium-treated uteri, affecting both amplitude and frequency of contractions. Uteri exposed to 75 mM KCl were less sensitive to Na 2S compared with uteri in 15 mM KCl. Na 2S-induced relaxations were abolished by DIDS, but unaffected by other modulators or by the absence of extracellular HCO 3−, suggesting the involvement of chloride ion channels. Na 2S in combination with different modulators provoked specific changes in the anti-oxidant profiles of uteri. The expression of BEST-1, both mRNA and protein, was demonstrated in rat uteri. Conclusions and ImplicationsThe relaxant effects of Na 2S in rat uteri are mediated mainly via a DIDS-sensitive Cl −-pathway. Components of the relaxation are redox- and Ca 2+-dependent.Tables of Links TARGETS | |
---|
GPCRsa,2006 | Transportersc,2006 | β-adrenoceptor | Cl-/HCO3- exchanger | Ion channelsb,2006 | Enzymesd,2006 | CaCC | Cystathionine β-synthase | KATP channels | Cystathionine γ-lyase | Kv channels | GR | TMEM16 channel | Guanylyl cyclase | Open in a separate window
LIGANDS | |
---|
4-AP | NaHS | Adrenaline | Niflumic acid (NFA) | CGRP | Nitric oxide (NO) | DIDS | Propranolol | Glibenclamide | S-Bay K 8644 | H2O2 | Tannic acid (TA) | IAA-94 | TEA | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,c,dAlexander et al., 2013a, b, c, d). 相似文献
19.
Background and PurposeEndogenous cannabinoids (endocannabinoids) in the periaqueductal grey (PAG) play a vital role in mediating stress-induced analgesia. This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific effects of endocannabinoids and the inhibitors of their degradation are largely unknown within this pain-modulating region. Experimental ApproachIn vitro electrophysiological recordings were conducted from PAG neurons in rat midbrain slices. The effects of the major endocannabinoids and their degradation inhibitors on inhibitory GABAergic synaptic transmission were examined. Key ResultsExogenous application of the endocannabinoid, anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), produced a reduction in inhibitory GABAergic transmission in PAG neurons. This AEA-induced suppression of inhibition was enhanced by the fatty acid amide hydrolase (FAAH) inhibitor, URB597, whereas a 2-AG-induced suppression of inhibition was unmasked by the monoacylglycerol lipase (MGL) inhibitor, JZL184. In addition, application of the CB 1 receptor antagonist, AM251, facilitated the basal GABAergic transmission in the presence of URB597 and JZL184, which was further enhanced by the dual FAAH/MGL inhibitor, JZL195. Conclusions and ImplicationsOur results indicate that AEA and 2-AG act via disinhibition within the PAG, a cellular action consistent with analgesia. These actions of AEA and 2-AG are tightly regulated by their respective degradative enzymes, FAAH and MGL. Furthermore, individual or combined inhibition of FAAH and/or MGL enhanced tonic disinhibition within the PAG. Therefore, the current findings support the therapeutic potential of FAAH and MGL inhibitors as a novel pharmacotherapy for pain.Table of Links TARGETS | LIGANDS |
---|
CB1 receptor | AM251 | FAAH | Anandamide (AEA) | GABAA receptor | CNQX | Glycine receptor | JZL184 | M1 receptor | Tetrahydrolipstatin (orlistat) | M3 receptor | URB597 | MGL | WWL70 | mGlu receptor | 2-AG | TRPV1 channel | Tetrodotoxin | Voltage-dependent sodium channel | | Open in a separate windowThis Table lists key protein targets and ligands in this document, which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (Alexander et al., 2013a, 2013b, 2013c, 2013d). 相似文献
20.
Many human malignancies are associated with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification. Protein and lipid kinases represent an important target class for treating human disorders. This review focus on ‘the 10 things you should know about protein kinases and their inhibitors'', including a short introduction on the history of protein kinases and their inhibitors and ending with a perspective on kinase drug discovery. Although the ‘10 things’ have been, to a certain extent, chosen arbitrarily, they cover in a comprehensive way the past and present efforts in kinase drug discovery and summarize the status quo of the current kinase inhibitors as well as knowledge about kinase structure and binding modes. Besides describing the potentials of protein kinase inhibitors as drugs, this review also focus on their limitations, particularly on how to circumvent emerging resistance against kinase inhibitors in oncological indications. Tables of LinksTARGETS | | |
---|
Catalytic receptorsa | Enzymesb | | ALK | ABL (Abl) | MAPK | AXL | Akt (PKB) | MEK1 | CSF1R | AMPK | MLKL | EGFR | Aurora kinase | mTOR | FGFR1 | B-Raf (BRAF) | PDK1 | FLT3 | BTK | PHK | HER2 (Neu) | CHEK1 (CHK1) | PI3Kδ | IGF1R | ELK (EphB1) | PIK3CA | Insulin receptor | FAK | PKCζ | KIT | Fes | PTEN | MET (c-Met) | Glucokinase | PTK | PDGFRα | GSK3β | RAF | PDGFRβ | Haspin | Ribosomal S6 kinase | RET | Hck | ROCK | ROS1 | JAK2 | STK11 | TIE2 | JNK1 | STRAD1 | TrkB | LKB1 | Src | Open in a separate windowLIGANDS | |
---|
ADP | Lapatinib | ATP | Myristate | Afatinib | Nilotinib | AZD6244 | Nintedanib | Crizotinib | Pertuzumab | Cyclosporine | Ponatinib | Dabrafenib | Sirolimus (rapamycin) | Dasatinib | Sorafenib | Erlotinib | Staurosporine | Fasudil (HA1077) | Sunitinib | Gefitinib | Tofacitinib | GNF-2 | Trametinib | Ibrutinib | Trastuzumab | Imatinib | Vemurafenib | Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,bAlexander et al., 2013 a, b). 相似文献
|