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| dexamethasone |
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| CHEBI:41879 |
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| A fluorinated steroid that is 9-fluoropregna-1,4-diene substituted by hydroxy groups at positions 11, 17 and 21, a methyl group at position 16 and oxo groups at positions 3 and 20. It is a synthetic member of the class of glucocorticoids. |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:41873, CHEBI:4461
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| No supplier information found for this compound. |
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Molfile
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SDF
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more structures >>
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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__5217904504818645__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__5217904504818645__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:41879","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__5217904504818645__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"5217904504818645","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__5217904504818645__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol DEX - Ideal conformer RDKit 3D starting HoverWatcher_5 Time for openFile(DEX - Ideal conformer RDKit 3D 57 60 0 0 0 0 0 0 0 0999 V2000 -1.5670 0.4360 -3.3110 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.4480 0.8180 -4.5730 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.2480 0.4460 -5.3410 C 0 0 0 0 0 0 0 0 0 0 0 0 0.8200 -0.2980 -4.6570 C 0 0 0 0 0 0 0 0 0 0 0 0 0.6820 -0.6640 -3.3900 C 0 0 0 0 0 0 0 0 0 0 0 0 1.8150 -1.4120 -2.7130 C 0 0 0 0 0 0 0 0 0 0 0 0 2.1440 -0.6920 -1.4010 C 0 0 0 0 0 0 0 0 0 0 0 0 0.8800 -0.5740 -0.5470 C 0 0 2 0 0 0 0 0 0 0 0 0 -0.1670 0.2940 -1.2620 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.5500 -0.3750 -2.5850 C 0 0 1 0 0 0 0 0 0 0 0 0 -1.4220 0.5010 -0.4210 C 0 0 2 0 0 0 0 0 0 0 0 0 -1.0870 1.0520 0.9730 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.0800 0.1090 1.6340 C 0 0 1 0 0 0 0 0 0 0 0 0 1.2080 0.1020 0.7700 C 0 0 1 0 0 0 0 0 0 0 0 0 2.1880 -0.6460 1.6790 C 0 0 0 0 0 0 0 0 0 0 0 0 1.8810 -0.0550 3.0820 C 0 0 2 0 0 0 0 0 0 0 0 0 0.4290 0.4800 3.0240 C 0 0 2 0 0 0 0 0 0 0 0 0 -0.6310 -1.3170 1.6360 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.1930 -1.7130 -2.2160 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.3880 -0.2120 4.0830 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.6620 0.4170 4.5840 C 0 0 0 0 0 0 0 0 0 0 0 0 2.8510 1.0860 3.3940 C 0 0 0 0 0 0 0 0 0 0 0 0 0.3990 1.5450 -1.5270 F 0 0 0 0 0 0 0 0 0 0 0 0 -0.1430 0.7480 -6.5150 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.0980 -0.7490 -0.2760 O 0 0 0 0 0 0 0 0 0 0 0 0 0.3810 1.8960 3.2080 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.0230 -1.2730 4.5300 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.2520 -0.4240 5.5770 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.4570 0.7310 -2.7740 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.2300 1.4000 -5.0380 H 0 0 0 0 0 0 0 0 0 0 0 0 1.7240 -0.5500 -5.1910 H 0 0 0 0 0 0 0 0 0 0 0 0 2.6920 -1.4160 -3.3600 H 0 0 0 0 0 0 0 0 0 0 0 0 1.5060 -2.4360 -2.5040 H 0 0 0 0 0 0 0 0 0 0 0 0 2.5280 0.3030 -1.6200 H 0 0 0 0 0 0 0 0 0 0 0 0 2.8980 -1.2600 -0.8550 H 0 0 0 0 0 0 0 0 0 0 0 0 0.4690 -1.5660 -0.3590 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.0810 1.2040 -0.9310 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9960 1.1360 1.5680 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.6100 2.0280 0.8820 H 0 0 0 0 0 0 0 0 0 0 0 0 1.5550 1.1210 0.5960 H 0 0 0 0 0 0 0 0 0 0 0 0 3.2180 -0.4390 1.3900 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9890 -1.7180 1.6600 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9630 -0.8330 3.8420 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.7140 -1.6760 0.6100 H 0 0 0 0 0 0 0 0 0 0 0 0 0.0440 -1.9660 2.1940 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.6140 -1.3270 2.1060 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1520 -2.3850 -3.0740 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.6540 -2.1570 -1.3800 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.2330 -1.5500 -1.9330 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.3570 0.5420 3.7540 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.4380 1.3910 5.0200 H 0 0 0 0 0 0 0 0 0 0 0 0 3.8700 0.7010 3.4190 H 0 0 0 0 0 0 0 0 0 0 0 0 2.7700 1.8520 2.6230 H 0 0 0 0 0 0 0 0 0 0 0 0 2.6020 1.5190 4.3630 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.8850 -0.5810 0.2590 H 0 0 0 0 0 0 0 0 0 0 0 0 0.7130 2.0740 4.0990 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.0620 0.0140 5.8700 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 1 10 1 0 1 29 1 0 2 3 1 0 2 30 1 0 3 4 1 0 3 24 2 0 4 5 2 0 4 31 1 0 5 6 1 0 5 10 1 0 6 7 1 0 6 32 1 0 6 33 1 0 7 8 1 0 7 34 1 0 7 35 1 0 8 9 1 0 8 14 1 0 8 36 1 1 9 10 1 0 9 11 1 0 9 23 1 6 10 19 1 1 11 12 1 0 11 25 1 0 11 37 1 6 12 13 1 0 12 38 1 0 12 39 1 0 13 14 1 0 13 17 1 0 13 18 1 1 14 15 1 0 14 40 1 6 15 16 1 0 15 41 1 0 15 42 1 0 16 17 1 0 16 22 1 0 16 43 1 1 17 20 1 0 17 26 1 1 18 44 1 0 18 45 1 0 18 46 1 0 19 47 1 0 19 48 1 0 19 49 1 0 20 21 1 0 20 27 2 0 21 28 1 0 21 50 1 0 21 51 1 0 22 52 1 0 22 53 1 0 22 54 1 0 25 55 1 0 26 56 1 0 28 57 1 0 M END): 17 ms reading 57 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. 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| Dexamethasone is a fluorinated glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive pulmonary disease (COPD), croup, brain swelling, eye pain following eye surgery, superior vena cava syndrome (a complication of some forms of cancer), and along with antibiotics in tuberculosis. In adrenocortical insufficiency, it may be used in combination with a mineralocorticoid medication such as fludrocortisone. In preterm labor, it may be used to improve outcomes in the baby. It may be given by mouth, as an injection into a muscle, as an injection into a vein, as a topical cream or ointment for the skin or as a topical ophthalmic solution to the eye. The effects of dexamethasone are frequently seen within a day and last for about three days.
The long-term use of dexamethasone may result in thrush, bone loss, cataracts, easy bruising, or muscle weakness. It is in pregnancy category C in the United States, meaning that it should only be used when the benefits are predicted to be greater than the risks. In Australia, the oral use is category A, meaning it has been frequently used in pregnancy and not been found to cause problems to the baby. It should not be taken when breastfeeding. Dexamethasone has anti-inflammatory and immunosuppressant effects.
Dexamethasone was first synthesized in 1957 by Philip Showalter Hench and was approved for medical use in 1958. It is on the World Health Organization's List of Essential Medicines. In 2022, it was the 234th most commonly prescribed medication in the United States, with more than 1 million prescriptions. It is available as a generic medication. In 2022, the combination of dexamethasone with neomycin and polymyxin B was the 274th most commonly prescribed medication in the United States, with more than 800,000 prescriptions. |
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Read full article at Wikipedia
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InChI=1S/C22H29FO5/c1- 12-8-16-15-5-4-13-9-14(25)6-7-19(13,2)21(15,23)17(26)10-20(16,3)22(12,28)18(27)11-24/h6-7,9,12,15-17,24,26,28H,4-5,8,10-11H2,1-3H3/t12-,15+,16+,17+,19+,20+,21+,22+/m1/s1 |
| UREBDLICKHMUKA-CXSFZGCWSA-N |
| C1=CC(C=C2[C@]1([C@@]3([C@@](CC2)([C@]4([C@](C[C@@H]3O)([C@]([C@@H](C4)C)(C(CO)=O)O)C)[H])[H])F)C)=O |
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environmental contaminant
Any minor or unwanted substance introduced into the environment that can have undesired effects.
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adrenergic agent
Any agent that acts on an adrenergic receptor or affects the life cycle of an adrenergic transmitter.
xenobiotic
A xenobiotic (Greek, xenos "foreign"; bios "life") is a compound that is foreign to a living organism. Principal xenobiotics include: drugs, carcinogens and various compounds that have been introduced into the environment by artificial means.
immunosuppressive agent
An agent that suppresses immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-cells or by inhibiting the activation of helper cells. In addition, an immunosuppressive agent is a role played by a compound which is exhibited by a capability to diminish the extent and/or voracity of an immune response.
hormone
Originally referring to an endogenous compound that is formed in specialized organ or group of cells and carried to another organ or group of cells, in the same organism, upon which it has a specific regulatory function, the term is now commonly used to include non-endogenous, semi-synthetic and fully synthetic analogues of such compounds.
(via steroid hormone )
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antiemetic
A drug used to prevent nausea or vomiting. An antiemetic may act by a wide range of mechanisms: it might affect the medullary control centres (the vomiting centre and the chemoreceptive trigger zone) or affect the peripheral receptors.
adrenergic agent
Any agent that acts on an adrenergic receptor or affects the life cycle of an adrenergic transmitter.
antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
immunosuppressive agent
An agent that suppresses immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-cells or by inhibiting the activation of helper cells. In addition, an immunosuppressive agent is a role played by a compound which is exhibited by a capability to diminish the extent and/or voracity of an immune response.
anti-inflammatory drug
A substance that reduces or suppresses inflammation.
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View more via ChEBI Ontology
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9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione
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dexametasona
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WHO MedNet
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dexaméthasone
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WHO MedNet
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dexamethasone
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WHO MedNet
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dexamethasonum
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WHO MedNet
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(11β,16α)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione
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ChemIDplus
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1-dehydro-16α-methyl-9α-fluorohydrocortisone
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NIST Chemistry WebBook
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16α-methyl-9α-fluoro-1-dehydrocortisol
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NIST Chemistry WebBook
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9α-fluoro-16α-methylprednisolone
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NIST Chemistry WebBook
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Dexamethasone
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KEGG DRUG
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dexamethasone
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UniProt
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fluormethylprednisolone
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VSDB
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Aeroseb-Dex
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ChemIDplus
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Auxiron
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ChemIDplus
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Azium
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ChemIDplus
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Calonat
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ChemIDplus
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Corson
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ChEBI
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Cortisumman
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ChemIDplus
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Decacort
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ChEBI
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Decadron
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KEGG DRUG
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Decaject
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ChemIDplus
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Decalix
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ChemIDplus
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Decameth
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ChemIDplus
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Dexacortal
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ChemIDplus
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Dexacortin
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ChemIDplus
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Dexason
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ChemIDplus
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Dexasone
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ChemIDplus
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DexPak
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ChemIDplus
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Diodex
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ChEBI
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Hexadrol
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ChemIDplus
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Maxidex
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ChemIDplus
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Millicorten
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ChemIDplus
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Oradexon
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ChemIDplus
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Ozurdex
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ChEBI
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Solurex
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ChEBI
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Zema-Pak
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ChEBI
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2066652
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Beilstein Registry Number
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Beilstein
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2066652
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Reaxys Registry Number
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Reaxys
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50-02-2
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CAS Registry Number
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ChemIDplus
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50-02-2
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CAS Registry Number
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NIST Chemistry WebBook
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Nofal AM, Sayyed TM, Mahmoud HS, Atia TY (2021)
Effects of dexamethasone on foetal Doppler flow velocimetry.
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology 41, 390-394 [PubMed:32496907]
[show Abstract]
Corticosteroid administration before anticipated preterm birth is a well known antenatal therapy available to improve newborn outcomes. Doppler studies of maternal and foetal vessels provide a way to understand how corticosteroid affects and improves foetal respiratory outcome. This study was registered on 8th of October, 2017 by Menoufia Faculty of Medicine Board with registration number 222-2-10-2017. It included 80 pregnant women divided into two groups. Each group consisted of 40 participants. Group A: participants were between 28 weeks and 34 weeks of gestation and were at risk of preterm labour. Group B: participants were those who had undergone an elective caesarean section (CS) before completing the 39th week of gestation. Each woman had received four doses of Dexamethasone 6 mg intramuscularly, 12 h apart. Doppler studies were performed before the Dexamethasone adminstration and 24 h after the Dexamethasone course. Among both groups, only pregnant women before 34 weeks of gestation showed a significant decrease in middle cerebral artery pulsatility index. However, the other Doppler parameters showed no significant effect. In conclusion, Dexamethasone administration affected only the middle cerebral artery pulsatility index before 34 weeks of gestation.IMPACT STATEMENTWhat is already known on this subject? Preterm births account for 75% of neonatal morbidity and pulmonary dysfunction plays an important role on such morbidities. Also, neonates born after an elective CS have significantly higher rates of respiratory morbidity and neonatal intensive care unit admission. Corticosteroids are wildly used to improve neonatal outcome in women who have expected preterm labour and before an elective CS.What do the results of this study add? Dexamethasone affected blood distribution of foetal brain only before 34 weeks of gestation that had been proved by changes of foetal middle cerebral artery pulsatility index without affecting other Doppler parameters of both groups. With the improvement of foetal respiratory outcome in both groups.What are the implications of these finding for clinical practice and/or further research? Maternal Dexamethasone injection is recommended for mothers at risk of preterm labour, especially if delivery is expected within six days and mothers who will undergo elective CS before completion of 39 weeks of gestation, in terms of improving neonatal respiratory functions and decreasing the possibility of admission to neonatal intensive care unit for transient tachypnoea of the newborn. | Lang SS, Ploof J, Atkin NJ, Tran-Du K, Kanuga BM, Storm PB, Heuer G, Yuan I, Abend NS, Kirschen MP, Topjian AA, Li Y, Waanders AJ, Zorc JJ, Huh JW (2021)
Decadron, Diamox, and Zantac: A Novel Combination for Ventricular Shunt Failure in Pediatric Neurosurgical Patients.
Pediatric emergency care 37, e1444-e1450 [PubMed:32195984]
[show Abstract]
ObjectiveCerebral ventricular shunt failure is common and presents with symptoms that range from headaches to death. The combination of Diamox (acetazolamide), Decadron (dexamethasone), and Zantac (ranitidine) (DDZ) is used at our institution to medically stabilize pediatric patients presenting with symptomatic shunt failure before shunt revision. We describe our experience of this drug combination as a temporizing measure to decrease symptoms associated with shunt failure.MethodsWe performed a single-center retrospective chart review of patients younger than 18 years with ventricular shunt failure who underwent a shunt revision between January 2015 to October 2017 and received DDZ before surgery. The outcome variables evaluated included pre-DDZ and post-DDZ clinical symptoms, pain scores, and vital signs.ResultsThere were 112 cases that received DDZ before shunt revision. The 4 most commonly reported symptoms were analyzed. Headache was observed in 42 cases pre-DDZ, and post-DDZ there was a 71% reduction in headache (P < 0.0001); emesis was reported pre-DDZ in 76 cases, and post-DDZ there was an 83% reduction (P < 0.0001); irritability was noted pre-DDZ in 30 cases, and post-DDZ there was a 77% reduction (P = 0.0003); lethargy pre-DDZ was observed in 60 cases, and post-DDZ 73% demonstrated improvement (P < 0.0001). Maximum pain scores significantly decreased post-DDZ (P < 0.0001). Heart rate, systolic, and diastolic blood pressures significantly decreased post-DDZ (P < 0.0001, P < 0.0001, P = 0.0002, respectively).ConclusionsThe combination of Decadron, Diamox, and Zantac is a novel treatment for ventricular shunt failure that may temporarily improve symptoms in patients awaiting shunt revision. Future studies could compare efficacy with other medical treatments. | Qin Z, Li S, Zhang X, Liu G, Gu M, Zhang N, Liu J, Ji Z, Li K, Han Y, Zhai H (2020)
Combination Therapy of Wuweizi (Schisandrae Chinensis Fructus) and Dexamethasone Alleviated Dexamethasone-Induced Glucocorticoid Osteoporosis in Rats with Idiopathic Pulmonary Fibrosis.
BioMed research international 2020, 6301697 [PubMed:32280693]
[show Abstract]
ObjectiveTo investigate the therapeutic effect of combined application of Wuweizi (Schisandrae Chinensis Fructus) and dexamethasone in rats with idiopathic pulmonary fibrosis (IPF) and the possible protective effect of Wuweizi against dexamethasone-induced glucocorticoid osteoporosis (GIOP).MethodsThere were five groups in this study, including the sham operation group, model group, Wuweizi group, dexamethasone group, and the combination group. A rat IPF model was made by the endotracheal injection of bleomycin. After modeling, rats were given drug interventions for 7 and 28 days. Rats were sacrificed for pathological morphology examination of the bone and lung and quantitative determination of biochemical markers of bone metabolism and angiogenesis-related cytokine to observe therapeutic efficacy on the 7th and 28th day. ELISA was used for the quantitative determination of tartrate-resistant acid phosphatase (TRACP), bone alkaline phosphatase (BALP), hypoxia-inducible factor (HIF-1α), platelet-derived growth factor (PDGF), pigment epithelium-derived factor (PEDF), and endostatin in serum. The concentrations of calcium (Ca) and phosphorus (P) were detected with the automatic biochemical analyzer.ResultsAfter drug interventions for 7 and 28 days, alveolitis and pulmonary fibrosis in treatment groups showed significant improvement compared with those in the model group (P < 0.05). Bone histopathological figures showed severely damaged trabecular bone and bone marrow cavity in the dexamethasone group, but it was significantly alleviated in the combination group. The concentrations of BALP and Ca in the combination group were significantly higher than those in the dexamethasone group after treatment, while the concentrations of TRACP and P were lower than those in the dexamethasone group (P < 0.05). Bone histopathological figures showed severely damaged trabecular bone and bone marrow cavity in the dexamethasone group, but it was significantly alleviated in the combination group. The concentrations of BALP and Ca in the combination group were significantly higher than those in the dexamethasone group after treatment, while the concentrations of TRACP and P were lower than those in the dexamethasone group (α), platelet-derived growth factor (PDGF), pigment epithelium-derived factor (PEDF), and endostatin in serum. The concentrations of calcium (Ca) and phosphorus (P) were detected with the automatic biochemical analyzer. P < 0.05). Bone histopathological figures showed severely damaged trabecular bone and bone marrow cavity in the dexamethasone group, but it was significantly alleviated in the combination group. The concentrations of BALP and Ca in the combination group were significantly higher than those in the dexamethasone group after treatment, while the concentrations of TRACP and P were lower than those in the dexamethasone group (P < 0.05). Bone histopathological figures showed severely damaged trabecular bone and bone marrow cavity in the dexamethasone group, but it was significantly alleviated in the combination group. The concentrations of BALP and Ca in the combination group were significantly higher than those in the dexamethasone group after treatment, while the concentrations of TRACP and P were lower than those in the dexamethasone group (α), platelet-derived growth factor (PDGF), pigment epithelium-derived factor (PEDF), and endostatin in serum. The concentrations of calcium (Ca) and phosphorus (P) were detected with the automatic biochemical analyzer.ConclusionsThe combination therapy of Wuweizi and dexamethasone effectively treated IPF rats by regulating angiogenesis, meanwhile distinctly alleviating dexamethasone-induced GIOP. | Theoharides TC, Conti P (2020)
Dexamethasone for COVID-19? Not so fast.
Journal of biological regulators and homeostatic agents 34, 1241-1243 [PubMed:32551464]
[show Abstract]
Recent announcements indicated, without sharing any distinct published set of results, that the corticosteroid dexamethasone may reduce mortality of severe COVID-19 patients only. The recent Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2]-associated multiorgan disease, called COVID-19, has high morbidity and mortality due to autoimmune destruction of the lungs stemming from the release of a storm of pro-inflammatory cytokines. Defense against this Corona virus requires activated T cells and specific antibodies. Instead, cytokines are responsible for the serious sequelae of COVID-19 that damage the lungs. Dexamethasone is a synthetic corticosteroid approved by the FDA 1958 as a broad-spectrum immunosuppressor and it is about 30 times as active and with longer duration of action (2-3 days) than cortisone. Dexamethasone would limit the production of and damaging effect of the cytokines, but will also inhibit the protective function of T cells and block B cells from making antibodies, potentially leading to increased plasma viral load that will persist after a patient survives SARS. Moreover, dexamethasone would block macrophages from clearing secondary, nosocomial, infections. Hence, dexamethasone may be useful for the short-term in severe, intubated, COVID-19 patients, but could be outright dangerous during recovery since the virus will not only persist, but the body will be prevented from generating protective antibodies. Instead, a pulse of intravenous dexamethasone may be followed by administration of nebulized triamcinolone (6 times as active as cortisone) to concentrate in the lungs only. These corticosteroids could be given together with the natural flavonoid luteolin because of its antiviral and anti-inflammatory properties, especially its ability to inhibit mast cells, which are the main source of cytokines in the lungs. At the end, we should remember that "The good physician treats the disease; the great physician treats the patient who has the disease" [Sir William Osler's (1849-1919)]. | Selvaraj V, Dapaah-Afriyie K, Finn A, Flanigan TP (2020)
Short-Term Dexamethasone in Sars-CoV-2 Patients.
Rhode Island medical journal (2013) 103, 39-43 [PubMed:32570995]
[show Abstract]
BackgroundDexamethasone, a synthetic glucocorticoid, has anti-inflammatory and immunosuppressive properties. There is a hyperinflammatory response involved in the clinical course of patients with pneumonia due to SARS-CoV-2. To date, there has been no definite therapy for COVID-19. We reviewed the charts of SARS-CoV-2 patients with pneumonia and moderate to severely elevated CRP and worsening hypoxemia who were treated with early, short-term dexamethasone.MethodsWe describe a series of 21 patients who tested positive for SARS-CoV-2 and were admitted to The Miriam Hospital in Providence, RI, and were treated with a short course of dexamethasone, either alone or in addition to current investigative therapies.ResultsCRP levels decreased significantly following the start of dexamethasone from mean initial levels of 129.52 to 40.73 mg/L at time of discharge. 71% percent of the patients were discharged home with a mean length of stay of 7.8 days. None of the patients had escalation of care, leading to mechanical ventilation. Two patients were transferred to inpatient hospice facilities on account of persistent hypoxemia, in line with their documented goals of care.ConclusionsA short course of systemic corticosteroids among inpatients with SARS-CoV-2 with hypoxic respiratory failure was well tolerated, and most patients had improved outcomes. This limited case series may not offer concrete evidence towards the benefit of corticosteroids in COVID-19. However, patients' positive response to short-term corticosteroids demonstrates that they may help blunt the severity of inflammation and prevent a severe hyperinflammatory phase, in turn reducing the length of stay, ICU admissions, and healthcare costs. | Liu X, Wang Y, Ortlund EA (2019)
First High-Resolution Crystal Structures of the Glucocorticoid Receptor Ligand-Binding Domain-Peroxisome Proliferator-Activated γ Coactivator 1-α Complex with Endogenous and Synthetic Glucocorticoids.
Molecular pharmacology 96, 408-417 [PubMed:31391291]
[show Abstract]
Both synthetic and endogenous glucocorticoids are important pharmaceutic drugs known to bind to the ligand-binding domain (LBD) of glucocorticoid receptor (GR), a member of the nuclear receptor (NR) superfamily. Ligand binding induces conformational changes within GR, resulting in subsequent DNA binding and differential coregulator recruitment, ultimately activating or repressing target gene expression. One of the most crucial coregulators is peroxisome proliferator-activated γ coactivator 1-α (PGC1α), which acts to regulate energy metabolism by directly interacting with GR to modulate gene expression. However, the mechanisms through which PGC1α senses GR conformation to drive transcription are not completely known. Here, an ancestral variant of the GR (AncGR2) LBD was used as a tool to produce stable protein for biochemical and structural studies. PGC1α is found to interact more tightly and form a more stable complex with AncGR2 LBD than nuclear receptor coactivator 2. We report the first high-resolution X-ray crystal structures of AncGR2 LBD in complex with PGC1α and dexamethasone (DEX) or hydrocortisone (HCY). Structural analyses reveal how distinct steroid drugs bind to GR with different affinities by unique hydrogen bonds and hydrophobic interactions. Important charge clamps are formed between the activation function 2 and PGC1α to mediate their specific interactions. These interactions lead to a high level of protection from hydrogen-deuterium exchange at the coregulator interaction site and strong intramolecular allosteric communication to ligand binding site. This is the first structure detailing the GR-PGC1α interaction providing a foundation for future design of specific therapeutic agents targeting these critical metabolic regulators. SIGNIFICANCE STATEMENT: High-resolution structures of AncGR2 LBD bound to DEX and HCY in complex with PGC1α reveal the molecular mechanism of PGC1α binding to AncGR2 LBD as well as the distinct affinities between DEX and HCY binding. Identifying the structural mechanisms that drive drug affinity is of pharmacologic interest to the glucocorticoid receptor field as an avenue to guide future drug design targeting GR-PGC1α signaling, which plays a crucial role in controlling hepatic glucose output. | Aceituno S, Gozalbo I, Appierto M, Lizán L (2018)
Cost-effectiveness of lenalidomide in combination with dexamethasone compared to bortezomib in combination with dexamethasone for the second-line treatment of multiple myeloma in Chile.
Medwave 18, e7220 [PubMed:29958267]
[show Abstract]
BackgroundMultiple myeloma is a hematologic malignancy affecting bone marrow derived plasma cells. Current therapies are not able to eradicate the disease and most patients become refractory to the treatment. Lenalidomide and bortezomib have proved effective in the second-line treatment of these patients.ObjectiveTo evaluate the cost-effectiveness of lenalidomide in combination with dexamethasone compared to bortezomib in combination with dexamethasone in patients with multiple myeloma previously treated with bortezomib, from the perspective of the Chilean National Health Service.MethodologyA four-state Markov model (preprogression on treatment; preprogression off treatment, progression and death) was used to simulate the evolution of a cohort of multiple myeloma patients over a 25-year time horizon. Efficacy data, resource use and frequency of adverse events were extracted from MM009/010 studies and a retrospective analysis of retreatment with bortezomib. All inputs were validated by experts. A 3% annual discount rate was used for costs and health outcomes. The robustness of the results was evaluated through univariate and probabilistic sensitivity analyses.ResultsLenalidomide in combination with dexamethasone treatment provided 1.41 incremental life years and 0.83 incremental quality-adjusted life years in comparison with bortezomib in combination with dexamethasone, with an incremental cost of 11 864 597.86 CLP (19 589.86 US$). The incremental cost-effectiveness and cost-utility ratio were estimated at 8 410 266.92 CLP (13 886,35 US$) / incremental life year and 14 271 896.16 CLP (23 564,59 US$)/incremental quality-adjusted life years, respectively.ConclusionsLenalidomide in combination with dexamethasone represents a potentially cost-effective alternative for the second-line treatment of patients with multiple myeloma who are not eligible for transplantation, from the perspective of the Chilean National Health Service. | Edman K, Hosseini A, Bjursell MK, Aagaard A, Wissler L, Gunnarsson A, Kaminski T, Köhler C, Bäckström S, Jensen TJ, Cavallin A, Karlsson U, Nilsson E, Lecina D, Takahashi R, Grebner C, Geschwindner S, Lepistö M, Hogner AC, Guallar V (2015)
Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints.
Structure (London, England : 1993) 23, 2280-2290 [PubMed:26602186]
[show Abstract]
Steroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6-7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors. | Seitz T, Thoma R, Schoch GA, Stihle M, Benz J, D'Arcy B, Wiget A, Ruf A, Hennig M, Sterner R (2010)
Enhancing the stability and solubility of the glucocorticoid receptor ligand-binding domain by high-throughput library screening.
Journal of molecular biology 403, 562-577 [PubMed:20850457]
[show Abstract]
The human glucocorticoid receptor ligand-binding domain (hGR-LBD) is an important drug target for the treatment of various diseases. However, the low intrinsic stability and solubility of hGR-LBD have rendered its purification and biophysical characterization difficult. In order to overcome these problems, we have stabilized hGR-LBD by a combination of random mutagenesis and high-throughput screening using fluorescence-activated cell sorting (FACS) with enhanced green fluorescent protein (eGFP) as folding reporter. Two plasmid-encoded gene libraries of hGR-LBD fused to the egfp gene were expressed in Escherichia coli, followed by eight rounds of FACS screening, in each of which 10(8) cells were analyzed. The hgr-lbd mutants isolated by this approach contained numerous amino acid exchanges, and four beneficial ones (A605V, V702A, E705G, and M752T) were followed up in detail. Their characterization showed that the fluorescence of hGR-LBD-eGFP fusions is correlated linearly with the stability and solubility of hGR-LBD in the absence of eGFP. When combined, the four exchanges increased the thermal stability of hGR-LBD by more than 8 °C and enhanced its purification yield after expression in E. coli by about 26-fold. The introduction of three beneficial exchanges into the homologous ligand-binding domain of mouse enabled its X-ray structure determination at high resolution, which showed how the exchanges stabilize the protein and revealed atomic details that will guide future drug design. Our results demonstrate that large eGFP fusion libraries can be screened by FACS with extreme sensitivity and efficiency, yielding stabilized eukaryotic proteins suitable for biophysical characterization and structure determination. | Bridgham JT, Ortlund EA, Thornton JW (2009)
An epistatic ratchet constrains the direction of glucocorticoid receptor evolution.
Nature 461, 515-519 [PubMed:19779450]
[show Abstract]
The extent to which evolution is reversible has long fascinated biologists. Most previous work on the reversibility of morphological and life-history evolution has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters. Further, despite theoretical work on the factors that could contribute to irreversibility, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. Using ancestral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent 'restrictive' mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution. | Narang VS, Fraga C, Kumar N, Shen J, Throm S, Stewart CF, Waters CM (2008)
Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier.
American journal of physiology. Cell physiology 295, C440-50 [PubMed:18524938]
[show Abstract]
Brain edema is an important factor leading to morbidity and mortality associated with primary brain tumors. Dexamethasone, a synthetic glucocorticoid, is routinely prescribed with antineoplastic agents to alleviate pain associated with chemotherapy and reduce intracranial pressure. We investigated whether dexamethasone treatment increased the expression and activity of multidrug resistance (MDR) transporters at the blood-brain barrier. Treatment of primary rat brain microvascular endothelial cells with submicromolar concentrations of dexamethasone induced significantly higher levels of drug efflux transporters such as breast cancer resistance protein (abcg2), P-glycoprotein (P-gp; abcb1a/abcb1b), and MDR protein 2 (Mrp2; abcc2) as indicted by protein and mRNA levels as well as by functional activity. The effect of dexamethasone on transporter function was significant within 6 h of treatment, was dose dependent, and was reversible. Dexamethasone-induced upregulation of Bcrp and P-gp expression and function was partially abrogated by the glucocorticoid receptor (GR) antagonist RU486. In contrast, RU486 had no effect on the dexamethasone-induced upregulation of Mrp2, suggesting a GR-independent regulation of Mrp2, and a GR-dependent regulation of P-gp and Bcrp. In addition to the dexamethasone-induced upregulation of MDR transporters, we measured a dose-dependent and reversible increase in the expression of the nuclear transcription factor pregnane xenobiotic receptor (PXR). Administering dexamethasone to rats caused increased expression of PXR in brain microvessels within 24 h. These results suggest that adjuvant therapy with corticosteroids such as dexamethasone in the treatment of brain tumors may increase the expression of MDR transporters at the blood-brain barrier through pathways involving GR and PXR. | Hung SH, Yeh CH, Huang HT, Wu P, Ho ML, Chen CH, Wang C, Chao D, Wang GJ (2008)
Pioglitazone and dexamethasone induce adipogenesis in D1 bone marrow stromal cell line, but not through the peroxisome proliferator-activated receptor-gamma pathway.
Life sciences 82, 561-569 [PubMed:18272184]
[show Abstract]
Osteoblasts and adipocytes share a common progenitor in bone marrow. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a critical role in adipogenesis. Using a mouse pluripotent mesenchymal cell, D1, as a model, several reports have demonstrated that dexamethasone, a glucocorticoid, can induce adipogenesis. We first examined whether adipogenesis induction in D1 cells is initiated by activation of PPAR-gamma. The results revealed that pioglitazone induces adipogenesis in D1 cells in a dose-dependent manner and decreases alkaline phosphatase activity in D1 cells. Interestingly, this adipogenesis was not blocked by bisphenol A diglycidyl ether, a PPAR-gamma antagonist. A PPAR-gamma-mediated reporter gene assay showed no response to pioglitazone. We then asked whether dexamethasone-induced adipogenesis can be repressed by mifepristone (RU486), an antagonist of glucocorticoid receptor. The results disclosed that mifepristone cannot counteract dexamethasone-induced adipogenesis, and mifepristone itself induced adipogenesis in D1 cells. Moreover, glucocorticoid receptor-mediated reporter gene assay was not responsive to dexamethasone or mifepristone. We concluded that the adipogenesis induced by pioglitazone and dexamethasone in D1 cells may not occur via a PPAR-gamma and glucocorticoid receptor pathway. Finally, we analyzed the gene expression profile of D1 by cDNA microarray after treatment with dexamethasone. We found that the expression of several adipogenesis-related genes is highly provoked by this agent. | Kauppi B, Jakob C, Färnegårdh M, Yang J, Ahola H, Alarcon M, Calles K, Engström O, Harlan J, Muchmore S, Ramqvist AK, Thorell S, Ohman L, Greer J, Gustafsson JA, Carlstedt-Duke J, Carlquist M (2003)
The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism.
The Journal of biological chemistry 278, 22748-22754 [PubMed:12686538]
[show Abstract]
Here we describe the three-dimensional crystal structures of human glucocorticoid receptor ligand-binding domain (GR-LBD) in complex with the antagonist RU-486 at 2.3 A resolution and with the agonist dexamethasone ligand together with a coactivator peptide at 2.8 A. The RU-486 structure was solved in several different crystal forms, two with helix 12 intact (GR1 and GR3) and one with a protease-digested C terminus (GR2). In GR1, part of helix 12 is in a position that covers the co-activator pocket, whereas in the GR3, domain swapping is seen between the crystallographically identical subunits in the GR dimer. An arm consisting of the end of helix 11 and beyond stretches out from one molecule, and helix 12 binds to the other LBD, partly blocking the coactivator pocket of that molecule. This type of GR-LBD dimer has not been described before but might be an artifact from crystallization. Furthermore, the subunits of the GR3 dimers are covalently connected via a disulfide bond between the Cys-736 residues in the two molecules. All three RU-486 GR-LBD structures show that GR has a very flexible region between the end of helix 11 and the end of helix 12. | Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE (2002)
Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition.
Cell 110, 93-105 [PubMed:12151000]
[show Abstract]
Transcriptional regulation by the glucocorticoid receptor (GR) is mediated by hormone binding, receptor dimerization, and coactivator recruitment. Here, we report the crystal structure of the human GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2. Despite structural similarity to other steroid receptors, the GR LBD adopts a surprising dimer configuration involving formation of an intermolecular beta sheet. Functional studies demonstrate that the novel dimer interface is important for GR-mediated activation. The structure also reveals an additional charge clamp that determines the binding selectivity of a coactivator and a distinct ligand binding pocket that explains its selectivity for endogenous steroid hormones. These results establish a framework for understanding the roles of protein-hormone and protein-protein interactions in GR signaling pathways. | Matsumura M, Kakishita H, Suzuki M, Banba N, Hattori Y (2001)
Dexamethasone suppresses iNOS gene expression by inhibiting NF-kappaB in vascular smooth muscle cells.
Life sciences 69, 1067-1077 [PubMed:11508649]
[show Abstract]
Bacterial lipopolysaccharide (LPS) and other immunostimulants induce an isoform of nitric oxide synthase (iNOS) gene expression in vascular smooth muscle cells (VSMC). This process is dependent on nuclear factor-kappa B (NF-kappaB) activation and is suppressed by glucocorticoids. The aim of this study was to investigate the molecular mechanisms of inhibition of iNOS expression by the synthetic glucocorticoid, dexamethasone (DEX), in rat VSMC. Treatment of VSMC with LPS plus interferon-gamma (LPS/IFN) caused activation of NF-kappaB and the iNOS promoter. LPS/IFN induced iNOS mRNA and NO synthesis. DEX markedly depressed LPS/IFN-stimulated iNOS mRNA expression and NO production. DEX also suppressed LPS/IFN-stimulated activity of a 1.7-kb iNOS promoter, indicating that the inhibition of iNOS expression by DEX occurs at the level of transcription. NF-kappaB activation by LPS/IFN was repressed by DEX. The inhibition of NF-kappaB by DEX exhibited dose-dependent kinetics, which corresponded to DEX suppression of iNOS promoter activation, iNOS mRNA expression, and NO production. However, activation of activator protein-1 (AP-1), which is also contained in the iNOS promoter, was not enhanced by LPS/IFN or inhibited by DEX. Thus, glucocorticoids appear to block iNOS expression, at least in part, through inhibition of NF-kappaB activation, which results in decreased NO production. |
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2014-05-12
