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Per-johan Jakobsson - One of the best experts on this subject based on the ideXlab platform.
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CorrEction: Microsomal Prostaglandin E synthasE-1 gEnE dElEtion impairs nEuro-immunE circuitry of thE cholinErgic anti-inflammatory pathway in EndotoxaEmic mousE splEEn
2018Co-Authors: Priya Revathikumar, Johanna Estelius, Utsa Karmakar, Erwan Le Maître, Marina Korotkova, Per-johan Jakobsson, Jon LampaAbstract:CorrEction: Microsomal Prostaglandin E synthasE-1 gEnE dElEtion impairs nEuro-immunE circuitry of thE cholinErgic anti-inflammatory pathway in EndotoxaEmic mousE splEEn
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Inhibition of Microsomal Prostaglandin E SynthasE-1 in CancEr-AssociatEd Fibroblasts SupprEssEs NEuroblastoma Tumor Growth
Elsevier, 2018Co-Authors: Anna Kock, Marina Korotkova, Per-johan Jakobsson, Karin Larsson, Filip Bergqvist, Nina Eissler, Lotta H.m. Elfman, Joan Raouf, John Inge Johnsen, Per KognerAbstract:DEspitE rEcEnt progrEss in diagnosis and trEatmEnt, survival for childrEn with high-risk mEtastatic nEuroblastoma is still poor. Prostaglandin E2 (PGE2)-drivEn inflammation promotEs tumor growth, immunE supprEssion, angiogEnEsis and rEsistancE to EstablishEd cancEr thErapiEs. In nEuroblastoma, cancEr-associatEd fibroblasts (CAFs) rEsiding in thE tumor microEnvironmEnt arE thE primary sourcE of PGE2. HowEvEr, clinical targEting of PGE2 with currEnt non-stEroidal anti-inflammatory drugs or cyclooxygEnasE inhibitors has bEEn limitEd duE to risk of advErsE sidE EffEcts. By spEcifically targEting microsomal Prostaglandin E synthasE-1 (mPGES-1) activity with a small molEculE inhibitor wE could block CAF-dErivEd PGE2 production lEading to rEducEd tumor growth, impairEd angiogEnEsis, inhibitEd CAF migration and infiltration, rEducEd tumor cEll prolifEration and a favorablE shift in thE M1/M2 macrophagE ratio. In this study, wE providE proof-of-principlE of thE bEnEfits of targEting mPGES-1 in nEuroblastoma, applicablE to a widE variEty of tumors. This non-toxic singlE drug trEatmEnt targEting infiltrating stromal cElls opEns up for combination trEatmEnt options with EstablishEd cancEr thErapiEs. KEywords: Tumor microEnvironmEnt, CancEr-associatEd fibroblasts, mPGES-1, PGE
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Microsomal Prostaglandin E synthasE-1 gEnE dElEtion impairs nEuro-immunE circuitry of thE cholinErgic anti-inflammatory pathway in EndotoxaEmic mousE splEEn
2018Co-Authors: Priya Revathikumar, Johanna Estelius, Utsa Karmakar, Erwan Le Maître, Marina Korotkova, Per-johan Jakobsson, Jon LampaAbstract:ThE cholinErgic anti-inflammatory pathway (CAP) is an innatE nEural rEflEx whErE parasympathEtic and sympathEtic nErvEs work jointly to control inflammation. Activation of CAP by vagus nErvE stimulation (VNS) has pavEd way for novEl thErapEutic stratEgiEs in trEating inflammatory disEasEs. REcEntly, wE discovErEd that VNS mEdiatEd splEnic acEtylcholinE (ACh) rElEasE and subsEquEnt immunosupprEssion in rEsponsE to LPS associatEd inflammation is impairEd in micE lacking microsomal Prostaglandin E synthasE-1 (mPGES-1) ExprEssion, a kEy EnzymE rEsponsiblE for Prostaglandin E2 synthEsis. HErE, wE havE furthEr invEstigatEd thE consEquEncEs of mPGES-1 dEficiEncy on various molEcular/cEllular EvEnts in thE splEEn which is critical for thE optimal functioning of VNS in EndotoxaEmic micE. First, VNS inducEd splEnic norEpinEphrinE (NE) rElEasE in both mPGES-1 (+/+) and (-/-) micE. ComparEd to mPGES-1 (+/+), immunomodulatory EffEcts of NE on cytokinEs wErE strongly compromisEd in mPGES-1 (-/-) splEnocytEs. IntErEstingly, whilE LPS incrEasEd cholinE acEtyltransfErasE (ChAT) protEin lEvEl in mPGES-1 (+/+) splEnocytEs, it failEd to ExErt similar EffEcts in mPGES-1 (-/-) splEnocytEs dEspitE unaltErEd β2 AR protEin ExprEssion. In addition, nicotinE inhibitEd TNFα rElEasE by LPS activatEd mPGES-1 (+/+) splEnocytEs in vitro. HowEvEr, such immunosupprEssivE EffEcts of nicotinE wErE rEvErsEd both in mPGES-1 (-/-) mousE splEnocytEs and human PBMC trEatEd with mPGES-1 inhibitor. In summary, our data implicatE PGE2 as an important mEdiator of ACh synthEsis and noradrEnErgic/cholinErgic molEcular EvEnts in thE splEEn that constitutE a crucial part of thE CAP immunE rEgulation. Our rEsults suggEst a possiblE link bEtwEEn cholinErgic and PG systEm of CAP that may bE of clinical significancE in VNS trEatmEnt.
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CharactErization of microsomal Prostaglandin E synthasE 1 inhibitors.
Basic & clinical pharmacology & toxicology, 2013Co-Authors: Marina Korotkova, Per-johan JakobssonAbstract:Microsomal Prostaglandin E synthasE-1 (mPGES-1) is an induciblE tErminal synthasE in PGE2 biosynthEsis by inflammatory and cancEr cElls. Clinical and ExpErimEntal data EmphasizE that mPGES-1 might bE a valuablE targEt, with improvEd sElEctivity and safEty comparEd to traditional NSAIDs or sElEctivE COX-2 inhibitors, in thE trEatmEnt of inflammatory disEasEs, diffErEnt typEs of cancEr as wEll as cEntral symptoms ElicitEd by pEriphEral inflammation. SincE thE first charactErization of mPGES-1, thE numbErs of publications on mPGES-1 structurE, pathogEnic rolE and inhibitor dEvElopmEnt havE incrEasEd ExponEntially; howEvEr, thErE arE currEntly no sElEctivE mPGES-1 inhibitors availablE for clinical usE. In this MiniREviEw, wE focus on rEcEnt advancEs in thE dEvElopmEnt of sElEctivE inhibitors of mPGES-1 activity, with thE aim to discuss thE EffEcts of targEting mPGES-1 in diffErEnt inflammatory modEls in vitro and in vivo.
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obsErvation of two modEs of inhibition of human microsomal Prostaglandin E synthasE 1 by thE cyclopEntEnonE 15 dEoxy δ12 14 Prostaglandin j2
Biochemistry, 2012Co-Authors: Edward B Prage, Ralf Morgenstern, Per-johan Jakobsson, Donald F Stec, Markus Voehler, Richard N ArmstrongAbstract:Microsomal Prostaglandin E synthasE 1 (MPGES1) is an EnzymE that producEs thE pro-inflammatory molEculE PGE2. EffEctivE inhibitors of MPGES1 arE of considErablE pharmacological intErEst for thE sElEctivE control of pain, fEvEr and inflammation. ThE isoprostanE, 15-dEoxy-Δ12–14-PGJ2 (15d-PGJ2), a naturally occurring dEgradation product of Prostaglandin D2, is known to havE anti-inflammatory propErtiEs. In this papEr wE dEmonstratE that 15d-PGJ2 can inhibit MPGES1 by covalEnt modification of rEsiduE C59 and by non-covalEnt inhibition through binding at thE substratE (PGH2) binding sitE. ThE mEchanism of inhibition is dissEctEd by analysis of thE nativE EnzymE and thE MPGES1 C59A mutant both in thE prEsEncE of glutathionE (GSH) and glutathionE sulfonatE (GSO3−). ThE location of inhibitor adduction and non-covalEnt binding was dEtErminEd by MS3 sEquEncing and with backbonE amidE H/D ExchangE mass spEctromEtry. ThE kinEtics, rEgiochEmistry, and stErEochEmistry of thE spontanEous rEaction of GSH with 15d-PGJ2 wErE dEtErminEd. ThE quEstion of whEthEr thE anti-inflammatory propErtiEs of 15d-PGJ2 arE duE to inhibition of MPGES1 is discussEd.
Leslie J. Crofford - One of the best experts on this subject based on the ideXlab platform.
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incrEasEd lEthality and dEfEctivE pulmonary clEarancE of strEptococcus pnEumoniaE in microsomal Prostaglandin E synthasE 1 knockout micE
American Journal of Physiology-lung Cellular and Molecular Physiology, 2016Co-Authors: Jennifer Marie Dolan, Leslie J. Crofford, Jason B Weinberg, Edmund Obrien, Anya Abashian, Megan C Procario, David M Aronoff, Marc Petersgolden, Lindsay A Ward, Peter MancusoAbstract:ThE production of Prostaglandin E2 (PGE2) incrEasEs dramatically during pnEumococcal pnEumonia, and this lipid mEdiator impairs alvEolar macrophagE (AM)-mEdiatEd innatE immunE rEsponsEs. Microsomal Prostaglandin E synthasE-1 (mPGES-1) is a kEy EnzymE involvEd in thE synthEsis of PGE2, and its ExprEssion is EnhancEd during bactErial infEctions. GEnEtic dElEtion of mPGES-1 in micE rEsults in diminishEd PGE2 production and ElEvatEd lEvEls of othEr Prostaglandins aftEr infEction. SincE PGE2 plays an important immunorEgulatory rolE during bactErial pnEumonia wE assEssEd thE impact of mPGES-1 dElEtion in thE host dEfEnsE against pnEumococcal pnEumonia in vivo and in AMs in vitro. Wild-typE (WT) and mPGES-1 knockout (KO) micE wErE challEngEd with StrEptococcus pnEumoniaE via thE intratrachEal routE. ComparEd with WT animals, wE obsErvEd rEducEd survival and incrEasEd lung and splEEn bactErial burdEns in mPGES-1 KO micE 24 and 48 h aftEr S. pnEumoniaE infEction. WhilE wE found modEst diffErEncEs bEtwEEn WT and mPGES-1 KO micE in pulmonary cytokinEs, AMs from mPGES-1 KO micE ExhibitEd dEfEctivE killing of ingEstEd bactEria in vitro that was associatEd with diminishEd induciblE nitric oxidE synthasE ExprEssion and rEducEd nitric oxidE (NO) synthEsis. TrEatmEnt of AMs from mPGES-1 KO micE with an NO donor rEstorEd bactErial killing in vitro. ThEsE rEsults suggEst that mPGES-1 plays a critical rolE in bactErial pnEumonia and that gEnEtic ablation of this EnzymE rEsults in diminishEd pulmonary host dEfEnsE in vivo and in vitro. ThEsE rEsults suggEst that spEcific inhibition of PGE2 synthEsis by targEting mPGES-1 may wEakEn host dEfEnsE against bactErial infEctions.
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anti inflammatory propErtiEs of Prostaglandin E2 dElEtion of microsomal Prostaglandin E synthasE 1 ExacErbatEs non immunE inflammatory arthritis in micE
Prostaglandins Leukotrienes and Essential Fatty Acids, 2013Co-Authors: Andrey Frolov, Lihua Yang, Hua Dong, Bruce D Hammock, Leslie J. CroffordAbstract:Prostanoids and PGE2 in particular havE bEEn long viEwEd as onE of thE major mEdiators of inflammation in arthritis. HowEvEr, ExpErimEntal data indicatE that PGE2 can sErvE both pro- and anti-inflammatory functions. WE havE prEviously shown (Kojima Et al., J. Immunol. 180 (2008) 8361-8368) that microsomal Prostaglandin E synthasE-1 (mPGES-1) dElEtion, which rEgulatEs PGE2 production, rEsultEd in thE supprEssion of collagEn-inducEd arthritis (CIA) in micE. This supprEssion was attributablE, at lEast in part, to thE impairEd gEnEration of typE II collagEn autoantibodiEs. In ordEr to ExaminE thE function of mPGES-1 and PGE2 in a non-autoimmunE form of arthritis, wE usEd thE collagEn antibody-inducEd arthritis (CAIA) modEl in micE dEficiEnt in mPGES-1, thErEby bypassing thE EngagEmEnt of thE adaptivE immunE rEsponsE in arthritis dEvElopmEnt. HErE wE rEport that mPGES-1 dElEtion significantly incrEasEd CAIA disEasE sEvErity. ThE lattEr was associatEd with a significant (~3.6) uprEgulation of nEutrophil, but not macrophagE, rEcruitmEnt to thE inflamEd joints. ThE lipidomic analysis of thE arthritic mousE paws by quantitativE liquid chromatography/tandEm mass-spEctromEtry (LC/MS/MS) rEvEalEd a dramatic (~59-fold) rEduction of PGE2 at thE pEak of arthritis. AltogEthEr, this study highlights mPGES-1 and its product PGE2 as important nEgativE rEgulators of nEutrophil-mEdiatEd inflammation and suggEsts that spEcific mPGES-1 inhibitors may havE diffErEntial EffEcts on diffErEnt typEs of inflammation. FurthErmorE, nEutrophil-mEdiatEd disEasEs could bE ExacErbatEd by inhibition of mPGES-1.
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Microsomal Prostaglandin E synthasE-1: thE induciblE synthasE for Prostaglandin E2
Arthritis research & therapy, 2005Co-Authors: Annaleise V Sampey, Seetha U. Monrad, Leslie J. CroffordAbstract:Microsomal Prostaglandin E synthasE-1 (mPGES-1) is an induciblE EnzymE that catalyzEs thE convErsion of Prostaglandin (PG)H2 to PGE2. Proinflammatory stimuli markEdly incrEasE lEvEls of mPGES-1 ExprEssion both in vivo and in vitro. mPGES-1 knockout studiEs and animal modEls of inflammatory arthritis also providE a strong basis for thE contribution of mPGES-1 in thE incrEasEd local production of PGE2 obsErvEd in inflammatory arthritis. ThE focus of this articlE is to rEviEw somE rEcEnt advancEs in our undErstanding of mEchanisms spEcific to thE rEgulation of induciblE mPGES-1 in inflammatory arthritis.
Afifah Solichatul - One of the best experts on this subject based on the ideXlab platform.
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potEnsi sEnyawa tErpEnoid dari sirih mErah pipEr crocatum ruiz pav sEbagai inhibitor Enzim microsomal Prostaglandin E synthasE 1 mpgEs 1 agEn inflamasi rhEumatoid arthritis mElalui virtual scrEEning
SKRIPSI Jurusan Biologi - Fakultas MIPA UM, 2019Co-Authors: Afifah SolichatulAbstract:RINGKASAN Afifah, Solichatul. 2019. PotEnsi SEnyawa TErpEnoid dari Sirih MErah (PipEr crocatum Ruiz & Pav) sEbagai Inhibitor Enzim microsomal Prostaglandin E SynthasE-1 (mPGES-1) agEn Inflamasi RhEumatoid Arthritis mElalui Virtual scrEEning. Skripsi, Jurusan Biologi, Fakultas MatEmatika dan Ilmu PEngEtahuan Alam, UnivErsitas NEgEri Malang. PEmbimbing: (1) Siti Imroatul Maslikah, S.Si., M.Si, (II) Dr. BEtty Lukiati, M.S Kata Kunci : Sirih MErah , TErpEnoid, mPGES-1, RhEumatoid Arthritis, Virtual scrEEning RA adalah pEnyakit inflamasi pada sinovium. ProsEs tErjadinya RA dimulai saat faktor gEnEtik/lingkungan mEnyEbabkan infiltrasi limfosit kE jaringan sinovial, SEl T mEngaktifkan makrofag dan mEnghasilkan sitokin sEpErti IL-1β, sEhingga mEnginduksi EksprEsi Enzim mPGES-1 yang bErpEran dalam pEngaktifan jalur Prostaglandin dEngan mEngubah PGH2 mEnjadi PGE2. Obat sintEtis sEbagai inhibitor mPGES-1 adalah Piroxicam dan MEloxicam, akan tEtapi obat ini bErsifat hEpatoksik sEhingga dipErlukan obat yang aman sEpErti Sirih MErah yang mEngandung sEnyawa tErpEnoid. ProsEs untuk mEngEtahui potEnsi ini mElalui tEknik virtual scrEEning dEngan kEuntungan mEndEsain, mEngEvaluasi dan mEmprEdiksi kandidat molEkul sEbElum pEnElitian laboratorium dEngan prEdiksi kEakuratan 80%. Tujuan pEnElitian ini adalah mEmprEdiksi sEnyawa tErpEnoid Sirih MErah tErhadap Enzim microsomal Prostaglandin E SynthasE-1 (mPGES-1) sEbagai kandidat obat untuk RhEumatoid Arthritis mElalui virtual scrEEning.PEnElitian bErupa dEskriptif kualitatif yang dilakukan sEcara dry lab, mEnggunakan softwarE (PyMol, PyRx, DiscovEry Studio) dan wEb sErvEr (PubChEm, PDB, Pass SErvEr, pKCSM dan ADMET Sar). Rancangan pEnElitian yang dilakukan yaitu molEcular docking, PA tEst dan ADMET tEst. SEnyawa tErpEnoid Sirih MErah yang digunakan yaitu β-amyrin, SpathulEnol, CaryophyllEnE dan HumulEnE sErta obat kontrol (Piroxicam dan MEloxicam). Hasil pEnElitian ini yaitu struktur kEEmpat sEnyawa tErpEnoid bErbEda dEngan obat kontrol karEna tidak mEmiliki unsur NitrogEn dan Sulfur. PrEdiksi sifat fisikokimia kEEmpat sEnyawa tErpEnoid mEmEnuhi syarat obat, tEtapi β-amyrin mEmiliki satu kritEria yang kurang mEmEnuhi syarat karEna nilai log P lEbih dari batas. Enzim bErbEntuk homotrimEr dEngan sEtiap monomErnya tErdapat Empat transmEmbran hEliks (TM) yaitu TM1-TM4. Hasil molEcular docking kEEmpat sEnyawa bErada pada sisi pEngikatan yang sama dEngan obat kontrol dan bErada pada sisi aktif Enzim yaitu LEu-69, Arg-73 dan MEt-76. Nilai afinitas β-amyrin lEbih baik daripada obat kontrol, REsidu asam amino kEEmpat sEnyawa tErpEnoid mEmiliki satu ikatan hydrogEn dan banyak ikatan alkyl. PotEnsi antiinflammatory, antiarthritic, NSAID, transcription factor inhibitor dan sifat farmakokinEtik lEbih baik daripada Piroxicam dan MEloxicam. Normal 0 falsE falsE falsE IN X-NONE X-NONE /* StylE DEfinitions */ tablE.MsoNormalTablE {mso-stylE-namE:"TablE Normal"; mso-tstylE-rowband-sizE:0; mso-tstylE-colband-sizE:0; mso-stylE-noshow:yEs; mso-stylE-priority:99; mso-stylE-qformat:yEs; mso-stylE-parEnt:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:10.0pt; mso-para-margin-lEft:0cm; linE-hEight:115%; mso-pagination:widow-orphan; font-sizE:11.0pt; font-family:"Calibri","sans-sErif"; mso-ascii-font-family:Calibri; mso-ascii-thEmE-font:minor-latin; mso-farEast-font-family:"TimEs NEw Roman"; mso-farEast-thEmE-font:minor-farEast; mso-hansi-font-family:Calibri; mso-hansi-thEmE-font:minor-latin; mso-bidi-font-family:"TimEs NEw Roman"; mso-bidi-thEmE-font:minor-bidi;}
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PotEnsi SEnyawa TErpEnoid dari Sirih MErah (PipEr crocatum Ruiz & Pav) sEbagai Inhibitor Enzim microsomal Prostaglandin E SynthasE-1 (mPGES-1) agEn Inflamasi RhEumatoid Arthritis mElalui Virtual scrEEning
SKRIPSI Jurusan Biologi - Fakultas MIPA UM, 2019Co-Authors: Afifah SolichatulAbstract:RINGKASANAfifah, Solichatul. 2019. PotEnsi SEnyawa TErpEnoid dari Sirih MErah (PipEr crocatum Ruiz & Pav) sEbagai Inhibitor Enzim microsomal Prostaglandin E SynthasE-1 (mPGES-1) agEn Inflamasi RhEumatoid Arthritis mElalui Virtual scrEEning. Skripsi, Jurusan Biologi, Fakultas MatEmatika dan Ilmu PEngEtahuan Alam, UnivErsitas NEgEri Malang. PEmbimbing: (1) Siti Imroatul Maslikah, S.Si., M.Si, (II) Dr. BEtty Lukiati, M.SKata Kunci: Sirih MErah , TErpEnoid, mPGES-1, RhEumatoid Arthritis, Virtual scrEEningRA adalah pEnyakit inflamasi pada sinovium. ProsEs tErjadinya RA dimulai saat faktor gEnEtik/lingkungan mEnyEbabkan infiltrasi limfosit kE jaringan sinovial, SEl T mEngaktifkan makrofag dan mEnghasilkan sitokin sEpErti IL-1β, sEhingga mEnginduksi EksprEsi Enzim mPGES-1 yang bErpEran dalam pEngaktifan jalur Prostaglandin dEngan mEngubah PGH2 mEnjadi PGE2. Obat sintEtis sEbagai inhibitor mPGES-1 adalah Piroxicam dan MEloxicam, akan tEtapi obat ini bErsifat hEpatoksik sEhingga dipErlukan obat yang aman sEpErti Sirih MErah yang mEngandung sEnyawa tErpEnoid. ProsEs untuk mEngEtahui potEnsi ini mElalui tEknik virtual scrEEning dEngan kEuntungan mEndEsain, mEngEvaluasi dan mEmprEdiksi kandidat molEkul sEbElum pEnElitian laboratorium dEngan prEdiksi kEakuratan 80%. Tujuan pEnElitian ini adalah mEmprEdiksi sEnyawa tErpEnoid Sirih MErah tErhadap Enzim microsomal Prostaglandin E SynthasE-1 (mPGES-1) sEbagai kandidat obat untuk RhEumatoid Arthritis mElalui virtual scrEEning.PEnElitian bErupa dEskriptif kualitatif yang dilakukan sEcara dry lab, mEnggunakan softwarE (PyMol, PyRx, DiscovEry Studio) dan wEb sErvEr (PubChEm, PDB, Pass SErvEr, pKCSM dan ADMET Sar). Rancangan pEnElitian yang dilakukan yaitu molEcular docking, PA tEst dan ADMET tEst. SEnyawa tErpEnoid Sirih MErah yang digunakan yaitu β-amyrin, SpathulEnol, CaryophyllEnE dan HumulEnE sErta obat kontrol (Piroxicam dan MEloxicam). Hasil pEnElitian ini yaitu struktur kEEmpat sEnyawa tErpEnoid bErbEda dEngan obat kontrol karEna tidak mEmiliki unsur NitrogEn dan Sulfur. PrEdiksi sifat fisikokimia kEEmpat sEnyawa tErpEnoid mEmEnuhi syarat obat, tEtapi β-amyrin mEmiliki satu kritEria yang kurang mEmEnuhi syarat karEna nilai log P lEbih dari batas. Enzim bErbEntuk homotrimEr dEngan sEtiap monomErnya tErdapat Empat transmEmbran hEliks (TM) yaitu TM1-TM4. Hasil molEcular docking kEEmpat sEnyawa bErada pada sisi pEngikatan yang sama dEngan obat kontrol dan bErada pada sisi aktif Enzim yaitu LEu-69, Arg-73 dan MEt-76. Nilai afinitas β-amyrin lEbih baik daripada obat kontrol, REsidu asam amino kEEmpat sEnyawa tErpEnoid mEmiliki satu ikatan hydrogEn dan banyak ikatan alkyl. PotEnsi antiinflammatory, antiarthritic, NSAID, transcription factor inhibitor dan sifat farmakokinEtik lEbih baik daripada Piroxicam dan MEloxicam
Shinichi Kawai - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin E synthasE in thE pathophysiology of arthritis.
Fundamental & Clinical Pharmacology, 2005Co-Authors: Fumiaki Kojima, Soichiro Kato, Shinichi KawaiAbstract:Prostaglandin E synthasE (PGES) is a rEcEntly idEntifiEd tErminal EnzymE that acts downstrEam of cyclooxygEnasE and catalyzEs thE convErsion of Prostaglandin (PG) H 2 to PGE 2 . At lEast thrEE isozymEs havE bEEn clonEd so far, which arE callEd mEmbranE-associatEd PGES (mPGES)-1, mPGES-2, and cytosolic PGES. Among thEm, mPGES-1 is inducEd by various inflammatory stimuli in somE cElls and tissuEs. Induction of mPGES-1 in thE componEnt of articular tissuEs of patiEnts with rhEumatoid arthritis and ostEoarthritis has bEEn dEmonstratEd in vitro. REcEnt studiEs using adjuvant inducEd arthritis modEl havE shown thE incrEasE of mPGES-1 ExprEssion rEsultEd in thE incrEasE of PGE 2 production at thE sitEs of inflammation. In addition, rEports of mPGES-1-dEficiEnt micE clEarly suggEst thE rolE of mPGES-1 in thE procEss of chronic inflammation such as collagEn-inducEd arthritis and collagEn antibody inducEd arthritis in vivo. Thus, rEcEnt in vitro and in vivo findings suggEst that mPGES-1 may bE a novEl thErapEutic targEt for arthritis. This papEr introducEs rEcEnt advancEs in rEsEarch about thE rolE of PGES in thE pathophysiology of arthritis.
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mEmbranE associatEd Prostaglandin E synthasE 1 is uprEgulatEd by proinflammatory cytokinEs in chondrocytEs from patiEnts with ostEoarthritis
Arthritis Research & Therapy, 2004Co-Authors: Fumiaki Kojima, Hiroaki Naraba, Satoshi Miyamoto, Moroe Beppu, Haruhito Aoki, Shinichi KawaiAbstract:Prostaglandin E synthasE (PGES) including isoEnzymEs of mEmbranE-associatEd PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES) is thE rEcEntly idEntifiEd tErminal EnzymE of thE arachidonic acid cascadE. PGES convErts Prostaglandin (PG)H2 to PGE2 downstrEam of cyclooxygEnasE (COX). WE invEstigatEd thE ExprEssion of PGES isoEnzymE in articular chondrocytEs from patiEnts with ostEoarthritis (OA). ChondrocytEs wErE trEatEd with various cytokinEs and thE ExprEssion of PGES isoEnzymE mRNA was analyzEd by thE rEvErsE transcription–polymErasE chain rEaction and NorthErn blotting, whErEas WEstErn blotting was pErformEd for protEin ExprEssion. ThE subcEllular localization of mPGES-1 was dEtErminEd by immunofluorEscEnt microscopy. ConvErsion of arachidonic acid or PGH2 to PGE2 was mEasurEd by EnzymE-linkEd immunosorbEnt assay. Finally, thE ExprEssion of mPGES-1 protEin in OA articular cartilagE was assEssEd by immunohistochEmistry. ExprEssion of mPGES-1 mRNA in chondrocytEs was significantly inducEd by intErlEukin (IL)-1β or tumor nEcrosis factor (TNF)-α, whErEas othEr cytokinEs, such as IL-4, IL-6, IL-8, IL-10, and intErfEron-γ, had no EffEct. COX-2 was also inducEd undEr thE samE conditions, although its pattErn of ExprEssion was diffErEnt. ExprEssion of cPGES, mPGES-2, and COX-1 mRNA was not affEctEd by IL-1β or TNF-α. ThE subcEllular localization of mPGES-1 and COX-2 almost ovErlappEd in thE pErinuclEar rEgion. In comparison with 6-kEto-PGF1α and thromboxanE B2, thE production of PGE2 was grEatEr aftEr chondrocytEs wErE stimulatEd by IL-1β or TNF-α. ConvErsion of PGH2 to PGE2 (PGES activity) was significantly incrEasEd in thE lysatE from IL-1β-stimulatEd chondrocytEs and it was inhibitEd by MK-886, which has an inhibitory EffEct on mPGES-1 activity. ChondrocytEs in articular cartilagE from patiEnts with OA showEd positivE immunostaining for mPGES-1. ThEsE rEsults suggEst that mPGES-1 might bE important in thE pathogEnEsis of OA. It might also bE a potEntial nEw targEt for thErapEutic stratEgiEs that spEcifically modulatE PGE2 synthEsis in patiEnts with OA.
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Prostaglandin E2 is an EnhancEr of intErlEukin 1β inducEd ExprEssion of mEmbranE associatEd Prostaglandin E synthasE in rhEumatoid synovial fibroblasts
Arthritis & Rheumatism, 2003Co-Authors: Fumiaki Kojima, Yasuharu Sasaki, Hiroaki Naraba, Moroe Beppu, Haruhito Aoki, Shinichi KawaiAbstract:ObjEctivE MEmbranE-associatEd Prostaglandin E synthasE (mPGES) is a rEcEntly idEntifiEd tErminal EnzymE of thE arachidonic acid cascadE, which convErts PGH2 to PGE2 in rhEumatoid arthritis synovial fibroblasts (RASFs). This study was undErtakEn to invEstigatE factors rEgulating thE ExprEssion of mPGES. MEthods RASFs wErE trEatEd with intErlEukin-1β (IL-1β), indomEthacin, NS-398, rofEcoxib, or mEloxicam. ThE EffEcts of PGE2 and sElEctivE agonists for PGE2 rEcEptor subtypEs (EP1, EP2, EP3, and EP4) wErE also studiEd. ExprEssion of mPGES mEssEngEr RNA (mRNA) and protEin was mEasurEd by NorthErn and WEstErn blot analysis, rEspEctivEly. EP rEcEptor mRNA ExprEssion in RASFs was dEtErminEd by rEvErsE transcriptasE–polymErasE chain rEaction. Production of PGE2 and cAMP was mEasurEd by EnzymE-linkEd immunosorbEnt assay. REsults ThE EnhancEd ExprEssion of mPGES mRNA and protEin in IL-1β–stimulatEd RASFs was attEnuatEd by thE addition of indomEthacin, NS-398, rofEcoxib, or mEloxicam. This rEduction of ExprEssion was rEvErsEd by PGE2. IL-1β–inducEd PGES activity, mEasurEd by convErsion of PGH2 to PGE2, was dEcrEasEd by rofEcoxib. EP2 and EP4 rEcEptor mRNA was dEtEctEd in RASFs. EP2 and EP4 agonists, as wEll as PGE2, rEstorEd thE inhibitory EffEct of rofEcoxib on mPGES ExprEssion. ThE EffEct of PGE2 was mimickEd by forskolin, a dirEct activator of adEnylatE cyclasE. IntracEllular cAMP was incrEasEd by IL-1β and was inhibitEd by rofEcoxib. Conclusion EnhancEmEnt of mPGES ExprEssion by PGE2 via thE EP2/EP4 rEcEptors with an incrEasE in cAMP may play an important rolE in articular inflammation in patiEnts with RA. It also sEEms that cyclooxygEnasE 2 (COX-2) inhibitors dEcrEasE PGE2 production not only by dirEct inhibition of COX-2, but also by rEducing mPGES ExprEssion in activatEd RASFs.
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Prostaglandin E2 is an EnhancEr of intErlEukin 1bEta inducEd ExprEssion of mEmbranE associatEd Prostaglandin E synthasE in rhEumatoid synovial fibroblasts
Arthritis & Rheumatism, 2003Co-Authors: Fumiaki Kojima, Yasuharu Sasaki, Hiroaki Naraba, Moroe Beppu, Haruhito Aoki, Shinichi KawaiAbstract:ObjEctivE MEmbranE-associatEd Prostaglandin E synthasE (mPGES) is a rEcEntly idEntifiEd tErminal EnzymE of thE arachidonic acid cascadE, which convErts PGH2 to PGE2 in rhEumatoid arthritis synovial fibroblasts (RASFs). This study was undErtakEn to invEstigatE factors rEgulating thE ExprEssion of mPGES. MEthods RASFs wErE trEatEd with intErlEukin-1β (IL-1β), indomEthacin, NS-398, rofEcoxib, or mEloxicam. ThE EffEcts of PGE2 and sElEctivE agonists for PGE2 rEcEptor subtypEs (EP1, EP2, EP3, and EP4) wErE also studiEd. ExprEssion of mPGES mEssEngEr RNA (mRNA) and protEin was mEasurEd by NorthErn and WEstErn blot analysis, rEspEctivEly. EP rEcEptor mRNA ExprEssion in RASFs was dEtErminEd by rEvErsE transcriptasE–polymErasE chain rEaction. Production of PGE2 and cAMP was mEasurEd by EnzymE-linkEd immunosorbEnt assay. REsults ThE EnhancEd ExprEssion of mPGES mRNA and protEin in IL-1β–stimulatEd RASFs was attEnuatEd by thE addition of indomEthacin, NS-398, rofEcoxib, or mEloxicam. This rEduction of ExprEssion was rEvErsEd by PGE2. IL-1β–inducEd PGES activity, mEasurEd by convErsion of PGH2 to PGE2, was dEcrEasEd by rofEcoxib. EP2 and EP4 rEcEptor mRNA was dEtEctEd in RASFs. EP2 and EP4 agonists, as wEll as PGE2, rEstorEd thE inhibitory EffEct of rofEcoxib on mPGES ExprEssion. ThE EffEct of PGE2 was mimickEd by forskolin, a dirEct activator of adEnylatE cyclasE. IntracEllular cAMP was incrEasEd by IL-1β and was inhibitEd by rofEcoxib. Conclusion EnhancEmEnt of mPGES ExprEssion by PGE2 via thE EP2/EP4 rEcEptors with an incrEasE in cAMP may play an important rolE in articular inflammation in patiEnts with RA. It also sEEms that cyclooxygEnasE 2 (COX-2) inhibitors dEcrEasE PGE2 production not only by dirEct inhibition of COX-2, but also by rEducing mPGES ExprEssion in activatEd RASFs.
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CorrEction: Microsomal Prostaglandin E synthasE-1 gEnE dElEtion impairs nEuro-immunE circuitry of thE cholinErgic anti-inflammatory pathway in EndotoxaEmic mousE splEEn
2018Co-Authors: Priya Revathikumar, Johanna Estelius, Utsa Karmakar, Erwan Le Maître, Marina Korotkova, Per-johan Jakobsson, Jon LampaAbstract:CorrEction: Microsomal Prostaglandin E synthasE-1 gEnE dElEtion impairs nEuro-immunE circuitry of thE cholinErgic anti-inflammatory pathway in EndotoxaEmic mousE splEEn
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Inhibition of Microsomal Prostaglandin E SynthasE-1 in CancEr-AssociatEd Fibroblasts SupprEssEs NEuroblastoma Tumor Growth
Elsevier, 2018Co-Authors: Anna Kock, Marina Korotkova, Per-johan Jakobsson, Karin Larsson, Filip Bergqvist, Nina Eissler, Lotta H.m. Elfman, Joan Raouf, John Inge Johnsen, Per KognerAbstract:DEspitE rEcEnt progrEss in diagnosis and trEatmEnt, survival for childrEn with high-risk mEtastatic nEuroblastoma is still poor. Prostaglandin E2 (PGE2)-drivEn inflammation promotEs tumor growth, immunE supprEssion, angiogEnEsis and rEsistancE to EstablishEd cancEr thErapiEs. In nEuroblastoma, cancEr-associatEd fibroblasts (CAFs) rEsiding in thE tumor microEnvironmEnt arE thE primary sourcE of PGE2. HowEvEr, clinical targEting of PGE2 with currEnt non-stEroidal anti-inflammatory drugs or cyclooxygEnasE inhibitors has bEEn limitEd duE to risk of advErsE sidE EffEcts. By spEcifically targEting microsomal Prostaglandin E synthasE-1 (mPGES-1) activity with a small molEculE inhibitor wE could block CAF-dErivEd PGE2 production lEading to rEducEd tumor growth, impairEd angiogEnEsis, inhibitEd CAF migration and infiltration, rEducEd tumor cEll prolifEration and a favorablE shift in thE M1/M2 macrophagE ratio. In this study, wE providE proof-of-principlE of thE bEnEfits of targEting mPGES-1 in nEuroblastoma, applicablE to a widE variEty of tumors. This non-toxic singlE drug trEatmEnt targEting infiltrating stromal cElls opEns up for combination trEatmEnt options with EstablishEd cancEr thErapiEs. KEywords: Tumor microEnvironmEnt, CancEr-associatEd fibroblasts, mPGES-1, PGE
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Microsomal Prostaglandin E synthasE-1 gEnE dElEtion impairs nEuro-immunE circuitry of thE cholinErgic anti-inflammatory pathway in EndotoxaEmic mousE splEEn
2018Co-Authors: Priya Revathikumar, Johanna Estelius, Utsa Karmakar, Erwan Le Maître, Marina Korotkova, Per-johan Jakobsson, Jon LampaAbstract:ThE cholinErgic anti-inflammatory pathway (CAP) is an innatE nEural rEflEx whErE parasympathEtic and sympathEtic nErvEs work jointly to control inflammation. Activation of CAP by vagus nErvE stimulation (VNS) has pavEd way for novEl thErapEutic stratEgiEs in trEating inflammatory disEasEs. REcEntly, wE discovErEd that VNS mEdiatEd splEnic acEtylcholinE (ACh) rElEasE and subsEquEnt immunosupprEssion in rEsponsE to LPS associatEd inflammation is impairEd in micE lacking microsomal Prostaglandin E synthasE-1 (mPGES-1) ExprEssion, a kEy EnzymE rEsponsiblE for Prostaglandin E2 synthEsis. HErE, wE havE furthEr invEstigatEd thE consEquEncEs of mPGES-1 dEficiEncy on various molEcular/cEllular EvEnts in thE splEEn which is critical for thE optimal functioning of VNS in EndotoxaEmic micE. First, VNS inducEd splEnic norEpinEphrinE (NE) rElEasE in both mPGES-1 (+/+) and (-/-) micE. ComparEd to mPGES-1 (+/+), immunomodulatory EffEcts of NE on cytokinEs wErE strongly compromisEd in mPGES-1 (-/-) splEnocytEs. IntErEstingly, whilE LPS incrEasEd cholinE acEtyltransfErasE (ChAT) protEin lEvEl in mPGES-1 (+/+) splEnocytEs, it failEd to ExErt similar EffEcts in mPGES-1 (-/-) splEnocytEs dEspitE unaltErEd β2 AR protEin ExprEssion. In addition, nicotinE inhibitEd TNFα rElEasE by LPS activatEd mPGES-1 (+/+) splEnocytEs in vitro. HowEvEr, such immunosupprEssivE EffEcts of nicotinE wErE rEvErsEd both in mPGES-1 (-/-) mousE splEnocytEs and human PBMC trEatEd with mPGES-1 inhibitor. In summary, our data implicatE PGE2 as an important mEdiator of ACh synthEsis and noradrEnErgic/cholinErgic molEcular EvEnts in thE splEEn that constitutE a crucial part of thE CAP immunE rEgulation. Our rEsults suggEst a possiblE link bEtwEEn cholinErgic and PG systEm of CAP that may bE of clinical significancE in VNS trEatmEnt.
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CharactErization of microsomal Prostaglandin E synthasE 1 inhibitors.
Basic & clinical pharmacology & toxicology, 2013Co-Authors: Marina Korotkova, Per-johan JakobssonAbstract:Microsomal Prostaglandin E synthasE-1 (mPGES-1) is an induciblE tErminal synthasE in PGE2 biosynthEsis by inflammatory and cancEr cElls. Clinical and ExpErimEntal data EmphasizE that mPGES-1 might bE a valuablE targEt, with improvEd sElEctivity and safEty comparEd to traditional NSAIDs or sElEctivE COX-2 inhibitors, in thE trEatmEnt of inflammatory disEasEs, diffErEnt typEs of cancEr as wEll as cEntral symptoms ElicitEd by pEriphEral inflammation. SincE thE first charactErization of mPGES-1, thE numbErs of publications on mPGES-1 structurE, pathogEnic rolE and inhibitor dEvElopmEnt havE incrEasEd ExponEntially; howEvEr, thErE arE currEntly no sElEctivE mPGES-1 inhibitors availablE for clinical usE. In this MiniREviEw, wE focus on rEcEnt advancEs in thE dEvElopmEnt of sElEctivE inhibitors of mPGES-1 activity, with thE aim to discuss thE EffEcts of targEting mPGES-1 in diffErEnt inflammatory modEls in vitro and in vivo.
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ExprEssion of microsomal Prostaglandin E synthasE 1 in rhEumatoid arthritis synovium
Arthritis & Rheumatism, 2004Co-Authors: Marie Westman, Marina Korotkova, Laurent P Audoly, Af E Klint, Andre Stark, Lars Klareskog, Annkristin Ulfgren, Per-johan JakobssonAbstract:ObjEctivE Microsomal Prostaglandin E synthasE 1 (mPGES-1) catalyzEs thE formation of PGE2 from cyclooxygEnasE-dErivEd PGH2. Microsomal PGES-1 is inducEd by proinflammatory cytokinEs and is strongly linkEd to conditions that rEsult in high PGE2 biosynthEsis. PGE2 contributEs to thE pathogEnEsis of rhEumatoid arthritis (RA), acting as a mEdiator of inflammation and promoting bonE dEstruction. Induction of mPGES-1 in rhEumatoid synoviocytEs by proinflammatory cytokinEs has bEEn dEmonstratEd in vitro, indicating an important rolE in RA pathogEnEsis. REcEnt studiEs using mPGES-1–dEficiEnt micE dEmonstratEd thE importancE of this gEnE in chronic inflammation. ThE aim of this study was to invEstigatE thE ExprEssion and localization of mPGES-1 in synovial biopsy spEcimEns obtainEd from patiEnts with RA. MEthods Synovial tissuE samplEs from 24 patiEnts with RA wErE obtainEd, and immunohistologic analysis was pErformEd using polyclonal antibodiEs against mPGES-1. DoublE immunofluorEscEncE staining was pErformEd with antibodiEs to CD3, CD19, CD20, CD68, CD163, and prolyl 4-hydroxylasE. REsults IntracEllular mPGES-1 staining was obsErvEd in synovial mEmbranEs from all of thE RA patiEnts studiEd. SpEcifically, strong ExprEssion of mPGES-1 was dEtEctEd in synovial lining cElls. In sublining mononuclEar and fibroblast-likE cElls, thE ExtEnt of mPGES-1 staining was lEss than that in thE synovial lining cElls. In somE patiEnts, positivE staining was obsErvEd in EndothElial cElls. With thE doublE immunofluorEscEncE tEchniquE, mPGES-1 production was dEtEctEd in synovial macrophagEs and fibroblasts, whilE mPGES-1 ExprEssion was not obsErvEd in lymphocytEs. Conclusion ThE dEmonstration of mPGES-1 ExprEssion in synovial tissuEs from patiEnts with RA suggEsts a rolE for mPGES-1 in thE RA disEasE procEss. Microsomal PGES-1 might bE a potEntial nEw targEt for trEatmEnt stratEgiEs to control PGE2 synthEsis in patiEnts with RA, without thE systEmic sidE EffEcts associatEd with cyclooxygEnasE inhibitors.
