208 results on '"Jakobsson PJ"'
Search Results
2. A6.36 Characterisation of anti-JO1 autoantibodies in myositis
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Fernandes-Cerqueira, C, Lundberg, I, and Jakobsson, PJ
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- 2015
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3. A2.1 The effect of mPGES-1 deletion on platelet function in mice
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Raouf, J, Mobarrez, F, Larsson, K, Jakobsson, PJ, and Korotkova, M
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- 2015
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4. A2.22 Influence of TNF on the proteome of rheumatoid arthritis synovial fibroblasts
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Ossipova, E, Wähämaa, H, Klareskog, L, Catrina, AI, and Jakobsson, PJ
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- 2015
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5. Circular disulfide-rich peptide scaffolds as anti-citrullinated peptide antibody inhibitors
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Gunasekera, S, additional, Fernandes-Cerqueira, C, additional, Eriksson, C, additional, Jakobsson, PJ, additional, and Göransson, U, additional
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- 2016
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6. A1.27 MPGES-1 deletion increases prostacyclin and evades the elevated systemic ADMA associated with COX-2 inhibitors: relevance to cardiovascular safety of mpges-1 inhibitors
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Raouf, J, primary, Kirkby, NS, additional, Ahmetaj-Shala, B, additional, Liu, B, additional, Mazi, SI, additional, Korotkova, M, additional, Zhou, Y, additional, Mitchell, JA, additional, and Jakobsson, PJ, additional
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- 2016
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7. A8.07 Characterising effects of epigenetic regulation in assays using peripheral blood mononuclear cells from patients with inflammatory diseases
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Aftab, O, primary, Sundström, Y, additional, Bergqvist, F, additional, Kultima, K, additional, Gustafsson, MG, additional, Larsson, R, additional, Sundström, M, additional, Ossipova, E, additional, Lengqvist, J, additional, Jakobsson, PJ, additional, Rubin, J, additional, and Berg, L, additional
- Published
- 2016
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8. A9.01 Characterisation of extracellular histidyl-trnasynthethase in myositis
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Fernandes-Cerqueira, C, primary, Sohrabian, A, additional, Albrecht, I, additional, Notarnicola, A, additional, Ossipova, E, additional, Lengqvist, J, additional, Fathi, M, additional, Pruijn, GJ, additional, Grunewald, J, additional, Rönnelid, J, additional, Lundberg, IE, additional, and Jakobsson, PJ, additional
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- 2016
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9. A6.15 Characterisation of systemic lupus erythematosus subgroups with features of antiphospholipid or sjögrens´s syndrome utilising affinity proteomics
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Idborg, H, primary, Zandian, A, additional, Gustafsson, JT, additional, Gunnarsson, I, additional, Svenungsson, E, additional, Nilsson, P, additional, and Jakobsson, PJ, additional
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- 2016
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10. A6.14 Dysregulations in the sphingolipid pathway in sle patients
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Checa, A, primary, Idborg, H, additional, Sar, D Garcia, additional, Jakobsson, PJ, additional, Wheelock, CE, additional, and Gunnarsson, I, additional
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- 2016
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11. Divergent effects of hyperforin on the release of arachidonic acid in human platelets and polymorphonuclear leukocytes
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Hoffmann, M, primary, Feisst, C, additional, Jakobsson, PJ, additional, Steinhilber, D, additional, and Werz, O, additional
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- 2008
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12. Lack of microsomal prostaglandin E(2) synthase-1 in bone marrow-derived myeloid cells impairs left ventricular function and increases mortality after acute myocardial infarction.
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Degousee N, Simpson J, Fazel S, Scholich K, Angoulvant D, Angioni C, Schmidt H, Korotkova M, Stefanski E, Wang XH, Lindsay TF, Ofek E, Pierre S, Butany J, Jakobsson PJ, Keating A, Li RK, Nahrendorf M, Geisslinger G, and Backx PH
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- 2012
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13. Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial infarction.
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Degousee N, Fazel S, Angoulvant D, Stefanski E, Pawelzik SC, Korotkova M, Arab S, Liu P, Lindsay TF, Zhuo S, Butany J, Li RK, Audoly L, Schmidt R, Angioni C, Geisslinger G, Jakobsson PJ, Rubin BB, Degousee, Norbert, and Fazel, Shafie
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- 2008
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14. NG2 glia protect against prion neurotoxicity by inhibiting microglia-to-neuron prostaglandin E2 signaling.
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Liu Y, Guo J, Matoga M, Korotkova M, Jakobsson PJ, and Aguzzi A
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- Animals, Mice, Mice, Inbred C57BL, Antigens metabolism, Proteoglycans metabolism, Receptors, Prostaglandin E, EP4 Subtype metabolism, Prions metabolism, Prions toxicity, Cerebellum metabolism, Cerebellum pathology, Microglia metabolism, Dinoprostone metabolism, Signal Transduction physiology, Neurons metabolism, Neurons drug effects, Neurons pathology, Neuroglia metabolism, Prion Diseases metabolism, Prion Diseases pathology
- Abstract
Oligodendrocyte-lineage cells, including NG2 glia, undergo prominent changes in various neurodegenerative disorders. Here, we identify a neuroprotective role for NG2 glia against prion toxicity. NG2 glia were activated after prion infection in cerebellar organotypic cultured slices (COCS) and in brains of prion-inoculated mice. In both model systems, depletion of NG2 glia exacerbated prion-induced neurodegeneration and accelerated prion pathology. Loss of NG2 glia enhanced the biosynthesis of prostaglandin E2 (PGE2) by microglia, which augmented prion neurotoxicity through binding to the EP4 receptor. Pharmacological or genetic inhibition of PGE2 biosynthesis attenuated prion-induced neurodegeneration in COCS and mice, reduced the enhanced neurodegeneration in NG2-glia-depleted COCS after prion infection, and dampened the acceleration of prion disease in NG2-glia-depleted mice. These data unveil a non-cell-autonomous interaction between NG2 glia and microglia in prion disease and suggest that PGE2 signaling may represent an actionable target against prion diseases., (© 2024. The Author(s).)
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- 2024
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15. High-mannose glycans from Schistosoma mansoni eggs are important for priming of Th2 responses via Dectin-2 and prostaglandin E2.
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Almeida L, van Roey R, Patente TA, Otto F, Veldhuizen T, Ghorasaini M, van Diepen A, Schramm G, Liu J, Idborg H, Korotkova M, Jakobsson PJ, Giera M, Hokke CH, and Everts B
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- Animals, Mice, Antigens, Helminth immunology, Dendritic Cells immunology, Dendritic Cells metabolism, Mice, Inbred C57BL, Ovum immunology, Ovum metabolism, OX40 Ligand metabolism, Schistosomiasis mansoni immunology, Schistosomiasis mansoni metabolism, Schistosomiasis mansoni parasitology, Dinoprostone metabolism, Lectins, C-Type metabolism, Lectins, C-Type immunology, Mannose metabolism, Mannose immunology, Polysaccharides immunology, Polysaccharides metabolism, Schistosoma mansoni immunology, Th2 Cells immunology, Th2 Cells metabolism
- Abstract
The parasitic helminth Schistosoma mansoni is a potent inducer of type 2 immune responses by stimulating dendritic cells (DCs) to prime T helper 2 (Th2) responses. We previously found that S. mansoni soluble egg antigens (SEA) promote the synthesis of Prostaglandin E
2 (PGE2) by DCs through ERK-dependent signaling via Dectin-1 and Dectin-2 that subsequently induces OX40L expression, licensing them for Th2 priming, yet the ligands present in SEA involved in driving this response and whether specific targeting of PGE2 synthesis by DCs could affect Th2 polarization are unknown. We here show that the ability of SEA to bind Dectin-2 and drive ERK phosphorylation, PGE2 synthesis, OX40L expression, and Th2 polarization is impaired upon cleavage of high-mannose glycans by Endoglycosidase H treatment. This identifies high-mannose glycans present on glycoproteins in SEA as important drivers of this signaling axis. Moreover, we find that OX40L expression and Th2 induction are abrogated when microsomal prostaglandin E synthase-1 (mPGES) is selectively inhibited, but not when a general COX-1/2 inhibitor is used. This shows that the de novo synthesis of PGE2 is vital for the Th2 priming function of SEA-stimulated DCs as well as points to the potential existence of other COX-dependent lipid mediators that antagonize PGE2-driven Th2 polarization. Lastly, specific PGE2 inhibition following immunization with S. mansoni eggs dampened the egg-specific Th cell response. In summary, our findings provide new insights in the molecular mechanisms underpinning Th2 induction by S. mansoni and identify druggable targets for potential control of helminth driven-Th2 responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Almeida, van Roey, Patente, Otto, Veldhuizen, Ghorasaini, van Diepen, Schramm, Liu, Idborg, Korotkova, Jakobsson, Giera, Hokke and Everts.)- Published
- 2024
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16. Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis.
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Liu J, Idborg H, Korotkova M, Lend K, van Vollenhoven R, Lampa J, Rudin A, Nordström D, Gudbjornsson B, Gröndal G, Uhlig T, Hørslev-Petersen K, Lund Hetland M, Østergaard M, Nurmohamed M, and Jakobsson PJ
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- Humans, Female, Prostaglandins, Tumor Necrosis Factor Inhibitors, Methotrexate, Certolizumab Pegol, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy, Dimaprit analogs & derivatives
- Abstract
Background: Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient's response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy., Methods: This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B
2 (TXBM), 2,3-dinor-6-keto prostaglandin F1a (PGIM), leukotriene E4 (LTE4 ) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography-mass spectrometry (LC-MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes., Results: Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24., Conclusions: Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy., (© 2024. The Author(s).)- Published
- 2024
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17. In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation.
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Pertsinidou E, Saevarsdottir S, Manivel VA, Klareskog L, Alfredsson L, Mathsson-Alm L, Hansson M, Cornillet M, Serre G, Holmdahl R, Skriner K, Jakobsson PJ, Westerlind H, Askling J, and Rönnelid J
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- Humans, Inflammation, Autoantibodies, Peptides, Cyclic, Immunoglobulin G, Immunoglobulin M, Immunoglobulin A, Rheumatoid Factor, Arthritis, Rheumatoid
- Abstract
Objectives: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis., Methods: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline., Results: Individually, all autoantibodies except immunoglobulin G (IgG) RF associated with low SJC and TJC and with high ESR. In IgM RF-negative patients, ACPA associated strictly with low number of swollen and tender joints. This association persisted in multiple regression and stratified analyses where IgM and IgA RF instead associated with inflammation expressed as ESR. Among subjects without any ACPA peptide reactivity, there was no association between RF isotypes and ESR. The effect of RF on ESR increased with the number of ACPA reactivities, especially for IgM RF. In patients fulfilling the 1987 ACR criteria without taking RF into account, associations between IgM RF and high ESR, as well as between ACPA and low joint counts, remained., Conclusion: Whereas ACPA associate with low counts of affected joints in early RA, RF associates with elevated measures of systemic inflammation in an ACPA-dependent manner. This latter finding corroborates in vitro models of ACPA and RF in immune complex-induced inflammation. These phenotypic associations are independent of classification criteria., Competing Interests: Competing interests: EP and LM-A are employees at Thermo Fisher Scientific. JA has had or have research agreements with AbbVie, BMS, Eli Lilly, Galapagos, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, mainly for the national safety monitoring of rheumatology immunomodulators in Sweden (ARTIS). JR has been a member of the Scientific Advisory Board for Thermo Fisher Scientific and for Inova/Werfen and has received consulting fees, speaking fees and/ or honoraria by Thermo Fisher Scientific. RH has received consulting fees from Regor, Lipum AB and Cyxone AB and is the founder of Vacara AB. LK has been a co-ordinator of several IMI-funded projects which included collaborations with Janssen, Pfizer, Sanofi, UCB, GSK and Eli-Lilly. This work has been presented as a poster in a preliminary form at EULAR (June 2019) and to the European Workshop for Rheumatology Research (March 2023)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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18. High-content screening of drug combinations of an mPGES-1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance.
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Zaghmi A, Aybay E, Jiang L, Shang M, Steinmetz-Späh J, Wermeling F, Kogner P, Korotkova M, Östling P, Jakobsson PJ, Seashore-Ludlow B, and Larsson K
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- Humans, Prostaglandin-E Synthases, Spheroids, Cellular, Drug Discovery methods, Drug Resistance, Neoplasm, Neuroblastoma drug therapy
- Abstract
High-throughput drug screening enables the discovery of new anticancer drugs. Although monolayer cell cultures are commonly used for screening, their limited complexity and translational efficiency require alternative models. Three-dimensional cell cultures, such as multicellular tumor spheroids (MCTS), mimic tumor architecture and offer promising opportunities for drug discovery. In this study, we developed a neuroblastoma MCTS model for high-content drug screening. We also aimed to decipher the mechanisms underlying synergistic drug combinations in this disease model. Several agents from different therapeutic categories and with different mechanisms of action were tested alone or in combination with selective inhibition of prostaglandin E
2 by pharmacological inhibition of microsomal prostaglandin E synthase-1 (mPGES-1). After a systematic investigation of the sensitivity of individual agents and the effects of pairwise combinations, GFP-transfected MCTS were used in a confirmatory screen to validate the hits. Finally, inhibitory effects on multidrug resistance proteins were examined. In summary, we demonstrate how MCTS-based high-throughput drug screening has the potential to uncover effective drug combinations and provide insights into the mechanism of synergy between an mPGES-1 inhibitor and chemotherapeutic agents., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)- Published
- 2024
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19. Failure to apply standard limit-of-detection or limit-of-quantitation criteria to specialized pro-resolving mediator analysis incorrectly characterizes their presence in biological samples.
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O'Donnell VB, Schebb NH, Milne GL, Murphy MP, Thomas CP, Steinhilber D, Gelhaus SL, Kühn H, Gelb MH, Jakobsson PJ, Blair IA, Murphy RC, Freeman BA, Brash AR, and FitzGerald GA
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- Humans, Docosahexaenoic Acids, Inflammation
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- 2023
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20. Microsomal prostaglandin E synthase-1 inhibition prevents adverse cardiac remodelling after myocardial infarction in mice.
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Zhang Y, Steinmetz-Späh J, Idborg H, Zhu L, Li H, Rao H, Chen Z, Guo Z, Hu L, Xu C, Chen H, Korotkova M, Jakobsson PJ, and Wang M
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- Animals, Mice, Prostaglandin-E Synthases metabolism, Celecoxib pharmacology, Cicatrix, Ventricular Remodeling, Stroke Volume, Cyclooxygenase 2 Inhibitors, Heart Failure, Myocardial Infarction genetics
- Abstract
Background and Purpose: Heart failure with reduced ejection fraction (HFrEF) is a major consequence of myocardial infarction (MI). The microsomal prostaglandin E synthase-1 (mPGES-1)/PGE
2 pathway has been shown to constrain reperfusion injury after acute myocardial ischaemia. However, it is unknown whether pharmacological inhibition of mPGES-1, a target with lower risk of thrombosis compared with selective inhibition of cyclooxygenase-2, affects chronic cardiac remodelling after MI., Experimental Approach: Mice were subjected to left anterior descending coronary artery ligation, followed by intraperitoneal treatment with the mPGES-1 inhibitor compound III (CIII) or 118, celecoxib (cyclooxygenase-2 inhibitor) or vehicle, once daily for 28 days. Urinary prostanoid metabolites were measured by liquid chromatography-tandem mass spectrometry., Key Results: Chronic administration of CIII improved cardiac function in mice after MI compared with vehicle or celecoxib. CIII did not affect thrombogenesis or blood pressure. In addition, CIII reduced infarct area, augmented scar thickness, decreased collagen I/III ratio, decreased the expression of fibrosis-related genes and increased capillary density in the ischaemic area. Shunting to urinary metabolites of PGI2 , not thromboxane B2 or PGD2 , after inhibition of mPGES-1 was positively correlated with cardiac function after MI. CIII administration significantly increased urinary PGI2 /PGE2 metabolite ratio compared to vehicle or celecoxib. The PGI2 /PGE2 metabolite ratio correlated positively with ejection fraction, fractional shortening and scar thickness. Treatment with 118 also improved cardiac function., Conclusion and Implications: Inhibition of mPGES-1 prevented chronic adverse cardiac remodelling via an augmented PGI2 /PGE2 metabolite ratio and therefore represents a potential therapeutic strategy for development of HFrEF after MI., (© 2023 British Pharmacological Society.)- Published
- 2023
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21. Microsomal prostaglandin E synthase-1 inhibition promotes shunting in arachidonic acid metabolism during inflammatory responses in vitro.
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Liu J, Peng B, Steinmetz-Späh J, Idborg H, Korotkova M, and Jakobsson PJ
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- Mice, Animals, Prostaglandin-E Synthases metabolism, Cyclooxygenase 2 metabolism, Arachidonic Acid, Dinoprostone metabolism, Eicosanoids, Prostaglandins, Inflammation drug therapy, Inflammation metabolism
- Abstract
Microsomal Prostaglandin E Synthase 1 (mPGES-1) is the key enzyme for the generation of the pro-inflammatory lipid mediator prostaglandin E
2 (PGE2 ), which contributes to several pathological features of many diseases. Inhibition of mPGES-1 has been shown to be a safe and effective therapeutic strategy in various pre-clinical studies. In addition to reduced PGE2 formation, it is also suggested that the potential shunting into other protective and pro-resolving prostanoids may play an important role in resolution of inflammation. In the present study, we analysed the eicosanoid profiles in four in vitro inflammation models and compared the effects of mPGES-1 inhibition with those of cyclooxygenase-2 (Cox-2) inhibition. Our results showed a marked shift to the PGD2 pathway under mPGES-1 inhibition in A549 cells, RAW264.7 cells and mouse bone marrow-derived macrophages (BMDMs), whereas enhanced prostacyclin production was observed in rheumatoid arthritis synovial fibroblasts (RASFs) treated with an mPGES-1 inhibitor. As expected, Cox-2 inhibition completely suppressed all prostanoids. This study suggests that the therapeutic effects of mPGES-1 inhibition may be mediated by modulation of other prostanoids in addition to PGE2 reduction., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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22. The anti-inflammatory and vasoprotective properties of mPGES-1 inhibition offer promising therapeutic potential.
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Steinmetz-Späh J and Jakobsson PJ
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- Female, Humans, Prostaglandin-E Synthases metabolism, Dinoprostone metabolism, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Cyclooxygenase 2 metabolism, Prostaglandins metabolism, Anti-Inflammatory Agents pharmacology
- Abstract
Introduction: Prostaglandin E
2 (PGE2 ) is produced by cyclooxygenases (COX-1/2) and the microsomal prostaglandin E synthase 1 (mPGES-1). PGE2 is pro-inflammatory in diseases such as rheumatoid arthritis, cardiovascular disorders, and cancer. While Nonsteroidal anti-inflammatory drugs (NSAIDs) targeting COX can effectively reduce inflammation, their use is limited by gastrointestinal and cardiovascular side effects resulting from the blockade of all prostanoids. To overcome this limitation, selective inhibition of mPGES-1 is being explored as an alternative therapeutic strategy to inhibit PGE2 production while sparing or even upregulating other prostaglandins. However, the exact timing and location of PGH2 conversion to PGD2 , PGI2 , TXB2 or PGF2α , and whether it hinders or supports the therapeutic effect of mPGES-1 inhibition, is not fully understood., Areas Covered: The article briefly describes prostanoid history and metabolism with a strong focus on the vascular effects of prostanoids. Recent advances in mPGES-1 inhibitor development and results from pre-clinical and clinical studies are presented. Prostanoid shunting after mPGES-1 inhibition is highlighted and particularly discussed in the context of cardiovascular diseases., Expert Opinion: The newest research demonstrates that inhibition of mPGES-1 is a potent anti-inflammatory treatment strategy and beneficial and safer regarding cardiovascular side effects compared to NSAIDs. Inhibitors of mPGES-1 hold great potential to advance to the clinic and there are ongoing phase-II trials in endometriosis.- Published
- 2023
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23. Editorial: Insights in inflammation pharmacology: 2022.
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Patrignani P, Ballerini P, Jakobsson PJ, and Steinhilber D
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2023
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24. Editorial: Disease-modifying antirheumatic drugs: Approaches and lessons learned from traditional medicine.
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Mei L, Gao K, He X, Jakobsson PJ, and Huang R
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2023
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25. Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies.
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Preger C, Notarnicola A, Hellström C, Wigren E, Fernandes-Cerqueira C, Kvarnström M, Wahren-Herlenius M, Idborg H, Lundberg IE, Persson H, Gräslund S, and Jakobsson PJ
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- Humans, Retrospective Studies, Autoantigens, Autoantibodies, Syndrome, Amino Acyl-tRNA Synthetases, Myositis, Lung Diseases, Interstitial, Arthritis
- Abstract
Objectives: Autoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to known myositis-specific autoantibodies. We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM., Methods: Plasma samples from 217 patients with IIM according to 2017 EULAR/ACR criteria, including 50 patients with ASSD, 165 without, and two with unknown ASSD status were identified retrospectively, as well as age and gender-matched sera from 156 population controls, and 219 disease controls. Patients with previously documented ASSD had to test positive for at least one of the five most common anti-aaRS autoantibodies (anti-Jo1, -PL7, -PL12, -EJ, and -OJ) and present with one or more of the following clinical manifestations: interstitial lung disease, myositis, arthritis, Raynaud's phenomenon, fever, or mechanic's hands. Demographics, laboratory, and clinical data of the IIM cohort (ASSD and non-ASSD) were compared. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 117 recombinant protein variants, representing 33 myositis-related proteins, including all nineteen cytoplasmic aaRS. Prospectively collected clinical data for the IIM cohort were retrieved and compared between groups within the IIM cohort and correlated with the results of the autoantibody screening. Principal component analysis was used to analyze clinical manifestations between ASSD, non-ASSD groups, and individuals with novel anti-aaRS autoantibodies., Results: We identified reactivity towards 16 aaRS in 72 of the 217 IIM patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four previously seronegative patients for myositis-specific autoantibodies and eight with previously detected myositis-specific autoantibodies. IIM individuals with novel anti-aaRS autoantibodies (n = 12) all had signs of myositis, and they had either muscle weakness and/or muscle enzyme elevation, 2/12 had mechanic's hands, 3/12 had interstitial lung disease, and 2/12 had arthritis. The individuals with novel anti-aaRS and a pathological muscle biopsy all presented widespread up-regulation of major histocompatibility complex class I. The reactivities against novel aaRS could be confirmed in ELISA and western blot. Using the multiplex bead array assay, we could confirm previously known reactivities to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n = 45)) and identified patients positive for anti-Zo, -KS, and -HA (n = 10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was also detected in controls., Conclusion: Our results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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26. Autoantibodies targeting malondialdehyde-modifications in rheumatoid arthritis regulate osteoclasts via inducing glycolysis and lipid biosynthesis.
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Sakuraba K, Krishnamurthy A, Sun J, Zheng X, Xu C, Peng B, Engström M, Jakobsson PJ, Wermeling F, Catrina S, Grönwall C, Catrina AI, and Réthi B
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- Humans, Malondialdehyde, Lipids, Autoantibodies, Arthritis, Rheumatoid
- Abstract
Proteins subjected to post-translational modifications, such as citrullination, carbamylation, acetylation or malondialdehyde (MDA)-modification are targeted by autoantibodies in seropositive rheumatoid arthritis (RA). Epidemiological and experimental studies have both suggested the pathogenicity of such humoral autoimmunity, however, molecular mechanisms triggered by anti-modified protein antibodies have remained to be identified. Here we describe in detail the pathways induced by anti-MDA modified protein antibodies that were obtained from synovial B cells of RA patients and that possessed robust osteoclast stimulatory potential and induced bone erosion in vivo. Anti-MDA antibodies boosted glycolysis in developing osteoclasts via an FcγRI, HIF-1α and MYC-dependent mechanism and subsequently increased oxidative phosphorylation. Osteoclast development required robust phosphoglyceride and triacylglyceride biosynthesis, which was also enhanced by anti-MDA by modulating citrate production and expression of the glycerol-3-phosphate dehydrogenase 1 (GPD1) and glycerol-3-phosphate acyltransferase 2 (GPAT2) genes. In summary, we described novel metabolic pathways instrumental for osteoclast differentiation, which were targeted by anti-MDA antibodies, accelerating bone erosion, a central component of RA pathogenesis., Competing Interests: Declaration of competing interest The authors have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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27. Biosynthesis of prostaglandin 15dPGJ 2 -glutathione and 15dPGJ 2 -cysteine conjugates in macrophages and mast cells via MGST3.
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Steinmetz-Späh J, Liu J, Singh R, Ekoff M, Boddul S, Tang X, Bergqvist F, Idborg H, Heitel P, Rönnberg E, Merk D, Wermeling F, Haeggström JZ, Nilsson G, Steinhilber D, Larsson K, Korotkova M, and Jakobsson PJ
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- Mice, Humans, Animals, Lipopolysaccharides metabolism, Mast Cells, Prostaglandin-E Synthases metabolism, Macrophages metabolism, Cyclooxygenase 2 metabolism, Glutathione metabolism, Glutathione Transferase metabolism, Prostaglandin D2 pharmacology, Prostaglandins, Cysteine
- Abstract
Inhibition of microsomal prostaglandin E synthase-1 (mPGES-1) results in decreased production of proinflammatory PGE
2 and can lead to shunting of PGH2 into the prostaglandin D2 (PGD2 )/15-deoxy-Δ12,14 -prostaglandin J2 (15dPGJ2 ) pathway. 15dPGJ2 forms Michael adducts with thiol-containing biomolecules such as GSH or cysteine residues on target proteins and is thought to promote resolution of inflammation. We aimed to elucidate the biosynthesis and metabolism of 15dPGJ2 via conjugation with GSH, to form 15dPGJ2 -glutathione (15dPGJ2 -GS) and 15dPGJ2 -cysteine (15dPGJ2 -Cys) conjugates and to characterize the effects of mPGES-1 inhibition on the PGD2 /15dPGJ2 pathway in mouse and human immune cells. Our results demonstrate the formation of PGD2 , 15dPGJ2 , 15dPGJ2 -GS, and 15dPGJ2 -Cys in RAW264.7 cells after lipopolysaccharide stimulation. Moreover, 15dPGJ2 -Cys was found in lipopolysaccharide-activated primary murine macrophages as well as in human mast cells following stimulation of the IgE-receptor. Our results also suggest that the microsomal glutathione S-transferase 3 is essential for the formation of 15dPGJ2 conjugates. In contrast to inhibition of cyclooxygenase, which leads to blockage of the PGD2 /15dPGJ2 pathway, we found that inhibition of mPGES-1 preserves PGD2 and its metabolites. Collectively, this study highlights the formation of 15dPGJ2 -GS and 15dPGJ2 -Cys in mouse and human immune cells, the involvement of microsomal glutathione S-transferase 3 in their biosynthesis, and their unchanged formation following inhibition of mPGES-1. The results encourage further research on their roles as bioactive lipid mediators., Competing Interests: Conflict of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. P.-J. J. is engaged in Gesynta Pharma AB, a company that develops mPGES-1 inhibitors., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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28. Where traditional Chinese medicine meets Western medicine in the prevention of rheumatoid arthritis.
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Jakobsson PJ, Robertson L, Welzel J, Zhang M, Zhihua Y, Kaixin G, Runyue H, Zehuai W, Korotkova M, and Göransson U
- Subjects
- Alleles, Autoantibodies, Clinical Trials as Topic, Epitopes genetics, Genetic Predisposition to Disease, HLA-DRB1 Chains genetics, Humans, Medicine, Chinese Traditional, Peptides, Rheumatoid Factor genetics, Tea, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid prevention & control, Drugs, Chinese Herbal therapeutic use
- Abstract
Chinese medicine has a long tradition of use against rheumatoid arthritis (RA). The formulations are based on combinations of typically 5-10 plants, which are usually boiled and administered as a decoction or tea. There are few clinical trials performed so the clinical evidence is sparse. One fundamental of traditional medicine is to prevent disease. RA is an autoimmune, inflammatory and chronic disease that primarily affects the joints of 0.5%-1% of the population. In two out of three of the cases, the patients are characterised by the presence of autoantibodies such as the rheumatoid factor and the more disease-specific autoantibody against citrullinated proteins, so-called 'ACPA' (anticitrullinated protein/peptide antibodies). ACPA positivity is also strongly associated with specific variations in the HLA-DRB1 gene, the shared epitope alleles. Together with smoking, these factors account for the major risks of developing RA. In this review, we will summarise the background using certain plant-based formulations based on Chinese traditional medicine for the treatment and prevention of RA and the strategy we have taken to explore the mechanisms of action. We also summarise the major pathophysiological pathways related to RA and how these could be analysed. Finally, we summarise our ideas on how a clinical trial using Chinese herbal medicine to prevent RA could be conducted., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)
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- 2022
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29. Helminthic dehydrogenase drives PGE 2 and IL-10 production in monocytes to potentiate Treg induction.
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Prodjinotho UF, Gres V, Henkel F, Lacorcia M, Dandl R, Haslbeck M, Schmidt V, Winkler AS, Sikasunge C, Jakobsson PJ, Henneke P, Esser-von Bieren J, and Prazeres da Costa C
- Subjects
- Child, Humans, Interleukin-10, Monocytes, Oxidoreductases, T-Lymphocytes, Regulatory, Cysts, Dinoprostone pharmacology
- Abstract
Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation. Here, we show that glutamate dehydrogenase from viable cysts instructs tolerogenic monocytes to release IL-10 and the lipid mediator PGE
2 . These act in concert, converting naive CD4+ T cells into CD127- CD25hi FoxP3+ CTLA-4+ Tregs, through the G protein-coupled receptors EP2 and EP4 and the IL-10 receptor. Moreover, while viable cyst products strongly upregulate IL-10 and PGE2 transcription in microglia, intravesicular fluid, released during cyst decay, induces pro-inflammatory microglia and TGF-β as potential drivers of epilepsy. Inhibition of PGE2 synthesis and IL-10 signaling prevents Treg induction by viable cyst products. Harnessing the PGE2 -IL-10 axis and targeting TGF-ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC., (© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)- Published
- 2022
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30. Omega-3 fatty acids decrease CRYAB, production of oncogenic prostaglandin E 2 and suppress tumor growth in medulloblastoma.
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Ljungblad L, Bergqvist F, Tümmler C, Madawala S, Olsen TK, Andonova T, Jakobsson PJ, Johnsen JI, Pickova J, Strandvik B, Kogner P, Gleissman H, and Wickström M
- Subjects
- Animals, Apoptosis drug effects, Carcinogenesis, Cell Line, Tumor, Cell Survival drug effects, Chromatography, Liquid methods, Dinoprostone metabolism, Docosahexaenoic Acids pharmacology, Eicosapentaenoic Acid pharmacology, Fatty Acids metabolism, Fatty Acids, Omega-3 metabolism, Female, Humans, Mice, Mice, Nude, Prostaglandins metabolism, Tandem Mass Spectrometry methods, Tumor Microenvironment, Xenograft Model Antitumor Assays methods, alpha-Crystallin B Chain drug effects, alpha-Crystallin B Chain metabolism, Fatty Acids, Omega-3 pharmacology, Medulloblastoma drug therapy, Medulloblastoma metabolism
- Abstract
Aims: Medulloblastoma (MB) is one of the most common malignant central nervous system tumors of childhood. Despite intensive treatments that often leads to severe neurological sequelae, the risk for resistant relapses remains significant. In this study we have evaluated the effects of the ω3-long chain polyunsaturated fatty acids (ω3-LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on MB cell lines and in a MB xenograft model., Main Methods: Effects of ω3-LCPUFA treatment of MB cells were assessed using the following: WST-1 assay, cell death probes, clonogenic assay, ELISA and western blot. MB cells were implanted into nude mice and the mice were randomized to DHA, or a combination of DHA and EPA treatment, or to control group. Treatment effects in tumor tissues were evaluated with: LC-MS/MS, RNA-sequencing and immunohistochemistry, and tumors, erythrocytes and brain tissues were analyzed with gas chromatography., Key Findings: ω3-LCPUFA decreased prostaglandin E2 (PGE
2 ) secretion from MB cells, and impaired MB cell viability and colony forming ability and increased apoptosis in a dose-dependent manner. DHA reduced tumor growth in vivo, and both PGE2 and prostacyclin were significantly decreased in tumor tissue from treated mice compared to control animals. All ω3-LCPUFA and dihomo-γ-linolenic acid increased in tumors from treated mice. RNA-sequencing revealed 10 downregulated genes in common among ω3-LCPUFA treated tumors. CRYAB was the most significantly altered gene and the downregulation was confirmed by immunohistochemistry., Significance: Our findings suggest that addition of DHA and EPA to the standard MB treatment regimen might be a novel approach to target inflammation in the tumor microenvironment., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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31. Effects of microsomal prostaglandin E synthase-1 inhibition on resistance artery tone in patients with end stage kidney disease.
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Steinmetz-Späh J, Arefin S, Larsson K, Jahan J, Mudrovcic N, Wennberg L, Stenvinkel P, Korotkova M, Kublickiene K, and Jakobsson PJ
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- Adrenergic Agents, Cyclooxygenase 1 metabolism, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 Inhibitors pharmacology, Etoricoxib, Humans, Microvessels metabolism, Microvessels physiology, Nitrobenzenes, Prostaglandins, Sulfonamides, Arteries metabolism, Arteries physiology, Kidney Failure, Chronic complications, Prostaglandin-E Synthases antagonists & inhibitors
- Abstract
Background: The microvasculature is a target organ for the early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES-1 inhibition and concomitant reduction of PGE
2 in vascular beds are of interest., Experimental Approach: The effects of mPGES-1 inhibition on constriction and relaxation of resistance arteries (diameter: 100-400 μm) from patients with end stage kidney disease (ESKD) and controls (Non-ESKD) were studied using wire-myography in combination with immunological and mass-spectrometry based analyses., Key Results: Inhibition of mPGES-1 in arteries from ESKD patients and Non-ESKD controls significantly reduced adrenergic vasoconstriction, which was unaffected by the COX-2 inhibitors NS-398 and Etoricoxib, or by the COX-1/COX-2 inhibitor Indomethacin tested in Non-ESKD controls. However, a significant increase of acetylcholine-induced dilatation was observed for mPGES-1 inhibition. In IL-1β treated arteries, inhibition of mPGES-1 significantly reduced PGE2 levels while PGI2 levels remained unchanged. In contrast, COX-2 inhibition blocked the formation of both prostaglandins. Blockade of PGI2 signalling with an IP receptor antagonist did not restore the reduced adrenergic constriction, neither did blocking PGE2 -EP4 or signalling through PPARγ. A biphasic effect was observed for PGE2 , inducing dilatation at nanomolar and constriction at micromolar concentrations. Immunohistochemistry demonstrated expression of mPGES-1, COX-1, PGIS, weak expression for COX-2, as well as receptor expression for PGE2 (EP1-4), thromboxane (TP) and PGI2 (IP) in ESKD and Non-ESKD., Conclusion: Our study demonstrates vasodilating effects following mPGES-1 inhibition in human microvasculature and suggests that several pathways besides shunting to PGI2 are involved., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2022
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32. Formation, Signaling and Occurrence of Specialized Pro-Resolving Lipid Mediators-What is the Evidence so far?
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Schebb NH, Kühn H, Kahnt AS, Rund KM, O'Donnell VB, Flamand N, Peters-Golden M, Jakobsson PJ, Weylandt KH, Rohwer N, Murphy RC, Geisslinger G, FitzGerald GA, Hanson J, Dahlgren C, Alnouri MW, Offermanns S, and Steinhilber D
- Abstract
Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schebb, Kühn, Kahnt, Rund, O’Donnell, Flamand, Peters-Golden, Jakobsson, Weylandt, Rohwer, Murphy, Geisslinger, FitzGerald, Hanson, Dahlgren, Alnouri, Offermanns and Steinhilber.)
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- 2022
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33. Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome.
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Notarnicola A, Preger C, Lundström SL, Renard N, Wigren E, Van Gompel E, Galindo-Feria AS, Persson H, Fathi M, Grunewald J, Jakobsson PJ, Gräslund S, Lundberg IE, and Fernandes-Cerqueira C
- Subjects
- Autoantibodies, Histidine-tRNA Ligase, Humans, Ligases, Lung Diseases, Interstitial, Myositis
- Abstract
Background: To address the reactivity and affinity against histidyl-transfer RNA synthetase (HisRS) autoantigen of anti-Jo1 autoantibodies from serum and bronchoalveolar lavage fluid (BALF) in patients with idiopathic inflammatory myopathies/anti-synthetase syndrome (IIM/ASSD). To investigate the associations between the reactivity profile and clinical data over time., Methods: Samples and clinical data were obtained from (i) 25 anti-Jo1
+ patients (19 sera with 16 longitudinal samples and 6 BALF/matching sera at diagnosis), (ii) 29 anti-Jo1- patients (25 sera and 4 BALF/matching sera at diagnosis), and (iii) 27 age/gender-matched healthy controls (24 sera and 3 BALF/matching sera). Reactivity towards HisRS full-length (HisRS-FL), three HisRS domains (WHEP, antigen binding domain (ABD), and catalytic domain (CD)), and the HisRS splice variant (SV) was tested. Anti-Jo1 IgG reactivity was evaluated by ELISA and western blot using IgG purified from serum by affinity chromatography. In paired serum-BALF, anti-Jo1 IgG and IgA reactivity was analyzed by ELISA. Autoantibody affinity was measured by surface plasmon resonance using IgG purified from sera. Correlations between autoantibody reactivity and clinical data were evaluated at diagnosis and longitudinally., Results: Anti-Jo1 IgG from serum and BALF bound HisRS-FL, WHEP, and SV with high reactivity at the time of diagnosis and recognized both conformation-dependent and conformation-independent HisRS epitopes. Anti-HisRS-FL IgG displayed high affinity early in the disease. At the time of IIM/ASSD diagnosis, the highest autoantibody levels against HisRS-FL were found in patients ever developing interstitial lung disease (ILD) and arthritis, but with less skin involvement. Moreover, the reactivity of anti-WHEP IgG in BALF correlated with poor pulmonary function. Levels of autoantibodies against HisRS-FL, HisRS domains, and HisRS splice variant generally decreased over time. With some exceptions, longitudinal anti-HisRS-FL antibody levels changed in line with ILD activity., Conclusion: High levels and high-affinity anti-Jo1 autoantibodies towards HisRS-FL were found early in disease in sera and BALF. In combination with the correlation of anti-HisRS-FL antibody levels with ILD and ILD activity in longitudinal samples as well as of anti-WHEP IgG in BALF with poor pulmonary function, this supports the previously raised hypothesis that the lung might have a role in the immune reaction in anti-Jo1-positive patients., (© 2022. The Author(s).)- Published
- 2022
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34. Temperature response to cold challenge and mobile phone thermography as outcome measures for systemic sclerosis-related Raynaud's phenomenon.
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Herrick AL, Heal C, Wilkinson J, Dinsdale G, Manning J, Gunnarsson K, Jakobsson PJ, and Murray A
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- Cell Phone, Cold Temperature, Humans, Iloprost, Outcome Assessment, Health Care, Pilot Projects, Raynaud Disease diagnosis, Scleroderma, Systemic complications, Scleroderma, Systemic therapy, Thermography
- Abstract
Objectives : Objective outcome measures of systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) are badly needed. Our objectives were to validate the thermographic response to a standard hand cold challenge as an outcome measure by assessing sensitivity to change, and to explore mobile phone thermography as a feasible, ambulatory tool. Method : Twelve patients with an SSc-spectrum disorder admitted for intravenous iloprost infusions underwent a standard cold challenge before and after one infusion. Thermographic measurements included area under the rewarming curve (AUC) and maximum rewarming temperature (MAX). Before and during another infusion, each patient underwent monitoring of finger skin temperature by two methods: continuous thermocouple recording (standard method) and mobile phone thermography. Results : All cold challenge summary measures, including AUC and MAX, increased after iloprost (most not significantly). However, when the response curves were modelled after averaging across fingers (linear mixed models, three versions), significant change was detected. For example, with Model 1 (no interaction between period and time), temperature was on average 1.67ºC [95% confidence interval (CI) 1.49-1.85, p < 0.001] higher post-iloprost. Mobile phone and thermocouple temperature measurements showed a strong estimated latent correlation (0.88, 95% CI 0.81-0.92). The estimated increases/hour were 0.25ºC (95% CI 0.05-0.45) for the thermocouple and 0.36ºC (95% CI 0.13-0.60) for mobile phone thermography. Conclusion : Our pilot study suggests that the thermographic response to a cold challenge is sensitive to change and mobile phone thermography could bring feasibility to thermographic parameters as outcome measures in later-phase, large-scale, community-based clinical trials of RP.
- Published
- 2021
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35. Editorial: Traditional Medicine and Rheumatology.
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Yang Z, Tang X, Liang H, Gao K, Wang M, He X, Jakobsson PJ, and Huang R
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2021
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36. Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses.
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Adams RA, Fernandes-Cerqueira C, Notarnicola A, Mertsching E, Xu Z, Lo WS, Ogilvie K, Chiang KP, Ampudia J, Rosengren S, Cubitt A, King DJ, Mendlein JD, Yang XL, Nangle LA, Lundberg IE, Jakobsson PJ, and Schimmel P
- Subjects
- Animals, Autoantibodies blood, Case-Control Studies, Cell Differentiation drug effects, Disease Models, Animal, Female, Histidine-tRNA Ligase immunology, Humans, Immunomodulation drug effects, Insulin-Like Growth Factor I pharmacology, Lung drug effects, Lung pathology, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Male, Mice, Inbred C57BL, Middle Aged, Muscle Cells drug effects, Muscle Cells enzymology, Muscles drug effects, Muscles pathology, Myositis blood, Myositis diagnostic imaging, Myositis immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Tomography, X-Ray Computed, Mice, Histidine-tRNA Ligase blood, Immunity drug effects, Organ Specificity drug effects
- Abstract
His-tRNA synthetase (HARS) is targeted by autoantibodies in chronic and acute inflammatory anti-Jo-1-positive antisynthetase syndrome. The extensive activation and migration of immune cells into lung and muscle are associated with interstitial lung disease, myositis, and morbidity. It is unknown whether the sequestration of HARS is an epiphenomenon or plays a causal role in the disease. Here, we show that HARS circulates in healthy individuals, but it is largely undetectable in the serum of anti-Jo-1-positive antisynthetase syndrome patients. In cultured primary human skeletal muscle myoblasts (HSkMC), HARS is released in increasing amounts during their differentiation into myotubes. We further show that HARS regulates immune cell engagement and inhibits CD4
+ and CD8+ T-cell activation. In mouse and rodent models of acute inflammatory diseases, HARS administration downregulates immune activation. In contrast, neutralization of extracellular HARS by high-titer antibody responses during tissue injury increases susceptibility to immune attack, similar to what is seen in humans with anti-Jo-1-positive disease. Collectively, these data suggest that extracellular HARS is homeostatic in normal subjects, and its sequestration contributes to the morbidity of the anti-Jo-1-positive antisynthetase syndrome.- Published
- 2021
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37. Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25 + /CD54 + NK cells.
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Chen Z, Yang Y, Neo SY, Shi H, Chen Y, Wagner AK, Larsson K, Tong L, Jakobsson PJ, Alici E, Wu J, Cao Y, Wang K, Liu LL, Mao Y, Sarhan D, and Lundqvist A
- Subjects
- Cytokines, Humans, Killer Cells, Natural, Signal Transduction, Cyclic Nucleotide Phosphodiesterases, Type 4 genetics, Dinoprostone
- Abstract
Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES). In vitro, IL-15, in contrast to IL-2, enriches for CD25
+ /CD54+ NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors in vitro and in vivo. Thus, strategies to enrich CD25+ /CD54+ NK cells for adoptive cell therapy should be considered., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2021
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38. Identifying novel B-cell targets for chronic inflammatory autoimmune disease by screening of chemical probes in a patient-derived cell assay.
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Sundström Y, Shang MM, Panda SK, Grönwall C, Wermeling F, Gunnarsson I, Lundberg IE, Sundström M, Jakobsson PJ, and Berg L
- Subjects
- Adult, Aged, B-Lymphocytes immunology, Case-Control Studies, Cells, Cultured, Cytokines metabolism, Epigenesis, Genetic, Female, Humans, Immunoglobulin Isotypes metabolism, Leukocytes, Mononuclear, Lupus Erythematosus, Systemic pathology, Male, Middle Aged, Molecular Probes chemistry, Myositis, Inclusion Body pathology, Piperidines pharmacology, Polymyositis pathology, Pyrimidines pharmacology, Autoimmune Diseases pathology, B-Lymphocytes drug effects, B-Lymphocytes pathology, Molecular Probes pharmacology
- Abstract
B-cell secretion of autoantibodies drives autoimmune diseases, including systemic lupus erythematosus and idiopathic inflammatory myositis. Few therapies are presently available for treatment of these patients, often resulting in unsatisfactory effects and helping only some of the patients. We developed a screening assay for evaluation of novel targets suspending B-cell maturation into antibody secreting cells, which could contribute to future drug development. The assay was employed for testing 43 high quality chemical probes and compounds inhibiting under-explored protein targets, using primary cells from patients with autoimmune disease. Probes inhibiting bromodomain family proteins and histone methyl transferases demonstrated abrogation of B-cell functions to a degree comparable to a positive control, the JAK inhibitor tofacitinib. Inhibition of each target rendered a specific functional cell and potential disease modifying effect, indicating specific epigenetic protein targets as potential new intervention points for future drug discovery and development efforts., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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39. Inhibition of mPGES-1 attenuates efficient resolution of acute inflammation by enhancing CX3CL1 expression.
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Rappl P, Rösser S, Maul P, Bauer R, Huard A, Schreiber Y, Thomas D, Geisslinger G, Jakobsson PJ, Weigert A, Brüne B, and Schmid T
- Subjects
- Animals, Antibodies, Neutralizing pharmacology, CX3C Chemokine Receptor 1 genetics, CX3C Chemokine Receptor 1 metabolism, Cell Adhesion, Cell Survival, Cells, Cultured, Chemokine CX3CL1 antagonists & inhibitors, Chemokine CX3CL1 genetics, Disease Models, Animal, Epithelial Cells drug effects, Female, Macrophages, Peritoneal enzymology, Macrophages, Peritoneal immunology, Mice, Inbred C57BL, Neutrophil Infiltration, Peritonitis genetics, Peritonitis immunology, Phenotype, Prostaglandin-E Synthases metabolism, Up-Regulation, Mice, Chemokine CX3CL1 metabolism, Dinoprostone metabolism, Enzyme Inhibitors pharmacology, Epithelial Cells metabolism, Macrophages, Peritoneal drug effects, Peritonitis enzymology, Prostaglandin-E Synthases antagonists & inhibitors
- Abstract
Despite the progress to understand inflammatory reactions, mechanisms causing their resolution remain poorly understood. Prostanoids, especially prostaglandin E
2 (PGE2 ), are well-characterized mediators of inflammation. PGE2 is produced in an inducible manner in macrophages (Mϕ) by microsomal PGE2 -synthase-1 (mPGES-1), with the notion that it also conveys pro-resolving properties. We aimed to characterize the role of mPGES-1 during resolution of acute, zymosan-induced peritonitis. Experimentally, we applied the mPGES-1 inhibitor compound III (CIII) once the inflammatory response was established and confirmed its potent PGE2 -blocking efficacy. mPGES-1 inhibition resulted in an incomplete removal of neutrophils and a concomitant increase in monocytes and Mϕ during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating Mϕ upon mPGES-1 inhibition. Besides elevated Cx3cr1 expression, its ligand CX3CL1 was enriched in the peritoneal lavage of the mice, produced by epithelial cells upon mPGES-1 inhibition. CX3CL1 not only increased adhesion and survival of Mϕ but its neutralization also completely reversed elevated inflammatory cell numbers, thereby normalizing the cellular, peritoneal composition during resolution. Our data suggest that mPGES-1-derived PGE2 contributes to the resolution of inflammation by preventing CX3CL1-mediated retention of activated myeloid cells at sites of injury.- Published
- 2021
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40. Extracellular miR-574-5p Induces Osteoclast Differentiation via TLR 7/8 in Rheumatoid Arthritis.
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Hegewald AB, Breitwieser K, Ottinger SM, Mobarrez F, Korotkova M, Rethi B, Jakobsson PJ, Catrina AI, Wähämaa H, and Saul MJ
- Subjects
- Cell Differentiation physiology, Extracellular Vesicles metabolism, HEK293 Cells, HeLa Cells, Humans, Osteoclasts pathology, Osteogenesis physiology, Synovial Fluid metabolism, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid metabolism, Arthritis, Rheumatoid pathology, MicroRNAs metabolism, Osteoclasts metabolism, Toll-Like Receptor 7 metabolism, Toll-Like Receptor 8 metabolism
- Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Cell-derived small extracellular vesicles (sEV) mediate cell-to-cell communication in the synovial microenvironment by carrying microRNAs (miRs), a class of small non-coding RNAs. Herein, we report that sEV from synovial fluid promote osteoclast differentiation which is attributed to high levels of extracellular miR-574-5p. Moreover, we demonstrate for the first time that enhanced osteoclast maturation is mediated by Toll-like receptor (TLR) 7/8 signaling which is activated by miR-574-5p binding. This is a novel mechanism by which sEV and miRs contribute to RA pathogenesis and indicate that pharmacological inhibition of extracellular miR-574-5p might offer new therapeutic strategies to protect osteoclast-mediated bone destruction in RA., (Copyright © 2020 Hegewald, Breitwieser, Ottinger, Mobarrez, Korotkova, Rethi, Jakobsson, Catrina, Wähämaa and Saul.)
- Published
- 2020
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41. Generation and validation of recombinant antibodies to study human aminoacyl-tRNA synthetases.
- Author
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Preger C, Wigren E, Ossipova E, Marks C, Lengqvist J, Hofström C, Andersson O, Jakobsson PJ, Gräslund S, and Persson H
- Subjects
- Humans, Recombinant Proteins chemistry, Recombinant Proteins immunology, Amino Acyl-tRNA Synthetases chemistry, Amino Acyl-tRNA Synthetases immunology, Single-Chain Antibodies chemistry, Single-Chain Antibodies immunology
- Abstract
Aminoacyl-tRNA synthetases (aaRSs) have long been viewed as mere housekeeping proteins and have therefore often been overlooked in drug discovery. However, recent findings have revealed that many aaRSs have noncanonical functions, and several of the aaRSs have been linked to autoimmune diseases, cancer, and neurological disorders. Deciphering these roles has been challenging because of a lack of tools to enable their study. To help solve this problem, we have generated recombinant high-affinity antibodies for a collection of thirteen cytoplasmic and one mitochondrial aaRSs. Selected domains of these proteins were produced recombinantly in Escherichia coli and used as antigens in phage display selections using a synthetic human single-chain fragment variable library. All targets yielded large sets of antibody candidates that were validated through a panel of binding assays against the purified antigen. Furthermore, the top-performing binders were tested in immunoprecipitation followed by MS for their ability to capture the endogenous protein from mammalian cell lysates. For antibodies targeting individual members of the multi-tRNA synthetase complex, we were able to detect all members of the complex, co-immunoprecipitating with the target, in several cell types. The functionality of a subset of binders for each target was also confirmed using immunofluorescence. The sequences of these proteins have been deposited in publicly available databases and repositories. We anticipate that this open source resource, in the form of high-quality recombinant proteins and antibodies, will accelerate and empower future research of the role of aaRSs in health and disease., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Preger et al.)
- Published
- 2020
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42. Anti-Citrullinated Protein Antibody Specificities, Rheumatoid Factor Isotypes, and Incident Cardiovascular Events in Patients With Rheumatoid Arthritis.
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Westerlind H, Rönnelid J, Hansson M, Alfredsson L, Mathsson-Alm L, Serre G, Cornillet M, Holmdahl R, Jakobsson PJ, Skriner K, Klareskog L, Saevarsdottir S, and Askling J
- Subjects
- Adult, Aged, Anti-Citrullinated Protein Antibodies blood, Antibody Specificity, Arthritis, Rheumatoid blood, Arthritis, Rheumatoid complications, Cardiovascular Diseases etiology, Case-Control Studies, Female, Humans, Incidence, Male, Middle Aged, Sweden, Arthritis, Rheumatoid immunology, Cardiovascular Diseases enzymology, Immunoglobulin Isotypes blood, Rheumatoid Factor immunology
- Abstract
Objective: To investigate the relationship between anti-citrullinated protein antibodies (ACPAs), specific ACPA subspecificities, rheumatoid factor (RF) isotypes, and incident cardiovascular (CV) events in patients with rheumatoid arthritis (RA)., Methods: Serum samples from Swedish patients with new-onset RA (diagnosed within 1 year of symptom onset between 1996 and 2009) were centrally typed for anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies, 20 ACPA subspecificities, and RF isotypes. Patients were followed up longitudinally in nationwide registers to monitor the occurrence of acute coronary syndrome (ACS), stroke, CV-related death, and major adverse CV events (MACE). The association between each serologic marker and CV outcome, and the impact of adjustment for the Disease Activity Score in 28 joints (DAS28), smoking status, and income at baseline, were assessed using Cox proportional hazards models. In addition, associations of serologic markers with all-cause mortality were explored., Results: In total, 2,814 patients with RA were included in the study. The median follow-up was 13 years, during which the CV end points of ACS, stroke, or CV-related death were reported to occur in 375 patients. Occurrence and/or levels of anti-CCP2 were associated with risk of incident ACS (hazard ratio [HR] 1.46, 95% confidence interval [95% CI] 1.03-2.06), stroke (HR 1.47, 95% CI 1.03-2.10), CV-related death (P = 0.024 for association with anti-CCP2 levels), and MACE (HR 1.34, 95% CI 1.06-1.70). Similarly, an association with the number of ACPA subspecificities was observed; however, this could not be attributed to any individual or group of ACPA subspecificities. Presence of IgM-RF was associated with all CV end points except ACS, and IgA-RF was exclusively associated with CV-related death. Adjustment for smoking status, income, and DAS28 scores decreased most of the HRs, whereas IgA-RF remained associated with CV-related death (HR 1.61, 95% CI 1.05-2.48). All of the assessed serologic makers were associated with all-cause mortality., Conclusion: RF isotypes and ACPAs are associated with future CV events in patients with RA. ACPA levels and number of subspecificities seem more important than the occurrence of particular subspecificities, and these associations were not explained by a history of ever smoking., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
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- 2020
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43. Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.
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Kirkby NS, Raouf J, Ahmetaj-Shala B, Liu B, Mazi SI, Edin ML, Chambers MG, Korotkova M, Wang X, Wahli W, Zeldin DC, Nüsing R, Zhou Y, Jakobsson PJ, and Mitchell JA
- Subjects
- Animals, Aorta drug effects, Arginine blood, Cyclooxygenase 2 Inhibitors pharmacology, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism, Female, Intramolecular Oxidoreductases genetics, Intramolecular Oxidoreductases metabolism, Kidney drug effects, Male, Mice, Knockout, PPAR-beta genetics, PPAR-beta metabolism, Prostaglandin-E Synthases antagonists & inhibitors, Prostaglandin-E Synthases genetics, Prostaglandins I blood, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Epoprostenol genetics, Receptors, Epoprostenol metabolism, Receptors, Prostaglandin E genetics, Receptors, Prostaglandin E metabolism, Aorta enzymology, Arginine analogs & derivatives, Cyclooxygenase 2 metabolism, Kidney enzymology, Prostaglandin-E Synthases metabolism
- Abstract
Aims: Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA., Methods and Results: Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors., Conclusion: These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2020
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44. Chinese Herbal Formula Huayu-Qiangshen-Tongbi Decoction Compared With Leflunomide in Combination With Methotrexate in Patients With Active Rheumatoid Arthritis: An Open-Label, Randomized, Controlled, Pilot Study.
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Wu J, Chen X, Lv Y, Gao K, Liu Z, Zhao Y, Chen X, He X, Chu Y, Wu X, Ou A, Wen Z, Zhang J, Peng J, Huang Z, Jakobsson PJ, Huang Q, and Huang R
- Abstract
Background: Traditional Chinese Medicine is complementary and an alternative to modern medicine. The combination therapies of herbal products with disease-modifying anti-rheumatic drugs are gradually and widely adopted in the management of rheumatoid arthritis (RA) in China. Purpose: To evaluate the efficacy and safety of Huayu-Qiangshen-Tongbi (HQT) decoction, a Chinese medicine formula, combined with methotrexate (MTX) in the treatment of patients with active RA, in comparison with the combination therapy of MTX with leflunomide (LEF). Methods: This pilot study was a monocenter, open-label, randomized controlled trial with two parallel arms. Ninety patients with active RA were randomly allocated to receive either HQT at a dose of 250 ml twice daily or LEF at a dose of 20 mg once daily, and all participants received MTX at a dose of 10-15 mg once weekly. The primary efficacy endpoint was the proportion of patients who achieved a 20% improvement in the American College of Rheumatology criteria (ACR20) after a 24-week treatment. Results: 84.4% (76/90) patients completed the 24-week observation. In the intention-to-treat analysis, the percentage values of patients achieving the ACR20 response criteria were 72.1% (31/43) in MTX + HQT group and 74.4% (32/43) in MTX + LEF group ( p = 0.808). No significant difference was observed in other parameters, including ACR50, ACR70, clinical disease activity index good responses, European League Against Rheumatism good response, remission rate, and low disease activity rate. The results of the per-protocol analysis showed consistency with those of the intention-to-treat analysis. The mean change from baseline at week 24 for the van der Heijde modified total sharp score had no significant difference between two groups (3.59 ± 4.75 and 1.34 ± 8.67 in the MTX + HQT group and MTX + LEF group, respectively, p = 0.613). The frequency of adverse events was similar in both groups (11 cases in the MTX + HQT and 17 cases in the MTX + LEF, p > 0.05). Conclusions: In patients with active RA, treatment with the combination of HQT and MTX was associated with improvement in signs, symptoms, and physical function. With a beneficial clinical response and acceptable tolerability, HQT or other Chinese medicine formula may be a good therapeutic option in combination with MTX for RA treatment. Trial registration: Chinese Clinical Trails Registry, ChiCTR-INR-16009031, Registered on 15th August 2016, http://www.chictr.org.cn/enindex.aspx., (Copyright © 2020 Wu, Chen, Lv, Gao, Liu, Zhao, Chen, He, Chu, Wu, Ou, Wen, Zhang, Peng, Huang, Jakobsson, Huang and Huang.)
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- 2020
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45. Establishment of an in vitro 3D model for neuroblastoma enables preclinical investigation of combined tumor-stroma drug targeting.
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Kock A, Bergqvist F, Steinmetz J, Elfman LHM, Korotkova M, Johnsen JI, Jakobsson PJ, Kogner P, and Larsson K
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- Animals, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Cell Line, Cell Proliferation drug effects, Cell Survival drug effects, Cyclooxygenase 2 metabolism, Dinoprostone metabolism, Disease Models, Animal, Drug Delivery Systems methods, Drug Evaluation, Preclinical methods, Female, Humans, Mice, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Neuroblastoma metabolism, Prostaglandin-E Synthases metabolism, Antineoplastic Agents pharmacology, Neuroblastoma drug therapy, Neuroblastoma pathology
- Abstract
The majority of anti-cancer therapies target the proliferating tumor cells, while the tumor stroma, principally unaffected, survives, and provide a niche for surviving tumor cells. Combining tumor cell and stroma-targeting therapies thus have a potential to improve patient outcome. The neuroblastoma stroma contains cancer-associated fibroblasts expressing microsomal prostaglandin E synthase-1 (mPGES-1). mPGES-1-derived prostaglandin E
2 (PGE2 ) is known to promote tumor growth through increased proliferation and survival of tumor cells, immune suppression, angiogenesis, and therapy resistance, and we, therefore, hypothesize that mPGES-1 constitutes an interesting stromal target. Here, we aimed to develop a relevant in vitro model to study combination therapies. Co-culturing of neuroblastoma and fibroblast cells in 3D tumor spheroids mimic neuroblastoma tumors with regard to the cyclooxygenase/mPGES-1/PGE2 pathway. Using the spheroid model, we show that the inhibition of fibroblast-derived mPGES-1 enhanced the cytotoxic effect of doxorubicin and vincristine and significantly reduced tumor cell viability and spheroid growth. Cyclic treatment with vincristine in combination with an mPGES-1 inhibitor abrogated cell repopulation. Moreover, inhibition of mPGES-1 potentiated the cytotoxic effect of vincristine on established neuroblastoma allografts in mice. In conclusion, we established a 3D neuroblastoma model, highlighting the potential of combining stromal targeting of mPGES-1 with tumor cell targeting drugs like vincristine., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)- Published
- 2020
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46. Presence of autoantibodies in "seronegative" rheumatoid arthritis associates with classical risk factors and high disease activity.
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Reed E, Hedström AK, Hansson M, Mathsson-Alm L, Brynedal B, Saevarsdottir S, Cornillet M, Jakobsson PJ, Holmdahl R, Skriner K, Serre G, Alfredsson L, Rönnelid J, and Lundberg K
- Subjects
- Anti-Citrullinated Protein Antibodies, Humans, Peptides, Cyclic, Rheumatoid Factor, Risk Factors, Arthritis, Rheumatoid diagnosis, Autoantibodies
- Abstract
Background: Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative., Methods: Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets., Results: Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined "seronegative" RA, associated with worse clinical outcome., Conclusions: "Seronegative" RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2-/IgM RF- patients with a high need for active treatment.
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- 2020
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47. Descriptive Proteome Analysis to Investigate Context-Dependent Treatment Responses to OXPHOS Inhibition in Colon Carcinoma Cells Grown as Monolayer and Multicellular Tumor Spheroids.
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Steinmetz J, Senkowski W, Lengqvist J, Rubin J, Ossipova E, Herman S, Larsson R, Jakobsson PJ, Fryknäs M, and Kultima K
- Abstract
We have previously identified selective upregulation of the mevalonate pathway genes upon inhibition of oxidative phosphorylation (OXPHOS) in quiescent cancer cells. Using mass spectrometry-based proteomics, we here investigated whether these responses are corroborated on the protein level and whether proteomics could yield unique insights into context-dependent biology. HCT116 colon carcinoma cells were cultured as monolayer cultures, proliferative multicellular tumor spheroids (P-MCTS), or quiescent (Q-MCTS) multicellular tumor spheroids and exposed to OXPHOS inhibitors: nitazoxanide, FCCP, oligomycin, and salinomycin or the HMG-CoA-reductase inhibitor simvastatin at two different doses for 6 and 24 h. Samples were processed using an in-depth bottom-up proteomics workflow resulting in a total of 9286 identified protein groups. Gene set enrichment analysis showed profound differences between the three cell systems and confirmed differential enrichment of hypoxia, OXPHOS, and cell cycle progression-related protein responses in P-MCTS and Q-MCTS. Treatment experiments showed that the observed drug-induced alterations in gene expression of metabolically challenged cells are not translated directly to the protein level, but the results reaffirmed OXPHOS as a selective vulnerability of quiescent cancer cells. This work provides rationale for the use of deep proteome profiling to identify context-dependent treatment responses and encourages further studies investigating metabolic processes that could be co-targeted together with OXPHOS to eradicate quiescent cancer cells., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)
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- 2020
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48. Anti-Inflammatory Properties of Chemical Probes in Human Whole Blood: Focus on Prostaglandin E 2 Production.
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Bergqvist F, Sundström Y, Shang MM, Gunnarsson I, Lundberg IE, Sundström M, Jakobsson PJ, and Berg L
- Abstract
We screened 57 chemical probes, high-quality tool compounds, and relevant clinically used drugs to investigate their effect on pro-inflammatory prostaglandin E
2 (PGE2 ) production and interleukin-8 (IL-8) secretion in human whole blood. Freshly drawn blood from healthy volunteers and patients with systemic lupus erythematosus (SLE) or dermatomyositis was incubated with compounds at 0.1 or 1 µM and treated with lipopolysaccharide (LPS, 10 µg/ml) to induce a pro-inflammatory condition. Plasma was collected after 24 h for lipid profiling using liquid chromatography tandem mass spectrometry (LC-MS/MS) and IL-8 quantification using enzyme-linked immunosorbent assay (ELISA). Each compound was tested in at least four donors at one concentration based on prior knowledge of binding affinities and in vitro activity. Our screening suggested that PD0325901 (MEK-1/2 inhibitor), trametinib (MEK-1/2 inhibitor), and selumetinib (MEK-1 inhibitor) decreased while tofacitinib (JAK inhibitor) increased PGE2 production. These findings were validated by concentration-response experiment in two donors. Moreover, the tested MEK inhibitors decreased thromboxane B2 (TXB2 ) production and IL-8 secretion. We also investigated the lysophophatidylcholine (LPC) profile in plasma from treated whole blood as these lipids are potentially important mediators in inflammation, and we did not observe any changes in LPC profiles. Collectively, we deployed a semi-high throughput and robust methodology to investigate anti-inflammatory properties of new chemical probes., (Copyright © 2020 Bergqvist, Sundström, Shang, Gunnarsson, Lundberg, Sundström, Jakobsson and Berg.)- Published
- 2020
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49. An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products.
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de Los Reyes Jiménez M, Lechner A, Alessandrini F, Bohnacker S, Schindela S, Trompette A, Haimerl P, Thomas D, Henkel F, Mourão A, Geerlof A, da Costa CP, Chaker AM, Brüne B, Nüsing R, Jakobsson PJ, Nockher WA, Feige MJ, Haslbeck M, Ohnmacht C, Marsland BJ, Voehringer D, Harris NL, Schmidt-Weber CB, and Esser-von Bieren J
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- Animals, Anti-Inflammatory Agents, Cyclooxygenase 2, Humans, Inflammation, Larva, Mice, Eicosanoids, Helminths
- Abstract
Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth Heligmosomoides polygyrus bakeri ( HpbE ), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the HpbE -driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E
2 (PGE2 ) and IL-10] and suppressed chemotaxis. HpbE also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with HpbE extract attenuated allergic airway inflammation in mice, and intranasal transfer of HpbE -conditioned macrophages led to reduced airway eosinophilia in a COX/PGE2 -dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and Hpb glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in HpbE Hpb GDH activity was required for anti-inflammatory effects of HpbE in macrophages, and local administration of recombinant Hpb GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2020
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50. A review on mPGES-1 inhibitors: From preclinical studies to clinical applications.
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Bergqvist F, Morgenstern R, and Jakobsson PJ
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- Animals, Clinical Trials as Topic, Humans, Prostaglandin-E Synthases metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Drug Evaluation, Preclinical methods, Prostaglandin-E Synthases antagonists & inhibitors
- Abstract
Prostaglandin E
2 (PGE2 ) is a lipid mediator of inflammation and cancer progression. It is mainly formed via metabolism of arachidonic acid by cyclooxygenases (COX) and the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). Widely used non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX activity, resulting in decreased PGE2 production and symptomatic relief. However, NSAIDs block the production of many other lipid mediators that have important physiological and resolving actions, and these drugs cause gastrointestinal bleeding and/or increase the risk for severe cardiovascular events. Selective inhibition of downstream mPGES-1 for reduction in only PGE2 biosynthesis is suggested as a safer therapeutic strategy. This review covers the recent advances in characterization of new mPGES-1 inhibitors in preclinical models and their future clinical applications., Competing Interests: Declaration of Competing Interest R.M. and P-J.J. are engaged in Gesynta Pharma AB, a company that develops mPGES-1 inhibitors. F.B. has no conflicts of interests to declare., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2020
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