The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Peter Vandenabeele - One of the best experts on this subject based on the ideXlab platform.
-
inhibitors targeting ripk1 ripk3 old and new drugs
Trends in Pharmacological Sciences, 2020Co-Authors: Sofie Martens, Sam Hofmans, Koen Augustyns, Wim Declercq, Peter VandenabeeleAbstract:The scaffolding function of receptor-interacting protein kinase 1 (RIPK1) regulates prosurvival signaling and inflammatory gene expression, while its kinase activity mediates both apoptosis and necroptosis; the latter involving RIPK3 kinase activity. The mutual transition between the scaffold and kinase functions of RIPK1 is regulated by (de)ubiquitylation and (de)phosphorylation. RIPK1-mediated cell death leads to disruption of epithelial barriers and/or release of damage-associated molecular patterns (DAMPs), cytokines, and chemokines, propagating inflammatory and degenerative Diseases. Many drug development programs have pursued targeting RIPK1, and to a lesser extent RIPK3 kinase activity. In this review, we classify existing and novel small-molecule drugs based on their pharmacodynamic (PD) type I, II, and III binding mode. Finally, we discuss their applicability and therapeutic potential in inflammatory and degenerative Experimental Disease models.
-
necroptosis in vivo detection in Experimental Disease models
Seminars in Cell & Developmental Biology, 2014Co-Authors: Sandrine Jouanlanhouet, Nozomi Takahashi, Linde Duprez, Franck B Riquet, Tom Vanden Berghe, Peter VandenabeeleAbstract:Over the last decade, our picture of cell death signals involved in Experimental Disease models totally shifted. Indeed, in addition to apoptosis, multiple forms of regulated necrosis have been associated with an increasing number of pathologies such as ischemia-reperfusion injury in brain, heart and kidney, inflammatory Diseases, sepsis, retinal disorders, neurodegenerative Diseases and infectious disorders. Especially necroptosis is currently attracting the attention of the scientific community. However, the in vivo identification of ongoing necroptosis in Experimental Disease conditions remains troublesome, mainly due to the lack of specific biomarkers. Initially, Receptor-Interacting Protein Kinase 1 (RIPK1) and RIPK3 kinase activity were uniquely associated with induction of necroptosis, however recent evidence suggests pleiotropic functions in cell death, inflammation and survival, obscuring a clear picture. In this review, we will present the last methodological advances for in vivo necroptosis identification and discuss past and recent data to provide an update of the so-called "necroptosis-associated pathologies".
-
necrostatin 1 blocks both ripk1 and ido consequences for the study of cell death in Experimental Disease models
Cell Death & Differentiation, 2013Co-Authors: Peter Vandenabeele, Sasker Grootjans, Nico Callewaert, Nozomi TakahashiAbstract:Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in Experimental Disease models
Bernd C Kieseier - One of the best experts on this subject based on the ideXlab platform.
-
erythropoietin ameliorates rat Experimental autoimmune neuritis by inducing transforming growth factor beta in macrophages
PLOS ONE, 2011Co-Authors: Anne K Mausberg, Gerd Meyer Zu Horste, Thomas Dehmel, Mark Stettner, Helmar C Lehmann, Kazim A Sheikh, Bernd C KieseierAbstract:Erythropoietin (EPO) is a pleiotropic cytokine originally identified for its role in erythropoiesis. In addition, in various preclinical models EPO exhibited protective activity against tissue injury. There is an urgent need for potent treatments of autoimmune driven disorders of the peripheral nervous system (PNS), such as the Guillain-Barre syndrome (GBS), a disabling autoimmune Disease associated with relevant morbidity and mortality. To test the therapeutic potential of EPO in Experimental autoimmune neuritis (EAN) - an animal model of human GBS – immunological and clinical effects were investigated in a preventive and a therapeutic paradigm. Treatment with EPO reduced clinical Disease severity and if given therapeutically also shortened the recovery phase of EAN. Clinical findings were mirrored by decreased inflammation within the peripheral nerve, and myelin was well maintained in treated animals. In contrast, EPO increased the number of macrophages especially in later stages of the Experimental Disease phase. Furthermore, the anti-inflammatory cytokine transforming growth factor (TGF)-beta was upregulated in the treated cohorts. In vitro experiments revealed less proliferation of T cells in the presence of EPO and TGF-beta was moderately induced, while the secretion of other cytokines was almost not altered by EPO. Our data suggest that EPO revealed its beneficial properties by the induction of beneficial macrophages and the modulation of the immune system towards anti-inflammatory responses in the PNS. Further studies are warranted to elaborate the clinical usefulness of EPO for treating immune-mediated neuropathies in affected patients.
Nozomi Takahashi - One of the best experts on this subject based on the ideXlab platform.
-
necroptosis in vivo detection in Experimental Disease models
Seminars in Cell & Developmental Biology, 2014Co-Authors: Sandrine Jouanlanhouet, Nozomi Takahashi, Linde Duprez, Franck B Riquet, Tom Vanden Berghe, Peter VandenabeeleAbstract:Over the last decade, our picture of cell death signals involved in Experimental Disease models totally shifted. Indeed, in addition to apoptosis, multiple forms of regulated necrosis have been associated with an increasing number of pathologies such as ischemia-reperfusion injury in brain, heart and kidney, inflammatory Diseases, sepsis, retinal disorders, neurodegenerative Diseases and infectious disorders. Especially necroptosis is currently attracting the attention of the scientific community. However, the in vivo identification of ongoing necroptosis in Experimental Disease conditions remains troublesome, mainly due to the lack of specific biomarkers. Initially, Receptor-Interacting Protein Kinase 1 (RIPK1) and RIPK3 kinase activity were uniquely associated with induction of necroptosis, however recent evidence suggests pleiotropic functions in cell death, inflammation and survival, obscuring a clear picture. In this review, we will present the last methodological advances for in vivo necroptosis identification and discuss past and recent data to provide an update of the so-called "necroptosis-associated pathologies".
-
necrostatin 1 blocks both ripk1 and ido consequences for the study of cell death in Experimental Disease models
Cell Death & Differentiation, 2013Co-Authors: Peter Vandenabeele, Sasker Grootjans, Nico Callewaert, Nozomi TakahashiAbstract:Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in Experimental Disease models
-
necrostatin 1 analogues critical issues on the specificity activity and in vivo use in Experimental Disease models
Cell Death and Disease, 2012Co-Authors: Nozomi Takahashi, Linde Duprez, Sasker Grootjans, Anje Cauwels, Wim Nerinckx, James B Duhadaway, Vera Goossens, Ria Roelandt, F Van Hauwermeiren, Claude LibertAbstract:Necrostatin-1 (Nec-1) is widely used in Disease models to examine the contribution of receptor-interacting protein kinase (RIPK) 1 in cell death and inflammation. We studied three Nec-1 analogs: Nec-1, the active inhibitor of RIPK1, Nec-1 inactive (Nec-1i), its inactive variant, and Nec-1 stable (Nec-1s), its more stable variant. We report that Nec-1 is identical to methyl-thiohydantoin-tryptophan, an inhibitor of the potent immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). Both Nec-1 and Nec-1i inhibited human IDO, but Nec-1s did not, as predicted by molecular modeling. Therefore, Nec-1s is a more specific RIPK1 inhibitor lacking the IDO-targeting effect. Next, although Nec-1i was ∼100 × less effective than Nec-1 in inhibiting human RIPK1 kinase activity in vitro, it was only 10 times less potent than Nec-1 and Nec-1s in a mouse necroptosis assay and became even equipotent at high concentrations. Along the same line, in vivo, high doses of Nec-1, Nec-1i and Nec-1s prevented tumor necrosis factor (TNF)-induced mortality equally well, excluding the use of Nec-1i as an inactive control. Paradoxically, low doses of Nec-1 or Nec-1i, but not Nec -1s, even sensitized mice to TNF-induced mortality. Importantly, Nec-1s did not exhibit this low dose toxicity, stressing again the preferred use of Nec-1s in vivo. Our findings have important implications for the interpretation of Nec-1-based data in Experimental Disease models.
Richard S Taylor - One of the best experts on this subject based on the ideXlab platform.
-
genetic variation of gross gill pathology and survival of atlantic salmon salmo salar l during natural amoebic gill Disease challenge
Aquaculture, 2009Co-Authors: Richard S Taylor, Peter D Kube, W J Muller, Nicholas G ElliottAbstract:Abstract Survival in an Experimental Disease challenge test or to natural Disease challenge is utilised by aquaculture breeding programs as the selection trait for Disease resistance. However, these trials are expensive and do not offer the ability to retest animals. The aim of this study was therefore to estimate genetic parameters for resistance to amoebic gill Disease (AGD) measured by a categorical scale of gross gill signs (“gill score”) and survival in a field challenge in order to establish whether gill score provides adequate measurement of genetic variation for AGD resistance compared to an AGD challenge survival. A total of 1504 Atlantic salmon smolt, representing 140 full-sib families, was transferred to a marine site in SE Tasmania. The gills were assessed by gill score prior to freshwater bathing on the first two rounds of infection, and then the Disease was allowed to develop until mortalities began. Gill score was reassessed after 50 days and mortality was allowed to continue until it had reached a plateau at 100 days. The overall survival rate was 32.3% but varied from 0% to 69% between families. Estimated narrow sense heritability for AGD resistance assessed by gill score varied between 0.23 and 0.48 over the three rounds of infection. Heritability of AGD survival challenge was 0.40 to 0.49 on the observed scale using binary and longitudinal measures. Gill score and survival showed a weak (− 0.19) to strong (− 0.96) negative genetic correlation which improved when assessed closer to the survival challenge. Estimated genetic gains by selection of the top one hundred estimated breeding values for gill score indicated that up to 82% of the expected gain in survival can be achieved when compared to estimated gain by selection upon survival (days to death), thus minimising selection costs and improving fish welfare whilst allowing repeat measures to be made. The results show that genetic variation of gill score at the early onset of losses closely compares with survival results if the Disease is allowed to progress without subsequent freshwater bathing. Gill score may therefore be utilised as a nondestructive and repeatable selection trait for breeding Atlantic salmon with greater resistance to AGD.
Sofie Martens - One of the best experts on this subject based on the ideXlab platform.
-
inhibitors targeting ripk1 ripk3 old and new drugs
Trends in Pharmacological Sciences, 2020Co-Authors: Sofie Martens, Sam Hofmans, Koen Augustyns, Wim Declercq, Peter VandenabeeleAbstract:The scaffolding function of receptor-interacting protein kinase 1 (RIPK1) regulates prosurvival signaling and inflammatory gene expression, while its kinase activity mediates both apoptosis and necroptosis; the latter involving RIPK3 kinase activity. The mutual transition between the scaffold and kinase functions of RIPK1 is regulated by (de)ubiquitylation and (de)phosphorylation. RIPK1-mediated cell death leads to disruption of epithelial barriers and/or release of damage-associated molecular patterns (DAMPs), cytokines, and chemokines, propagating inflammatory and degenerative Diseases. Many drug development programs have pursued targeting RIPK1, and to a lesser extent RIPK3 kinase activity. In this review, we classify existing and novel small-molecule drugs based on their pharmacodynamic (PD) type I, II, and III binding mode. Finally, we discuss their applicability and therapeutic potential in inflammatory and degenerative Experimental Disease models.
