scholarly journals Inhibition des caspases

2020 ◽  
Vol 36 (12) ◽  
pp. 1143-1154
Author(s):  
Étienne Jacotot
Keyword(s):  
Caspase 3 ◽  
Phase Iii ◽  
Étude Clinique ◽  
Mort Cellulaire ◽  
Caspase 2

Les caspases sont une famille de cystéines protéases bien connues pour leurs rôles centraux au cours de l’apoptose et de l’inflammation. Elles interviennent aussi dans des voies de mort cellulaire régulées non-apoptotiques, et contribuent à de très nombreux mécanismes physiologiques. Le développement d’approches thérapeutiques ciblant les caspases a engendré un fort intérêt industriel dès les années 1990, suscitant d’intenses recherches sur les mécanismes biologiques, et conduisant à la mise au point de nombreux inhibiteurs synthétiques. La plupart de ces inhibiteurs sont des dérivés de peptides, ou mimétiques, capables d’interagir avec le site actif des caspases. Cependant, la conservation structurelle observée entre les différentes caspases est un défi pour le développement d’inhibiteurs sélectifs. À ce jour, cinq inhibiteurs de caspases ont été évalués pour leur efficacité clinique, mais aucune autorisation de mise sur le marché n’a été délivrée à ce jour. Contrairement aux présomptions initiales, les inhibiteurs sélectifs de la Caspase-3 n’ont pas atteint le stade d’essais cliniques, alors que le QPI-1007, un siARN dirigé contre la Caspase-2, a fait l’objet d’une étude clinique de phase III pour le traitement de neuropathies optiques ischémiques.

scholarly journals Bax, Caspase-2, and Caspase-3 Are Required for Ovarian Follicle Loss Caused by 4-Vinylcyclohexene Diepoxide Exposure of Female Mice in Vivo

Endocrinology ◽  
2003 ◽  
Vol 144 (1) ◽  
pp. 69-74 ◽  
Author(s):  
Yasushi Takai ◽  
Jacqueline Canning ◽  
Gloria I. Perez ◽  
James K. Pru ◽  
Jennifer J. Schlezinger ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Ovarian Follicle ◽  
Female Mice ◽  
Vinylcyclohexene Diepoxide ◽  
Caspase 2

scholarly journals Salmonella-Induced Caspase-2 Activation in Macrophages

2000 ◽  
Vol 192 (7) ◽  
pp. 1035-1046 ◽  
Author(s):  
Veronika Jesenberger ◽  
Katarzyna J. Procyk ◽  
Junying Yuan ◽  
Siegfried Reipert ◽  
Manuela Baccarini
Keyword(s):  
Type Iii Secretion ◽  
Caspase 3 ◽  
Secretion System ◽  
Caspase 1 ◽  
Chemical Inhibition ◽  
Induction Of Apoptosis ◽  
Caspase 2 ◽  
Induced Apoptosis

The enterobacterial pathogen Salmonella induces phagocyte apoptosis in vitro and in vivo. These bacteria use a specialized type III secretion system to export a virulence factor, SipB, which directly activates the host's apoptotic machinery by targeting caspase-1. Caspase-1 is not involved in most apoptotic processes but plays a major role in cytokine maturation. We show that caspase-1–deficient macrophages undergo apoptosis within 4–6 h of infection with invasive bacteria. This process requires SipB, implying that this protein can initiate the apoptotic machinery by regulating components distinct from caspase-1. Invasive Salmonella typhimurium targets caspase-2 simultaneously with, but independently of, caspase-1. Besides caspase-2, the caspase-1–independent pathway involves the activation of caspase-3, -6, and -8 and the release of cytochrome c from mitochondria, none of which occurs during caspase-1–dependent apoptosis. By using caspase-2 knockout macrophages and chemical inhibition, we establish a role for caspase-2 in both caspase-1–dependent and –independent apoptosis. Particularly, activation of caspase-1 during fast Salmonella-induced apoptosis partially relies on caspase-2. The ability of Salmonella to induce caspase-1–independent macrophage apoptosis may play a role in situations in which activation of this protease is either prevented or uncoupled from the induction of apoptosis.

The interferon-inducible gene IFI16, a member of the HIN200 family, triggers primary endothelial cell apoptosis through caspase 2 and caspase 3 pathway

Cytokine ◽  
2009 ◽  
Vol 48 (1-2) ◽  
pp. 85
Author(s):  
Francesca Gugliesi ◽  
Marco De Andrea ◽  
Michele Mondini ◽  
Paola Cappello ◽  
Mirella Giovarelli ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Endothelial Cell Apoptosis ◽  
Caspase 2 ◽  
Inducible Gene

scholarly journals A novel anti-proliferative role of HMGA2 in induction of apoptosis through caspase 2 in primary human fibroblast cells

2015 ◽  
Vol 35 (1) ◽  
Author(s):  
Xi Shi ◽  
Baoqing Tian ◽  
Wenlong Ma ◽  
Na Zhang ◽  
Yuehua Qiao ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Flow Cytometric Analysis ◽  
Ectopic Expression ◽  
High Mobility ◽  
Primary Human Fibroblast ◽  
Primary Cell Lines ◽  
Induction Of Apoptosis ◽  
Caspase 2 ◽  
Induced Apoptosis ◽  
High Level

The HMGA2 (high-mobility group AT-hook) protein has previously been shown as an oncoprotein, whereas ectopic expression of HMGA2 is found to induce growth arrest in primary cells. The precise mechanisms underlying this phenomenon remain to be unravelled. In the present study, we determined that HMGA2 was able to induce apoptosis in WI38 primary human cells. We show that WI38 cells expressing high level of HMGA2 were arrested at G2/M phase and exhibited apoptotic nuclear phenotypes. Meanwhile, the cleaved caspase 3 (cysteine aspartic acid-specific protease 3) was detected 8 days after HMGA2 overexpression. Flow cytometric analysis confirmed that the ratio of cells undergoing apoptosis increased dramatically. Concurrently, other major apoptotic markers were also detected, including the up-regulation of p53, Bax and cleaved caspase 9, down-regulation of Bcl-2; as well as release of cytochrome c from the mitochondria. We further demonstrate that the shRNA (small-hairpin RNA)-mediated Apaf1 (apoptotic protease activating factor 1) silencing partially rescued the HMGA2-induced apoptosis, which was accompanied by the decrease of cleaved caspase-3 level and a decline of cell death ratio. Our results also reveal that γH2A was accumulated in nuclei during the HMGA2-induced apoptosis along with the up-regulation of cleaved caspase 2, suggesting that the HMGA2-induced apoptosis was dependent on the pathway of DNA damage. Overall, the present study unravelled a novel function of HMGA2 in induction of apoptosis in human primary cell lines, and provided clues for clarification of the mechanistic action of HMGA2 in addition to its function as an oncoprotein.

scholarly journals Coupling Activation of Pro-Apoptotic Caspases With Autophagy in the Meckel´s Cartilage

2018 ◽  
pp. 135-140 ◽  
Author(s):  
P. Bíliková ◽  
E. Švandová ◽  
B. Veselá ◽  
J. Doubek ◽  
A. Poliard ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Beclin 1 ◽  
Hypertrophic Chondrocytes ◽  
Caspase 8 ◽  
Major Mechanism ◽  
Histological Sections ◽  
Temporary Structure ◽  
Caspase 2 ◽  
First Time

Mammalian Meckel´s cartilage is a temporary structure associated with mandible development. Notably, its elimination is not executed by apoptosis, and autophagy was suggested as the major mechanism. Simultaneous reports point to pro-apoptotic caspases as novel participants in autophagic pathways in general. The aim of this research was to find out whether activation of pro-apoptotic caspases (-2, -3, -6, -7, -8 and -9) was associated with autophagy of the Meckel´s cartilage chondrocytes. Active caspases were examined in serial histological sections of mouse mandible using immunodetection and were correlated with incidence of autophagy based on Beclin-1 expression. Caspase-2 and caspase-8 were found in Beclin-1 positive regions, whereas caspase-3, -6, -7 and -9 were not present. Caspase-8 was further correlated with Fas/FasL and HIF-1alpha, potential triggers for its activation. Some Fas and FasL positivity was observed in the chondrocytes but caspase-8 activation was found also in FasL deficient cartilage. HIF-1alpha was abundantly present in the hypertrophic chondrocytes. Taken together, caspase-8 activation in the Meckel´s cartilage was demonstrated for the first time. Caspase-8 and caspase-2 were the only pro-apoptotic caspases detected in the Beclin-1 positive segment of the cartilage. Activation of caspase-8 appears FasL/Fas independent but may be switched on by HIF-1alpha.

Caspase 2 and Caspase 3 Protein Levels as Predictors of Survival in Acute Myelogenous Leukemia

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3090-3097 ◽  
Author(s):  
Zeev Estrov ◽  
Peter F. Thall ◽  
Moshe Talpaz ◽  
Elihu H. Estey ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Acute Myelogenous Leukemia ◽  
Caspase 3 ◽  
Myelogenous Leukemia ◽  
Prognostic Variables ◽  
Normal Peripheral Blood ◽  
Protein Levels ◽  
Acute Myelogenous ◽  
Caspase 2 ◽  
High Level

Abstract Because caspase activation is an essential step in programmed cell death (apoptosis) and cytotoxic drug-induced apoptosis is mediated by caspase 2 and caspase 3, we hypothesized that caspase 2 and 3 levels predict clinical outcome in acute myelogenous leukemia (AML). Using quantitative Western blot analysis, we studied the levels of nonactivated (uncleaved) caspase 2 and 3 in peripheral blood low-density cells from 185 patients with newly diagnosed AML. We also measured the level of activated (cleaved) caspase 3 in 41 randomly selected samples from the 185 patients. Finally, we analyzed the effect of caspase 2 and 3 levels and other prognostic variables on patient survival using a multivariate Cox model. We found that median levels of nonactivated caspase 2 and 3 were higher in AML than in normal peripheral blood cells (P < .001 and P <.02, respectively). There was no association between caspase level and either the percentage of peripheral blasts or any specific type of leukemia cell cytogenetic abnormalities. When the effect of each uncleaved caspase was considered individually, a high level of uncleaved caspase 3 (P = .04), but not of caspase 2 (P = .16), was associated with decreased survival. Conversely, a high level of cleaved caspase 3 denoted improved survival and correlated with the inactivation of the DNA-repair enzyme poly(ADP-ribose) polymerase. Thus, cleaved caspase 3 could stimulate the apoptotic cascade further, and lack of its activation likely caused an accumulation of the uncleaved caspase. Although uncleaved caspase 2 level per se had no prognostic significance, the interactive effect of high levels of both uncleaved caspase 2 and 3 denoted very poor survival (P < .001) and had the largest effect of all prognostic variables (P < .001; estimated relative risk, 2.49; 95% confidence interval, 1.59 to 3.90). Taken together, caspase 2 and caspase 3 protein levels obtained at diagnosis may constitute a reliable prognostic factor in AML. © 1998 by The American Society of Hematology.

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