The triptolide-induced apoptosis of osteoclast precursor by degradation of cIAP2 and treatment of rheumatoid arthritis of TNF-transgenic mice

2018 ◽  
Vol 33 (2) ◽  
pp. 342-349 ◽  
Author(s):  
Shengli Wang ◽  
Zhigang Liu ◽  
Jingchun Wang ◽  
Yifei Wang ◽  
Jianhua Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transgenic Mice ◽  
Osteoclast Precursor ◽  
Induced Apoptosis

scholarly journals Expression of a Dominant Negative Mutant of Interleukin-1β Converting Enzyme in Transgenic Mice Prevents Neuronal Cell Death Induced by Trophic Factor Withdrawal and Ischemic Brain Injury

1997 ◽  
Vol 185 (5) ◽  
pp. 933-940 ◽  
Author(s):  
Robert M. Friedlander ◽  
Valeria Gagliardini ◽  
Hideaki Hara ◽  
Klaus B. Fink ◽  
Weiwei Li ◽  
...  
Keyword(s):  
Brain Injury ◽  
Transgenic Mice ◽  
Dorsal Root ◽  
Neuron Specific Enolase ◽  
Dominant Negative ◽  
Trophic Factor ◽  
Dominant Negative Mutant ◽  
Lacz Gene ◽  
Converting Enzyme ◽  
Induced Apoptosis

To explore the role of the interleukin (IL)-1β converting enzyme (ICE) in neuronal apoptosis, we designed a mutant ICE gene (C285G) that acts as a dominant negative ICE inhibitor. Microinjection of the mutant ICE gene into embryonal chicken dorsal root ganglial neurons inhibits trophic factor withdrawal–induced apoptosis. Transgenic mice expressing the fused mutant ICE-lacZ gene under the control of the neuron specific enolase promoter appeared neurologically normal. These mice are deficient in processing pro–IL-1β, indicating that mutant ICEC285G blocks ICE function. Dorsal root ganglial neurons isolated from transgenic mice were resistant to trophic factor withdrawal–induced apoptosis. In addition, the neurons isolated from newborn ICE knockout mice are similarly resistant to trophic factor withdrawal–induced apoptosis. After permanent focal ischemia by middle cerebral artery occlusion, the mutant ICEC285G transgenic mice show significantly reduced brain injury as well as less behavioral deficits when compared to the wild-type controls. Since ICE is the only enzyme with IL-1β convertase activity in mice, our data indicates that the mutant ICEC285G inhibits ICE, and hence mature IL-1β production, and through this mechanism, at least in part, inhibits apoptosis. Our data suggest that genetic manipulation using ICE family dominant negative inhibitors can ameliorate the extent of ischemia-induced brain injury and preserve neurological function.

scholarly journals Mitomycin C Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes via a Mitochondrial-Mediated Pathway

2015 ◽  
Vol 35 (3) ◽  
pp. 1125-1136 ◽  
Author(s):  
Chuqi Yan ◽  
Dechao Kong ◽  
Dong Ge ◽  
Yanming Zhang ◽  
Xishan Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Viability ◽  
Mitomycin C ◽  
Apoptotic Cell ◽  
Chronic Inflammatory Disease ◽  
Cell Counting ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Control Treatment ◽  
Induced Apoptosis ◽  
Fibroblast Like Synoviocytes

Background/Aims: Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterised by prominent synoviocyte hyperplasia and a potential imbalance between the growth and death of fibroblast-like synoviocytes (FLS). Mitomycin C (MMC) has previously been demonstrated to inhibit fibroblast proliferation and to induce fibroblast apoptosis. However, the effects of MMC on the proliferation and apoptosis of human RA FLS and the potential mechanisms underlying its effects remain unknown. Methods: Cell viability was determined using the Cell Counting Kit-8 assay. Apoptotic cell death was analysed via Annexin V-FITC/PI double staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling. The production of intracellular reactive oxygen species (ROS) was assessed via flow cytometry, and the changes in mitochondrial membrane potential (ΔΨm) were visualized based on JC-1 staining via fluorescence microscopy. The expression of apoptosis-related proteins was determined via Western blot. Results: Treatment with MMC significantly reduced cell viability and induced apoptosis in RA FLS. Furthermore, MMC exposure was found to stimulate the production of ROS and to disrupt the ΔΨm compared to the control treatment. Moreover, MMC increased the release of mitochondrial cytochrome c, the ratio of Bax/Bcl-2, the activation of caspase-9 and caspase-3, and the subsequent cleavage of poly(ADP-ribose) polymerase. Conclusion: Our findings suggest that MMC inhibits cell proliferation and induces apoptosis in RA FLS, and the mechanism underlying this MMC-induced apoptosis may involve a mitochondrial signalling pathway.

Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice

1999 ◽  
Vol 277 (3) ◽  
pp. G702-G708 ◽  
Author(s):  
Alix de la Coste ◽  
Monique Fabre ◽  
Nathalie McDonell ◽  
Arlette Porteu ◽  
Helène Gilgenkrantz ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transgenic Mice ◽  
Fas Ligand ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tnf Α ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Factor Α

Fas ligand (CD95L) and tumor necrosis factor-α (TNF-α) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-α-mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing[Formula: see text]in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous[Formula: see text]or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-α caused massive apoptosis and death only when transcription was inhibited. Under these conditions,[Formula: see text]mice were partially protected from liver injury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-α receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.

scholarly journals Susceptibility of rheumatoid arthritis synovial fibroblasts to FasL- and TRAIL-induced apoptosis is cell cycle-dependent

2009 ◽  
Vol 11 (1) ◽  
pp. R16 ◽  
Author(s):  
Noreen Pundt ◽  
Marvin A Peters ◽  
Christina Wunrau ◽  
Simon Strietholt ◽  
Carsten Fehrmann ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Cycle ◽  
Synovial Fibroblasts ◽  
Induced Apoptosis ◽  
Cycle Dependent

Induced Apoptosis of Chondrocytes by Porphyromonas gingivalis as a Possible Pathway for Cartilage Loss in Rheumatoid Arthritis

2010 ◽  
Vol 87 (4) ◽  
pp. 333-340 ◽  
Author(s):  
E. Röhner ◽  
J. Detert ◽  
P. Kolar ◽  
A. Hocke ◽  
P. N’Guessan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Porphyromonas Gingivalis ◽  
Cartilage Loss ◽  
Induced Apoptosis

Myc Promotes Tumorigenesis by Supressing Nfkb2.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1422-1422
Author(s):  
Ulrich Keller ◽  
Juergen Huber ◽  
Jonas Nilsson ◽  
Mark Hall ◽  
Christian Peschel ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
Burkitt Lymphoma ◽  
Transcriptional Repression ◽  
Early Passage ◽  
Transgenic Expression ◽  
Myc Oncogene ◽  
Protein Levels ◽  
Induced Apoptosis

Abstract Rel/NF-kappaB transcription factors are mediators of immune responses, cell survival, and transformation, and are frequently deregulated in cancer. The NF-kappaB2 subunit is associated with chromosomal translocations or deletions in lymphoid malignancies, and deletion of the COOH-terminal ankyrin domain of NF-kappaB2 results in increased lymphocyte proliferation. Here, we report that activation of the Myc oncogene leads to suppression of Nfkb2 expression in early passage mouse embryonic fibroblasts and primary bone marrow-derived B cells. Accordingly, transgenic expression of c-Myc in the Eμ-Myc model of human Burkitt lymphoma results in reduced nfkb2 transcript and NF-kappaB2 p100 and p52 protein levels in pre-cancerous B cells. Nfkb2 expression is further reduced in the majority of Eμ-Myc lymphomas and in human Burkitt lymphoma. Nfkb2 suppression by Myc occurs at least in part by transcriptional repression as shown by promoter studies. To evaluate the relevance of Myc-mediated suppression of Nfkb2 for tumorigenesis, consequences of complete Nfkb2 loss were evaluated in vivo. In pre-cancerous B cells of Myc-transgenic mice, loss of Nfkb2 affects Myc-induced apoptosis while B cell proliferation is unaffected. Deletion of Nfkb2 results in an acceleration of lymphoma development in Eμ-Myc transgenic mice. Therefore, Myc-induced Nfkb2 suppression promotes lymphomagenesis.

Occlusive Lung Arterial Lesions in Endothelial-Targeted, Fas-Induced Apoptosis Transgenic Mice

2015 ◽  
Vol 53 (5) ◽  
pp. 712-718 ◽  
Author(s):  
Heather Goldthorpe ◽  
Jin-Yi Jiang ◽  
Mohamad Taha ◽  
Yupu Deng ◽  
Tammy Sinclair ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Arterial Lesions ◽  
Induced Apoptosis

Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1423-1431 ◽  
Author(s):  
Stephan von Gunten ◽  
Shida Yousefi ◽  
Michael Seitz ◽  
Stephan M. Jakob ◽  
Thomas Schaffner ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Diseases ◽  
Interferon Α ◽  
Gm Csf ◽  
Independent Form ◽  
Blood Neutrophils ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Induced Apoptosis

Abstract We report about new apoptotic and non-apoptotic death pathways in neutrophils that are initiated via the surface molecule sialic acid-binding immunoglobulin-like lectin (Siglec)-9. In normal neutrophils, Siglec-9 ligation induced apoptosis. Inflammatory neutrophils obtained from patients with acute septic shock or rheumatoid arthritis demonstrated increased Siglec-9, but normal Fas receptor-mediated cytotoxic responses when compared with normal blood neutrophils. The increased Siglec-9-mediated death was mimicked in vitro by short-term preincubation of normal neutrophils with proinflammatory cytokines, such as granulocyte/macrophage colony-stimulating factor (GM-CSF), interferon-α (IFN-α), and IFN-γ, and was demonstrated to be caspase independent. Experiments using scavengers of reactive oxygen species (ROS) or neutrophils unable to generate ROS indicated that both Siglec-9-mediated caspase-dependent and caspase-independent forms of neutrophil death depend on ROS. Interestingly, the caspase-independent form of neutrophil death was characterized by cytoplasmic vacuolization and several other nonapoptotic morphologic features, which were also seen in neutrophils present in joint fluids from rheumatoid arthritis patients. Taken together, these data suggest that apoptotic (ROS- and caspase-dependent) and nonapoptotic (ROS-dependent) death pathways are initiated in neutrophils via Siglec-9. The new insights have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases such as sepsis and rheumatoid arthritis. (Blood. 2005;106:1423-1431)

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