scholarly journals FADD (Fas-Associated Protein With Death Domain), Caspase-3, and Caspase-8 and Incidence of Ischemic Stroke

Stroke ◽  
2018 ◽  
Vol 49 (9) ◽  
pp. 2224-2226 ◽  
Author(s):  
Iram Faqir Muhammad ◽  
Yan Borné ◽  
Olle Melander ◽  
Marju Orho-Melander ◽  
Jan Nilsson ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Caspase 3 ◽  
Caspase 8 ◽  
Death Domain

scholarly journals LIGHT, a Member of the Tumor Necrosis Factor Ligand Superfamily, Prevents Tumor Necrosis Factor-α-mediated Human Primary Hepatocyte Apoptosis, but Not Fas-mediated Apoptosis

2002 ◽  
Vol 277 (51) ◽  
pp. 50054-50061 ◽  
Author(s):  
Hideki Matsui ◽  
Yukiko Hikichi ◽  
Isamu Tsuji ◽  
Takao Yamada ◽  
Yasushi Shintani
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Time Course ◽  
Caspase 3 ◽  
Nuclear Factor Κb ◽  
Caspase 8 ◽  
Death Domain ◽  
Human Primary Hepatocytes ◽  
Induced Apoptosis ◽  
Necrosis Factor

LIGHT is a member of tumor necrosis factor (TNF) superfamily, and its receptors have been identified as lymphotoxin-β receptor (LTβR) and the herpesvirus entry mediator (HVEM)/ATAR/TR2, both of which lack the cytoplasmic sequence termed the “death domain.” The present study has demonstrated that LIGHT inhibits TNFα-mediated apoptosis of human primary hepatocytes sensitized by actinomycin D (ActD), but not Fas- or TRAIL-mediated apoptosis. Furthermore, LIGHT does not prevent some cell lines such as HepG2 or HeLa from undergoing ActD/TNFα-induced apoptosis. This protective effect requires LIGHT pretreatment at least 3 h prior to ActD sensitization. LIGHT stimulates nuclear factor-κB (NF-κB)-dependent transcriptional activity in human hepatocytes like TNFα. The time course of NF-κB activation after LIGHT administration is similar to that of the pretreatment required for the anti-apoptotic effect of LIGHT. LIGHT inhibits caspase-3 processing on the apoptotic protease cascade in TNFα-mediated apoptosis but not Fas-mediated apoptosis. In addition, increased caspase-3 and caspase-8 activities in ActD/TNFα-treated cells are effectively blocked by LIGHT pretreatment. However, LIGHT does not change the expression of TNFRp55, TNFRp75, and Fas. These results indicate that LIGHT may act as an anti-apoptotic agent against TNFα-mediated liver injury by blocking the activation of both caspase-3 and caspase-8.

scholarly journals Association of Active Caspase 8 with the Mitochondrial Membrane during Apoptosis: Potential Roles in Cleaving BAP31 and Caspase 3 and Mediating Mitochondrion-Endoplasmic Reticulum Cross Talk in Etoposide-Induced Cell Death

2004 ◽  
Vol 24 (15) ◽  
pp. 6592-6607 ◽  
Author(s):  
Dhyan Chandra ◽  
Grace Choy ◽  
Xiaodi Deng ◽  
Bobby Bhatia ◽  
Peter Daniel ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Cross Talk ◽  
Membrane Fraction ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
Dominant Negative ◽  
Caspase 8 ◽  
Death Domain ◽  
Active Caspase

ABSTRACT It was recently demonstrated that during apoptosis, active caspase 9 and caspase 3 rapidly accumulate in the mitochondrion-enriched membrane fraction (D. Chandra and D. G. Tang, J. Biol. Chem.278:17408-17420, 2003). We now show that active caspase 8 also becomes associated with the membranes in apoptosis caused by multiple stimuli. In MDA-MB231 breast cancer cells treated with etoposide (VP16), active caspase 8 is detected only in the membrane fraction, which contains both mitochondria and endoplasmic reticulum (ER), as revealed by fractionation studies. Immunofluorescence microscopy, however, shows that procaspase 8 and active caspase 8 predominantly colocalize with the mitochondria. Biochemical analysis demonstrates that both procaspase 8 and active caspase 8 are localized mainly on the outer mitochondrial membrane (OMM) as integral proteins. Functional analyses with dominant-negative mutants, small interfering RNAs, peptide inhibitors, and Fas-associated death domain (FADD)- and caspase 8-deficient Jurkat T cells establish that the mitochondrion-localized active caspase 8 results mainly from the FADD-dependent and tumor necrosis factor receptor-associated death domain-dependent mechanisms and that caspase 8 activation plays a causal role in VP16-induced caspase 3 activation and cell death. Finally, we present evidence that the OMM-localized active caspase 8 can activate cytosolic caspase 3 and ER-localized BAP31. Cleavage of BAP31 leads to the generation of ER- localized, proapoptotic BAP20, which may mediate mitochondrion-ER cross talk through a Ca2+-dependent mechanism.

scholarly journals Role of Insulin Receptor and Balance in Insulin Receptor Isoforms A and B in Regulation of Apoptosis in Simian Virus 40-immortalized Neonatal Hepatocytes

2008 ◽  
Vol 19 (3) ◽  
pp. 1185-1198 ◽  
Author(s):  
Carmen Nevado ◽  
Manuel Benito ◽  
Angela M. Valverde
Keyword(s):  
Insulin Receptor ◽  
Caspase 3 ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Caspase 8 ◽  
Death Domain ◽  
Cytochrome C Release ◽  
Insulin Receptor Isoforms ◽  
Neonatal Hepatocytes

We have investigated the unique role of the insulin receptor (IR) and the balance of its isoforms A and B in the regulation of apoptosis in simian virus 40 (SV40)-immortalized neonatal hepatocytes. Immortalized hepatocytes lacking (HIR KO) or expressing the entire IR (HIR LoxP), and cells expressing either IRA (HIR RecA) or IRB (HIR RecB) have been generated. IR deficiency in hepatocytes increases sensitivity to the withdrawal of growth factors, because these cells display an increase in reactive oxygen species, a decrease in Bcl-xL, a rapid accumulation of nuclear Foxo1, and up-regulation of Bim. These events resulted in acceleration of caspase-3 activation, DNA laddering, and cell death. The single expression of either IRA or IRB produced a stronger apoptotic phenotype. In these cells, protein complexes containing IRA or IRB and Fas/Fas-associating protein with death domain activated caspase-8, and, ultimately, caspase-3. In hepatocytes expressing IRA, Bid cleavage and cytochrome C release were increased whereas direct activation of caspase-3 by caspase-8 and a more rapid apoptotic process occurred in hepatocytes expressing IRB. Conversely, coexpression of IRA and IRB in IR-deficient hepatocytes rescued from apoptosis. Our results suggest that balance alteration of IRA and IRB may serve as a ligand-independent apoptotic trigger in hepatocytes, which may regulate liver development.

scholarly journals DR4-Associated Death Receptor Signal Promotes Cartilage Damage in Patients With Kashin-Beck Disease

Cartilage ◽  
2019 ◽  
pp. 194760351988662 ◽  
Author(s):  
Shixun Wu ◽  
Zhi Yi ◽  
Ming Ling ◽  
Shizhang Liu ◽  
Zhengming Sun ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Cartilage Damage ◽  
Mrna Level ◽  
Death Receptor ◽  
Caspase 8 ◽  
Complete Medium ◽  
Death Domain ◽  
Hoechst 33258 ◽  
Oa Chondrocytes ◽  
Beck Disease

Purpose. To explore the relationship between the death receptor (DR) and the pathological progression of Kashin-Beck disease (KBD). Design. KBD cartilage samples were collected from 15 patients diagnosed according to the “National Diagnostic Criteria of KBD” in China. In vitro monolayer chondrocytes were cultured in complete medium. Caspase-3 and caspase-8 activities in chondrocytes were analyzed using a kit. Nuclear morphology was observed by Hoechst 33258 staining, apoptosis was verified by flow cytometry analysis, and DR molecules were detected using Western blotting and quantitative real-time reverse transcription polymerase chain reaction analysis. Results. Early apoptotic rates of KBD and osteoarthritis (OA) chondrocytes were higher than those of normal control (NC) cells. Excessive apoptotic nuclei were observed in OA and KBD cells after Hoechst 33258 staining. Activities of both caspase-3 and caspase-8 were higher in KBD and OA cells than in NC cells. The average DR4 mRNA level in KBD cells was 3.301-fold higher than that in NC cells, Fas-associating protein with death domain (FADD) transcript level in KBD cells was 2.528-fold higher than that in NC cells. Western blot analyses showed that FAS, DR4, DR5, caspase-3, and FADD were upregulated in the KBD and OA groups compared with the NC group. High expression of caspase-8 in KBD compared with NC was verified, whereas cellular FLICE-inhibitory protein (c-FLIP) in KBD was significantly downregulated. Conclusions. KBD and OA chondrocytes showed obvious FADD-caspase-dependent apoptosis, which is related to the DR pathway. Apoptosis in KBD articular cartilage is mainly related to FAS/DR4-FADD-caspase signaling, and OA is associated with FAS/DR4/DR5-FADD-caspase signaling.

scholarly journals TNF-αInduced the Enhanced Apoptosis of Mesenchymal Stem Cells in Ankylosing Spondylitis by Overexpressing TRAIL-R2

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Zhenhua Liu ◽  
Liangbin Gao ◽  
Peng Wang ◽  
Zhongyu Xie ◽  
Shuizhong Cen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ankylosing Spondylitis ◽  
Cytochrome C ◽  
Caspase 3 ◽  
Death Receptor ◽  
Unknown Etiology ◽  
Caspase 8 ◽  
Necrosis Factor Alpha ◽  
Cytosolic Cytochrome

Ankylosing spondylitis (AS) is an autoimmune disease with unknown etiology. Dysregulated mesenchymal stem cells (MSCs) apoptosis may contribute to the pathogenesis of autoimmune diseases. However, apoptosis of MSCs from patients with AS (ASMSCs) has not been investigated yet. The present study aims to assess the apoptosis of bone marrow-derived ASMSCs and to investigate the underlying mechanisms of altered ASMSCs apoptosis. We successfully induced the apoptosis of ASMSCs and MSCs from healthy donors (HDMSCs) using the combination of tumor necrosis factor alpha (TNF-α) and cycloheximide (CHX). We found that ASMSCs treated with TNF-αand CHX showed higher apoptosis levels compared to HDMSCs. During apoptosis, ASMSCs expressed significantly more TRAIL-R2, which activated both the death receptor pathway and mitochondria pathway by increasing the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3. Inhibiting TRAIL-R2 expression using shRNA eliminated the apoptosis differences between HDMSCs and ASMSCs by partially reducing ASMSCs apoptosis but minimally affecting that of HDMSCs. Furthermore, the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3 were comparable between HDMSCs and ASMSCs after TRAIL-R2 inhibition. These results indicated that increased TRAIL-R2 expression results in enhanced ASMSCs apoptosis and may contribute to AS pathogenesis.

Synthesis and biological activities of chaetocin and its derivatives

2012 ◽  
Vol 84 (6) ◽  
pp. 1369-1378 ◽  
Author(s):  
Mikiko Sodeoka ◽  
Kosuke Dodo ◽  
Yuou Teng ◽  
Katsuya Iuchi ◽  
Yoshitaka Hamashima ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Caspase 3 ◽  
Biological Activities ◽  
Caspase 8 ◽  
Human Leukemia ◽  
Mechanistic Studies ◽  
Anticancer Activities ◽  
Histone Methyltransferases ◽  
Structure Activity ◽  
Apoptosis Inducer

Chaetocin, a natural product isolated from fungi of Chaetomium species, is a member of the epipolythiodiketopiperazines (ETPs), which have various biological activities, including cytostatic and anticancer activities. Recently, the inhibitory activity toward histone methyltransferases (HMTs) was discovered for chaetocin. We previously reported the first total synthesis of chaetocin and various derivatives. During studies on the structure–activity relationship for HMT inhibition, we found that the enantiomer of chaetocin (ent-chaetocin) is a more potent apoptosis inducer than natural chaetocin in human leukemia HL-60 cells. Mechanistic studies showed that ent-chaetocin induces apoptosis through the caspase-8/caspase-3 pathway.

scholarly journals PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Nilsa Rivera-Del Valle ◽  
Shan Gao ◽  
Claudia P. Miller ◽  
Joy Fulbright ◽  
Carolina Gonzales ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Hydroxamic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Leukemia Cells ◽  
Ros Generation ◽  
Caspase 8 ◽  
Death Domain ◽  
Apoptosis Induction ◽  
Tumor Types ◽  
Insight Into

Histone deacetylase inhibitors (HDACi) have become a promising new avenue for cancer therapy, and many are currently in Phase I/II clinical trials for various tumor types. In the present study, we show that apoptosis induction and histone alterations by PCI-24781, a novel hydroxamic acid-based HDAC inhibitor, require caspase-8 and the adaptor molecule, Fas-associated death domain (FADD), in acute leukemia cells. PCI-24781 treatment also causes an increase in superoxide levels, which has been reported for other HDACi. However, an antioxidant does not reverse histone alterations caused by PCI-24781, indicating that ROS generation is likely downstream of the effects that PCI-24781 exerts on histone H3. Taken together, these results provide insight into the mechanism of apoptosis induction by PCI-24781 in leukemia by highlighting the roles of caspase-8, FADD and increased superoxide levels.

Abstract WP62: Enhanced Neuroprotection of Normobaric Oxygenation with Ethanol Conferred by Apoptosis Reduction in Acute Ischemic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Sweena Parmar ◽  
Xiaokun Geng ◽  
Changya Peng ◽  
Murali Guthikonda ◽  
Yuchuan Ding
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Neuroprotective Effect ◽  
Apoptotic Cell Death ◽  
Ethanol Administration ◽  
Sprague Dawley ◽  
Apoptotic Proteins

Objectives: Normobaric oxygenation (NBO) has been shown to provide neuroprotection in vivo and in vitro . Yet, a recent Phase 2 clinical trial investigating NBO therapy in acute ischemic stroke was terminated due to questionable therapeutic benefit. NBO therapy alone may be insufficient to produce improved outcomes. In our recent study, we demonstrated a strong neuroprotective effect of ethanol at a dose of 1.5 g/kg (equivalent to the human legal driving limit). In this study, we sought to identify whether low-dose ethanol administration enhances the neuroprotection offered by NBO and whether combined administration of NBO with ethanol is associated with reduced apoptosis. Methods: Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion. Ischemic animals received either an intraperitoneal injection of 1.0 g/kg ethanol, 2 h of 100% NBO, or both ethanol and NBO. The Cell Death Detection ELISA Assay (Roche) was performed to determine apoptotic cell death at 24 h after reperfusion. Levels of pro-apoptotic (Caspase-3, Bcl-2-associated X-BAX, and Apoptosis-Inducing Factor-AIF) and anti-apoptotic proteins (Bcl-2 and Bcl-xL) were determined by Western blot analysis at 3 and 24 h after reperfusion. Results: As expected, untreated ischemic rats had the highest apoptotic cell death. Combined NBO/ethanol therapy decreased cell death by 48%, as compared to 29% with ethanol and 22% with NBO. Similarly, combined NBO/ethanol therapy promoted the greatest expression of anti-apoptotic factors and the lowest expression of pro-apoptotic proteins at 3 h after reperfusion. This effect was maintained at 24 h and even more pronounced for AIF and Caspase-3. Conclusions: Given singularly, NBO and ethanol improved the degree of cell death, decreased the expression of pro-apoptotic proteins, and increased the expression of anti-apoptotic proteins. Yet, when administered together, their effects largely compounded. These results suggest a synergistic neuroprotection offered by NBO with ethanol, which may be attributed at least in part to their shared role in modulating neuronal apoptosis.

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