Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute cardiac graft rejection (ACGR) is associated with cardiomyocyte apoptosis. We investigated the respective role of the Fas/FasL and mitochondrial permeability transition pore (mPTP) pathways in cardiomyocyte apoptosis accompanying ACGR. Heterotopic cardiac transplantations were performed in 7-9-week old C57BL6 or C3H mice. Wild type or Fas-deficient (lpr) mice underwent syngeneic (GS) or allogeneic (GA) transplantation, and received either saline or NIM811, a specific inhibitor of the mPTP. At day 5, we assessed ACGR by histology, cardiomyocyte apoptosis by caspase-3 activity and cytochrome c release, Ca(2+)-induced mPTP opening by a potentiometric approach, and expression of Fas, FasL, TNFalpha, perforin, granzyme using RT-PCR. Myocardial infiltration of CD8(+) T lymphocytes was performed by immunohistochemistry. Allogenic transplantation increased infiltration of inflammatory cells, upregulated FasL, perforin, granzyme, and TNFalpha, favored Ca(2+)-induced mPTP opening and increased caspase-3 activity and cytochrome c release in WT grafts. NIM811, but not Fas-deficiency, significantly reduced all these effects. NIM811 also limited infiltration of CD8(+) into WT and lpr transplants. These data suggest that the mPTP pathway plays a major role in cardiomyocyte apoptosis associated with ACGR. Inhibition of mPTP opening may attenuate cardiomyocyte apoptosis either directly or indirectly via a limitation of CD8(+) T-cell activation.
 ...
PMID:Link between immune cell infiltration and mitochondria-induced cardiomyocyte death during acute cardiac graft rejection. 1646 57

Cerebral malaria is a serious complication of Plasmodium falciparum infection. We have investigated the role of perforin in the pathogenesis of cerebral malaria in a murine model (Plasmodium berghei ANKA (PbA) infection). C57BL/6 mice demonstrated the typical neuropathological symptoms of experimental cerebral malaria infection from day 5p.i. and became moribund on day 6p.i. This pathology was not seen in PbA-infected, perforin-deficient (pfp-/-) mice. From days 5-6p.i. onwards there was a significant increase in mRNA for granzyme B and CD8, but not CD4, in brain tissue from PbA-infected C57BL/6 and pfp-/- mouse brains. Perforin mRNA was strongly increased in the brains of PbA-infected C57BL/6 mice on day 6p.i. Immunohistochemistry revealed increased perforin staining and elevated numbers of CD8(+) cells within the cerebral microvessels in PbA-infected C57BL/6 at days 5 and 6p.i. compared with uninfected animals. At day 6p.i., there were TUNEL-positive cells and activated caspase-3 positive cells of endothelial morphology in the CNS of PbA-infected C57BL/6 mice. The TUNEL-positive cells were greatly reduced in pfp-/- mice. These results suggest that CD8(+)T lymphocytes induce apoptosis of endothelial cells via a perforin-dependent process, contributing to the fatal pathogenic process in murine cerebral malaria.
 ...
PMID:Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria. 1650 Jun 56

BID is an essential component of many apoptotic pathways. Cytosolic proteases cleave BID within an extended loop region, generating an active truncated fragment which synergizes with BAX and BAK to induce release of apoptogenic factors from mitochondria. To determine whether other proteins are cleaved in a similar manner as BID, we performed a database search for proteins which possess sequence similarity with the BID loop region. One of the proteins identified was the Hsc70-interacting protein (HIP). We analyzed the cleavage pattern of HIP using two known activators of BID: granzyme B and caspase-8. In in vitro cleavage assays using recombinant proteins, human and rat HIP were cleaved by granzyme B. Furthermore, the granzyme B-mediated cleavage site was mapped to the BID loop-like region of HIP by site-directed mutagenesis. This region was also the target for caspase-8-mediated cleavage in rat HIP. However, human HIP was not proteolyzed by caspase-8, which probably reflects sequence differences between human and rat HIP proteins at the P(1)' position of the caspase-8 recognition sequence. To determine whether HIP is cleaved during apoptosis, human Jurkat T cells were exposed to granzyme B and perforin. The results of these studies suggest that granzyme B-mediated loss of HIP expression occurs in vivo, and in a coordinate fashion with loss of BID, pro-caspase-8 and pro-caspase-3. These data implicate the Hsp70 co-chaperone HIP in the proteolytic cascade of some apoptotic pathways.
 ...
PMID:Proteolysis of HIP during apoptosis occurs within a region similar to the BID loop. 1701 59

Immunologic memory is associated with the activation and expansion of antigen-specific T cells, followed by clonal deletion and survival of a small number of memory T cells. This study establishes that effector and rested memory T cells can acquire major histocompatibility complex (MHC)/CD80 molecules (antigen presentasome [APS]) upon activation in vitro and after vaccination in vivo. We demonstrate for the first time that acquisition of APS by rested memory T cells is correlated with increased levels of apoptosis in vivo and up-regulation of caspase-3, bcl-x, bak, and bax in our in vitro studies. Moreover, our results demonstrate that memory T cells with acquired APS can indeed become cytotoxic T lymphocytes and kill other cells through perforin-mediated lysis. In addition, they retained the production of interferon gamma and T-helper 2 (Th2) type cytokines. The acquisition of APS by memory T cells might be an important checkpoint leading to the clonal deletion of the majority of effector T cells, possibly allowing the surviving cells to become long-term memory cells by default.
 ...
PMID:Acquisition of antigen presentasome (APS), an MHC/costimulatory complex, is a checkpoint of memory T-cell homeostasis. 1710 11

Increasing evidence has suggested that infection with high-risk human papillomavirus (HPVs) is closely associated with esophageal squamous cell carcinoma (ESCC) in China. The E6 and E7 oncoproteins expressed in ESCC are considered as attractive tumor-specific antigen targets for immunotherapy. We have reported that the HPV16 mE6delta/mE7/TBhsp70delta fusion protein vaccination induced powerful anti-tumor immunity against TC-1 tumor cells in a C57BL/6 mouse model. In the present study, we further evaluate the protective efficacy of this fusion protein vaccine using an HPV E7-expressing human ESCC cell line (EC9706) and a Hu-PBL-SCID mouse model. We demonstrated that immunization with the fusion protein vaccine caused significant inhibition of tumor growth with the delay time to tumor detection (tests vs. controls, 16 d vs. 9 d, p<0.01) and much smaller tumor size (p<0.01) in vivo. The inhibitory rate was ca. 69.6%, and 25% of the fusion protein vaccinated-mice remained tumor free by the end of the experiment (42 d). Furthermore, the activated lymphocytes (CD8+) were capable of infiltrating into the tumor site, and much more apoptotic cells along with activation of caspase-3 were observed in the tumors from vaccinated-mice. Also, high expression levels of human IFN-gamma, TNF-alpha, granzyme B and perforin were detected in the tumors from vaccinated-mice. Therefore, we concluded that the HPV16 mE6delta/mE7/TBhsp70delta fusion protein vaccine is able to stimulate cellular-mediated immune response against E7-containing ESCC cells through CD8+-dependent CTL-induced apoptosis in Hu-PBL-SCID mice. These findings provide a scientific basis for HPV E7-expressing ESCC active immunotherapy.
 ...
PMID:Immunological protection against HPV16 E7-expressing human esophageal cancer cell challenge by a novel HPV16-E6/E7 fusion protein based-vaccine in a Hu-PBL-SCID mouse model. 1720 76

The investigation deals with the role of Fas, FasL, RIP, caspase 3, and PARP taking part in Fas-mediated apoptosis, and contributing to in vitro interaction of hepatoma MH-22a and histiocytic sarcoma J-774 in mice with syngenic splenocytes. Protein expression was identified by means of indirect immunofluorescence. There were two patterns of interaction of tumor cells and splenocytes: apoptosis occurred either in 80% or in an insignificant number of tumor cells. In the latter case, high Fas expression was identified before and when it dropped after the experiment. FasL expression in tumor cells often peaked before the experiment and then it decreased after contact with lymphocytes. That mechanism was reversed in splenocytes: contact with tumor cells boosted expression. RIP, caspase 3 and PARP expression was very low and failed to show until the experiments on both patterns of cells were undertaken. After the experiments, it either remained latent or soared up. In the latter case, simultaneous expression of all proteins took place both in tumor cells and lymphocytes. A second battery of experiments demonstrated maximum rates of apoptosis both of tumor cells and splenocytes. However, the situation was different: Fas expression intensified in both patterns of cells after their interaction which was followed by post-experimental drop in RIP, caspase 3, and PARP expression in tumor cells; hence, the importance of perforin/granzyme-mediated apoptosis which occurred at the early stages of tumor growth in the midst of interaction with immune system cells. That pattern of apoptosis was highly cytotoxic. It is suggested that Fas-mediated apoptosis or any other receptor-sensitive pathway might take place during tumor progression, i.e. at a stage when tumor is most susceptible to change.
 ...
PMID:[Role of proteins in Fas-mediated apoptosis in tumor cells and lymphocytes co-cultured in vitro]. 1766 73

Lymphocyte-mediated cytotoxicity via granule exocytosis operates by the perforin-mediated transfer of granzymes from CTLs and NK cells into target cells where caspase activation and other death pathways are triggered. Granzyme B (GzB) is a major cytotoxic effector in this pathway, and its fate in target cells has been studied by several groups using immunodetection. In this study, we have used a newly developed cell-permeable fluorogenic GzB substrate to measure this protease activity in three different living targets following contact with cytotoxic effectors. Although no GzB activity is measurable in CTL or NK92 effector cells, this activity rapidly becomes detectable throughout the target cytoplasm after effector-target engagement. We have combined the GzB substrate with a second fluorogenic substrate selective for caspase 3 to allow both flow cytometry and fluorescence confocal microscopy studies of cytotoxicity. With both effectors, caspase 3 activity appears subsequent to that of GzB inside all three targets. Overexpression of Bcl-2 in target cells has minimal effects on lysis, NK- or CTL-delivered GzB activity, or activation of target caspase 3. Detection of target GzB activity followed by caspase 3 activation provides a unique readout of a potentially lethal injury delivered by cytotoxic lymphocytes.
 ...
PMID:Granzyme B activity in target cells detects attack by cytotoxic lymphocytes. 1778 18

Rituximab (Rit) was the first monoclonal antibody approved for therapeutic use in cancer patients. Rit is a chimeric mouse/human monoclonal antibody, consisting of the human IgG1 and k constant Fc region, and a mouse variable Fab region specific against the B-cell antigen CD20. Rit exerts its antilymphoma activity through many different mechanisms. Binding of antibody to CD20 antigen, provokes apoptosis through downstream signals that lead to caspase-3 activation. Complement activation by the Fc portion of the antibody results in complement-dependent cytotoxicity. However, the most effective mechanism of action seems to be antigen-dependent cellular cytotoxicity. Effector cytotoxic cells such as natural killer cells (NK) are activated after binding to the Fc portion of the anti-CD20 molecule. Activated NK cells kill the coated lymphoma cells with the use of granzyme-perforin system. More recently, pre-clinical data support the concept that Rituximab can provoke a vaccination-like effect. Finally in-vitro experiments and clinical trials have shown that co-administration of the antibody with cytotoxics confers a strong synergistic effect. The relative contribution of these mechanisms in vivo and in different lymphoma subtypes is not well known and remains to be further evaluated. Among the different histological groups, follicular lymphoma (FL) has been proven to be the most sensitive to Rit when used as a single agent, with overall response rates of 80% and 50% in untreated and previously treated patients, respectively. Moreover, Rit in combination with chemotherapy is superior to chemotherapy alone in terms of response rate and event-free survival, while early data indicate a significant prolongation in overall survival as well. Similarly, the addition of Rit to standard chemotherapy improves the disease-free and overall survival of patients with diffuse large B-cell lymphoma. There is no doubt that Rit represents one of the greatest achievements of biotechnology engineering. However, we need to understand better the mechanisms of its action as well as the mechanisms of resistance to Rit, in order to design more effective treatment modalities.
 ...
PMID:Monoclonal antibodies in the treatment of lymphoid malignancies. 1793 74

Cyclopentenyl cytosine (CPEC) has been shown to induce apoptosis in human T lymphoblastic cell lines and T cells from leukaemia patients. In this study we have addressed the question of whether CPEC is able to decrease proliferation and effector functions of human alloresponsive T lymphocytes and induce T cell anergy. The proliferative capacity of human peripheral blood mononuclear cells in response to allogeneic stimulation was measured by 5,6-carboxy-succinimidyl-diacetate-fluorescein-ester staining. Flow cytometric analysis was performed using surface CD4, CD8, CD25, CD103 and intracellular perforin, granzyme A, granzyme B, caspase-3 and forkhead box P3 (FoxP3) markers. The in vivo immunosuppressive capacity was tested in a murine skin graft model. Addition of CPEC at a concentration of 20 nM strongly decreased the expansion and cytotoxicity of alloreactive T cells. Specific restimulation in the absence of CPEC showed that the cells became anergic. The drug induced caspase-dependent apoptosis of alloreactive T lymphocytes. Finally, CPEC increased the percentage of CD25(high) FoxP3+ CD4+ and CD103+ CD8+ T cells, and potentiated the effect of rapamycin in increasing the numbers of alloreactive regulatory T cells. Treatment with CPEC of CBA/CA mice transplanted with B10/Br skin grafts significantly prolonged graft survival. We conclude that CPEC inhibits proliferation and cytotoxicity of human alloreactive T cells and induces alloantigen non-responsiveness in vitro.
 ...
PMID:The pyrimidin analogue cyclopentenyl cytosine induces alloantigen-specific non-responsiveness of human T lymphocytes. 1806 97

With melanoma, as with many other malignancies, aberrant transcriptional repression is a hallmark of refractory cancer. To restore gene expression, use of a histone deacetylase inhibitor (HDACi) is expected to be effective. Our recent DNA micro-array analysis showed that the HDACi depsipeptide (FK228) significantly enhances gp100 antigen expression. Herein, we demonstrate that depsipeptide promotes tumor-specific T-cell-mediated killing of B16/F10 murine melanoma cells. First, by a quantitative assay of caspase-3/7 activity, a sublethal dose of depsipeptide was determined (ED50: 5 nM), in which p21(Waf1/Cip1) and Fas were sufficiently evoked concomitantly with histone H3 acetylation. Second, the sublethal dose of depsipeptide treatment with either a recombinant Fas ligand or tumor-specific T cells synergistically enhanced apoptotic cell death in B16/F10 cells in vitro. Furthermore, we found that depsipeptide increased levels of perforin in T cells. Finally, in vivo metastatic growth of B16/F10 in the lung was significantly inhibited by a combination of depsipeptide treatment and immune cell adoptive transfer from immunized mice using irradiated B16 cells and gp100-specific (Pmel-1) TCR transgenic mice (P<0.05, vs cell transfer alone). Consequently, employment of a transcriptional modulation strategy using HDACis might prove to be a useful pretreatment for human melanoma immunotherapy.
 ...
PMID:Transcriptional modulation using HDACi depsipeptide promotes immune cell-mediated tumor destruction of murine B16 melanoma. 1818 35


<< Previous 1 2 3 4 5 6 7 Next >>