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

Broad spectrum caspase inhibitors have been found to reduce neurodegeneration caused by cerebral ischemia. We studied whether blockade of group I caspases, mainly caspase-1, using the inhibitor Ac-YVAD.cmk reduced infarct volume and produced prolonged neuroprotection. Ac-YVAD.cmk (300 ng/rat) was injected intracerebroventricularly 10 min after permanent middle cerebral artery occlusion in the rat. Drug treatment induced a significant reduction of infarct volume not only 24 hr after ischemia (total damage, percentage of hemisphere volume: control, 41.1 +/- 2.3%; treated, 26.5 +/- 2.1%; p < 0.05) but also 6 d later (total damage: control, 30.6 +/- 2.2%; treated, 23.0 +/- 2.2%; p < 0.05). Ac-YVAD. cmk treatment resulted in a reduction not only of caspase-1 (control, 100 +/- 20.3%; treated, 3.4 +/- 10.4%; p < 0.01) but also of caspase-3 (control, 100 +/- 30.3%; treated, 13.2 +/- 9.5%; p < 0.05) activity at 24 hr and led to a parallel decrease of apoptosis as measured by nucleosome quantitation (control, 100 +/- 11.8%; treated, 47 +/- 5.9%; p < 0.05). Six days after treatment no differences in these parameters could be detected between control and treated animals. Likewise, brain levels of the proinflammatory cytokines IL-1beta and TNF-alpha were reduced at 24 hr (39.5 +/- 23.7 and 51.9 +/- 10.3% of control, respectively) but not at 6 d. Other cytokines, IL-10, MCP-1, MIP-2, and the gaseous mediator nitric oxide, were not modified by the treatment. These findings indicate that blockade of caspase-1-like activity induces a long-lasting neuroprotective effect that, in our experimental conditions, takes place in the early stages of damage progression. Finally, this effect is achieved by interfering with both apoptotic and inflammatory mechanisms.
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PMID:Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. 1084 8

The pathogenesis of Acanthamoeba keratitis begins when Acanthamoeba trophozoites bind specifically to mannosylated glycoproteins upregulated on the surfaces of traumatized corneal epithelial cells. When Acanthamoeba castellanii trophozoites are grown in methyl-alpha-D-mannopyranoside, they are induced to secrete a novel 133-kDa protein that is cytolytic to corneal epithelial cells. Clinical isolates of Acanthamoeba spp., and not the soil isolates, were proficient at producing a mannose-induced protein (MIP-133) and generating disease in Chinese hamsters. The purified protein was efficient at killing corneal epithelial cells, the first mechanistic barrier, by inducing apoptosis in a caspase 3-dependent pathway. Subsequent steps in pathogenesis require the amoebae to penetrate and degrade collagen. Only the clinical isolates tested were efficient at migrating through a collagenous matrix in vitro, presumably by MIP-133 degradation of both human type I and human type IV collagen. A chicken anti-MIP-133 antiserum effectively bound to the protein and blocked collagenolytic activity, migration, and cytopathic effects (CPE) against corneal cells in vitro. Chinese hamsters orally immunized with MIP-133 displayed a >30% reduction in disease. Immunoglobulin A isolated from immunized animals bound MIP-133 and blocked CPE on corneal cells in vitro. Animals induced to generate severe chronic infections displayed significant reductions in disease symptoms upon oral immunization postinfection. These data suggest that MIP-133 production might be necessary to initiate corneal disease and that it may play an important role in the subsequent steps of the pathogenic cascade of Acanthamoeba keratitis. Furthermore, as antibodies produced both prior to and after infection reduced clinical symptoms of disease, the protein may represent an important immunotherapeutic target for Acanthamoeba keratitis.
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PMID:Pathogenic Acanthamoeba spp secrete a mannose-induced cytolytic protein that correlates with the ability to cause disease. 1457 43

Intrahippocamal injections of kainic acid (KA) significantly increase the expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) in the ipsilateral hippocampus at 2-4 h and 21-45 days post-administration, suggesting the possible involvement of these chemokines in both neurodegenerative and regenerative processes. To examine the possible role of these chemokines on neuronal cell death, hippocampal neurons were incubated with either MCP-1 or MIP-2 in vitro and examined to assess the effects on neuronal cell viability. These treatments resulted in significant neuronal apoptosis that could be abrogated by prior treatment with the caspase-1 inhibitor, Z-VAD-FMK, the caspase-3 inhibitor, Z-DEVD-FMK, the Galphai inhibitor, pertussis toxin, or the MAO-B inhibitor, (-)deprenyl. Furthermore, this chemokine apoptotic effect could also be observed in vivo as intrahippocampal injections of MCP-1 or MIP-2 resulted in the apoptosis of hippocampal neurons, thus supporting a direct role of these chemokines in neuronal death. In contrast, immunohistological analysis of kainic acid lesions on days 21-45 revealed significant expression of MCP-1 and MIP-2 associated with reactive astrocytes and macrophages, respectively, with no apoptotic populations being observed. These results suggested that these chemokines might also mediate distinct biological effects on local microenvironmental cell populations at various stages post truama and during cellular repair. To address this possibility, astrocyte were cultured in the presence or absence of these chemokines and examined by microarray analysis for effects on astrocytes gene expression. A number of genes encoding proteins associated with inflammation, cellular signaling, differentiation, and repair were directly modulated by chemokine treatment. More specifically, the RNA and protein expression of the neurotrophic factor, basic fibroblast growth factor (bFGF), was found to be significantly increased upon culture with MCP-1 and MIP-2. Conditioned media derived from chemokine-stimulated astrocytes also facilitated bFGF-dependent neuronal cell differentiation and promoted survival of H19-7 neurons in vitro, suggesting a possible role for chemokine-activated astrocytes as a source of trophic support. Taken together, these data support possible autocrine and paracrine roles for MCP-1 and MIP-2 in both the "death and life" of hippocampal neurons following CNS injury.
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PMID:Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration. 1519 36

Chemokines play an important role in immune and inflammatory responses by inducing migration and adhesion of leukocytes, and have also been reported to modulate osteoclast differentiation from hemopoietic precursor cells of the monocyte-macrophage lineage. In this study, we examined the effect of MIP-1 gamma, a C-C chemokine family member, on receptor activator of NF-kappa B ligand (RANKL)-stimulated osteoclast differentiation, survival, and activation. RANKL induced osteoclasts to dramatically increase production of MIP-1 gamma and to also express the MIP-1 gamma receptor CCR1, but had only minor effects on the related C-C chemokines MIP-1 alpha and RANTES. Neutralization of MIP-1 gamma with specific Ab reduced RANKL-stimulated osteoclast differentiation by 60-70%. Mature osteoclasts underwent apoptosis within 24 h after removal of RANKL, as shown by increased caspase 3 activity and DNA fragmentation. Apoptosis was reduced by the addition of exogenous MIP-1 gamma or RANKL, both of which increased NF-kappa B activation in osteoclasts. Neutralization studies showed that the prosurvival effect of RANKL was in part dependent on its ability to induce MIP-1 gamma. Finally, osteoclast activation for bone resorption was stimulated by MIP-1 gamma. Taken together, these results demonstrate that MIP-1 gamma plays an important role in the differentiation and survival of osteoclasts, most likely via an autocrine pathway.
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PMID:MIP-1 gamma promotes receptor-activator-of-NF-kappa-B-ligand-induced osteoclast formation and survival. 1526 44

There is mounting evidence that apoptosis plays a significant role in tissue damage during acute lung injury. To evaluate the role of the apoptosis mediators Fas and FasL in acute lung injury, Fas (lpr)- or FasL (gld)-deficient and wild-type mice were challenged with intrapulmonary deposition of IgG immune complexes. Lung injury parameters ((125)I-albumin leak, accumulation of myeloperoxidase, and wet lung weights) were measured and found to be consistently reduced in both lpr and gld mice. In wild-type mice, lung injury was associated with a marked increase in Fas protein in lung. Inflamed lungs of wild-type mice showed striking evidence of activated caspase-3, which was much diminished in inflamed lungs from lpr mice. Intratracheal administration of a monoclonal Fas-activating antibody (Jo2) in wild-type mice induced MIP-2 and KC production in bronchoalveolar lavage fluids, and a murine alveolar macrophage cell line (MH-S) showed significantly increased MIP-2 production after incubation with this antibody. Bronchoalveolar lavage fluid content of MIP-2 and KC was substantially reduced in lpr mice after lung injury when compared to levels in wild-type mice. These data suggest that the Fas/FasL system regulates the acute lung inflammatory response by positively affecting CXC-chemokine production, ultimately leading to enhanced neutrophil influx and tissue damage.
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PMID:Relationship of acute lung inflammatory injury to Fas/FasL system. 1574 81

Fas (CD95) is a membrane surface receptor, which, in the lungs, is expressed in macrophages, neutrophils, and epithelial cells. In mice, Fas activation leads to a form of lung injury characterized by increased alveolar permeability. We investigated whether Fas-mediated lung injury occurs primarily as a result of Fas activation in myeloid cells (such as macrophages) or in nonmyeloid cells (such as epithelial cells). Chimeric mice lacking Fas in either myeloid or nonmyeloid cells were generated by transplanting marrow cells from lpr mice (which lack Fas) into lethally irradiated C57BL/6 mice (MyFas(-) group) or vice versa (MyFas(+) group). Additional mice transplanted with marrow cells from their same strain served as controls (Fas(+) ctr and Fas(-) ctr groups). Sixty days after transplantation, the mice received intratracheal instillations of the Fas-activating mAb Jo2 (n = 10/group), or an isotype control Ab (n = 10/group), and were euthanized 24-h later. Only animals expressing Fas in nonmyeloid cells (Fas(+) ctr and MyFas(-)) showed significant increases in lung neutrophil content and in alveolar permeability. These same mice showed tissue evidence of lung injury and caspase-3 activation in cells of the alveolar walls. Despite differences in the neutrophilic response and lung injury, there was no statistical difference in the lung cytokine concentrations (KC and MIP-2) among groups. We conclude that Fas-mediated lung injury requires expression of Fas on nonmyeloid cells of the lungs. These findings suggest that the alveolar epithelium is the primary target of Fas-mediated acute lung injury, and demonstrate that apoptotic processes may be associated with neutrophilic inflammation.
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PMID:Fas-mediated acute lung injury requires fas expression on nonmyeloid cells of the lung. 1614 56

IL-13 is an important stimulator of inflammation and tissue remodeling at sites of Th2 inflammation, which plays a key role in the pathogenesis of a variety of human disorders. We hypothesized that the ubiquitous transcription factor, early growth response-1 (Egr-1), plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of Egr-1 and related moieties in lungs from wild type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of Egr-1 on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 stimulates Egr-1 via an Erk1/2-independent Stat6-dependent pathway(s). They also demonstrate that IL-13 is a potent stimulator of eosinophil- and mononuclear cell-rich inflammation, alveolar remodeling, and tissue fibrosis in mice with wild type Egr-1 loci and that these alterations are ameliorated in the absence of Egr-1. Lastly, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates select CC and CXC chemokines (MIP-1alpha/CCL-3, MIP-1beta/CCL-4, MIP-2/CXCL2/3, MCP-1/CCL-2, MCP-2/CCL-8, MCP-3/CCL-7, MCP-5/CCL-12, KC/CXCL-1, and Lix/CXCL-5), matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and apoptosis regulators (caspase-3, -6, -8, and -9 and Bax) and activates transforming growth factor-beta1 and pulmonary caspases via Egr-1-dependent pathways. These studies demonstrate that Egr-1 plays a key role in the pathogenesis of IL-13-induced inflammatory and remodeling responses.
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PMID:Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling. 1643 63

Posterior capsule opacification is the main complication of cataract surgery. Using adenovirus-mediated gene transfer, we recently reported that it was feasible to prevent PCO by overexpressing pro-apoptotic molecules such as pro-caspase 3 or Bax in the residual lens epithelial cells post-cataract surgery. However, this approach is feasible only if gene transfer can be restricted to the residual cells responsible for PCO. Initially, we tested an adenovirus (human serotype 5, HAd5), a lentivirus (HIV) and an oncoretrovirus (MLV) vector for the their in vivo transduction efficiency of rabbit lens cells. We found that HAd5 vectors were the most efficient (>90% of the cells could be transduced). Six potential lens-specific promoters were then cloned into HAd5 vectors and assayed for their ability to target expression to a specific population of cells, using in vitro, ex vivo and in vivo rabbit tissues and human lens capsular bags. We found that the LEP503, MIP and Filensin promoters induced strong lens-specific expression of a reporter gene, in human lens cells. Following this ex vivo assay, we showed in a rabbit PCO model that gene transfer could be spatially restricted to the capsular bag by confining the vector with Matrigel. Our combined approach using a lens-specific promoter and a biocompatible gel should render feasible a novel therapeutic strategy for PCO that targets the remaining lens cells.
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PMID:Lens cell targetting for gene therapy of prevention of posterior capsule opacification. 1672 94

In this study, we have investigated the role of the cannabinoid CB(2) (CB(2)) receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB(2) receptor in TNF-alpha-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB(2) receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-alpha, MIP-1alpha, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB(2) receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB(2) receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
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PMID:Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis. 1765 47

As human colorectal cancer (CRC) cells metastasize to distant sites, they are susceptible to detachment-induced cell death or anoikis - a form of apoptosis that occurs when anchorage-dependent CRC cells go into suspension. Our goal was to identify whether tumor necrosis factor receptor apoptosis-inducing ligand (TRAIL) receptors mediate anoikis in human CRC cells. First, we assessed whether caspases of the extrinsic (caspase-8) or intrinsic (caspase-9) death pathways were involved. Caspase-8 was cleaved during exposure to suspension culture in four CRC lines, and cell death was inhibited by caspase-3 and caspase-8 inhibitors but not by a caspase-9 inhibitor. Gene transcripts in macrophage inflammatory protein-101 (MIP-110), a weakly metastatic human CRC, were increased at least 2-fold for TRAIL-R2 (DR5) and TRAIL after 24 h of suspension culture compared with cells in monolayer culture. The increased expression of DR5 was confirmed at the protein level at 24 h, and exposure of MIP-101 cells to an antagonistic antibody to DR5 decreased caspase-8 activation. The antagonistic antibody to DR5 inhibited anoikis in four human CRC lines. Treatment with an antagonistic DR4 antibody or a neutralizing antibody to TRAIL ligand did not reduce anoikis consistently. Knockdown of DR5 or TRAIL also inhibited anoikis, whereas exogenous TRAIL or FasL did not consistently increase anoikis. In summary, DR5 receptor mediates death signals for anoikis in human CRC cells through the extrinsic apoptotic pathway.
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PMID:DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. 1824 94


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