UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Production of alpha-1-antitrypsin by human monocytes is an important factor in controlling tissue damage by proteases in the microenvironment of inflammation. Increases of four- to eightfold in levels of native and fragmented forms of alpha-1-antitrypsin have been detected in inflammatory loci in vivo. In this study we have extended our previous observation that the carboxyl-terminal peptide (C-36) of alpha-1-antitrypsin produced by specific proteinase cleavage, when added in its fibrillar form at concentrations of 5 microM or more to monocytes in culture, induces cytotoxic effects. Experiments with synthetic amyloid-forming peptides suggest fibril cytotoxicity to be mediated via a common oxidative stress mechanism. We undertook to determine whether C-36 fibril cytotoxicity also involves this common pathway. Monocytes stimulated with C-36 fibrils for 1 h showed significant elevation in monocyte chemoattractant protein-1 expression, induced reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, increased intracellular lipid peroxidation, altered mitochondrial membrane potential, and increased cytosolic cytochrome c and caspase-3 activity. Treatment of monocytes with C-36 fibrils after 24 h also resulted in increased cytosolic cathepsin D activity, suggesting that lysosomes may also be destabilized over longer periods of time. In contrast, native alpha-1-antitrypsin only showed concentration and time-dependent effects on chemoattractant protein-1 expression, and these appear to be independent of oxidative stress. These results indicate that the cytotoxicity of the fibrillar fragment is mediated via oxidative mechanisms and support important multiple roles for native and also for cleaved forms of alpha-1-antitrypsin in monocyte recruitment and activation during inflammatory processes such as atherosclerosis.
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PMID:Fibrillogenic C-terminal fragment of alpha-1-antitrypsin activates human monocytes via oxidative mechanisms. 1151 75

Recent studies have demonstrated the activation of caspase-1 and caspase-3 in mice expressing mutant superoxide dismutase 1 (SOD1), models of amyotrophic lateral sclerosis. Caspase-1 converts the prointerleukin-1beta into a potent proinflammatory molecule involved in the innate immune response and in neurodegenerative diseases. We report on the chronic expression of interleukin-1beta mRNA in the spinal cord of SOD1G37R mice, together with robust mRNA expression for the nuclear factor-kappaB (NF-kappaB) inhibitor IkappaBalpha, for other proinflammatory cytokines and chemokines (interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1) and for the toll-like receptor TLR2 involved in innate immunity. To further assess the interleukin-1beta contribution to neurodegeneration, we generated mice expressing SOD1G37R in a context of interleukin-1beta gene knockout. Surprisingly, the absence of interleukin-1beta had no effect on the life span of SOD1G37R mice, nor on the extent of motor axon degeneration at age 7 and 10 months. Whereas neither compensatory induction of the interleukin-1alpha mRNA nor increases in mRNA levels for IkappaBalpha, tumor necrosis factor-alpha and macrophage chemoattractant protein-1 occurred as a result of interleukin-1beta gene disruption, enhanced levels of TLR2 mRNA were detected in SOD1G37R mice lacking interleukin-1beta. We conclude that interleukin-1beta does not directly contribute to motor neuron degeneration in SOD1G37R mice, but it may act as a modulator of the innate immune response.
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PMID:Induction of proinflammatory molecules in mice with amyotrophic lateral sclerosis: no requirement for proapoptotic interleukin-1beta in neurodegeneration. 1170 69

The mechanisms regulating retrograde neuronal degeneration and subsequent death of thalamic neurons following cortical injury are not well understood. However, the delay in the onset of retrograde cell death and observed morphological changes are consistent with apoptosis. Our previous studies demonstrated that monocyte chemoattractant protein-1 (MCP-1), a beta-chemokine that attracts cells of monocytic origin to sites of injury, is rapidly and specifically expressed in the lateral geniculate nucleus following visual cortical lesions. To determine the potential role of MCP-1 in retrograde degeneration, the present study examined the effect of genetic deletion of MCP-1 (MCP-1 KO or -/-) or its high affinity receptor CCR2 (CCR2 KO or -/-) on thalamic microglial activation and neuronal cell death following aspiration lesions of the visual cortex in adult mice. Deletion of the MCP-1 gene delayed microglial activation and transiently improved the survival of thalamic neurons. Deletion of the CCR2 receptor resulted in a significant increase in apoptosis as measured by nucleosomal fragmentation after injury compared to wild-type mice, but did not alter neuron survival, suggesting that glial apoptosis is increased in the receptor knockout mice. Investigation of Bcl-2, Bax, Fas, Fas ligand (FasL) and activated caspase-3, key regulators of apoptosis that can be modulated by cytokines, revealed complex alterations of mRNA and protein levels in MCP-1(-/-) and CCR2(-/-) mice. As examples, Bcl-2 protein was detected in wild-type, but not in MCP-1(-/-) mice. Caspase-3 activity was higher in MCP-1(-/-) mice compared to wild-type and CCR2(-/-) mice at 5 days after injury. High levels of activated caspase-3 correlate with the beginning of a period of delayed, but rapid cell death in the thalami of MCP-1(-/-) mice. In summary, our data strongly suggest that MCP-1 is involved in early microglial response to axotomy and that modulation of this chemokine could provide a novel strategy for improved neuronal survival following injury to the central nervous system.
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PMID:Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules. 1210 88

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

Induction of heme oxygenase-1 (HO-1) expression in recipients of allogeneic islets can lead to long-term survival (>100 d) of those islets. We tested whether administration of bilirubin would substitute for the beneficial effects of HO-1 expression in islet transplantation. Administering bilirubin to the recipient (B6AF1) or incubating islets in a bilirubin-containing solution ex vivo led to long-term survival of allogeneic islets in a significant percentage of cases. In addition, administering bilirubin to only the donor frequently led to long-term survival of DBA/2 islets in B6AF1 recipients and significantly prolonged graft survival of BALB/c islets in C57BL/6 recipients. Donor treatment with bilirubin up-regulated mRNA expression of protective genes such as HO-1 and bcl-2 and suppressed proinflammatory and proapoptotic genes including monocyte chemoattractant protein-1 and caspase-3 and -8 in the islet grafts before transplantation. Furthermore, treatment of only the donor suppressed the expression of proinflammatory cytokines including TNF-alpha, inducible nitric oxide synthase, monocyte chemoattractant protein-1, and other proapoptotic and proinflammatory genes normally seen in the islets after transplantation. Donor treatment also reduced the number of macrophages that infiltrated the islet grafts in the recipients. Preincubation of betaTC3 cells with bilirubin also protected the cells from lipid peroxidation. Our data suggests that the potent antioxidant and antiinflammatory actions of bilirubin may contribute to islet survival.
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PMID:Bilirubin can induce tolerance to islet allografts. 1625 33

Although heat preconditioning has been known to be protective in various types of injury, the precise molecular mechanism for this is unclear. Recent observations that indicate that previous heat shock has an anti-inflammatory, antiapoptotic effect led to this investigation of the in vivo effect of heat preconditioning on NF-kappaB activation and inflammation and also on tubular cell injury in ischemic acute renal failure (ARF). Heat preconditioning provided marked functional protection and also reduced histologic evidence of tubular necrosis. Ischemia/reperfusion-induced NF-kappaB activation was suppressed by heat preconditioning with a subsequent decrease in monocyte chemoattractant protein-1 expression and inflammatory cell infiltration. Heat preconditioning also suppressed the accumulation of phosphorylated inhibitory kappaBalpha (IkappaBalpha) with a resultant depletion of cytoplasmic IkappaBalpha, indicating that heat preconditioning blocked the activation of the IkappaB kinase complex. Tubular cell apoptosis, determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, also was decreased by heat preconditioning, and this was accompanied by decreased caspase 3 activation. Among several heat-shock proteins (HSP), HSP-70 was induced primarily by heat preconditioning. Inhibition of HSP-70 by quercetin almost completely reversed the functional protection that was provided by heat preconditioning. These data provide evidence that HSP-70 affords protection via inhibition of NF-kappaB-mediated inflammation and also inhibition of the cell death pathway in ischemic ARF. Further elucidation of the cytoprotective mechanism of stress proteins could facilitate new target or drug development in the treatment of ARF.
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PMID:Heat preconditioning attenuates renal injury in ischemic ARF in rats: role of heat-shock protein 70 on NF-kappaB-mediated inflammation and on tubular cell injury. 1702 Dec 70

Kallistatin is a serine proteinase inhibitor that has been shown to reduce joint swelling and to inhibit inflammation in a rat model of arthritis. In this study, we investigated the effect and mechanisms of kallistatin on cardiac function after myocardial ischemia-reperfusion (I/R) injury. The human kallistatin gene in an adenoviral vector was delivered locally into rat heart 4 days before 30-min ischemia followed by 24-hr reperfusion. Kallistatin gene transfer significantly reduced myocardial infarct size and left ventricle end-diastolic pressure and improved cardiac contractility. Kallistatin significantly reduced I/R-induced cardiomyocyte apoptosis as identified by TUNEL and Hoechst staining, DNA laddering, cell viability, and caspase-3 activity in ischemic myocardium and in primary cultured cardiomyocytes. Kallistatin also reduced intramyocardial monocyte/macrophage and neutrophil accumulation in conjunction with decreased expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and intercellular adhesion molecule-1. Kallistatin delivery promoted cardiac endothelial nitric oxide synthase activation and increased nitric oxide (NO) formation, but inhibited NADH oxidase activity, p22phox expression, and superoxide production. Moreover, kallistatin reduced the phosphorylation of apoptosis signal-regulating kinase-1 and mitogen-activated protein kinases (MAPKs), but increased Akt and glycogen synthase kinase-3beta phosphorylation. The effects of kallistatin on cardiac function, oxidative stress, and these signal transduction events were all blocked by Nomega-nitro-L-argi-nine methyl ester. These results indicate a novel role of kallistatin in cardiac protection after I/R injury through increased NO formation and Akt-glycogen synthase kinase-3beta signaling and suppression of oxidative stress and MAPK activation.
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PMID:Novel role of kallistatin in protection against myocardial ischemia-reperfusion injury by preventing apoptosis and inflammation. 1708 Oct 80

Liver ischemia/reperfusion has been shown to result in injury of remote organs such as the heart and lungs. Whether or not acute liver injury also results in kidney injury has so far not been adequately addressed. In anesthetized Wistar rats, partial (70%) normothermic hepatic ischemia was applied for 75 min. After 24 h of reperfusion, renal injury was assessed by histology, creatinine and blood urea nitrogen (BUN) serum concentrations, renal expression of proinflammatory genes [quantitative real-time polymerase chain reaction (qRT-PCR)], caspase-3 activation (Western blot), and neutrophil accumulation (myeloperoxidase assay). Twenty-four hours after hepatic ischemia, creatinine (0.57+/-0.06 vs. 0.32+/-0.04 mg/dL) and BUN (40.7+/-15.3 vs. 14.3+/-2.0 mg/dL) were increased when compared to sham. qRT-PCR revealed higher renal intercellular adhesion molecule-1 gene expression following hepatic ischemia (166+/-45% when compared to sham) but no differences in renal monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and inducible NO synthase expression. In both groups, kidneys showed no morphological damage and no increase in caspase-3 and myeloperoxidase activity. Severe hepatic ischemia results in a moderate impairment of renal function in rats but does not trigger an inflammatory response in the kidney and does not result in morphological damage of the kidney.
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PMID:Remote renal injury following partial hepatic ischemia/reperfusion injury in rats. 1770 Oct 74

Resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound found in plant products, including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties. Using an animal model of multiple sclerosis (MS), we investigated the use of resveratrol for the treatment of autoimmune diseases. We observed that resveratrol treatment decreased the clinical symptoms and inflammatory responses in experimental allergic encephalomyelitis (EAE)-induced mice. Furthermore, we observed significant apoptosis in inflammatory cells in spinal cord of EAE-induced mice treated with resveratrol compared with the control mice. Resveratrol administration also led to significant down-regulation of certain cytokines and chemokines in EAE-induced mice including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-9, IL-12, IL-17, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), and Eotaxin. In vitro studies on the mechanism of action revealed that resveratrol triggered high levels of apoptosis in activated T cells and to a lesser extent in unactivated T cells. Moreover, resveratrol-induced apoptosis was mediated through activation of aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) and correlated with up-regulation of AhR, Fas, and FasL expression. In addition, resveratrol-induced apoptosis in primary T cells correlated with cleavage of caspase-8, caspase-9, caspase-3, poly(ADP-ribose) polymerase, and release of cytochrome c. Data from the present study demonstrate, for the first time, the ability of resveratrol to trigger apoptosis in activated T cells and its potential use in the treatment of inflammatory and autoimmune diseases including, MS.
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PMID:Resveratrol (trans-3,5,4'-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. 1787 69

Despite recent advances in understanding molecular mechanisms involved in glioblastoma progression, the prognosis of the most malignant brain tumor continues to be dismal. Because the flavonoid kaempferol is known to suppress growth of a number of human malignancies, we investigated the effect of kaempferol on human glioblastoma cells. Kaempferol induced apoptosis in glioma cells by elevating intracellular oxidative stress. Heightened oxidative stress was characterized by an increased generation of reactive oxygen species (ROS) accompanied by a decrease in oxidant-scavenging agents such as superoxide dismutase (SOD-1) and thioredoxin (TRX-1). Knockdown of SOD-1 and TRX-1 expression by small interfering RNA (siRNA) increased ROS generation and sensitivity of glioma cells to kaempferol-induced apoptosis. Signs of apoptosis included decreased expression of Bcl-2 and altered mitochondrial membrane potential with elevated active caspase-3 and cleaved poly(ADP-ribose) polymerase expression. Plasma membrane potential and membrane fluidity were altered in kaempferol-treated cells. Kaempferol suppressed the expression of proinflammatory cytokine interleukin-6 and chemokines interleukin-8, monocyte chemoattractant protein-1, and regulated on activation, normal T-cell expressed and secreted. Kaempferol inhibited glioma cell migration in a ROS-dependent manner. Importantly, kaempferol potentiated the toxic effect of chemotherapeutic agent doxorubicin by amplifying ROS toxicity and decreasing the efflux of doxorubicin. Because the toxic effect of both kaempferol and doxorubicin was amplified when used in combination, this study raises the possibility of combinatorial therapy whose basis constitutes enhancing redox perturbation as a strategy to kill glioma cells.
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PMID:Kaempferol induces apoptosis in glioblastoma cells through oxidative stress. 1787 51

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