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)

Interleukin (IL)-1alpha and IL-6 are powerful inflammatory cytokines produced in brain primarily by microglia and astrocytes. Here we demonstrate, using an in vitro assay system, that they can have a direct neuroprotective action against oxidative attack. Exposure of retinoic acid-differentiated human SH-SY5Y neuroblastoma cells to 270 microM hydrogen peroxide caused activation of caspase 3 and significant neuronal death. Treatment with IL-1alpha or IL-6 caused a dose-dependent increase in survival as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. An antibody against single-strand DNA demonstrated many apoptotic neuroblastoma cells following exposure to hydrogen peroxide, with a decrease following cytokine treatment. These data indicate that IL-1alpha and IL-6 can, under appropriate circumstances, protect neurons from oxidative damage in addition to their well-known action of stimulating inflammation.
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PMID:Interleukin 1alpha and interleukin 6 protect human neuronal SH-SY5Y cells from oxidative damage. 1513 88

The p38 mitogen-activated protein kinase (MAPK) is a key mediator of stress, extracellular-, growth factor-, and cytokine-induced signaling, and has been implicated in the development of cancer. Our previous work showed evidence for p38 MAPK activation in a subset of transformed follicular lymphomas (Elenitoba-Johnson et al. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 7259). We demonstrated that inhibition of p38 MAPK by SB203580 resulted in dose- and time-dependent caspase-3-mediated apoptosis. In order to further elucidate the basis of the cellular effects of SB203580, we have employed a systems biologic approach involving cDNA microarray and quantitative proteomic analysis of transformed follicular lymphoma derived-cells (OCI Ly-1) treated with SB203580. Gene expression profiling revealed differential expression (>/=1.5-fold) of 374 genes/ESTs in cells treated for 3 h and 515 genes/ESTs in cells treated for 21 h. The majority (52% at 3 h and 91% at 21 h) were down-regulated, including genes encoding growth cytokines, transcriptional regulators and cytoskeletal proteins. Quantitative proteomic analysis using ICAT-LC-MS/MS identified 277 differentially expressed proteins at 3 h and 350 proteins at 21 h of treatment with SB203580, the majority of which were also down-regulated. Analysis of functional groups of the differentially expressed proteins implicated components of diverse overlapping pathways including the IL-6/phosphatidylinositol 3-kinase, insulin-like growth factor 2/Ras/Raf, WNT8d/Frizzled, MAPK-activated protein kinase 2, and nuclear factor kappaB. The differential phosphorylation status of selected kinase-active proteins was validated by Western blotting analysis. Our complementary genomic and proteomic approach reveal the global cellular consequences of SB203580 treatment and provide insights into its growth inhibitory effect on transformed follicular lymphoma cells.
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PMID:Quantitative proteomic and transcriptional analysis of the response to the p38 mitogen-activated protein kinase inhibitor SB203580 in transformed follicular lymphoma cells. 1516 74

A Chlorella powder was screened using 52 in vitro assay systems for enzyme activity, receptor binding, cellular cytokine release, and B and T cell proliferation. The screening revealed a very potent inhibition of human protein tyrosine phosphatase (PTP) activity of CD45 and PTP1C with 50% inhibitory concentration (IC(50)) values of 0.678 and 1.56 microg/mL, respectively. It also showed a moderate inhibition of other PTPs, including PTP1B (IC(50) = 65.3 microg/mL) and T-cell-PTP (114 microg/mL). Other inhibitory activities and their IC(50) values included inhibition of the human matrix metalloproteinases (MMPs) MMP-1 (127 microg/mL), MMP-3 (185 microg/mL), MMP-7 (18.1 microg/mL), and MMP-9 (237 microg/mL) and the human peptidase caspases caspase 1 (300 microg/mL), caspase 3 (203 microg/mL), caspase 6 (301 microg/mL), caspase 7 (291 microg/mL), and caspase 8 (261 microg/mL), as well as release of the cytokines interleukin (IL)-1 (44.9 microg/mL), IL-2 (14.8 microg/mL), IL-4 (49.2 microg/mL), IL-6 (34.7 microg/mL), interferon-gamma (31.6 microg/mL), and tumor necrosis factor-alpha (11 microg/mL) from human peripheral blood mononuclear cells. Chlorella also inhibited B cell proliferation (16.6 microg/mL) in mouse splenocytes and T cell proliferation (54.2 microg/mL) in mouse thymocytes. The binding of a phorbol ester, phorbol 12,13-dibutyrate, to its receptors was also inhibited by Chlorella with an IC(50) of 152 microg/mL. These results reveal potential pharmacological activities that, if confirmed by in vivo studies, might be exploited for the prevention or treatment of several serious pathologies, including inflammatory disease and cancer.
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PMID:Effects of chlorella on activities of protein tyrosine phosphatases, matrix metalloproteinases, caspases, cytokine release, B and T cell proliferations, and phorbol ester receptor binding. 1529 60

Activated protein C (APC) is a physiological serine protease that regulates blood clotting and inflammation. Keratinocytes are a major cell type of human skin and play a fundamental role in normal skin metabolism and cutaneous wound healing. In this study, we investigated the regulatory role of APC on the function of human primary cultured keratinocytes. In an in vitro wounding assay, APC accelerated wound closure which was due jointly to increased cell proliferation and migration. APC attenuated calcium-induced cell death via prevention of cell apoptosis, as indicated by a decrease in both active caspase-3 and morphologically apoptotic cells. APC dramatically enhanced the expression and activation of MMP-2 by keratinocytes, whilst having no effect on MMP-9. GM6001, a broad spectrum MMP inhibitor, abolished cell migration in a dose-dependent manner and delayed in vitro wound healing. APC also significantly increased the production of IL-6 and IL-8 and suppressed calcium- and LPS-stimulated NF-kappaB activity. These results demonstrate a central role for APC in promoting cell proliferation and migration, preventing apoptosis and increasing MMP-2 activity in cultured keratinocytes. This regulatory activity implicates APC as having potential to promote re-epithelialisation during wound healing.
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PMID:Activated protein C stimulates proliferation, migration and wound closure, inhibits apoptosis and upregulates MMP-2 activity in cultured human keratinocytes. 1530 79

Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-alpha, IL-1beta, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-alpha, IL-1beta, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R.
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PMID:Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion. 1537 31

IL-1 is one of the key mediators involved in the pathogenesis of rheumatoid arthritis (RA) and is known to affect the level of gene expression in various settings. We investigated the effects of IL-1beta on the expression of 240 genes in rheumatoid synovial fibroblasts (RSFs) using a cDNA microarray. Total RNAs were prepared from RSFs stimulated with IL-1beta and hybridized to the microarray. The fluorescence intensity of each gene was compared between the control and IL-1beta-treated cells. To confirm the data obtained from the microarray analysis, the level of gene expression was also examined by ELISA, Northern blot, or Western blot depending on the genes to be analyzed. The genes whose levels were significantly changed by IL-1beta in the microarray analysis could be divided into three categories; inflammatory mediators, matrix-modifying enzymes, and apoptosis-associated molecules. The increase in the mRNA levels of IL-6, IL-8, MCP-1, and GRO-1 was confirmed by determining their protein levels from the cell culture supernatant using ELISA. The increase in the level of two matrix-degrading enzymes, MMP-1 and MMP-3, was reproducibly observed by an ELISA method, while the decrease in the level of TIMP-3, an inhibitor of MMPs, was confirmed by Northern blot analysis. The fluorescence intensity of two apoptosis-related genes, caspase-3 and Bcl-xL, was significantly lowered. The decreased protein level of caspase-3 was also found. Our data suggested that IL-1beta could provoke a series of responses in RSFs leading to the pathologic status of RA, including enhancement of inflammatory cytokines, imbalanced production of MMPs and TIMPs, and dysregulation of apoptosis.
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PMID:Effects of IL-1beta on gene expression in human rheumatoid synovial fibroblasts. 1546 74

We examined metallothionein (MT)-induced neuroprotection during kainic acid (KA)-induced excitotoxicity by studying transgenic mice with MT-I overexpression (TgMT mice). KA induces epileptic seizures and hippocampal excitotoxicity, followed by inflammation and delayed brain damage. We show for the first time that even though TgMT mice were more susceptible to KA, the cerebral MT-I overexpression decreases the hippocampal inflammation and delayed neuronal degeneration and cell death as measured 3 days after KA administration. Hence, the proinflammatory responses of microglia/macrophages and lymphocytes and their expression of interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor-alpha and matrix metalloproteinases (MMP-3, MMP-9) were significantly reduced in hippocampi of TgMT mice relative to wild-type mice. Also by 3 days after KA, the TgMT mice showed significantly less delayed damage, such as oxidative stress (formation of nitrotyrosine, malondialdehyde, and 8-oxoguanine), neurodegeneration (neuronal accumulation of abnormal proteins), and apoptotic cell death (judged by TUNEL and activated caspase-3). This reduced bystander damage in TgMT mice could be due to antiinflammatory and antioxidant actions of MT-I but also to direct MT-I effects on the neurons, in that significant extracellular MT presence was detected. Furthermore, MT-I overexpression stimulated astroglia and increased immunostaining of antiinflammatory IL-10, growth factors, and neurotrophins (basic fibroblastic growth factor, transforming growth factor-beta, nerve growth factor, brain-derived neurotrophic factor, glial-derived neurotrophic factor) in hippocampus. Accordingly, MT-I has different functions that likely contribute to the increased neuron survival and improved CNS condition of TgMT mice. The data presented here add new insight into MT-induced neuroprotection and indicate that MT-I therapy could be used against neurological disorders.
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PMID:Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acid-induced epileptic seizures. 1561 85

In the search for a more effective adjuvant therapy to treat multiple myeloma (MM), we investigated the effects of the traditional Chinese herbal medicines Huang-Lian-Jie-Du-Tang (HLJDT), Gui-Zhi-Fu-Ling-Wan (GZFLW), and Huang-Lian-Tang (HLT) on the proliferation and apoptosis of myeloma cells. HLJDT inhibited the proliferation of myeloma cell lines and the survival of primary myeloma cells, especially MPC-1- immature myeloma cells, and induced apoptosis in myeloma cell lines via a mitochondria-mediated pathway by reducing mitochondrial membrane potential and activating caspase-9 and caspase-3. Further experiments confirmed that Scutellaria radix was responsible for the suppressive effect of HLJDT on myeloma cell proliferation, and the baicalein in Scutellaria radix showed strong growth inhibition and induction of apoptosis in comparison with baicalin or wogonin. Baicalein as well as baicalin suppressed the survival in vitro of MPC-1- immature myeloma cells rather than MPC-1+ myeloma cells from myeloma patients. Baicalein inhibited the phosphorylation of IkB-alpha, which was followed by decreased expression of the IL-6 and XIAP genes and activation of caspase-9 and caspase-3. Therefore, HLJDT and Scutellaria radix have an antiproliferative effect on myeloma cells, especially MPC-1- immature myeloma cells, and baicalein may be responsible for the suppressive effect of Scutellaria radix by blocking IkB-alpha degradation.
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PMID:Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells. 1562 42

Exposure to complex mixtures of bacteria and fungi in moisture-damaged buildings is a potential cause of inflammatory related symptoms among occupants. The present study assessed interactions between two characteristic moldy house microbes Streptomyces californicus and Stachybotrys chartarum. Differences in cytotoxic and inflammatory responses in mouse (RAW264.7) macrophages were studied after exposure to the spores of co-cultivated microbes, the mixture of separately cultivated spores, and the spores of either of these microbes cultivated alone. The RAW264.7 cells were exposed to six doses (1 x 10(4) to 3 x 10(6) spores/ml) for 24 h, and the time course of the induced responses was evaluated after 4, 8, 16, and 24 h of exposure (1 x 10(6) spores/ml). The cytotoxic potential of the spores was characterized by the MTT test, DNA content analysis, and enzyme assay for caspase-3 activity. The production of cytokines (IL-1beta, IL-6, IL-10, TNFalpha, and MIP2) was measured immunochemically and nitric oxide by the Griess method. Co-cultivation increased the ability of the spores to cause apoptosis by more than 4-fold and the proportion of RAW264.7 cells at the G2/M stage increased nearly 2-fold when compared to the response induced by the mixture of spores. In contrast, co-cultivation decreased significantly the ability of the spores to trigger the production of NO and IL-6 in RAW264.7 cells. In conclusion, these data suggest that co-culture of S. californicus and S. chartarum can result in microbial interactions that significantly potentiate the ability of the spores to cause apoptosis and cell cycle arrest in mammalian cells.
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PMID:Interactions between Streptomyces californicus and Stachybotrys chartarum can induce apoptosis and cell cycle arrest in mouse RAW264.7 macrophages. 1566 33

Pollutant particles induce apoptosis and inflammation, but the relationship between these two biological processes is not entirely clear. In this study, we compared the proapoptotic and proinflammatory effects of four particles: residual oil fly ash (ROFA), St. Louis particles SRM 1648 (SL), Chapel Hill PM10 (CHP), and Mount St. Helens dust (MSH). Human alveolar macrophages (AM) were incubated with these particles at 100 microg/ml. Cell death was assessed by annexin V (AV) expression, histone release, nuclear morphology, caspase 3-like activity and release of caspase 1 for apoptosis, and propidium iodide (PI) for necrosis, and inflammation was measured by interleukin (IL)-1beta and IL-6. We found that particle effects on these cell death measurements varied, and ROFA affected most (four out of five) endpoints, including nuclear morphological changes. CHP and SL also caused necrosis. For cytokine release, the potency was CHP > SL > ROFA > MSH. The proapoptotic and proinflammatory effects induced by the whole particles were unaltered after the particles were washed with water. The water-soluble fraction was relatively inactive, as were individual soluble metals (V, Ni, Fe). ROFA-induced nuclear fragmentation was associated with upregulation and mitochondrial release of apoptosis-inducing factor (AIF), a caspase-independent chromatin condensation factor, and upregulation of DNase II, a lysosomal acid endonuclease. These results indicate that the potential for particles to induce apoptosis does not correlate with their proinflammatory properties, although active components for both processes reside in the water-insoluble core. Both apoptosis and inflammatory endpoints should be included when the toxicity of different pollutant particles is assessed.
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PMID:Apoptotic and inflammatory effects induced by different particles in human alveolar macrophages. 1576 74


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