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)

In the present study, we investigated the protective mechanism of quercetin (QUE) and its glycosides, rutin (RUT) and quercitrin (QUI), on reactive oxygen species (ROS)-dependent (H(2)O(2)) and -independent (chemical anoxia) cell death in rat glioma C6 cells. Induction of HO-1 protein expression was detected in QUE- but not RUT- or QUI-treated C6 cells, and this was prevented by cycloheximide and actinomycin D. Incubation of C6 cells with QUE, but not RUT or QUI, protected C6 cells from H(2)O(2)- and chemical anoxia-induced cytotoxicity according to the MTT and LDH release assays. Apoptotic characteristics including chromatin condensation, DNA ladders, and hypodiploid cells appeared in H(2)O(2)-and chemical anoxia-treated C6 cells, and those events were significantly suppressed by adding QUE (but not RUT or QUI). Increases in caspase 3, 8, and 9 enzyme activities with decreases in pro-PARP and pro-caspase 3 protein levels and an increase in cleaved D4-GDI protein were identified in H(2)O(2)-and chemical anoxia-treated C6 cells, and these were blocked by the addition of QUE, but not by RUT or QUI. Intracellular peroxide levels increased with H(2)O(2) and decreased with chemical anoxia, and the addition of QUE reduced the intracellular peroxide levels induced by H(2)O(2). Results of an anti-DPPH radical assay showed that QUE, RUT, and QUI dose-dependently inhibited the production of DPPH radicals in vitro; however, QUE (but not RUT or QUI) prevention of DNA damage induced by OH radicals was identified with a plasmid digestion assay. Increases in phosphorylated ERK and p53 protein expressions were detected in H(2)O(2)- but not chemical anoxia-treated C6 cells, and the addition of QUE significantly blocked H(2)O(2)-induced phosphorylated ERK and p53 protein expressions. Adding the HO-1 inhibitors, SnPP, CoPP, and ZnPP, reversed the protective effect of QUE against H(2)O(2)- and chemical anoxia-induced cell death according to the MTT assay and morphological observations. Additionally, QUE exhibited inhibitory effects on LPS/TPA-induced transformation in accordance with a decrease in MMP-9 enzyme activity and iNOS protein expression in C6 cells. Taken together, the results of this study suggest that QUE exhibits an inhibitory effect on both ROS-dependent and -independent cell death, and induction of HO-1 protein expression is involved.
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PMID:Quercetin inhibition of ROS-dependent and -independent apoptosis in rat glioma C6 cells. 1664 78

Recent findings indicate that enhanced glucose uptake protects enterocytes from excessive apoptosis and barrier defects induced by LPS exposure. The aim of this study was to characterize the mechanisms responsible for increased sodium-dependent glucose cotransporter (SGLT)-1 activity in enterocytes challenged with LPS. SGLT-1-transfected Caco-2 cells were incubated with LPS in high glucose media. LPS increased SGLT-1 activity in dose- and time-dependent fashion, and is due to increased V(max) of the cotransporter. Elevated apical expression of SGLT-1 was also demonstrated. This LPS-induced effect was colchicine-inhibitable, suggesting microtubule-dependent translocation of SGLT-1 onto apical surface. Immunofluorescence staining showed expression of CD14 on the apical surface, but no TLR-4, on these cells. Neutralizing anti-CD14 decreased the LPS-induced upregulation of SGLT-1 activity, whereas anti-TLR-4 had no effect. Pharmacological studies indicated that signaling for LPS-mediated SGLT-1 glucose uptake depends on caspase-8 and -9 activation, but occurs independently of caspase-3. The findings describe a novel feedback mechanism within the apoptotic signaling pathway for SGLT-1-dependent cytoprotection. The observation suggests a new function for CD14 on enterocytes, involving the induction of the caspase-dependent SGLT-1 activity, which ultimately leads to cell rescue. The understanding of these signaling events may shed light on enterocytic cytoprotection and homeostasis mechanism upon pro-apoptotic challenges.
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PMID:LPS/CD14 activation triggers SGLT-1-mediated glucose uptake and cell rescue in intestinal epithelial cells via early apoptotic signals upstream of caspase-3. 1686 Mar 18

TNF-alpha influences morbidity and mortality during the course of endotoxemia. However, the complex pleiotropic functions of TNF-alpha remain poorly understood. We evaluated how hepatic induction of NF-kappaB and TNF-alpha influence survival and hepatocellular death in a lethal murine model of endotoxic shock. Using dominant-negative viral vectors to inhibit the IKK complex, we demonstrate through this study that the liver is a major source of TNF-alpha during the course of lethal endotoxemia and that IKKbeta (but not IKKalpha) is predominantly responsible for activating NF-kappaB and TNF-alpha in the liver after LPS administration. Using TNF-alpha knockout mice and hepatic-specific inhibition of IKKbeta, we demonstrate that the status of TNF-alpha and NF-kappaB balances necrotic and apoptotic fates of hepatocytes in the setting of endotoxemia. In the presence of TNF-alpha, inhibiting hepatic IKKbeta resulted in increased survival, reduced serum proinflammatory cytokines, and reduced hepatocyte necrosis in response to a lethal dose of endotoxin. In contrast, inhibiting hepatic IKKbeta in TNF-alpha knockout mice resulted in decreased survival and increased caspase 3-mediated hepatocyte apoptosis after endotoxin challenge, despite a reduced proinflammatory cytokine response. In the presence of TNF-alpha, NF-kappaB-dependent hepatocellular necrosis predominated, while in the absence of TNF-alpha, NF-kappaB primarily influenced apoptotic fate of hepatocytes. Changes in JNK phosphorylation after LPS challenge were also dynamically affected by both IKKbeta and TNF-alpha; however, this pathway could not solely explain the differential outcomes in hepatocellular fates. In conclusion, our studies demonstrate that induction of NF-kappaB and TNF-alpha balances protective (antiapoptotic) and detrimental (proinflammatory) pathways to determine hepatocellular fates during endotoxemia.
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PMID:Pleiotropic functions of TNF-alpha determine distinct IKKbeta-dependent hepatocellular fates in response to LPS. 1693 50

Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. Wang Y, Singh R, Lefkowitch JH, Rigoli RM, Czaja MJ. In vitro studies of hepatocytes have implicated over-activation of c-Jun N-terminal kinase (JNK) signaling as a mechanism of tumor necrosis factor-alpha (TNF)-induced apoptosis. However, the functional significance of JNK activation and the role of specific JNK isoforms in TNF-induced hepatic apoptosis in vivo remain unclear. JNK1 and JNK2 function was, therefore, investigated in the TNF-dependent, galactosamine/lipopolysaccharide (GalN/LPS) model of liver injury. The toxin GalN converted LPS-induced JNK signaling from a transient to prolonged activation. Liver injury and mortality from GalN/LPS was equivalent in wild-type and jnk1-/- mice but markedly decreased in jnk2-/- mice. This effect was not secondary to down-regulation of TNF receptor 1 expression or TNF production. In the absence of jnk2, the caspase-dependent, TNF death pathway was blocked, as reflected by the failure of caspase-3 and -7 and poly(ADP-ribose) polymerase cleavage to occur. JNK2 was critical for activation of the mitochondrial death pathway, as in jnk2-/- mice Bid cleavage and mitochondrial translocation and cytochrome c release were markedly decreased. This effect was secondary to the failure of jnk2-/- mice to activate caspase-8. Liver injury and caspase activation were similarly decreased in jnk2 null mice after GalN/TNF treatment. Ablation of jnk2 did not inhibit GalN/LPS-induced c-Jun kinase activity, although activity was completely blocked in jnk1-/- mice. Toxic liver injury is, therefore, associated with JNK over-activation and mediated by JNK2 promotion of caspase-8 activation and the TNF mitochondrial death pathway through a mechanism independent of c-Jun kinase activity. [Abstract reproduced by permission of J Biol Chem 2006;281:15258-67].
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PMID:The role of JNK2 in toxic liver injury. 1697 78

Dykellic acid, a novel factor initially identified from the culture broth of Westerdykella multispora F50733, has been shown to inhibit matrix metalloprotease 9 activity, caspase-3 activity, B cell proliferation and LPS-induced IgM production, suggesting that this factor may have anti-cancer effects. In an effort to further address the possible anti-tumoral effects of dykellic acid, we used wound healing, invasion and RhoA-GTP assays to examine the effects of dykellic acid on cell migration, invasion and angiogenesis. Our results revealed that dykellic acid dose-dependently inhibits B16 cell migration and motility, and inhibits HUVEC tube formation. Western blot analysis of the active form of RhoA (RhoA-GTP) showed that dykellic acid treatment decreased the levels of RhoA-GTP. These findings collectively suggest that dykellic acid may have both anti-metastatic and anti-angiogenic acitivites, and provides the first evidence for the involvement of RhoA in dykellic acid-induced effects.
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PMID:Dykellic acid inhibits cell migration and tube formation by RhoA-GTP expression. 1707 24

S100A9 is a pro-inflammatory protein expressed in infiltrating granulocytes and monocytes. We determined role of S100A9 in endotoxin (LPS)-induced uveitis (EIU) and keratitis in Wistar rats. Anti-S100A9 antibody decreased partially clinical scores, protein, and cells in the aqueous humor at 18-36 h, compared with the LPS group. S100A9-positive cells were expressed in the iris-ciliary body (ICB) and cornea at 24-48 h. Activated caspase-3 (related to apoptosis) and S100A9 co-expressed in ICB at 18-48 h after LPS injection. S100A9 was not expressed in ED2-positive cells in ICB. Dexamethasone (DEX) increased S100A9 mRNA and protein levels in the circulating blood leukocytes, but reduced S100A9 mRNA and protein levels in ICB after LPS injection. BAY 11-7085 (an inhibitor of I-kappaB phosphorylation) suppressed S100A9 mRNA in leukocytes (43.5%) and ICB (68.5%), respectively, after LPS injection. It is possible that S100A9-positive granulocytes and monocyte/macrophages may play a role in the late phase of EIU and keratitis that DEX may inhibit the migration of S100A9-positive granulocytes and monocytes from the blood into the extravascular tissues, and that nuclear factor (NF)-kappaB pathway may be involved in S100A9 expression. S100A9 could play a role in the clearance of inflammatory cells at the late phase of EIU.
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PMID:S100A9-positive granulocytes and monocytes in lipopolysaccharide-induced anterior ocular inflammation. 1710 Nov 29

The effect of endotoxin (lipopolysacharide, LPS) exposure on luteal cells was studied using an in vitro cell culture system. Buffalo luteal cells were isolated from corpora lutea of the late luteal phase (days 14-16 post estrus) and exposed to various LPS doses (5, 10 and 100 microg/ml) for different time periods (6, 12, 18 or 24 h). The cultured cells were subsequently evaluated for oxidative stress (super oxide, nitric oxide, inducible nitric oxide synthase activity, reduced glutathione depletion and lipid peroxidation) and apoptotic markers (mitochondrial membrane potential, DNA fragmentation, apoptotic cells and cell viability). LPS exposure significantly increased the production of super oxide (P<0.05) and nitric oxide (P<0.01) and increased inducible nitric oxide synthase activity (P<0.01). LPS exposure further depleted reduced glutathione (P<0.05) levels and induced lipid peroxidation (P<0.05). LPS exposure also induced the loss of mitochondrial membrane potential (P<0.05), increased DNA fragmentation (P<0.01) and apoptosis (P<0.01) and decreased cell viability (P<0.01). LPS mediated apoptotic pathway in luteal cells was further characterized using a selected LPS dose (10 microg/ml). It was observed that LPS exposure induced mitochondrial translocation of proapoptotic protein Bax, increased the total Bad expression and down regulated the expression of antiapoptotic proteins Bcl2 and BclXL. LPS exposure further induced cytochrome c release and increased Caspase-9 (P<0.01) and Caspase-3 (P<0.01) activities. LPS exposure also inhibited luteal progesterone secretion (P<0.01). It was evident that the LPS mediated apoptotic effects could be prevented by the coincubation of luteal cells with mitochondrial permeability transition pore blocker Cyclosporine A, inducible nitric oxide synthase inhibitor N-[3-(aminomethyl)benzyl]acetamidine and oxidative stress scavenger N-acetyl cysteine. Our study clearly indicates that LPS induces oxidative stress mediated apoptosis in luteal cells through the mitochondrial pathway.
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PMID:Endotoxin induces luteal cell apoptosis through the mitochondrial pathway. 1725 74

The antioxidant and hepatoprotective actions of Terminalia catappa L. collected from Okinawa Island were evaluated in vitro and in vivo using leaves extract and isolated antioxidants. A water extract of the leaves of T. catappa showed a strong radical scavenging action for 1,1-diphenyl-2-picrylhydrazyl and superoxide (O(2)(.-)) anion. Chebulagic acid and corilagin were isolated as the active components from T. catappa. Both antioxidants showed a strong scavenging action for O(2)(.-) and peroxyl radicals and also inhibited reactive oxygen species production from leukocytes stimulated by phorbol-12-myristate acetate. Galactosamine (GalN, 600 mg/kg, s.c.,) and lipopolysaccharide (LPS, 0.5 microg/kg, i.p.)-induced hepatotoxicity of rats as seen by an elevation of serum alanine aminotransferase, aspartate aminotransferase and glutathione S-transferase (GST) activities was significantly reduced when the herb extract or corilagin was given intraperitoneally to rats prior to GalN/LPS treatment. Increase of free radical formation and lipid peroxidation in mitochondria caused by GalN/LPS treatment were also decreased by pretreatment with the herb/corilagin. In addition, apoptotic events such as DNA fragmentation and the increase in caspase-3 activity in the liver observed with GalN/LPS treatment were prevented by the pretreatment with the herb/corilagin. These results show that the extract of T. catappa and its antioxidant, corilagin are protective against GalN/LPS-induced liver injury through suppression of oxidative stress and apoptosis.
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PMID:Antioxidant and hepatoprotective actions of medicinal herb, Terminalia catappa L. from Okinawa Island and its tannin corilagin. 1729 97

IFN regulatory factor (IRF)-2(-/-) mice are significantly more resistant to LPS challenge than wild-type littermates, and this was correlated with increased numbers of apoptotic Kupffer cells. To assess the generality of this observation, and to understand the role of IRF-2 in apoptosis, responses of peritoneal macrophages from IRF-2(+/+) and IRF-2(-/-) mice to apoptotic stimuli, including the fungal metabolite, gliotoxin, were compared. IRF-2(-/-) macrophages exhibited a consistently higher incidence of apoptosis that failed to correlate with caspase-3/7 activity. Using microarray gene expression profiling of liver RNA samples derived from IRF-2(+/+) and IRF-2(-/-) mice treated with saline or LPS, we identified >40 genes that were significantly down-regulated in IRF-2(-/-) mice, including Stat3, which has been reported to regulate apoptosis. Compared with IRF-2(+/+) macrophages, STAT3alpha mRNA was up-regulated constitutively or after gliotoxin treatment of IRF-2(-/-) macrophages, whereas STAT3beta mRNA was down-regulated. Phospho-Y705-STAT3, phospho-S727-STAT1, and phospho-p38 protein levels were also significantly higher in IRF-2(-/-) than control macrophages. Activation of the STAT signaling pathway has been shown to elicit expression of CASP1 and apoptosis. IRF-2(-/-) macrophages exhibited increased basal and gliotoxin-induced caspase-1 mRNA expression and enhanced caspase-1 activity. Pharmacologic inhibition of STAT3 and caspase-1 abolished gliotoxin-induced apoptosis in IRF-2(-/-) macrophages. A novel IFN-stimulated response element, identified within the murine promoter of Casp1, was determined to be functional by EMSA and supershift analysis. Collectively, these data support the hypothesis that IRF-2 acts as a transcriptional repressor of Casp1, and that the absence of IRF-2 renders macrophages more sensitive to apoptotic stimuli in a caspase-1-dependent process.
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PMID:IFN regulatory factor-2 regulates macrophage apoptosis through a STAT1/3- and caspase-1-dependent mechanism. 1733 57

Francisella tularensis is an obligate, intracellular bacterium that causes acute, lethal disease following inhalation. As an intracellular pathogen F. tularensis must invade cells, replicate, and disseminate while evading host immune responses. The mechanisms by which virulent type A strains of Francisella tularensis accomplish this evasion are not understood. Francisella tularensis has been shown to target multiple cell types in the lung following aerosol infection, including dendritic cells (DC) and macrophages. We demonstrate here that one mechanism used by a virulent type A strain of F. tularensis (Schu4) to evade early detection is by the induction of overwhelming immunosuppression at the site of infection, the lung. Following infection and replication in multiple pulmonary cell types, Schu4 failed to induce the production of proinflammatory cytokines or increase the expression of MHCII or CD86 on the surface of resident DC within the first few days of disease. However, Schu4 did induce early and transient production of TGF-beta, a potent immunosuppressive cytokine. The absence of DC activation following infection could not be attributed to the apoptosis of pulmonary cells, because there were minimal differences in either annexin or cleaved caspase-3 staining in infected mice compared with that in uninfected controls. Rather, we demonstrate that Schu4 actively suppressed in vivo responses to secondary stimuli (LPS), e.g., failure to recruit granulocytes/monocytes and stimulate resident DC. Thus, unlike attenuated strains of F. tularensis, Schu4 induced broad immunosuppression within the first few days after aerosol infection. This difference may explain the increased virulence of type A strains compared with their more attenuated counterparts.
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PMID:Active suppression of the pulmonary immune response by Francisella tularensis Schu4. 1737 12


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