Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal proximal tubular epithelial cells (PTEC) are target for LPS during sepsis and renal infections. In the present study, we evaluated whether stimulation of human PTEC by LPS is modulated through the soluble or the membrane form of the LPS receptor CD14. We found that PTEC lacked expression of the membrane form of CD14 and did not release soluble CD14 (sCD14). sCD14 was detected in the urine of normal subjects and it was increased in patients with renal sepsis or with proteinuria. In the presence of sCD14 and LPS binding protein (LBP), PTEC were 10 to 100-fold more sensitive to LPS activation, resulting in cytokine production (IL-6, IL-8 and TNF-alpha) and NO release. We found that sCD14 purified from urine was biologically active on PTEC. Moreover, the presence of sCD14 and LBP was required for cytotoxicity induced by low concentrations of LPS (1-10 ng/ml) in PTEC. Cell death showed the characteristics of both necrosis and apoptosis, as demonstrated by LDH release and by TUNEL and acridine orange staining and caspase-3 activation. Whereas the LPS alone was sufficient to induce necrosis, sCD14 and LBP were required for apoptosis. Our results suggest that sCD14 excreted in urine may participate with endotoxin in the activation and injury of renal proximal tubules. In particular, sCD14 may contribute to the tubulo-interstitial injury in clinical settings characterised by proteinuria and enhanced susceptibility to infections such as in diabetes.
 ...
PMID:Urinary soluble CD14 mediates human proximal tubular epithelial cell injury induced by LPS. 1223 91

Cyclooxygenase-2 (COX-2) expression and certain growth hormones, such as gastrin, have been related to gastric carcinogenesis, but little is known about the factors that enhance this COX-2 expression and whether specific blockade of this enzyme has any influence on tumor growth and progression. Our objective was to determine the influence of a specific COX-2 inhibitor, rofecoxib (Vioxx), on serum and tumor levels of gastrin and its precursor, progastrin, as well as on tumor gene expression of COX-2, peroxisome proliferator-activated receptor gamma (PPARgamma), and apoptosis-related proteins (Bax and Bcl-2, caspase-3, and survivin). Twenty-four gastric cancer (GC) patients entered this study and were examined twice, once before and then following a 14-day treatment with Vioxx at a dose of 25 mg twice daily. For comparison, 48 age- and sex-matched healthy controls and 24 similarly matched Helicobacter pylori (Hp)-positive subjects were enrolled and treated with Vioxx as GC patients. Serum levels of anti-Hp and anti-CagA antibodies as well as IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA), while serum and tumor contents of progastrin and amidated gastrin were determined by specific RIA. Tumor gene and protein expressions of COX-2, PPARgamma, Bax and Bcl-2, caspase-3, and survivin were determined by RT-PCR and western blot. The overall Hp and CagA seropositivity in 24 GC patients was significantly higher (82% and 47%) than in 48 controls (61% and 22%) but not in 24 Hp-infected subjects (100% and 38%). Serum IL-8 and TNF-alpha values were significantly higher in GC patients than in controls without GC or Hp-infected controls. Median serum progastrin and gastrin levels were found to be significantly higher in GC than in controls without GC and in Hp-positive subjects. Treatment of GC patients with Vioxx resulted in a significant decrease in plasma and tumor contents of both progastrin and gastrin, and this was accompanied by the increment in tumor expression of COX-2, PPARy, Bax, and caspase-3 with a concomitant reduction in Bcl-2 and survivin expression. We conclude that: (1) GC patients show significantly higher Hp and CagA seropositivity than age- and sex-matched controls, but not Hp-positive subjects, indicating that infection with cytotoxic Hp is linked to GC. (2) Serum progastrin and gastrin levels are significantly higher in GC patients than in matched controls, confirming that both gastrins may be implicated in gastric carcinogenesis. (3) GC patients exhibit significantly higher levels of IL-8 and TNF-alpha than non-GC controls and Hp-positive subjects, probably reflecting more widespread gastritis in GC. (4) COX-2, PPARgamma, Bcl-2, and survivin were overexpressed in gastric tumor, but the inhibition of COX-2 activity by Vioxx resulted in a significant reduction in serum and tumor levels of progastrin and gastrin and serum IL-8 and TNF-alpha levels, suggesting that gastrin and proinflammatory cytokines could mediate the up-regulation of COX-2 in gastric cancerogenesis. (5) Vioxx also enhanced expression of COX-2, PPARy, Bax, and caspase-3, while inhibiting the expression of Bcl-2 and survivin, suggesting that COX-2 blockade might be useful in chemoprevention against gastric cancer possibly due to enhancement of the PPARy- and proapoptotic proteins-dependent apoptosis and the reduction in progastrin/gastrin-induced promotion of tumor growth.
 ...
PMID:Influence of COX-2 inhibition by rofecoxib on serum and tumor progastrin and gastrin levels and expression of PPARgamma and apoptosis-related proteins in gastric cancer patients. 1462 49

The obligate intracellular bacterial pathogen Chlamydia pneumoniae (Cp) is responsible for a range of human diseases, including acute respiratory infection. Although experimental intratracheal infection with Cp results in a massive recruitment of neutrophil granulocytes (polymorphonuclear neutrophils (PMN)), the role of these cells in the defense against Cp is unclear. In this study the interactions of PMN with Cp were investigated. In vitro coincubation experiments showed that human granulocytes were able to internalize Chlamydia in an opsonin-independent manner. Importantly, phagocytosed Cp were not killed; the ingested bacteria survived and multiplied within PMN. Although uninfected granulocytes became apoptotic within 10 h, infected PMN survived up to 90 h. Coincubation with Cp significantly decreased the ratio of apoptotic PMN, as detected by morphological analysis, annexin V, and TUNEL staining. The observed antiapoptotic effect was associated with a markedly lower level of procaspase-3 processing and, consequently, reduced caspase-3 activity in infected PMN. LPS was found as a major, but not exclusive, component responsible for the observed antiapoptotic effect. Chlamydia LPS affected PMN apoptosis both by acting directly on the cells and by inducing the autocrine production of the antiapoptotic cytokine IL-8. These data show that, in contrast to other microbial pathogens that drive phagocytes into apoptosis to escape killing, Cp can extend the life span of neutrophil granulocytes, making them suitable host cells for survival and multiplication within the first hours/days after infection.
 ...
PMID:Chlamydia pneumoniae multiply in neutrophil granulocytes and delay their spontaneous apoptosis. 1473 60

Constitutive expression of the pro-molecule of IL-16 has been found in T cells, mast cells, eosinophils, epithelial cells, fibroblasts, and dendritic cells. Here we show that IL-16 is also constitutively present in >98% of freshly isolated human CD14-positive peripheral blood monocytes when analyzed by flow cytometry. Because pro-IL-16 is cleaved to its bioactive mature form by caspase-3, and caspase-3 is also the pivotal effector of apoptosis in monocytes, we asked whether IL-16 release occurs in monocytes that undergo spontaneous apoptosis. As expected, freshly isolated, unstimulated monocytes underwent spontaneous caspase-3 activation. This apoptosis was paralleled by the loss of intracellular IL-16, as detected by flow cytometry, and the concurrent release of IL-16, as detected by ELISA. In contrast, stimulation with bacterial LPS inhibited caspase-3 activation and significantly inhibited the release of IL-16. As a specificity control, IL-1beta and IL-8 were not released during spontaneous monocyte apoptosis. In summary, our data demonstrate that monocytes contain IL-16 that is released during spontaneous apoptosis.
 ...
PMID:IL-16 is constitutively present in peripheral blood monocytes and spontaneously released during apoptosis. 1518 55

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.
 ...
PMID:Activated protein C stimulates proliferation, migration and wound closure, inhibits apoptosis and upregulates MMP-2 activity in cultured human keratinocytes. 1530 79

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.
 ...
PMID:Effects of IL-1beta on gene expression in human rheumatoid synovial fibroblasts. 1546 74

The Jurkat T-cell line was used to study potential impact of deoxynivalenol (DON) and related 8-ketotrichothecenes on human immune function. DON (250-1000 ng/ml) readily induced caspase-3 and apoptosis in Jurkat cells. DON (62.5-500 ng/ml) also significantly upregulated IL-2 and IL-8 production following prestimulation with phorbol myristate acetate and ionomycin. DON markedly induced phosphorylation of p38, JNK 1/2, and ERK2. SB203580, a specific inhibitor of p38, reduced DON-induced apoptosis. The MEK1 inhibitor PD98059 which blocks ERK activation had only a small inhibitory effect on DON-induced apoptosis while the JNK inhibitor SP600125 was without effect. Inhibition of p38 attenuated DON-induced upregulation of IL-2 while all three MAPK inhibitors suppressed IL-8 upregulation. When effects of DON were compared to other 8-ketotrichothecenes, the concentrations of DON, 3-acetyl deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon X (FX) causing 50% apoptosis were 0.6, 0.5, 0.5, 0.5 and 7.5 microg/ml, respectively. Relative to IL-2 upregulation, FX was suppressive whereas 3-ADON, 15-ADON and NIV had no effect at concentrations of 62.5-500 ng/ml. In contrast, 15-ADON at 62.5-500 ng/ml and 3-ADON at 625-5000 ng/ml upregulated IL-8 production but FX and NIV had no effect. Taken together, these data suggest that DON's effects on apoptosis and cytokine production were differentially regulated by MAPKs. Although DON shared its capacity to induce apoptosis and potentiate IL-8 production with other 8-ketotrichothecenes, it appeared to be unique in its capacity to upregulate IL-2.
 ...
PMID:Induction of apoptosis and cytokine production in the Jurkat human T cells by deoxynivalenol: role of mitogen-activated protein kinases and comparison to other 8-ketotrichothecenes. 1558 14

Asthma is an inflammatory disease of the lungs and the transcription factor NF-kappa B regulates the production of numerous inflammatory mediators that may have a role in the pathogenesis of asthma. Hence, the signalling pathways leading to NF-kappa B activation are considered prime targets for novel anti-inflammatory therapies. The prevention of NF-kappa B activity in mice, through the knockout of IKK beta or p65, causes fatal liver degeneration in utero making it difficult to determine the full implications of inhibiting NF-kappaB activity in tissues physiologically relevant to human diseases. This study used adenovirus delivery of a dominant inhibitor of NF-kappaB (I kappa B alpha delta N) and dominant-negative IKK alpha (IKK alpha(KM)) and IKK beta (IKK beta(KA)) to investigate the role of the individual IKKs in NF-kappa B activation and inflammatory gene transcription by human pulmonary A549 cells. Overexpression of IKK beta(KA) or I kappa B alpha delta N prevented NF-kappa B-dependent transcription and DNA binding. IKK beta(KA) also prevented I kappa B alpha kinase activity. Similarly, IKK beta(KA) and I kappa B alpha delta N overexpression also inhibited IL-1beta- and TNF alpha-dependent increases in ICAM-1, IL-8 and GM-CSF in addition to IL-1beta-mediated increases in cyclooxygenase-2 expression, whereas IKK alpha(KM) overexpression had little effect on these outputs. IKK beta(KA) also reduced cell viability and induced caspase-3 and PARP cleavage regardless of the stimuli, indicating the induction of apoptosis. This effect seemed to be directly related to IKK beta kinase activity since I kappa B alpha delta N only induced PARP cleavage in TNF alpha-treated cells. These results demonstrate that inhibition of IKK beta and NF-kappa B suppresses inflammatory mediator production and reduces A549 cell viability. Thus, novel therapies that target IKK beta could have potent anti-inflammatory effects and may be beneficial in the treatment of certain cancers.
 ...
PMID:Validation of IKK beta as therapeutic target in airway inflammatory disease by adenoviral-mediated delivery of dominant-negative IKK beta to pulmonary epithelial cells. 1572 90

Helicobacter pylori has been known to provoke gastric inflammation, ulceration, and DNA damage, based on which WHO defined H. pylori as a class I carcinogen. Although ginseng, the root of Panax ginseng C.A. Meyer, has been reported to possess antiadhesion or antimicrobial activity against H. pylori, in this study, we examined the protective effect of red ginseng extracts (RGE) against H. pylori-induced cytotoxicity and DNA damage. RGE significantly attenuated both H. pylori-induced DNA damage assessed by comet assay and apoptosis measured by DNA fragmentation. Inactivation of ERK1/2 signaling and attenuation of caspase-3 activation and PARP cleavage were revealed with RGE against H. pylori infection. RGE decreased H. pylori-stimulated IL-8 gene expression, which resulted from the transcriptional regression of NF-kappaB. In conclusion, RGE showed significant gastroprotective effects against H. pylori-associated gastric mucosal cell damage, suggesting that red ginseng could be used as a medicinal phytonutrient against H. pylori infection.
 ...
PMID:Rescue of Helicobacter pylori-induced cytotoxicity by red ginseng. 1604 63

Hepatitis C virus (HCV) infection is associated with inflammation of liver endothelium, which contributes to the pathogenesis of chronic hepatitis. The mechanism of this endothelitis is not understood, since the virus does not appear to infect endothelial cells productively. Here, an 'innocent bystander' mechanism related to HCV proteins was hypothesized and it was investigated whether the binding of HCV particles to human endothelium induced functional changes in the cells. Exposure of human umbilical vein endothelial cells (HUVECs) to HCV-like particles (HCV-LPs) resulted in increased interleukin 8 (IL8) production and induction of apoptosis. The IL8 supernatants collected after stimulation of HUVECs with HCV-LPs, BV-GUS (control baculovirus containing beta-glucuronidase) and appropriate controls were used to assay the transendothelial migration of neutrophils. This assay confirmed that HCV-LP-induced IL8 was functionally active. Using specific NF-kappaB inhibitors, it was also shown that HCV-LP-induced NF-kappaB activity mediated IL8 production in HUVECs. Apoptosis appeared to be mediated by the Fas/Fas-L pathway, as neutralizing antibodies for Fas and Fas-L significantly protected HUVECs against HCV-LP-induced apoptosis. Treatment of HUVECs with HCV-LPs also enhanced cellular Fas-L expression and augmented caspase-3 activation. This was confirmed by using a specific caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluoromethyl ketone. As shown by blocking of specific chemokine receptors for IL8 on HUVECs, the induction of IL8 did not appear to contribute to HCV-LP-induced apoptosis. These results suggest that HCV proteins can trigger the release of inflammatory chemokines such as IL8 and cause endothelial apoptosis, thereby facilitating endothelitis.
 ...
PMID:Structural proteins of Hepatitis C virus induce interleukin 8 production and apoptosis in human endothelial cells. 1629 74


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>