Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Norcantharidin (NCTD) is known to have anti-cancer potentials. The aim of this study was to assess the apoptosis-inducing effect of NCTD on human leukemic Jurkat cells. We found that NCTD preferentially inhibited the growth of Jurkat cells in a dose- and time-dependent manner, but not the growth of normal blood mononuclear cells (MNC). Pretreatment with agonistic (CH-11) and antagonistic (ZB4) Fas antibodies on Jurkat cells showed that NCTD-induced apoptosis might not involve Fas-FasL signaling. Flow cytometric assay of Jurkat cells treated with NCTD showed a markedly increased sub-G1 DNA phase and cell cycle arrest at S phase. Western blot analysis of NCTD-treated cells showed increased expressions of cytochrome c, active caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP), but the expressions of Bcl-2, Bax and apoptosis-inducing factor were not increased. The transcription factor STAT1 was translocated from cytosol to nucleus. Pancaspase inhibitor z-VAD-FMK not only limited the level of sub-G1 phase, but also prevented the degradation of PARP in NCTD-treated cells. The NCTD-induced cell cycle arrest and apoptosis were mediated through the regulation of ataxia-telangiectasia mutated (ATM), rather than P63 protein. The conditioned medium produced from human MNC (NCTD-MNC-CM) increased the percentage of apoptotic cells and the expression of PARP cleavage in Jurkat cells. Protein array assay of NCTD-MNC-CM showed 32.4- and 6.2-folds increases in TNF-alpha and GM-CSF, respectively, and the expression of MCP-1, GRO, RANTES and IL-10 was decreased. We conclude that NCTD can induce apoptosis in human leukemic Jurkat cells via a caspase-dependent pathway without affecting the viability of normal MNC, and that the apoptosis-inducing effect of NCTD can also be achieved by soluble cytokines produced from peripheral MNC.
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PMID:Norcantharidin preferentially induces apoptosis in human leukemic Jurkat cells without affecting viability of normal blood mononuclear cells. 1744 74

Almost 19 members of the tumor necrosis factor (TNF) superfamily have been identified that interact with 29 different receptors. Whether these receptors communicate with each other is not understood. Recently, we have shown that receptor activator of NF-kappaB ligand signaling is modulated by genetic deletion of the TNF receptor. In the current report, we investigated the possibility of a cross-talk between Fas and TNF-alpha signaling pathway in macrophage cell lines derived from wild-type (WT) mice and from mice with genetic deletion of the type 1 TNF receptor (p60(-/-)), the type 2 TNF receptor (p80(-/-)), or both receptors (p60(-/-)p80(-/-)). We found that the macrophages expressing TNF receptors were highly sensitive to apoptosis induced by anti-Fas. The genetic deletion of TNF receptors, however, made the cells resistance to anti-Fas-induced apoptosis. Anti-Fas induced activation of caspase-3 and PARP cleavage in WT cells but not in TNF receptor-deleted cells. This difference was found to be independent of the expression of Fas, Fas-associated protein with death domain (FADD) or TNF receptor-associated death domain (TRADD). We found that anti-Fas induced recruitment of TNFR1 into Fas-complex. We also found that TRADD, which mediates TNF signaling, was constitutively bound to Fas receptor in TNF receptor-deleted cells but not in wild-type cells. Transient transfection of TNFR1 in TNFR1-deleted cells sensitized them to anti-Fas-induced apoptosis. Overall our results demonstrate that Fas signaling is modulated by the TNF receptors and thus provide the evidence of cross-talk between the receptors of two cytokines.
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PMID:Evidence that genetic deletion of the TNF receptor p60 or p80 inhibits Fas mediated apoptosis in macrophages. 1769 26

Poly(ADP-ribose) polymerase (PARP)-1, which plays a key role in DNA repair, inflammation and transcription, has recently been shown to be involved in angiogenesis. The aim of this study was to investigate PARP-1 role in melanoma aggressiveness and chemoresistance in vivo using clones stably silenced for PARP-1 expression. Whilst the growth characteristics of PARP-1-deficient melanoma cells were comparable to those of PARP-1-proficient cells in vitro, their tumourigenic potential in vivo was significantly compromised. In fact, mice challenged intra-muscle with PARP-1-deficient cells showed a delayed development of measurable tumour nodules, which were also significantly reduced in size with respect to those of mice inoculated with PARP-1-proficient cells. Moreover, animals challenged intra-cranially with PARP-1-deficient cells, a model that mimics CNS localisation of melanoma, showed an increased survival. Immunohistochemical analyses of PARP-1-depleted melanoma grafts indicated a reduced expression of the angiogenesis marker PECAM-1/CD31 and of the pro-inflammatory mediators TNF-alpha and GITR. Notably, PARP-1-silenced melanoma was extremely sensitive to temozolomide, an anticancer agent used for the treatment of metastatic melanoma. These results provide novel evidence for a direct role of PARP-1 in tumour aggressiveness and chemoresistance.
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PMID:Stable depletion of poly (ADP-ribose) polymerase-1 reduces in vivo melanoma growth and increases chemosensitivity. 1844 Feb 22

One of the major conceptual advances in our understanding of the pathogenesis of age-associated cardiovascular diseases has been the insight that age-related oxidative stress may promote vascular inflammation even in the absence of traditional risk factors associated with atherogenesis (e.g., hypertension or metabolic diseases). In the present review we summarize recent experimental data suggesting that mitochondrial production of reactive oxygen species, innate immunity, the local TNF-alpha-converting enzyme (TACE)-TNF-alpha, and the renin-angiotensin system may underlie NF-kappaB induction and endothelial activation in aged arteries. The theme that emerges from this review is that multiple proinflammatory pathways converge on NF-kappaB in the aged arterial wall, and that the transcriptional activity of NF-kappaB is regulated by multiple nuclear factors during aging, including nuclear enzymes poly(ADP-ribose) polymerase (PARP-1) and SIRT-1. We also discuss the possibility that nucleophosmin (NPM or nuclear phosphoprotein B23), a known modulator of the cellular oxidative stress response, may also regulate NF-kappaB activity in endothelial cells.
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PMID:Inflammation and endothelial dysfunction during aging: role of NF-kappaB. 1859 77

Furanodiene, a natural product isolated from Curcuma wenyujin, has been reported to produce cytotoxic effect. In this study, we investigated its effects on human leukemia HL60 cells. Furanodiene induced apoptosis of HL60 cells, characterized by DNA fragmentation, cleavage of poly (ADP-ribose) polymerase (PARP), caspase-3, caspase-8 and caspase-9. In the Bcl-2 family proteins, Bid protein (a substrate of caspase-8) was activated by furanodiene, but Bcl-2, Bax and Bcl-xL proteins were not influenced by furanodiene stimulation. Moreover, furanodiene treatment caused the upregulation of tumor necrosis factor receptor 1 (TNFR1), the formation of TNFR1 complex and an obvious production of TNF-alpha in HL60 cells. The soluble TNFR1 receptor effectively inhibited furanodiene-induced apoptosis. Taken together, furanodiene could inhibit the growth of leukemia cells via induction of apoptosis, and TNFR1-mediated extrinsic apoptotic pathways explains furanodiene-induced apoptosis.
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PMID:Induction of apoptosis by furanodiene in HL60 leukemia cells through activation of TNFR1 signaling pathway. 1866 67

Almost 2% of the population of western industrialized countries are affected by Alzheimer's disease (AD). Nevertheless the pathogenetic process leading to this neurodegenerative disease is widely unknown. Thus, we focus on novel pathophysiological aspects of AD. We hypothesize that AD patients reveal increased levels of peripheral blood mononuclear cells (PBMCs) expressing proinflammatory (COX-2, TNF-alpha, CD40), proapoptotic (PARP-1), adhesion-relevant (CD38) or AD associated (C99, BACE1, Presenilin-1) proteins as well as elevated proinflammatory biochemical plasma parameters. Therefore, PBMCs of AD patients and age-matched control subjects were studied by two color fluorescence-activated cell sorter (FACS) analysis. Furthermore, concentration of plasma oxidized low-density lipoprotein (oxLDL) and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA). We found a significantly increased percentage of TNF-alpha, COX-2, PARP-1, CD38, C99 or presenilin-1 positive PBMCs in AD patients compared with healthy subjects. FACS analyses revealed that the percentage of C99 or presenilin-1 positive PBMCs, which also express TNF-alpha, COX-2, PARP-1 or CD38 is also increased in AD patients. Additionally, AD patients had significantly increased plasma oxLDL and TNF-alpha levels. Furthermore, we found positive correlations between plasma oxLDL or TNF-alpha concentrations and the percentage of TNFalpha+, COX-2+ or PARP-1+, as well as PS-1+, C99+ or BACE+ PBMCs. Our findings suggest that immunocytological investigations, based on immunophenotyping of AD relevant proteins combined with measurement of proinflammatory, proapoptotic and adhesion-relevant proteins in PBMCs may provide more insight into the pathophysiology of AD.
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PMID:Novel systemic markers for patients with Alzheimer disease? - a pilot study. 1869 Aug 33

PRV infection causes apoptosis in vitro and in vivo. However, the significance of PRV-induced apoptosis and its signaling pathways is still unknown. This work investigates the role of MAPK pathways in mediating PRV-induced apoptosis. Flow cytometry, apoptosis ELISA and western blotting using antibodies against cleaved caspase-3, -6 and PARP demonstrated that PRV induces apoptosis in a time- and dose-dependent manner. p38 and JNK/SAPK inhibitors significantly protected cells from PRV-induced apoptosis. Inhibitor treatment did not affect Us3a gene transcription and progeny virus production. Western blotting revealed that PRV activates p38 and JNK/SAPK signaling. Inhibition of NF-kappaB had no effect on PRV-mediated apoptosis. Non-replicative PRV failed to activate p38 and JNK/SAPK or induce apoptosis. PRV infection increases TNF-alpha transcription, translation and secretion, as well as TNF-alpha receptor expression. Inhibition of p38 and JNK/SAPK reduced PRV-induced TNF-alpha up-regulation. Neutralization assay confirmed that TNF-alpha is a key mediator involved in PRV-induced apoptosis.
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PMID:TNF-alpha mediates pseudorabies virus-induced apoptosis via the activation of p38 MAPK and JNK/SAPK signaling. 1879 79

Apoptotic phenomena observed in vitro following isolation and following transplantation contribute significantly to islet graft loss. Strategies to reduce apoptosis of islet tissue prior to and posttransplantation may improve graft survival and function and reduce the amount of tissue necessary to achieve insulin independence. The expression of cytoprotective proteins is one such strategy that may prolong islet survival. In this light, heme-oxygenase 1 (HO-1) upregulation has been studied in both allo- and xenotransplantation models. In this study, the effect of HO-1 on apoptosis in neonatal porcine islet-like cell clusters (NPICC) was assessed. In in vitro assessments of NPICC apoptosis, NPICC showed a high sensitivity to apoptotic stimulation using a combination of TNF-alpha and cycloheximide. Stimulation with TNF-alpha alone was sufficient to induce reproducible apoptotic responses as demonstrated by caspase-3,-7 activation and subdiploid DNA analysis. Dose-dependent, high-level HO-1 protein expression was achieved following culture of NPICC in medium containing either cobalt protoporphyrin (CoPP) or cobalt mesoporphyrin (CoMP). CoPP treatment resulted in the reduction of caspase-3,-7 enzyme activity following TNF-alpha stimulation. However, such an effect was not associated with a reduction in the levels of cell death. Indeed, the inhibition of caspase enzyme activity resulted in decreased PARP-1 cleavage, which may lead to heightened levels of necrosis in treated NPICC cultures, possibly explaining the observed commitment of NPICC to the death pathway.
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PMID:Cobalt protoporpyhrin reduces caspase-3,-7 enzyme activity in neonatal porcine islets, but does not inhibit cell death induced by TNF-alpha. 1881 47

The aim of the present study was to examine the effects of phenylpropanoid glycoside, teupolioside, biotechnologically produced by IRBN22 Ajuga reptans cell line, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Teupolioside was administered daily orally (0.2 or 2mgkg(-1)). On Day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. Four days after DNBS administration, colon TNF-alpha and IL-1beta productions were increased, associated with colon damage. Neutrophil infiltration, by myeloperoxidase activity, in the mucosa was associated with up-regulation of ICAM-1 and P-selectin and high levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) showed an intense staining in the inflamed colon. Biochemical methods and zymography were used to analyze MMP-9 and -2 activities in colon tissues from DNBS-injured rats. Treatment with teupolioside significantly reduced the appearance of diarrhoea and the loss of body weight. This was associated with a remarkable amelioration in the disruption of the colonic architecture and a significant reduction in colonic myeloperoxidase activity and malondialdehyde levels. Teupolioside also reduced the pro-inflammatory cytokines release, the appearance of nitrotyrosine and PARP immunoreactivity in the colon and reduced the up-regulation of ICAM-1 and the expression of P-selectin. Therefore, teupolioside also reduced proMMP-9 and -2 activity induced in the colon by DNBS administration. The results of this study suggested that administration of teupolioside may be beneficial for treatment of inflammatory bowel disease.
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PMID:Teupolioside, a phenylpropanoid glycosides of Ajuga reptans, biotechnologically produced by IRBN22 plant cell line, exerts beneficial effects on a rodent model of colitis. 1907 Jun 2

Intervertebral disks degenerate far earlier than other musculoskeletal tissues and apoptosis has been suggested to have a vital function in promoting the degeneration process that is strongly associated with back pain. However, the molecular mediators of apoptosis in the intervertebral disk are poorly understood. Fas/FasL, TRAIL/DR4, TRAIL/DR5 and TNF-alpha/TNFR1 are ligand/receptor pairs of the tumor necrosis factor/nerve growth factor family, which are able to induce apoptosis by trimerization of the receptor by its corresponding ligand. We investigated which of these molecules are expressed in intervertebral disks and whether their expression correlates to disk degeneration. Intervertebral disks from 28 donors (age 12-70 years) suffering from scoliosis, vertebrae fracture or disk degeneration were scored histologically for degeneration and analyzed for gene expression of FasL/Fas, TRAIL/DR4, TNF-alpha/TNFR1 and caspase 8. Protein expression of FasL and TRAIL was assessed by immunohistology and apoptotic cell death was quantified by poly(ADP-ribose) polymerase (PARP) p85 staining. Isolated disk cells were analyzed by flow cytometry for Fas, FasL, TRAIL, DR4 and DR5 expression. Gene expression of TRAIL (P=0.002) and caspase 8 (P=0.027) significantly correlated with degeneration. TRAIL expression further correlated with cellularity (P=0.04), muccoid matrix changes (P=0.009) and tears and cleft formation (P=0.019). FasL and TRAIL expression was confirmed by immunohistology and PARP cleavage was significantly associated with degeneration (P=0.027). Flow cytometry on isolated disk cells revealed correlations between DR4 and degeneration (P=0.014), DR4/DR5 double-positive cells and degeneration (P=0.019), as well as DR5 and changes in tissue granularity (P=0.03). This is the first study that shows that intervertebral disk cells express TRAIL, DR4 and DR5, which correlate to the degenerative state of the disk. Therefore, disk cells inherit the molecular machinery to induce and undergo cellular apoptosis, and the frequency of cytokine expression suggests that the TRAIL/DR4/DR5 axis is an important molecular mediator of apoptosis induction in disk tissue.
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PMID:Expression of TRAIL and the death receptors DR4 and DR5 correlates with progression of degeneration in human intervertebral disks. 1930 84


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