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

Alveolar macrophages (AMs) are the principal target cells of silica and occupy a key position in the pathogenesis of silica-related diseases. Silica has been found to induce apoptosis in AMs, whereas its underlying mechanisms involving the initiation and execution of apoptosis are largely unknown. The main objective of the present study was to examine the form of cell death caused by silica and the mechanisms involved. Silica-induced apoptosis in AMs was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay and cell cycle/DNA content analysis. The elevated level of reactive oxygen species (ROS), caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage in silica-treated AMs were also determined. The results showed that there was a temporal pattern of apoptotic events in silica-treated AMs, starting with ROS formation and followed by caspase-9 and caspase-3 activation, PARP cleavage, and DNA fragmentation. Silica-induced apoptosis was significantly attenuated by a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp aldehyde, and ebselen, a potent antioxidant. These findings suggest that apoptosis is an important form of cell death caused by silica exposure in which the elevated ROS level that results from silica exposure may act as an initiator, leading to caspase activation and PARP cleavage to execute the apoptotic process.
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PMID:Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages. 1113 90

Studies have shown that silica induces apoptosis through mechanisms that also regulate the inflammatory responses of lung cells to silica exposure. Although implicated in cell culture studies, the major in vivo pathway through which silica induces apoptosis has not been characterized. The present study is to study the role of mitochondria in silica-induced oxidative stress and apoptosis in vivo. Rats were intratracheally instilled with saline or silica (20 mg/kg) and sacrificed at 3 days post-exposure unless otherwise specified. Alveolar macrophages (AM) were harvested by bronchoalveolar lavage and measured for apoptosis and secretion of inflammatory mediators in the presence or absence of appropriate inhibitors. Concurrent studies were carried out to determine the presence of intracellular reactive oxygen species (ROS) via confocal microscopy, mitochondrial trans-membrane potential by flow cytometry, mitochondrial release of cytochrome c, and the activation of caspase activities in AM by Western blot analysis. Silica was shown to induce elevated levels of intracellular ROS, resulting in a marked decrease in intracellular glutathione (GSH) and cysteine and a sustained presence of apoptotic AM in silica-exposed rats up to two weeks post-exposure. The apoptotic AM were characterized by decreased mitochondrial trans-membrane potential, increased mitochondrial release of cytochrome c, activated caspase 9 (but not caspase 8) and caspase 3 activities, and PARP degradation, comparing to cells from the saline control. Silica induced AM production of IL-1 and TNF-alpha, which may be inhibited by ex vivo treatment of cells with N-acetylcysteine (NAC) or microtubule modifiers such as tetrandrine and taxol. NAC was shown to prevent intracellular GSH depletion and silica-induced production of IL-1beta and TNF-alpha but not apoptosis in AM from silica-exposed rats. These results show that silica-induced apoptosis is mediated through the mitochondrial pathway but not through cellular production of inflammatory cytokines, ROS generation, however, induces both apoptosis and cellular secretion of inflammatory mediators.
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PMID:Silica-induced apoptosis in alveolar macrophages: evidence of in vivo thiol depletion and the activation of mitochondrial pathway. 1675 40

Silica was listed as a human carcinogen by International Agency for Research on Cancer (IARC) in 1996. However, the molecular mechanisms to induce cancer are not understood yet. Our recent published study showed that silica inhibited the expression of poly(ADP-ribose) polymerases-1 (PARP-1) mRNA. However, the mechanisms responsible for low PARP-1 expression have not yet been elucidated. In this study, the human bronchial epithelial cells (16HBE) were treated with 300 microg/ml silicon dioxide for 35 passages, the mode of silica-associated malignant transformation of human bronchial epithelial cells (M-16HBE) was established and identified by soft agar assay and nude mouse tumorigenesis. The mRNA expression and methylation status of PARP-1 in M-16HBE with or without treatment of the cytosine methylation inhibitor 5-aza-2'-deoxycytidine (5-aza) were detected by real-time PCR and methylation-specific PCR (MSP), respectively. The data showed that silica decreased PARP-1 expression at the transcriptional levels in M-16HBE and the above epigenetic inhibitors reversed the transcriptional inhibition of PARP-1 through the demethylation of PARP-1, suggesting that the epigenetic mediated transcriptional activation of PARP-1.
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PMID:Epigenetic mediated transcriptional activation of PARP-1 participates in silica-associated malignant transformation of human bronchial epithelial cells. 2012 7