Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anti-cancer drug arsenic trioxide (AT) induces apoptosis in a variety of transformed or proliferating cells. However, little is known regarding its ability to induce apoptosis in terminally differentiated cells, such as neutrophils. Because neutropenia has been reported in some cancer patients after AT treatment, we hypothesised that AT could induce neutrophil apoptosis, an issue that has never been investigated. Herein, we found that AT-induced neutrophil apoptosis and gelsolin degradation via caspases. AT did not increase neutrophil superoxide production and did not induce mitochondrial generation of reactive oxygen species. AT-induced apoptosis in PLB-985 and X-linked chronic granulomatous disease (CGD) cells (PLB-985 cells deficient in gp91(phox) mimicking CGD) at the same potency. Addition of catalase, an inhibitor of H2O2, reversed AT-induced apoptosis and degradation of the cytoskeletal proteins gelsolin, alpha-tubulin and lamin B1. Unexpectedly, AT-induced de novo protein synthesis, which was reversed by catalase. Cycloheximide partially reversed AT-induced apoptosis. We conclude that AT induces neutrophil apoptosis by a caspase-dependent mechanism and via de novo protein synthesis. H2O2 is of major importance in AT-induced neutrophil apoptosis but its production does not originate from nicotinamide adenine dinucleotide phosphate dehydrogenase activation and mitochondria. Cytoskeletal structures other than microtubules can now be considered as novel targets of AT.
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PMID:Arsenic trioxide (AT) is a novel human neutrophil pro-apoptotic agent: effects of catalase on AT-induced apoptosis, degradation of cytoskeletal proteins and de novo protein synthesis. 1640

Neutropenia is the primary dose-limiting effect of etoposide toxicity resulting in a decreased efficiency of cancer treatment. Hence, the protection of neutrophils has important clinical implications. We investigated whether quercetin, due to its antioxidant properties, is able to modulate the damaging activity of etoposide. DNA damage, evaluated by the comet assay, and apoptosis, determined by FACScan flow cytometry using Annexin/PI, increased with etoposide doses. The intracellular level of reactive oxygen species (ROS) was enhanced in resting neutrophils incubated with etoposide at concentrations up to 25 microM; above this concentration etoposide revealed antioxidant properties. Only in latex-activated neutrophils, i.e. with latex-stimulated respiratory burst was the ROS production inhibited, as assessed by the luminol amplified chemiluminescence. The characteristic electron spin resonance (ESR) signal of etoposide phenoxyl radical, which occurs in the presence of myeloperoxidase, H2O2 and etoposide, was quenched by quercetin in a dose-dependent manner (0.1-0.5 microM). Quercetin also inhibited DNA damage induced by etoposide and enhanced the inhibitory action of etoposide on the ROS formation in neutrophils. However, quercetin (1 microM) lowered early and late apoptosis/necrosis only when apoptosis was induced by 25 microM etoposide; at higher etoposide concentration apoptosis was enhanced. Summing up, antioxidant adjuvant therapy using quercetin can be beneficial in prolonging neutrophils' lifespan in peripheral blood only when etoposide plasma concentration is low.
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PMID:Lifespan of etoposide-treated human neutrophils is affected by antioxidant ability of quercetin. 1746 52

Carbamazepine (CBZ) and phenytoin (PHN) are associated with a relatively high incidence of idiosyncratic drug reactions. Most such reactions are believed to be due to reactive metabolites. The reactions associated with these two drugs are similar, and if a patient has a reaction to one, he or she is at increased risk of having a reaction to the other, suggesting that a similar reactive metabolite may be involved. CBZ causes neutropenia in approximately 10% of patients; this suggests that reactive metabolites are formed by myeloperoxidase (MPO), the major oxidative enzyme in neutrophils. Major metabolites of CBZ are the 2- and 3-OH metabolites, and that of PHN is the 4-OH metabolite. We found that both 2-OH-CBZ and 3-OH-CBZ were further oxidized by MPO/H2O2, and the oxidation of 3-OH-CBZ was much faster than the oxidation of 2-OH-CBZ or CBZ itself. Oxidation by MPO formed dimers of 3-OH-CBZ and 4-OH-PHN and, in the presence of N-acetyltyrosine, cross dimers were formed. This strongly suggests free radical intermediates. Bioactivation of 3-OH-CBZ and 4-OH-PHN by MPO/H2O2 led to covalent binding to the tyrosine of a model protein. Free radicals usually generate reactive oxygen species (ROS). We also tested the ability of these metabolites to generate ROS and found that 3-OH-CBZ generated more ROS than 2-OH-CBZ, which was, in turn, greater than that generated by CBZ. These results suggest that bioactivation of 3-OH-CBZ and 4-OH-PHN to free radicals by peroxidases may play a role in the ability of these drugs to cause idiosyncratic drug reactions.
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PMID:Peroxidase-mediated bioactivation of hydroxylated metabolites of carbamazepine and phenytoin. 1846 99

The mitis group, a member of the genetically diverse viridans group streptococci, predominately colonizes the human oropharynx. This group has been shown to cause a wide range of infectious complications in humans, including bacteremia in patients with neutropenia, orbital cellulitis and infective endocarditis. Hydrogen peroxide (H2O2) has been identified as a virulence factor produced by this group of streptococci. More importantly, it has been shown that Streptococcus oralis and S. mitis induce epithelial cell and macrophage death via the production of H2O2. Previously, H2O2 mediated killing was observed in the nematode Caenorhabditis elegans in response to S. oralis and S. mitis. The genetically tractable model organism C. elegans is an excellent system to study mechanisms of pathogenicity and stress responses. Using this model, we observed rapid H2O2 mediated killing of the worms by S. gordonii in addition to S. mitis and S. oralis. Furthermore, we observed colonization of the intestine of the worms when exposed to S. gordonii suggesting the involvement of an infection-like process. In response to the H2O2 produced by the mitis group, we demonstrate the oxidative stress response is activated in the worms. The oxidative stress response transcription factor SKN-1 is required for the survival of the worms and provides protection against H2O2 produced by S. gordonii. We show during infection, H2O2 is required for the activation of SKN-1 and is mediated via the p38-MAPK pathway. The activation of the p38 signaling pathway in the presence of S. gordonii is not mediated by the endoplasmic reticulum (ER) transmembrane protein kinase IRE-1. However, IRE-1 is required for the survival of worms in response to S. gordonii. These finding suggests a parallel pathway senses H2O2 produced by the mitis group and activates the phosphorylation of p38. Additionally, the unfolded protein response plays an important role during infection.
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PMID:The activation of the oxidative stress response transcription factor SKN-1 in Caenorhabditis elegans by mitis group streptococci. 3011 61


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