Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increasing evidence indicates that T cell-dependent, interferon gamma (IFN gamma)-induced activation of murine macrophages and nitric oxide (NO) production plays an important role in host defenses against many microorganisms. A role for this mechanism in pulmonary defenses against infectious agents has not been examined. Previous studies demonstrated that both CD4 and CD8 T cells were required for lung clearance of encapsulated Cryptococcus neoformans (Cne). The current studies investigated whether IFN gamma-induced NO production was involved in the protective T cell-mediated immune response against Cne. Intratracheal inoculation of a low-virulence strain of Cne into mice resulted in an infection that was progressively cleared in immunocompetent C.B-17, but not severe combined immunodeficient (SCID) mice. The onset of Cne lung clearance in immunocompetent mice coincided with a marked increase in inflammatory cells in the lung, local expression of IFN gamma-inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and an increase in systemic NO production as measured by urinary nitrate excretion. None of these changes were observed in infected SCID mice. Inflammatory lung cells isolated from Cne-infected C.B-17 mice inhibited the growth of endogenous Cne in vitro by a NO-dependent mechanism. Moreover, lung clearance of Cne in immunocompetent mice was blocked by treatment with (1) antibody to IFN gamma, which blocked iNOS gene expression and NO production, or (2) the arginine analogue, NGmonomethyl-L-arginine (MMA), which only blocked NO production. However, neither anti-IFN gamma nor MMA treatment decreased the numbers or types of recruited inflammatory cells. Thus, these studies demonstrated that, although recruitment of effector cells was required, it was not sufficient to initiate clearance of Cne from the lung. Rather, an IFN gamma-induced effector mechanism, i.e., NO production, was also required.
Am J Respir Cell Mol Biol 1995 Jul
PMID:A role for gamma interferon-induced nitric oxide in pulmonary clearance of Cryptococcus neoformans. 759 35

Induction of nitric oxide synthase (iNOS) and nitric oxide (NO) production have been demonstrated using three macrophage cell lines from different anatomical sites, which had been immortalized using a rapid and convenient procedure previously described. Lysis of tumor cells presumably was caused by NO accumulation in the supernatants of cultures of the three cell lines after induction with a mixture of recombinant murine interferon gamma (rMuIFNgamma) and lipopolysaccharide (LPS). Induction by these two biological response modifiers (BRM) caused lysis of tumor cells and was repressed by addition of 1 microM (final concentration) of methyl-L-arginine (MMA) to the mixture during induction of the enzyme. Research using readily generated macrophage cell lines may facilitate clarify basic aspects of iNOS induction in these cells.
Cell Mol Biol (Noisy-le-grand) 1998 May
PMID:Nitric oxide synthase induction in lines of macrophages from different anatomical sites. 962 Apr 50

We describe the association between structural chromosome aberrations (CAs) and parameters of exposure to arsenic among 42 individuals exposed to arsenic through well waters in Finland. The median concentration of arsenic in the wells was 410 microg/l, the total arsenic concentrations in urine (As-tot) was 180 microg/l, and in hair 1.3 microg/g, for current users (n = 32) of contaminated wells. Urinary arsenic species and CAs were also analyzed in eight control individuals from the same village who consumed water which contained arsenic <1.0 microg/l (detection limit). Increased arsenic exposure, indicated best by increased concentrations of arsenic species (inorganic arsenic, methylarsonic acid (MMA), dimethylarsinic acid (DMA)) in urine, was associated with increased frequency of CAs. The increased urinary ratio of MMA/As-tot and the decreased ratio of DMA/As-tot were associated with increased CAs when all aberration types, including gaps, were considered. Associations between CAs and arsenic exposure indicators were stronger among current users than among persons who had stopped using the contaminated well water for 2-4 months before sampling (ex-users, n = 10). Furthermore, there was a positive but not statistically significant association between CAs and arsenic in hair among the current users, but not among the ex-users, who still had relatively high arsenic concentrations in hair. The results suggest that the effect observed in the present study reflects relatively recent arsenic exposure.
Environ Mol Mutagen 1998
PMID:Association between the clastogenic effect in peripheral lymphocytes and human exposure to arsenic through drinking water. 988 4

To clarify the possible link between radicals and cytotoxicity of eugenol-related compounds, dimeric compounds were synthesized from eugenol (4-allyl-2-methoxy-phenol), butylated hydroxyanisole (BHA) (2-t-butyl-4-methoxyphenol) or MMP (2 methoxy-4-methylphenol); bis-EUG (3,3'-dimethoxy-5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol), bis-BHA (3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diol), and bis-MMP (3,3'-di-methoxy-5,5'-dimethyl-1,1'-biphenyl-2,2'-diol). The cytotoxic activity of these compounds was determined using a salivary gland tumor cell line (HSG), oral squamous cell carcinoma cell line (HSC-2) and human promyelocytic leukemia cell line (HL-60). A parabolic relationship between the cytotoxicity and log P (the octanol-water partition coefficient) was observed, showing that both BHA and bis-MMP, with a log P of 3-4, were the most cytotoxic. The cytotoxic activity of the 2-methoxy derivatives, eugenol, MMP and bis-MMP, against HSG cells was significantly enhanced by visible-light irradiation, possibly due to their high redox potential. Electron spin resonance (ESR) spectroscopy indicated that eugenol and BHA alone produced radicals under alkaline conditions (pH > 9.5), and eugenol most efficiently scavenges reactive oxygen species (O2-). Antioxidative reactivity of eugenol-related compounds was determined by measuring the inhibiting periods of the AIBN (2,2'-azobisisobutyronitrile)/MMA (methyl methacrylate) polymerization system, and the number of moles of peroxy radical trapped by moles of the relevant phenols (stoichiometric factor, n). It was found that the n values of eugenol and MMP were approximately 1, whereas those of BHA >2, suggesting that eugenol and MMP undergo dimerization through radical-radical couplings through quinone methides, whereas BHA undergoes the competitive interaction with poly-MMA radicals after oxidation by AIBN-peroxy radicals. BHA was an efficient peroxy radical-scavenger, but possibly reacted with polymer radicals of the lipid, thus mediating the cytotoxicity. The n value of bis-BHA was two, whereas those of bis-EUG and bis-MMP were 1.6-1.7, suggesting that the latter were further oxidized. The enthalpies of phenoxyl radical formation were determined using the semi-empirical PM3 quantum-mechanical method and the possible link to redox potential was discussed.
In Vitr Mol Toxicol 2000
PMID:Radical generation, radical-scavenging activity, and cytotoxicity of eugenol-related compounds. 1131 78

Lyophilization is frequently used to increase the shelf-life of biopharmaceuticals containing antibodies. A case in which an anti-idiotypic antibody, MMA 383, substantially lost its in vivo immunogenic properties although the protein was not degraded, is investigated. The scanning transmission electron microscope allowed the MMA 383 Fab and Fc moieties to be resolved. By averaging the single antibodies, the angle between the Fab moieties can be calculated. Non-lyophilized antibodies displayed a wider range of shapes than their reconstituted, lyophilized counterparts. Accordingly, the angle between the two Fab fragments varied more, indicating greater flexibility. The tryptophan steady-state fluorescence intensity, steady-state fluorescence anisotropy and fluorescence lifetime, were smaller for the lyophilized antibodies. These were also more resistant towards thermal denaturation/aggregation. Circular dichroism spectra detected temperature-dependent differences between the two antibody types in the 236 nm region. The subtle but reproducible structural changes induced by lyophilization may be related to the loss of in vivo immunogenic properties.
J Mol Biol 2001 Jun 29
PMID:Modulation of antigenicity related to changes in antibody flexibility upon lyophilization. 1141 44

A detailed careful analysis of the infrared resonance (IR) spectra of polystyrene (PSt), polymethyl methacrylate (PMMA), polyacrylonitrile (PAN) and their co-mixtures were performed. Through this study the absorption peak area to weight ratios as well as working curves were obtained to test for their reliability as well as their suitability. Satisfactory results were achieved and these working curves were then used to measure the polymerized components of binary and ternary co-polymers. By investigating the acquired data we conclude that the monomer preferential polymeric sequence is St > MMA > AN. A quantitative method to measure P (St/AN/MMA) concentrations by IR spectroscopy is proposed in this work.
Spectrochim Acta A Mol Biomol Spectrosc 2002 Feb
PMID:Quantitative analysis of (styrene/acrylonitrile/methyl methacrylate) co-polymer systems by infrared resonance spectroscopy. 1190 38

Arsenic is a natural drinking water contaminant that impacts the health of large populations of people throughout the world; however, the mode or mechanism by which arsenic induces cancer is unclear. In a series of in vitro studies, we exposed leukocytes from humans, mice, rats, and guinea pigs to a range of sodium arsenite concentrations to determine whether the lymphocytes from these species showed differential sensitivity to the induction of micronuclei (MN) assessed in cytochalasin B-induced binucleate cells. We also determined the capacity of the leukocytes to methylate arsenic by measuring the production of MMA [monomethylarsinic acid (MMA(V)) and monomethylarsonous acid (MMA(III))] and DMA [dimethylarsinic acid (DMA(V)) and dimethylarsonous acid (DMA(III))]. The results indicate that cells treated for 2 hr at the G(0) stage of the cell cycle with sodium arsenite showed only very small to negligible increases in MN after mitogenic stimulation. Treatment of actively cycling cells produced induction of MN with increasing arsenite concentration, with the human, rat, and mouse lymphocytes being much more sensitive to MN induction than those of the guinea pig. These data gave an excellent fit to a linear model. The leukocytes of all four species, including the guinea pig (a species previously thought not to methylate arsenic), were able to methylate arsenic, but there was no clear correlation between the ability to methylate arsenic and the induction of MN.
Environ Mol Mutagen 2002
PMID:Induction of genotoxic damage is not correlated with the ability to methylate arsenite in vitro in the leukocytes of four mammalian species. 1211 84

Arsenite is a human multisite carcinogen, but its mechanism of action is not known. We recently found that extremely low concentrations (</=0.1 microM) of arsenite transform human osteosarcoma TE85 (HOS) cells to anchorage-independence. In contrast to other carcinogens which transform these cells within days of exposure, almost 8 weeks of arsenite exposure are required for transformation. We decided to reexamine the question of arsenite mutagenicity using chronic exposure in a spontaneous mutagenesis assay we previously developed. Arsenite was able to cause a delayed increase in mutagenesis at extremely low concentrations (</=0.1 microM) in a dose-dependent manner. The increase in mutant frequency occurred after almost 20 generations of growth in arsenite. Transformation required more than 30 generations of continuous exposure. We also found that arsenite induced gene amplification of the dihydrofolate reductase (DHFR) gene in a dose-dependent manner. Since HOS cells are able to methylate arsenite at a very low rate, it was possible that active metabolites such as monomethylarsonous acid (MMA(III)) contributed to the delayed mutagenesis and transformation in these cells. However, when the assay was repeated with MMA(III), we found no significant increase in mutagenesis or transformation, suggesting that arsenite-induced delayed mutagenesis and transformation are not caused by arsenite's metabolites, but by arsenite itself. Our results suggest that long-term exposure to low concentrations of arsenite may affect signaling pathways that result in a progressive genomic instability.
Environ Mol Mutagen 2003
PMID:Arsenite induces delayed mutagenesis and transformation in human osteosarcoma cells at extremely low concentrations. 1280 2

Arsenic is a prevalent human carcinogen whose mutagenicity has not been characterized fully. Exposure to either form of inorganic arsenic, As(III) or As(V), can result in the formation of at least four organic metabolites: monomethylarsonic acid, monomethylarsonous acid (MMA(III)), dimethylarsinic acid, and dimethylarsinous acid (DMA(III)). The methylated trivalent species, as well as some of the other species, have not been evaluated previously for the induction of chromosome aberrations, sister chromatid exchanges (SCE), or toxicity in cultured human peripheral blood lymphocytes; for mutagenicity in L5178Y/Tk(+/-) mouse lymphoma cells or in the Salmonella reversion assay; or for prophage-induction in Escherichia coli. Here we evaluated the arsenicals in these assays and found that MMA(III) and DMA(III) were the most potent clastogens of the six arsenicals in human lymphocytes and the most potent mutagens of the six arsenicals at the Tk(+/-) locus in mouse lymphoma cells. The dimethylated arsenicals were also spindle poisons, suggesting that they may be ultimate forms of arsenic that induce aneuploidy. Although the arsenicals were potent clastogens, none were potent SCE inducers, similar to clastogens that act via reactive oxygen species. None of the six arsenicals were gene mutagens in Salmonella TA98, TA100, or TA104; and neither MMA(III) nor DMA(III) induced prophage. Our results show that both methylated As(V) compounds were less cytotoxic and genotoxic than As(V), whereas both methylated As(III) compounds were more cytotoxic and genotoxic than As(III). Our data support the view that MMA(III) and DMA(III) are candidate ultimate genotoxic forms of arsenic and that they are clastogens and not gene mutagens. We suggest that the clastogenicity of the other arsenicals is due to their metabolism by cells to MMA(III) or DMA(III).
Environ Mol Mutagen 2003
PMID:Methylated trivalent arsenicals as candidate ultimate genotoxic forms of arsenic: induction of chromosomal mutations but not gene mutations. 1455 26

Vitamin B12 (cobalamin) is an essential cofactor for two enzymes: methionine synthase (MS), which requires methylcobalamin (MeCbl), and methylmalonyl-CoA mutase (MUT), which requires adenosylcobalamin (AdoCbl). A number of individually rare inborn errors of cobalamin metabolism are known and are distinguished by complementation analysis (mut, cblA-cblH). From 1984 to 2005, we have performed prenatal diagnosis for 117 high-risk pregnancies. We identified a total of 21 affected pregnancies (18%): cblA, 2/8; cblB, 0/5; cblC, 10/52; cblE, 2/3; cblF, 0/5; cblG, 0/5; transcobalamin deficiency, 0/2; methylmalonyl-CoA mutase (mut) deficiency, 7/30; and unclassified MMA, 0/7. Studies were performed on amniotic fluid, cultured chorionic villus cells (CCVC), cultured amniocytes (CA), or various combinations of these three types of sample. Analyses done include propionate and methyltetrahydrofolate incorporation into protein and cobalamin cofactor levels (CA: 92%, CCVC: 18%), amniotic fluid metabolite measurement either by gas chromatography/mass spectrometry (GC/MS) or by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (49%), and direct mutation analysis (5%). There was one false negative CCVC result in a pregnancy at risk for cblC and one false positive CCVC in a pregnancy at risk for mutase deficiency. One unaffected pregnancy at risk for an unclassified form of MMA and another unaffected pregnancy at risk for cblC, had higher than control MMA amniotic fluid levels. Our experience suggests that prenatal diagnosis for these disorders should be done by application of two independent methods, and that CA studies appear more reliable than CCVC studies.
Mol Genet Metab
PMID:Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B12 metabolism and transport. 1615 Jun 26


1 2 3 4 Next >>