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PubMed2001

Biological stereoselective reduction of 3,3,5-trimethylcyclohexanone by Glomerella cingulata.

The microbial transformation of 3,3,5-trimethylcyclohexanone was investigated using the plant pathogenic fungus, Glomerella cingulata. With this organism 3,3,5-trimethylcyclohexanone gave the corresponding cis- and trans-3,3,5-trimethylcyclohexanols with the ratio of 20:1 forming the cis-isomer highly stereoselectively, upon 5 days incubation together with 3,3,5-trimethyl-2-cyclohexen-1-one (isophrone) as a minor product.

Ascomycota↗
PubMed2001

Evidence for an essential arginine in the flavoprotein nitroalkane oxidase.

The flavoprotein nitroalkane oxidase from the fungus Fusarium oxysporum catalyzes the oxidative denitrification of primary or secondary nitroalkanes to yield the respective aldehydes or ketones, hydrogen peroxide and nitrite. The enzyme is inactivated in a time-dependent fashion upon treatment with the arginine-directed reagents phenylglyoxal, 2,3-butanedione, and cyclohexanedione. The inactivation shows first order kinetics with all reagents. Valerate, a competitive inhibitor of the enzyme, fully protects the enzyme from inactivation, indicating that modification is active site directed. The most rapid inactivation is seen with phenylglyoxal, with a k(inact) of 14.3 +/- 1.1 M(-1) min(-1) in phosphate buffer at pH 7.3 and 30 degrees C. The lack of increase in the enzymatic activity of the phenylglyoxal-inactivated enzyme after removing the unreacted reagent by gel filtration is consistent with inactivation being due to covalent modification of the enzyme. A possible role for an active site arginine in substrate binding is discussed.

Arginine↗
PubMed2004

Cytotoxic and topographical properties of 6-arylidene-2-dimethylaminomethylcyclohexanone hydrochlorides and related compounds.

A number of 2-arylidenecyclohexanones (1a-h) were converted into the corresponding Mannich bases (2a-h) and (3a,f). Evaluation against murine L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes revealed the marked cytotoxicity of the Mannich bases and also the fact that almost invariably these compounds were more potent than the precursor enones (1a-h). Further evaluation of most of the Mannich bases towards a panel of nearly 60 human tumour cell lines confirmed their utility as potent cytotoxins. In this assay, the compounds showed growth-inhibiting properties greater than the anticancer alkylator melphalan. QSAR studies revealed that in some cell lines compounds possessing small electron-attracting aryl substituents showed the greatest potencies. Molecular modeling and X-ray crystallography demonstrated that various interatomic distances and torsion angles correlated with cytotoxicity. A representative compound (2a) demonstrated weak inhibiting properties towards human N-myristoyltransferase and stimulated a tyrosine protein kinase. A single dose of 100 mg/kg of most of the compounds did not prove to be lethal in mice.

Acyltransferases↗
PubMedDate not supplied

Early life stage toxicity tests with a saltwater fish: effects of eight chemicals on survival growth, and development of sheepshead minnows (Cyprinodon variegatus).

Flow-through, acute (96-h), and early life stage (28-d after hatch) toxicity tests were performed with eight chemical on a saltwater fish, sheepshead minnows (Cyprinodon variegatus). Chemical effects on survival, growth, and development were determined. Maximum acceptable toxicant concentrations (MATCs) were greater than 3.2 less than 7.7 mg/l for toluene, greater than 0.52 greater than 0.97 mg/l for acenaphthene, greater than 80 less than 156 mg/l for isophorone, greater than 10 less than 16 mg/l for 4-nitrophenol, greater than 4.8 less than 8.5 mg/l for bromoform, greater than 0.39 less than 0.79 mg/l for 1-chloronaphthalene, greater than 0.09 less than 0.18 mg/l for 1, 2, 4, 5-tetrachlorobenzene, and less than 0.36 mg/l for 2, 4-dichloro-6-methylphenol; application factors were 0.25-0.59, 0.17-0.31, greater than or equal to 0.57, 0.31-0.50, greater than or equal to 0.68, greater than or equal to 0.56, 0.27-0.54, and less than 0.10. respectively. Test results reported here were compared with results of static, acute toxicity tests conducted previously with six species of aquatic organisms and the same chemicals.

Acenaphthenes↗
PubMed1990

Effects of selected chemicals on the glutathione status in the male reproductive system of rats.

Previous studies have suggested a significant role for reproductive tract glutathione in protecting against chemical-induced germ-cell mutations. Therefore, a number of compounds were tested for their ability to perturb glutathione levels in the testes and epididymides as well as liver following single acute dosages to rats. Phorone (250 mg/kg), isophorone (500 mg/kg), and diethyl maleate (500 mg/kg) significantly reduced glutathione in the liver and in both reproductive organs examined. Methyl iodide (100 mg/kg), trimethyl phosphate (600 mg/kg), naphthalene (500 mg/kg), acetaminophen (1500 mg/kg), and pentachlorophenol (25 mg/kg) affected hepatic and epididymal glutathione, but had little or no effect on testicular levels. The ability of isophorone to enhance the covalent binding of tritiated ethyl methanesulfonate (3H-EMS) to spermatocytes was assessed. Perturbation of reproductive tract glutathione by isophorone treatment significantly enhanced the extent of 3H-EMS-induced binding to sperm heads. The temporal pattern of ethylations in sperm heads was consistent with the stage of sperm development known to be susceptible to ethylations by EMS. Therefore, chemical-induced lowering of glutathione in the male reproductive tract may be a mechanism for potentiation of chemical-induced germ-cell mutations.

Animals↗
PubMed2001

Inhalation toxicity studies of the alpha,beta-unsaturated ketones: 2-cyclohexene-1-one.

2-Cyclohexene-1-one (CHX) is a cyclic alpha,beta-unsaturated ketone with broad human exposure. CHX is an environmental pollutant and is present in tobacco smoke and in soft drinks sweetened with cyclamate. Interest in the toxicity of this class of compounds is due to their structural similarity to the cytotoxin acrolein. In a pilot study, rats and mice were exposed to 0, 20, 40, or 80 ppm CHX for 6 h/day. The study was terminated after 4 days due to acute toxicity in the high-dose groups. In a subsequent 14-day study, mice and rats were exposed to 0, 2.5, 5, or 10 ppm CHX for 6 h/day. All animals survived exposure until terminal sacrifice. Body weights were not significantly different from controls after 14 days of exposure. Liver/body weights were increased in male and female mice exposed to 5 and 10 ppm, and in male and female rats exposed to 10 ppm CHX. Ninety-day toxicity studies were conducted to provide data required to design chronic toxicity and carcinogenicity studies of CHX if it is determined such studies are necessary. Groups of 10 male and female F-344 rats and B6C3F1 mice were exposed to 0, 2.5, 5, or 10 ppm CHX for 6 h/day for 13 wk. All animals survived until sacrifice. Body weights were not significantly different from controls after 13 wk of exposure. Liver weights were increased in male and female mice exposed to 5 and 10 ppm and in male and female rats exposed to 10 ppm CHX. No adverse effects on bone-marrow micronuclei, sperm motility, or vaginal cytology were observed. Microscopic lesions included hyperplasia, and squamous metaplasia in the nasal cavity in rats and mice of both sexes at all doses. Nasal-cavity erosion and suppurative inflammation also occurred in high-dose mice. Larynx and lung were not affected in either sex or species. Dose-related hepatic centrilobular cytoplasmic vacuolation was seen in male rats only. These data suggest that CHX acts as an alkylating agent primarily producing toxicity at the exposure site.

Administration, Inhalation↗
PubMed1999

N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression.

E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent, homotypic cell-cell adhesion and plays a role in maintaining the normal phenotype of epithelial cells. Decreased expression of E-cadherin has been correlated with increased invasiveness of breast cancer. In other systems, inappropriate expression of a nonepithelial cadherin, such as N-cadherin, by an epithelial cell has been shown to downregulate E-cadherin expression and to contribute to a scattered phenotype. In this study, we explored the possibility that expression of nonepithelial cadherins may be correlated with increased motility and invasion in breast cancer cells. We show that N-cadherin promotes motility and invasion; that decreased expression of E-cadherin does not necessarily correlate with motility or invasion; that N-cadherin expression correlates both with invasion and motility, and likely plays a direct role in promoting motility; that forced expression of E-cadherin in invasive, N-cadherin-positive cells does not reduce their motility or invasive capacity; that forced expression of N-cadherin in noninvasive, E-cadherin-positive cells produces an invasive cell, even though these cells continue to express high levels of E-cadherin; that N-cadherin-dependent motility may be mediated by FGF receptor signaling; and that cadherin-11 promotes epithelial cell motility in a manner similar to N-cadherin.

Blotting, Western↗
PubMed1982

Direct cytochemical localization of catalytic subunits dissociated from cAMP-dependent protein kinase in Reuber H-35 hepatoma cells. I. Development and validation of fluorescinated inhibitor.

A specific and sensitive procedure has been developed that reliably localizes intracellular sites of free catalytic unit (C) dissociated from cAMP-dependent protein kinase. The method is based on a FITC conjugate (F:PKI) of affinity column-purified heat-stable protein inhibitor (PKI) of free C. The fidelity of this cytochemical probe was determined using cultures of Reuber H-35 hepatoma cells that had been stimulated for 2 h with 0.1 mM DBcAMP, or with diluent, then fixed with anhydrous acetone at -30 degrees C. In these preparations the F:PKI probe complexed with free C in cytoplasm, nucleolus, and, to a minor extent, in nucleoplasm. Binding of the F:PKI molecule to free C was competitively diminished by arginine analogues, guanidinium HCI and polyarginine, each used over a 2-log dose range. When the inhibitor's arginine residues were blocked by reaction with cyclohexanedione it no longer inhibited phosphotransferase activity of free C, and when fluorescinated it failed to localize C in stimulated cells. Similarly, when F:PKI was preabsorbed with excess pure C it no longer functioned as a cytochemical stain. Affinity column-purified antibody to free C also reduced significantly the ability of F:PKI to complex with C in cell cultures stimulated with 0.1 mM DBcAMP. 1 microgram of antibody reduced by approximately 10% the binding of F:PKI to all cell compartments while 5 microgram of antibody diminished binding by greater than 50%. Together, these results indicate that the F:PKI binds specifically, perhaps exclusively, to the catalytic units of cAMP-dependent protein kinase. The cytochemical procedure, unlike its biochemical counterparts, is able to locate the dissociation of cAMP-dependent protein kinase in individual cells of functionally or histologically complex cultures. Also, it reveals variations in the time- and dose-dependent activation of the kinase amongst clonal cells stimulated with cyclic nucleotide analogues or hormones.

Animals↗
PubMed1998

NTBC and alkaptonuria.

Explore the source record for details and available documents.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1998

Ex vivo hepatic gene therapy of a mouse model of Hereditary Tyrosinemia Type I.

Previously, this lab has reported the use of hepatocyte transplantation and in vivo gene therapy for the correction of a mouse model of Hereditary Tyrosinemia Type I (HT1). Here, we demonstrate repopulation of fumarylacetoacetate hydrolase (FAH)-deficient livers with cultured hepatocytes. Correction of the disease phenotype was achieved by retrovirally transducing cultured FAH- hepatocytes ex vivo, followed by transplantation and selective repopulation. Treated mice were phenotypically normal and had corrected plasma amino acid levels and liver function tests. Our results demonstrate that efficient hepatic repopulation using ex vivo genetically manipulated hepatocytes is feasible.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

In vivo antitumor activity of the NF-kappaB inhibitor dehydroxymethylepoxyquinomicin in a mouse model of adult T-cell leukemia.

Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type I (HTLV-I). The nuclear transcription factor, NF-kappaB, is induced by HTLV-I and is central to the ensuing neoplasia. To examine the effect of a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on ATL in vivo, we developed an improved severe combined immunodeficiency (SCID) mouse model for ATL. Five-week-old SCID mice in which natural killer (NK) cell activity had been eliminated were inoculated intraperitoneally with the HTLV-I-infected cell lines, TL-Om1, MT-1, MT-2 and HUT-102. No engraftment of TL-Om1 cells and little tumorigenesis of MT-1 cells were detected 40 days after injection. In contrast, inoculation of mice with MT-2 and HUT-102 cells elicited high mortality, 100% frequency of gross tumor formation and tumor cell infiltration of various organs, all of which were reduced by coadministration of DHMEQ during the inoculation. Moreover, tumors from mice treated with DHMEQ had a high frequency of apoptosis. These results suggest that DHMEQ induces apoptosis in HTLV-I-transformed cells in vivo, resulting in inhibition of tumor formation and organ infiltration, thereby enhancing survival.

Animals↗
PubMed1996

The role of perceptual and structural similarity in cross-adaptation.

Cross-adaptation, the decrease in sensitivity to one odorant following exposure to a different odorant, is affected by odorant similarity, both perceptual and structural, but the precise relationship is obscure. The present series of studies was designed to explore various aspects of perceptual and structural similarity as they relate to cross-adaptation. In Experiment 1, cross-adaptation was assessed between androstenone and five odorants that share a common urinous note with androstenone, but retain unique perceptual characteristics; only the compound judged most perceptually similar to androstenone cross-adapted it. In Experiment 2, odorants both perceptually and structurally similar (androstenone and androstanone) displayed significant, mutual cross-adaptation. Furthermore, magnitude estimates for androstanone were significantly reduced following exposure to 3-methylidene-5 alpha-androstane (3M5A), a structurally similar, perceptually odorless compound. This finding appears to be the first demonstration that an odorless compound can affect, via cross-adaptation, the perception of an odorous compound. Finally, in Experiment 3, significant, asymmetric cross-adaptation was observed between compounds that are perceptually and structurally dissimilar (4-cyclohexylcyclohexanone [4-CHCH] and androstenone). These findings indicate that the role of similarity in cross-adaptation is difficult to quantify and emphasize the numerous odorant characteristics that can affect cross-adaptation.

Adaptation, Physiological↗
PubMed1998

Antimicrobial activity of the semisynthetic compound, hexahydrocolupulone.

In this study we demonstrate that hexahydrocolupulone (HHC) more effectively inhibits the growth in vitro of Gram-positive organisms than Mycobacterium tuberculosis or Escherichia coli. Vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and coagulase-negative staphylococci were inhibited by HHC at concentrations < or = 4.06 mg/L. Growth inhibition profiles varied according to the microorganism evaluated (static for S. aureus and bactericidal for Bacillus subtilis).

Anti-Bacterial Agents↗
PubMed2004

Antimicrobial activity of clofazimine is not dependent on mycobacterial C-type phospholipases.

We have used a phospholipase C (PLC)-deletion mutant (plcABC) of the H37Rv strain of Mycobacterium tuberculosis (MTB), as well as a plcA-insertion mutant of Mycobacterium smegmatis, to investigate the possible involvement of PLCs in clofazimine-mediated inhibition of mycobacterial K(+) transport and growth. Inactivation of the PLCs of MTB and insertion of the plcA gene into M. smegmatis resulted in a substantial reduction and increase in hydrolysis of phosphatidylcholine (PC), respectively. However, both the mutant and wild-type strains of MTB and M. smegmatis were equally sensitive to the inhibitory effects of clofazimine on K(+) uptake and growth. These observations demonstrate that the PLCs of MTB are not involved in the antimicrobial activity of clofazimine.

Anti-Infective Agents↗
PubMed2006

Sethoxydim affects lipid synthesis and acetyl-CoA carboxylase activity in soybean.

With rare exceptions, dicot plastids have been reported to contain only a multisubunit (prokaryotic) form of acetyl-coA carboxylase (ACCase), the first committed step of lipid biosynthesis. The sensitivity of most monocots to cyclohexanediones (CHDs) such as sethoxydim, has been shown to be associated with the presence in their plastids of a multifunctional (eukaryotic) form of ACCase. Little is known about the effects of sethoxydim on lipid metabolism and ACCase activity in dicots. Here it is shown that foliar lipid biosynthesis is differentially affected by the herbicide treatment in two dicot species, Nicotiana sylvestris (wild tobacco) and Glycine max (soybean). In N. sylvestris, the total lipid content of neoformed leaves harvested 2 weeks after the sethoxydim treatment was unaffected by doses of up to 10(-3) M sethoxydim. In soybean, lipid content decreased by 45% when 10(-5) M sethoxydim was used, and this was associated with a 30% reduction in fatty acid synthesis activity. ACCase activity of soybean plastidial preparations was 60% reduced in the presence of sethoxydim, whereas that of N. sylvestris was unaffected. Finally, the presence of a biotinylated 220 kDa polypeptide, corresponding in size to multifunctional ACCase, was observed in soybean plastids. Possible relationships between sensitivity of plastidial soybean ACCase towards sethoxydim, plastidial protein content, and altered de novo lipid biosynthesis in herbicide-treated plants are discussed.

Acetyl-CoA Carboxylase↗
PubMed2003

Alpha,beta-unsaturated carbonyl compounds: induction of oxidative DNA damage in mammalian cells.

Alpha,beta-unsaturated carbonyl compounds occur in food and other environmental media. Due to their reactivity with cellular nucleophiles (e.g. Michael adduct formation with DNA bases and with glutathione) they might represent a potential health risk. In this study, induction of oxidative DNA damage was investigated in mammalian cells, as a consequence of glutathione depletion induced by selected food relevant 2-alkenals, including E-(2)-hexenal (HEX), (2E,4E)-2,4-hexadienal (HEXDI) and (E)-2-cinnamaldehyde (CA) and the cyclic analogue 2-cyclohexen-1-one (CHX). Oxidative DNA breakage was monitored with the Comet assay, using treatment with formamidopyrimidine-DNA glycosylase (FPG). Total cellular glutathione (tGSH) was determined in a kinetic, photometric assay. After 1 h incubation of V79 cells with HEX (100 microM) and CHX (300 microM), HEXDI and CA (300 microM each), tGSH was depleted down to <20% of control (viability >85%). Under these conditions, FPG-sensitive sites were not observed; moderate direct DNA breakage, however, was detectable. During 3 h post-incubation (without test compound) distinct oxidative DNA breakage occurred in HEX- and CA-, but not in CHX- and HEXDI-pretreated cells. Direct DNA breakage was markedly diminished, most probably by repair processes, and tGSH concentrations were observed to increase again within 3 h post-treatment. The results give strong evidence for alkenal-mediated oxidative stress contributing to cytotoxic/genotoxic cell damage. The extent of oxidative stress appears to be influenced by structure-specific properties of the alkenals.

Acrolein↗
PubMed1996

Importance of the phospholipase D-initiated sequential pathway for arachidonic acid release and prostaglandin D2 generation by rat peritoneal mast cells.

The association of prostaglandin D2 (PGD2) production as well as arachidonic acid release with the phospholipase D (PLD)-linked mechanism was studied in rat peritoneal mast cells. Stimulation of mast cells with cross-linking of the high-affinity Fc receptor for IgE caused increases in the release of arachidonic acid and PGD2, which are suppressed almost completely by ethanol or RHC 80267, a diacylglycerol lipase inhibitor. Ethanol did not influence inositol phosphate release in response to an antigen. An increase in diacylglycerol, that is inhibited by propranolol, was observed, with a peak within 1 min. Antigen stimulation induced little production of lysophosphatidylcholine, while ionomycin as a control markedly induced the production. However, the phospholipase A2 (PLA2) activity in the cytosol of antigen-stimulated cells increased to the level in ionomycin-stimulated cells. The addition of the ADP-ribosylation factor-containing fraction prepared from bovine brain, that is known to specifically activate PLD, to permeabilized mast cells in the presence of GTP gamma S, apparently increased arachidonic acid and PGD2 release, but not in the presence of ethanol. Furthermore, arachidonic acid release by an antigen was enhanced by melittin, that activates PLA2, but PGD2 production was not. These results suggest that antigen-stimulated PGD2 production as well as arachidonic acid release are strongly associated with the sequential PLD-linked pathway.

ADP-Ribosylation Factors↗