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Biomedical subjects

S Abel

Publications and source records attributed to S Abel.

At least 37 records · Page 2Linked to original sources
PubMed2000

Functional detection of chemopreventive glucosinolates in Arabidopsis thaliana.

Natural isothiocyanates, derived from glucosinolates by myrosinase-catalyzed hydrolysis, are potent chemopreventive agents that favorably modify carcinogen metabolism in mammals by inhibiting metabolic activation of carcinogens and/or by inducing carcinogen-detoxifying enzymes. Methylsulfinylalkyl isothiocyanates are potent selective inducers of mammalian Phase 2 detoxification enzymes such as quinone reductase [NADP(H):quinone-acceptor oxidoreductase, EC 1.6.99.2]. Members of the Cruciferae family, including the model plant species Arabidopsis thaliana (L.) Heyhn, synthesize methylsulfinylalkyl glucosinolates. We have adapted a colorimetric bioassay for quinone reductase activity in Hepa 1c1c7 murine hepatoma cells as a versatile tool to rapidly monitor methylsulfinylalkyl glucosinolate content in A. thaliana leaf extracts. Using wild type plants and mutant plants defective in the synthesis of 4-methylsulfinylbutyl glucosinolate (glucoraphanin), we have demonstrated that A. thaliana (ecotype Columbia) is a rich source of Phase 2 enzyme inducers and that methylsulfinylalkyl glucosinolates, predominantly glucoraphanin, account for about 80% of the quinone reductase inducer potency of Columbia leaf extracts. We have optimized leaf extraction conditions and the quinone reductase bioassay to allow for screening of large numbers of plant extracts in a molecular genetic approach to dissecting glucosinolate biosynthesis in A. thaliana.

Journal Article↗
PubMed2000

[Dengue or acute retroviral syndrome?].

BACKGROUND: The diagnosis of primary HIV infection is a crucial element in the fight against the AIDS epidemic. Clinical manifestations associated with primary infection are nonspecific. Dengue is a possible differential diagnosis. CASE REPORT: A 15-year-old adolescent living in Martinique consulted for a syndrome suggestive of infectious mononucleosis. The annual dengue epidemic was at its acme at this time. Serum was positive for IgM and the diagnosis of dengue was retained. The diagnosis of recent HIV infection was made two months later (unprotected homosexual intercourse two weeks before onset of clinical signs). Retrospective analysis of the earlier samples at the time of the viral syndrome demonstrated that the patient actually had an acute retroviral syndrome. DISCUSSION: The clinical and biological manifestations of dengue and primary HIV infection are nonspecific and similar to those of infectious mononucleosis. Potential exposure to HIV and recent presence in endemic dengue regions (tropical areas in America, Asia and Africa) can provide helpful guidance for differential diagnosis.

Acute Disease↗
PubMed2000

Conditional identification of phosphate-starvation-response mutants in Arabidopsis thaliana.

Plants have evolved elaborate metabolic and developmental adaptations to low phosphorus availability. Biochemical responses to phosphate limitation include increased production and secretion of phosphate-acquisition proteins such as nucleases, acid phosphatases, and high-affinity phosphate transporters. However, the signal transduction pathways that sense phosphate availability and integrate the phosphate-starvation response in plants are unknown. We have devised a screen for conditional mutants in Arabidopsis thaliana (L.) Heynh. to dissect signaling of phosphate limitation. Our genetic screen is based on the facultative ability of wild-type Arabidopsis plants to metabolize exogenous DNA when inorganic phosphate is limiting. After screening 50,000 M2 seedlings, we isolated 22 confirmed mutant lines that showed severely impaired growth on medium containing DNA as the only source of phosphorus, but which recovered on medium containing soluble inorganic phosphate. Characterization of nine such mutant lines demonstrated an inability to utilize either DNA or RNA. One mutant line, psr1 (phosphate starvation response), had significantly reduced activities of phosphate-starvation-inducible isoforms of ribonuclease and acid phosphatase under phosphate-limiting conditions. The data suggest that a subset of the selected mutations impairs the expression of more than one phosphate-starvation-inducible enzyme required for utilization of exogenous nucleic acids, and may thus affect regulatory components of a Pi starvation response pathway in higher plants.

Arabidopsis↗
PubMed2000

Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide.

AIMS: The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. METHODS: Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 microg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1-2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. RESULTS: Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml-1 increase in plasma dofetilide concentration produced a 17-19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. CONCLUSIONS: These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2-receptor antagonist class effect but is specific to cimetidine. If therapy with an H2-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative.

Adult↗
PubMed2000

Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat, dog and human.

1. UK-224,671 is a sulphamide-containing NK2 antagonist with moderate lipophilicity and basicity. 2. The physicochemical properties of UK-224,671 are reflected in its pharmacokinetics following intravenous (i.v.) administration. The compound partitioned extensively into red blood cells in all species examined and the blood clearance was moderate to low with respect to liver blood flow and distribution into tissues was extensive. 3. UK-224,671 exhibited species differences in oral bioavailability. In dog, the compound exhibited moderate bioavailability (55%), whereas in rat and man oral bioavailability was < 10%. 4. In rat and dog, the major excreted form after i.v. administration was unchanged UK-224,671 in both urine and faeces. In addition, of three metabolites observed, the most abundant was the N-descyclopropylmethyl (UK-280,045). 5. The profile of radioactivity in rat following oral administration of [14C]-UK-224,671 was not consistent with a 10% absorbed compound with 40% of the dose present as metabolites. This suggests that the low bioavailability of UK-224,671 in rat is due to a combination of moderate intestinal permeability and extensive first-pass metabolism by the gut and does not result from poor gastrointestinal absorption per se.

Administration, Oral↗
PubMed2000

The effect of evening primrose oil on the radiation response and blood flow of mouse normal and tumour tissue.

PURPOSE: To investigate the effect of the oral administration of evening primrose oil on the radiation response and the blood flow of normal tissue and a tumour in BALB/c mice. METHODS AND MATERIALS: Aliquots of evening primrose oil were fed to BALB/c mice daily and the radiation response of the skin was assessed by the determination of ED50 values for the incidence of moist desquamation, using probit analysis. Tumour radiosensitivity was investigated by determining the growth delay caused by irradiation of a transplantable rhabdomyosarcoma. The 86RbCl uptake technique was used to determine the blood flow in normal foot and tumour tissue. The fatty-acid content of red blood cells, plasma and tumour tissue was measured using gas chromatography. RESULTS: Daily evening primrose oil dietary supplementation reduced the sensitivity of skin to radiation-induced moist desquamation and prevented the radiation-associated increase in blood flow that was observed in this tissue. No modification of tumour blood flow or of tumour sensitivity to radiation resulted from evening primrose oil supplementation of mice. Evening primrose oil supplementation resulted in changes in plasma levels of linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA). These changes were contingent on whether the mice had been irradiated or not. In red blood cells evening primrose oil supplementation increased the GLA level of unirradiated mice and the LA level at 20 days after irradiation. There were no changes in tumour fatty-acid levels as a result of evening primrose oil treatment. CONCLUSIONS: Daily evening primrose oil supplementation reduced the sensitivity of skin to radiation-induced moist desquamation but did not alter tumour sensitivity to radiation.

Administration, Oral↗
PubMed2000

Induction of an extracellular cyclic nucleotide phosphodiesterase as an accessory ribonucleolytic activity during phosphate starvation of cultured tomato cells.

During growth under conditions of phosphate limitation, suspension-cultured cells of tomato (Lycopersicon esculentum Mill.) secrete phosphodiesterase activity in a similar fashion to phosphate starvation-inducible ribonuclease (RNase LE), a cyclizing endoribonuclease that generates 2':3'-cyclic nucleoside monophosphates (NMP) as its major monomeric products (T. Nürnberger, S. Abel, W. Jost, K. Glund [1990] Plant Physiol 92: 970-976). Tomato extracellular phosphodiesterase was purified to homogeneity from the spent culture medium of phosphate-starved cells and was characterized as a cyclic nucleotide phosphodiesterase. The purified enzyme has a molecular mass of 70 kD, a pH optimum of 6.2, and an isoelectric point of 8.1. The phosphodiesterase preparation is free of any detectable deoxyribonuclease, ribonuclease, and nucleotidase activity. Tomato extracellular phosphodiesterase is insensitive to EDTA and hydrolyzes with no apparent base specificity 2':3'-cyclic NMP to 3'-NMP and the 3':5'-cyclic isomers to a mixture of 3'-NMP and 5'-NMP. Specific activities of the enzyme are 2-fold higher for 2':3'-cyclic NMP than for 3':5'-cyclic isomers. Analysis of monomeric products of sequential RNA hydrolysis with purified RNase LE, purified extracellular phosphodiesterase, and cleared -Pi culture medium as a source of 3'-nucleotidase activity indicates that cyclic nucleotide phosphodiesterase functions as an accessory ribonucleolytic activity that effectively hydrolyzes primary products of RNase LE to substrates for phosphate-starvation-inducible phosphomonoesterases. Biosynthetical labeling of cyclic nucleotide phopshodiesterase upon phosphate starvation suggests de novo synthesis and secretion of a set of nucleolytic enzymes for scavenging phosphate from extracellular RNA substrates.

Cells, Cultured↗
PubMed2000

Aux/IAA proteins are phosphorylated by phytochrome in vitro.

Auxin/indole-3-acetic acid (Aux/IAA) genes encode short-lived transcription factors that are induced as a primary response to the plant growth hormone IAA or auxin. Gain-of-function mutations in Arabidopsis genes, SHY2/IAA3, AXR3/IAA17, and AXR2/IAA7 cause pleiotropic phenotypes consistent with enhanced auxin responses, possibly by increasing Aux/IAA protein stability. Semidominant mutations shy2-1D, shy2-2, axr3-1, and axr2-1 induce ectopic light responses in dark-grown seedlings. Because genetic studies suggest that the shy2-1D and shy2-2 mutations bypass phytochrome requirement for certain aspects of photomorphogenesis, we tested whether SHY2/IAA3 and related Aux/IAA proteins interact directly with phytochrome and whether they are substrates for its protein kinase activity. Here we show that recombinant Aux/IAA proteins from Arabidopsis and pea (Pisum sativum) interact in vitro with recombinant phytochrome A from oat (Avena sativa). We further show that recombinant SHY2/IAA3, AXR3/IAA17, IAA1, IAA9, and Ps-IAA4 are phosphorylated by recombinant oat phytochrome A in vitro. Deletion analysis of Ps-IAA4 indicates that phytochrome A phosphorylation occurs on the N-terminal half of the protein. Metabolic labeling and immunoprecipitation studies with affinity-purified antibodies to IAA3 demonstrate increased in vivo steady-state levels of mutant IAA3 in shy2-2 plants and phosphorylation of the SHY2-2 protein in vivo. Phytochrome-dependent phosphorylation of Aux/IAA proteins is proposed to provide one molecular mechanism for integrating auxin and light signaling in plant development.

Arabidopsis↗
PubMed2000

Maori infant care practices: implications for health messages, infant care services and SIDS prevention in Maori communities.

This paper uses findings from the Maori section of a multiethnic infant care practices (ICP) study undertaken in Auckland, New Zealand/Aotearoa, in 1998. It aims to increase understanding of present day Maori infant care practices in order, firstly, to inform infant health message and service delivery to Maori and, secondly, to understand the context of practices that comprise modifiable risk factors for SIDS. Publicity about modifiable SIDS risk factors since the early 1990s brought about a significant reduction in the national SIDS rate but the Māori rate reduced more slowly and in 1998 was still three times that of non-Māori. The ICP study was a qualitative study that, for the Māori section, involved seven focus groups and a one-on-one interview comprising 26 caregivers of under 12 month old infants. This paper focuses on five selected areas explored within the ICP study: sources of support, customary practices, infant feeding, infant sleeping arrangements and smoking. It discusses both valued infant care norms and factors that inhibit changes known to reduce SIDS risk. It argues that valued practices need recognition in order to make messages effective. It also challenges the emphasis on individual behaviour change as the primary means to reduce SIDS risk and argues that there is a need to extend prevention strategies beyond simple behaviour change messages to include structural change to reduce 'non modifiable' risk factors.

Female↗
PubMed1999

Drug resistance mutations among HIV-1 strains from antiretroviral-naive patients in Martinique, French West Indies.

We report on the frequency of genetic mutations associated with drug resistance in antiretroviral treatment-naive patients from Martinique (French West Indies), where zidovudine (ZDV) has been available since 1987 and where combination therapy developed simultaneously with its use in continental France. Genotypic resistance was studied in plasma HIV RNA from samples collected between 1988 and 1998 from 70 antiretroviral-naive study subjects, half presenting with either primary infection or documented seroconversion. A line probe assay (LIPA) was used to detect substitutions on the reverse transcriptase (RT) codons 41, 69, 70, 74, 184, and 215. Direct sequencing was used to complete the data for RT codons which were uninterpretable by LIPA. Of these patients, 17 harbored mutated viruses with one or more mutations in the RT gene codons analyzed. ZDV resistance mutations T215Y/F, M41L, and K70R were found in 2, 5, and 12 individuals, respectively. Mutant strains L74V (didanosine [ddI] and dideoxycytidine [ddC]) were detected in 3 patients and M184V (lamivudine/ddI/ddC) in 4 patients. However, pure mutant results at one or more codons of interest were observed in only 5 (7%; 95% confidence interval [CI], 1%-13%) patients, all involving ZDV resistance. One carried both mutations T215Y and M41L known to confer a high degree of phenotypic resistance to ZDV. Among a subgroup of 28 patients with a timepoint of infection after 1995, 24 [86%; approximately 95% CI, 73%-99%) presented with a wild-type pattern. The significance of the high prevalence of mixed patterns observed in drug-naive patients remains unclear. However, the frequency of primary mutant genotypes associated with high levels of drug resistance is low in Martinique and in this study we did not observe any currently increased tendency in this frequency.

Anti-HIV Agents↗
PubMed1999

The effects of dietary iron overload on fumonisin B1-induced cancer promotion in the rat liver.

The present study was performed to determine whether excess hepatic iron modulates the cancer-initiating and promoting properties of FB1. Thirty-eight male F344 rats were divided into four dietary treatment groups: (i) control diet (AIN, n = 8); (ii) FB1 250 mg/kg diet (FB1, n = 10); (iii) 1-2% carbonyl iron (CI, n = 10); or (iv) FB1 plus iron loading (FB1/CI, n = 10) for 5 weeks (2 x 2 factorial design). Hepatic iron concentrations in iron-loaded animals at 5 weeks were 444 +/- 56 (CI) and 479 +/- 80 micromol/g dry weight (FB1/CI) (mean +/- SEM). All the FB1-fed rats, in the presence or absence of CI, developed a toxic hepatitis with a 4-fold rise in serum alanine transaminase (ALT) levels. FB1 appeared to augment iron-induced hepatic lipid peroxidation, as measured by the generation of thiobarbituric acid reacting substances (TBARS) in liver homogenates (P < 0.0001). Morphometric analysis showed that FB1 caused a significantly greater mean +/- SEM number of 'enzyme-altered' foci and nodules per cm2 (5.34 +/- 1.42 vs. 1.50 +/- 0.52, P < 0.05), as well as a greater area (%) of liver occupied by foci and nodules (0.33 +/- 0.12% vs. 0.05 +/- 0.03%, P < 0.001), compared with FB1/CI. The addition of FB1 to dietary iron loading caused a shift in distribution of iron from hepatocytes to Kupffer cells, probably due to phagocytosis of necrotic iron-loaded hepatocytes. In conclusion, (i) FB1 appears to cause toxicity in the liver independently from effects on lipid peroxidation; (ii) FB1 has a potentiating effect on iron-induced lipid peroxidation; and (iii) dietary iron loading appears to protect against the cancer promoting properties of FB1, possibly due to a stimulatory effect of iron on hepatocyte regeneration.

Animals↗
PubMed1999

Biochemical characterization of recombinant polypeptides corresponding to the predicted betaalphaalpha fold in Aux/IAA proteins.

The plant hormone indoleacetic acid (IAA or auxin) transcriptionally activates a select set of early genes. The Aux/IAA class of early auxin-responsive genes encodes a large family of short-lived, nuclear proteins. Aux/IAA polypeptides homo- and heterodimerize, and interact with auxin-response transcription factors (ARFs) via C-terminal regions conserved in both protein families. This shared region contains a predicted betaalphaalpha motif similar to the prokaryotic beta-ribbon DNA binding domain, which mediates both protein dimerization and DNA recognition. Here, we show by circular dichroism spectroscopy and by chemical cross-linking experiments that recombinant peptides corresponding to the predicted betaalphaalpha region of three Aux/IAA proteins from Arabidopsis thaliana contain substantial alpha-helical secondary structure and undergo homo- and heterotypic interactions in vitro. Our results indicate a similar biochemical function of the plant betaalphaalpha domain and suggest that the betaalphaalpha fold plays an important role in mediating combinatorial interactions of Aux/IAA and ARF proteins to specifically regulate secondary gene expression in response to auxin.

Amino Acid Sequence↗
PubMed1999

Regulation of fatty acid biosynthesis as a possible mechanism for the mitoinhibitory effect of fumonisin B1 in primary rat hepatocytes.

The mitoinhibitory effect of fumonisin B1 (FB1) on the mitogenic response of epidermal growth factor (EGF) was investigated in primary hepatocyte cultures with respect to the alterations in the omega6 fatty acid metabolic pathway. Fatty acid analyses of hepatocytes showed that EGF treatment resulted in a significant decrease in the relative levels of 20:4omega6 (arachidonic acid) and an increase in 18:2omega6 (linoleic acid). Supplementation of the hepatocyte cultures with 20:4omega6 in the absence of EGF resulted in an increase in the total omega6 and omega6/omega3 fatty acid ratio. Addition of 20:5omega3 (eicosapentaenoic acid) resulted in an increase of the relative levels of the long chain omega3 fatty acids at the expense of the omega6 fatty acids. When 20:4omega6 and 20:5omega3 was added in the presence of EGF, the mitogenic response of EGF was increased and decreased respectively. When compared to the fatty acid profiles in the absence of EGF, the decreased mitogenic response coincided with a decrease of total omega6 fatty acids and total polyunsaturated fatty acids (PUFA). In addition, the saturated and mono-unsaturated fatty acids increased and the polyunsaturated/saturated (P/S) fatty acid ratio decreased which implied a more rigid membrane structure. Addition of prostaglandin E2 (PGE2) and prostaglandin E1 (PGE1) stimulated and inhibited the mitogenic response respectively. Ibuprofen, a known cyclooxygenase inhibitor, and FB1 inhibited the EGF-induced mitogenic response in a dose-dependent manner. The mitoinhibitory effect of FB1 on the EGF response was counteracted by the addition of PGE2. FB1 also disrupts the omega6 fatty acid metabolic pathway in primary hepatocytes, resulting in the accumulation of C18:2omega6 in phospatidylcholine and triacylglicerol. The disruption of the omega6 fatty acid metabolic pathway and/or prostaglandin synthesis is likely to be an important event in the mitoinhibitory effect of FB1 on growth factor responses.

Alprostadil↗
PubMed1998

Oxidative damage and fumonisin B1-induced toxicity in primary rat hepatocytes and rat liver in vivo.

Dietary fumonisin B1 (FB1) levels of 250 and 500 mg FB1/kg increased the level of thiobarbituric acid reactive substances (TBARS) significantly (P < 0.05) in the liver of rats fed FB1 over 21 days. Levels of 10, 50 and 100 mg FB1/kg also markedly (not significantly) increased the level of TBARS in the liver homogenate. Subcellular fractionation of the liver of the rats fed the 250 mg FB1/kg diet, showed a marginally significant increase of TBARS in the plasma membranes (0.05 < P < 0.1) and a significant increase in the microsomes (P < 0.05). In vitro investigations in primary rat hepatocytes indicated that the level of TBARS was increased in a dose dependent manner associated with an increase in cytotoxicity. Addition of the antioxidant, alpha-tocopherol, significantly decreased the cytotoxicity whereas the level of TBARS was decreased to basal levels, suggesting that lipid peroxidation is likely to contribute to the cytotoxic effect of FB1. Addition of cumene hydroperoxide (CMHP) to primary hepatocytes exposed to FB1 for 44 h, enhanced the CMHP-induced TBARS release suggesting that the hepatocytes exposed to FB1 are more susceptible to chemically-induced oxidative stress. Free radical production could result in excessive cellular damage and/or metabolic abnormalities that are likely to be involved in FB1-induced altered growth responses and cell death in primary hepatocytes. The hepatotoxic effects and resultant oxidative damage induced by FB1 may be important during cancer induction in rat liver by this apparently non-genotoxic compound.

Animals↗