Control of the actin cytoskeleton by extracellular signals.
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Actins↗
Biomedical subjects
T Beck
Publications and source records attributed to T Beck.
Different stereoselectivity in the reduction of pulegone by Mentha species.
Aqueous solutions of [2H]-labeled pulegone enantiomers were fed to Mentha spicata ssp. spicata L. and Mentha spicata ssp. crispata L. shoot tip and first leaf pair. After solid phase microextraction the essential oil was analysed with enantioselective multidimensional gas chromatography/mass spectrometry. Both Mentha spicata species were able to convert labelled (1R)- and (1S)-pulegone at the same rate into the corresponding menthone and isomenthone, indicating an unspecific process. The reduction of both pulegone enantiomers preferably led to the cis-stereoisomers. The observed stereoselectivity is completely different from those of pulegone reduction by Mentha x piperita L.
Cyclohexane Monoterpenes↗
[On the general basis of naturopathy and complementary medicine].
UNLABELLED: On the General Basis of Naturopathy and Complementary Medicine BACKGROUND: Naturopathy and complementary medicine are discussed controversially in public: On the one hand naturopathy is increasingly accepted by the interested public, on the other hand members of the medical community display a critical or even rejecting attitude towards naturopathy. Clarification of the terminology and methods of medical science as well as of naturopathy is necessary. The goal is not only to reestablish the communication between 'classical medicine' and naturopathy but also to gain impulses for the health care system from a cooperation of both, especially with regard to cost development and the search for new solutions and therapies, for example for 'incurable' diseases. PROCEDURE: Here we describe the different view of naturopathy on humans and their diseases and investigate the current scientific knowledge. Naturopathy often has a different, a 'holistic' basis (anthropology), a different therapeutic approach (pathogenesis, salutogenesis). RESULTS: The understanding of science in today's medicine has its origin in history, therefore it is not only continuously changeable but also in need of change. On the one hand new findings from other scientific disciplines should be embraced, on the other hand especially medical science should react to the acute needs and questions of patients. Naturopathy in theory and in applied medicine proves its efficacy (different validities for different procedures). It is followed by the search for the principle of functioning (extension of science). Starting here, an extended understanding of mankind and nature and new models of disease and therapy can be developed. Also, medical ethics in the sense of naturopathy would demand as a first step the use of agents causing the least possible damage. Only when those agents fail, stronger interventions should be chosen. CONCLUSIONS: Due to the necessary enhancement of scientific evaluation of naturopathy and the development of explanatory models, impulses for better therapy approaches are to be expected. Qualitative (new therapy models) and economic (cost reduction) impulses for the health care system would be the result.
Attitude of Health Personnel↗
Enantioselective analysis of ketone bodies in patients with beta-ketothiolase deficiency, medium-chain acyl coenzyme A dehydrogenase deficiency and ketonemic vomiting.
Enantioselective multidimensional gas chromatography-mass spectrometry (enantio-MDGC-MS) is a valuable tool for the differentiation of enantiomers from complex matrices when present in trace amounts. The separation of chiral compounds provides further information on the diagnosis of diseases, and on normal and abnormal biochemical pathways. The formation of the normal urinary metabolite 3-hydroxy-2-methylbutanoic acid (HMBA), excreted in abnormally high amounts in beta-ketothiolase deficiency, is not absolutely clarified. Metabolic pathways involving this metabolite are isoleucine catabolism, as well as presumably beta-oxidation of fatty acids and ketogenesis. The latter two pathways are distinguishable in their enantioselectivity. Enantioselective analysis gives further information on interfering metabolic pathways and the selectivity of the enzyme(s) forming HMBA. Different ratios of the stereoisomers of HMBA in control urine samples and patients with beta-ketothiolase deficiency were detected. Analogous to HMBA urinary 3-hydroxybutanoic acid (HBA) was investigated in several diseases. The formation of HBA and HMBA is expected to result from the same or similar metabolic pathways. Differences in the enantiomeric ratio of HMBA may originate from the enantioselectivity of different enzyme systems.
Acetyl-CoA C-Acyltransferase↗
Stereodifferentiation of 3-hydroxyisobutyric- and 3-aminoisobutyric acid in human urine by enantioselective multidimensional capillary gas chromatography-mass spectrometry.
The chiral metabolites 3-hydroxyisobutyric acid (HIBA) and 3-aminoisobutyric acid (AIBA) are intermediates in the pathways of L-valine and thymine and play an important role in the diagnosis of the very rare inherited metabolic diseases 3-hydroxyisobutyric aciduria (McKusick 236975) and methylmalonic semialdehyde dehydrogenase deficiency (McKusick 603178-MSDD). Until now only a few approaches have been made in enantioselective analysis of HIBA and AIBA and for that reason very little information is available on enantiomeric ratios of these metabolites in man. This paper reports on the simultaneous stereodifferentiation of HIBA and AIBA in human urine as corresponding N(O)-methoxycarbonyl methyl esters by derivatization with methyl chloroformate (MCF) using enantioselective multidimensional gas chromatography-mass spectrometry (enantio-MDGC/MS) with heptakis-(2, 3-di-O-methyl-6-O-tert.-butyl-dimethylsilyl)-beta-cyclodextrin as the chiral stationary phase. During this investigation urine samples from different patients and healthy controls were analyzed in order to reveal characteristic enantiomeric patterns of these metabolites. A trend of dominating R-HIBA excretion in the control urine samples investigated was observed. An excretion of more than 80% S-HIBA was found in the urines of two patients with ketonemic vomiting. There are some clues indicating a possible renal reabsorbtion of S-HIBA similar to those of S-AIBA. Furthermore, there was a significant finding with regard to the enantiomeric distribution of AIBA in a patient with MSDD - a markedly increased excretion of the S-enantiomer in contrast to the other samples. Using the enantiomeric ratios of AIBA, a previously investigated case of benign methylmalonic aciduria (bMMA) could be excluded from the diagnosis of MSDD.
Aldehyde Oxidoreductases↗
Multicenter phase II study to evaluate a 28-day regimen of oral fluorouracil plus eniluracil in the treatment of patients with previously untreated metastatic colorectal cancer.
PURPOSE: To determine the efficacy of fluorouracil (5-FU) plus eniluracil when administered to patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: In this single-arm phase II study, patients with previously untreated metastatic colorectal cancer received oral eniluracil plus 5-FU (10:1 dose ratio), at 5-FU doses of 1.00 mg/m(2) or 1.15 mg/m(2) twice daily (every 12 hours) for 28 consecutive days repeated every 5 weeks (one cycle). Treatment continued until there was documented disease progression or unacceptable toxicity. RESULTS: Thirty and 25 patients were enrolled at a starting dose of 1.00 mg/m(2) and 1.15 mg/m(2), respectively. Fourteen (25%) of 55 patients (95% confidence interval, 15% to 39%) had a partial response, and 20 patients (36%) had stable disease. The median durations of the partial responses and stable disease were 23.9 weeks (range, 12.3 to 52.1+ weeks) and 24.1 weeks (range, 17.1 to 55.6+ weeks), respectively. The median durations of progression-free and overall survival were 22.6 weeks (range, 21.0 to 29.0 weeks) and 59 weeks (range, 4 to 84+ weeks), respectively. The response rate in the 1.15 mg/m(2)-dose group was similar to the 1.00 mg/m(2)-dose group (28% v 23%, respectively). Severe (grade 3/4) nonhematologic treatment-related toxicity included diarrhea (nine patients), nausea/vomiting (one patient each), mucositis (two patients), and anorexia (one patient). Severe hematologic toxicities were rare. At the 1.15 mg/m(2)-dose level, two patients exhibited grade 3 granulocytopenia, and two patients had grade 3 anemia. CONCLUSION: The response rate with oral 5-FU plus eniluracil is comparable with that observed with infusional 5-FU or bolus 5-FU and leucovorin. The toxicity profile of this oral regimen is acceptable for use in an outpatient home-based setting.
Administration, Oral↗
The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors.
The rapamycin-sensitive TOR signalling pathway in Saccharomyces cerevisiae activates a cell-growth program in response to nutrients such as nitrogen and carbon. The TOR1 and TOR2 kinases (TOR) control cytoplasmic protein synthesis and degradation through the conserved TAP42 protein. Upon phosphorylation by TOR, TAP42 binds and possibly inhibits type 2A and type-2A-related phosphatases; however, the mechanism by which TOR controls nuclear events such as global repression of starvation-specific transcription is unknown. Here we show that TOR prevents transcription of genes expressed upon nitrogen limitation by promoting the association of the GATA transcription factor GLN3 with the cytoplasmic protein URE2. The binding of GLN3 to URE2 requires TOR-dependent phosphorylation of GLN3. Phosphorylation and cytoplasmic retention of GLN3 are also dependent on the TOR effector TAP42, and are antagonized by the type-2A-related phosphatase SIT4. TOR inhibits expression of carbon-source-regulated genes by stimulating the binding of the transcriptional activators MSN2 and MSN4 to the cytoplasmic 14-3-3 protein BMH2. Thus, the TOR signalling pathway broadly controls nutrient metabolism by sequestering several transcription factors in the cytoplasm.
14-3-3 Proteins↗
Starvation induces vacuolar targeting and degradation of the tryptophan permease in yeast.
In Saccharomyces cerevisiae, amino acid permeases are divided into two classes. One class, represented by the general amino acid permease GAP1, contains permeases regulated in response to the nitrogen source. The other class, including the high affinity tryptophan permease, TAT2, consists of the so-called constitutive permeases. We show that TAT2 is regulated at the level of protein stability. In exponentially growing cells, TAT2 is in the plasma membrane and also accumulates in internal compartments of the secretory pathway. Upon nutrient deprivation or rapamycin treatment, TAT2 is transported to and degraded in the vacuole. The ubiquitination machinery and lysine residues within the NH(2)-terminal 31 amino acids of TAT2 mediate ubiquitination and degradation of the permease. Starvation-induced degradation of internal TAT2 is blocked in sec18, sec23, pep12, and vps27 mutants, but not in sec4, end4, and apg1 mutants, suggesting that, upon nutrient limitation, internal TAT2 is diverted from the late secretory pathway to the vacuolar pathway. Furthermore, our results suggest that TAT2 stability and sorting are controlled by the TOR signaling pathway, and regulated inversely to that of GAP1.
Amino Acid Sequence↗
Conversion of citronellyl diphosphate and citronellyl beta-D-glucoside into rose oxide by Pelargonium graveolens.
Deuterium-labeled citronellyl diphosphate and citronellyl beta-D-glucoside were fed to Pelargonium graveolens. Both precursors were converted into cis-/trans-rose oxide. Citronellyl diphosphate is more effectively converted into rose oxide. The phloem exudate of P. graveolens was analyzed after enzymatic cleavage of the glucosidated and phosphorylated volatiles. It could be shown that glucosidically bound citronellol is translocated in the plant. Phosphorylated citronellol could not be detected.
Deuterium↗
Structure elucidation, enantioselective analysis, and biogenesis of nerol oxide in Pelargonium species.
A novel enantioselective synthesis of nerol oxide (3, 6-dihydro-4-methyl-2-(2-methyl-1-propenyl)-2H-pyran) was used for the determination of the absolute configuration at C-2. The order of elution of the enantiomers on octakis-(2, 3-di-O-butyryl-6-O-tert-butyldimethylsilyl)-gamma-cyclodextrin in OV 1701-vi as the chiral stationary phase in enantioselective GC was determined as (2R) before (2S). Enantioselective multidimensional GC/MS (enantio-MDGC/MS) was used for the determination of the enantiomeric ratios of nerol oxide in different geranium oils. As a result, in all investigated oils nerol oxide occurs as a racemate. The biogenesis of nerol oxide in Pelargonium species was investigated by feeding experiments using deuterium-labeled neryl glucoside as the precursor. The Pelargonium plants were able to convert the fed precursor into racemic nerol oxide, which has to be considered as a "natural racemate".
Acyclic Monoterpenes↗
Biogenetic studies in Mentha x piperita. 1. deuterium-labeled monoterpene ketones: synthesis and stereoselective analysis.
Pulegone, menthone, and isomenthone isotopomers are synthesized as regioselectively deuterated d(5)- and d(8)-stereoisomers. Deuterium-labeled menthone and isomenthone enantiomers are analyzed using enantioselective multidimensional gas chromatography/mass spectrometry. The deuterated stereoisomers of menthone and isomenthone are separated from the unlabeled menthone and isomenthone on a glass capillary column, coated with 50% octakis(2, 3-di-O-butyryl-6-O-tert- butyldimethylsilyl)-gamma-cyclodextrin in OV 1701vi as the chiral stationary phase. These deuterium-labeled monoterpene ketones are proved to be highly valuable substrates in biosynthetic studies of terpenoid compounds.
Deuterium↗
Biogenetic studies in Mentha x piperita. 2. Stereoselectivity in the bioconversion of pulegone into menthone and isomenthone.
Mentha x piperita shoot tips and first leaf pairs were fed with aqueous solutions of different deuterium-labeled pulegone and various enantiomeric distributions. The essential oil was extracted by solid-phase microextraction and analyzed using enantioselective multidimensional gas chromatography/mass spectrometry. The genuine p-menthan-3-ones (-)-menthone and (+)-isomenthone as well as their labeled analogues were analyzed simultaneously. Both enantiomers of labeled pulegone were converted into the corresponding labeled p-menthan-3-ones by Mentha x piperita, indicating an unspecific reduction process. The generation of 4S- and 4R-configured p-menthan-3-ones differed in their stereoselectivities. Labeled (S)-pulegone was reduced by Mentha x piperita more rapidly rather than (R)-pulegone. From a comparison of labeled pulegone enantiomers the bioconversion preferrably led to 4S-configured diastereomers.
Biotransformation↗
Biosynthesis of menthofuran in Mentha x piperita: stereoselective and mechanistic studies.
Mentha x piperita shoot tips and first leaf pair were fed with aqueous solutions of [(2)H(2)]- and [(2)H(2)]/[(18)O]-labeled pulegone. The essential oil was analyzed by solid phase microextraction and enantioselective multidimensional gas chromatography/mass spectrometry. After feeding experiments with labeled pulegone racemate, both labeled (S)-menthofuran and (R)-menthofuran were detectable simultaneously together with genuine (R)-menthofuran. It could be shown that both labeled pulegone enantiomers are converted by Mentha x piperita to the corresponding labeled menthofuran enantiomers, favoring the labeled analogue of the nongenuine (S)-pulegone. The oxygen in menthofuran is introduced by enzymatic oxidation of pulegone, as concluded from feeding experiments with mixed labeled [(2)H(2)]/[(18)O]pulegone.
Cyclohexane Monoterpenes↗
The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease.
The Saccharomyces cerevisiae targets of rapamycin, TOR1 and TOR2, signal activation of cell growth in response to nutrient availability. Loss of TOR or rapamycin treatment causes yeast cells to arrest growth in early G1 and to express several other physiological properties of starved (G0) cells. As part of this starvation response, high affinity amino acid permeases such as the tryptophan permease TAT2 are targeted to the vacuole and degraded. Here we show that the TOR signalling pathway phosphorylates the Ser/Thr kinase NPR1 and thereby inhibits the starvation-induced turnover of TAT2. Overexpression of NPR1 inhibits growth and induces the degradation of TAT2, whereas loss of NPR1 confers resistance to rapamycin and to FK506, an inhibitor of amino acid import. NPR1 is controlled by TOR and the type 2A phosphatase-associated protein TAP42. First, overexpression of NPR1 is toxic only when TOR function is reduced. Secondly, NPR1 is rapidly dephosphorylated in the absence of TOR. Thirdly, NPR1 dephosphorylation does not occur in a rapamycin-resistant tap42 mutant. Thus, the TOR nutrient signalling pathway also controls growth by inhibiting a stationary phase (G0) programme. The control of NPR1 by TOR is analogous to the control of p70 s6 kinase and 4E-BP1 by mTOR in mammalian cells.
Adaptor Proteins, Signal Transducing↗
Enantioselective multidimensional gas chromatography-mass spectrometry in the analysis of urinary organic acids.
Enantioselective multidimensional gas chromatography-mass spectrometry is a valuable tool for the enantioselective analysis of compounds from complex matrices. Samples are separated initially on a precolumn and selected substances then transferred on-line to a main-column coated with suitable chiral stationary phase for enantioselective analysis with subsequent mass selective detection. In this paper the method is used as an adjunct to urinary organic acid analysis to provide information in patients with suspected inborn errors of metabolism. Lactic acid, alpha-hydroxyisocaproic acid, 3-phenyllactic acid and 3-(4-hydroxyphenyl)-lactic acid are separated in a single run. In addition, the enantioselective analysis of pyroglutamic acid is presented. D-Enantiomers of amino acids and alpha-hydroxycarboxylic acids derived from amino acids, point to a bacterial origin whereas the L-enantiomer is predominantly of endogenous origin. Therefore the enantiomeric ratio of chiral metabolites is an important parameter for the understanding of metabolic processes.
Carboxylic Acids↗
Has psoriasis its own characteristic trichogram?
The aim of this study was to determine if there were characteristic trichogram changes in scalp psoriasis in patients without clinically evident effluvium or alopecia. A total of 45 patients (17 men and 28 women, aged from 15 to 73 years) with clinically and histologically confirmed psoriasis vulgaris with scalp involvement were included. The control group consisted of 60 volunteers (23 males and 37 females aged from 15 to 74 years) with no scalp involvement. Our results from the psoriatic group showed highly increased proportions of dysplastic hair roots. Median proportion was 50% with 95% confidence interval (CI) for median 30-60%, whereas telogen hair ratio was slightly increased-median proportion was 16% with 95% CI for median 15-20%. Within the psoriasis patients' group no statistically significant correlations were found between the proportion of dysplastic hairs and the patients' age, sex, and the intensity and duration of disease. According to the results of this study, the dysplastic hairs in scalp psoriasis are statistically significant much more frequently compared with the control group. Thus, the increased proportion of dysplastic hairs in scalp psoriasis without effluvium or alopecia might be its characteristic trichogram sign.
Adolescent↗
MOPP/ABV hybrid chemotherapy for advanced Hodgkin's disease significantly improves failure-free and overall survival: the 8-year results of the intergroup trial.
PURPOSE: To compare the efficacy of sequential mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) followed by doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus the MOPP/ABV hybrid regimen in advanced-stage Hodgkin's disease. PATIENTS AND METHODS: A total of 737 patients with previously untreated stages III2A, IIIB, IVA, or IVB Hodgkin's disease and patients in first relapse after radiotherapy were prospectively randomized to sequential MOPP-ABV or MOPP/ABV hybrid. Of 691 eligible patients, 344 received the sequential regimen and 347 received the hybrid. RESULTS: The overall response rate was 95%, with complete responses (CRs) in 79%: 83% on the MOPP/ABV hybrid and 75% on the sequential MOPP-ABVD arm (P = .02). With a median follow-up time of 7.3 years, the 8-year failure-free survival (FFS) rates were 64% for MOPP/ABV hybrid and 54% far sequential MOPP-ABVD (P = .01; 0.69 relative risk of failure, comparing MOPP/ABV hybrid v MOPP-ABVD). The 8-year overall survival rate was significantly better for the MOPP/ABV hybrid (79%) as compared with sequential MOPP-ABVD (71%) (P = .02; relative risk, 0.65). MOPP/ABV hybrid had significantly more life-threatening or fatal neutropenia and pulmonary toxicity than the sequential MOPP-ABVD arm, which was associated with significantly greater thrombocytopenia. Nine cases of acute myelogenous leukemia or myelodysplasia were reported on the sequential regimen as compared with only one on the hybrid (P = .01). CONCLUSION: MOPP/ABV hybrid chemotherapy was significantly more effective than sequential MOPP-ABVD. FFS and overall survival were significantly improved on the hybrid arm, which was also associated with a lower incidence of acute leukemia or myelodysplasia.
Adolescent↗
Reduced 11beta-hydroxysteroid dehydrogenase activity in the remaining kidney following nephrectomy.
Intracellular access of steroids to gluco- and mineralocorticoid receptors is regulated by reduced 11beta-hydroxysteroid dehydrogenase (OHSD) 1 and 2. These enzymes convert active 11beta-OH-steroids into inactive 11-keto-steroids. The purpose of the present study was to establish whether the 11beta-OHSD1 and 11beta-OHSD2 are modulated in the remnant kidney 24 h or 14 days after uninephrectomy (UNX) in rats. Overall, 11beta-OHSD activity was analyzed by measuring the ratio of the exogenous 11beta-OH-steroid prednisolone to its 11-keto metabolite prednisone in vivo in kidney tissue using high performance liquid chromatography. To determine which isoenzyme accounts for the changed activity 24 h after UNX, the oxidation and reduction attributable to 11beta-OHSD1 and oxidation to 11beta-OHSD2 were analyzed in total renal extracts and in isolated glomeruli, proximal convoluted tubules (PCT), cortical ascending limbs, and cortical convoluted tubules (CCT). The messenger RNA content of 11beta-OHSD1 and 11beta-OHSD2 was measured by RT-PCR in renal tissues and single segments, using glyceraldehyde-3-phosphate-dehydrogenase as an internal standard. Protein amounts of 11beta-OHSD1 and 11beta-OHSD2 were assessed by Western blot. The prednisolone/prednisone ratio increased 24 h after UNX in 9 out of 10 animals (P < or = 0.0011), and was unchanged 14 days after UNX. 11Beta-OHSD1 oxidation (P < or = 0.032) and reduction activity (P < or = 0.002) declined 24 h after UNX in total extracts. 11Beta-OHSD1 oxidase activity was more than 3 times higher in PCT than in glomeruli, cortical ascending limbs, and CCT, and declined by 50% after UNX (P < or = 0.001). The reductase activity did not change following UNX in PCT. 11Beta-OHSD2 activity was 5-15 times higher in CCT than in the other segments, and decreased significantly after UNX (P < or = 0.008). UNX did not affect messenger RNA and protein levels of both enzymes in total renal extracts. In conclusion, 11beta-OHSD1 and 11beta-OHSD2 are predominantly expressed in PCT and CCT, respectively, and their corresponding oxidative activities decline after UNX. Thus, the access of 11beta-glucocorticosteroids to gluco- and mineralocorticoid receptors in the remaining kidney is facilitated after UNX.
11-beta-Hydroxysteroid Dehydrogenases↗