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Induction of specific enzymes of the oxidative pentose phosphate pathway by glucono-delta-lactone in Saccharomyces cerevisiae.

Growth of Saccharomyces cerevisiae on D-glucono-delta-lactone (delta gl) was found to be associated with a specific coordinate induction of the synthesis of two enzymes of the oxidative pentose phosphate pathway--6-phosphogluconate dehydrogenase and 6-phosphogluconolactonase--together with that of a third enzyme, gluconokinase. The gnd1 mutation, responsible for an approximately 80% loss of 6-phosphogluconate dehydrogenase activity and the inability of the cells to grow on delta gl, completely abolished the induction of all three enzymes, while the gnd2 mutation affected this only partially. One class of gnd1 revertants, selected for growth on delta gl, was found to have recovered normal dehydrogenase activity and the ability to synthesize the three enzymes when induced by delta gl. Another class of delta gl-positive revertants possessed constitutively elevated levels of gluconokinase. In contrast, glucose-positive revertants of gnd1, with restored constitutive dehydrogenase activity, continued to remain deficient in induction of the three enzymes and also failed to grow on delta gl. Induction of 6-phosphogluconate dehydrogenase activity was associated with increased transcription of the gene coding for the major isoenzyme; the transcript remained undetectable in the gnd1 mutant. Induction of these specific enzymes thus appears to be essential for growth of S. cerevisiae on delta gl.

Carboxylic Ester Hydrolases↗

Sesquiterpene lactone mix patch testing supplemented with dandelion extract in patients with allergic contact dermatitis, atopic dermatitis and non-allergic chronic inflammatory skin diseases.

We investigated the value of patch testing with dandelion (Compositae) extract in addition to sesquiterpene lactone (SL) mix in selected patients. After we detected a case of contact erythema multiforme after patch testing with dandelion and common chickweed (Caryophyllaceae), additional testing with common chickweed extract was performed. A total of 235 adults with a mean age of 52.3 years were tested. There were 66 men and 169 women: 53 consecutive patients with allergic contact dermatitis (ACD); 43 with atopic dermatitis (AD); 90 non-atopics suffering from non-allergic chronic inflammatory skin diseases; 49 healthy volunteers. All were tested with SL mix 0.1% petrolatum (pet.) and diethyl ether extracts from Taraxacum officinale (dandelion) 0.1 and 3.0% pet. and from Stellaria media (common chickweed) 0.1 and 3% pet. A total of 14 individuals (5.9%) showed allergic reaction (AR) to at least 1 of the plant allergens, 4 (28.6%) to common chickweed extract, and 11 (78.6%) to Compositae allergens. These 11 persons made the overall prevalence of 4.7%: 8 (3.4%) were SL-positive and 3 (1.3%) reacted to dandelion extract. 5 persons (45.5%) had AD, 2 had ACD, 2 had psoriasis and 2 were healthy controls. The Compositae allergy was relevant in 8 cases (72.7%). The highest frequency of SL mix sensitivity (9.3%) was among those with AD. Half the SL mix-sensitive individuals had AD. ARs to dandelion extract were obtained only among patients with eczema. A total of 9 irritant reactions (IRs) in 9 individuals (3.8%) were recorded, 8 to SL mix and 1 to common chickweed extract 3.0% pet. No IR was recorded to dandelion extract (P = 0.007). Among those with relevant Compositae allergy, 50.0% had AR to fragrance mix and balsam of Peru (Myroxylon pereirae resin) and colophonium. SLs were detected in dandelion but not in common chickweed. Our study confirmed the importance of 1 positive reaction for emerging, not fully established, Compositae allergy. In conclusion, the overall prevalence of 4.7% in our study represents a basal SL mix detection rate of 3.4% reinforced and safely supplemented by testing with the dandelion extract.

Adolescent↗

The contribution of MvfR to Pseudomonas aeruginosa pathogenesis and quorum sensing circuitry regulation: multiple quorum sensing-regulated genes are modulated without affecting lasRI, rhlRI or the production of N-acyl-L-homoserine lactones.

The transcriptional regulator MvfR is required for full Pseudomonas aeruginosa virulence, the function of multiple quorum sensing (QS)-regulated virulence factors and the synthesis of 4-hydroxy-2-alkylquinolines (HAQs), including the Pseudomonas quinolone signal (PQS). Here we investigate the role of MvfR in the QS circuitry and P. aeruginosa pathogenesis. We demonstrate using a combination of biochemical and molecular approaches, including transcription profiling, that MvfR is involved in the regulation of multiple P. aeruginosa QS-controlled genes without altering the expression of lasRI/rhlRI or the production of N-acyl-L-homoserine lactone (AHL) signals. Dissection of how mvfR is interwoven into the P. aeruginosa QS circuitry reveals that the MvfR system, through the essential contribution of PqsE, positively regulates a subset of genes dependant on both LasR and RhlR. Animal studies show that MvfR contributes to P. aeruginosa virulence by controlling the transcription of genes not under RhlR regulation, and that reduced virulence of a mvfR mutant is caused by the loss of pqsE expression and not only a deficiency in HAQs/PQS production. This study provides novel insights into the unique role of the MvfR system in AHL-mediated QS and further supports its importance in P. aeruginosa pathogenesis.

Animals↗

Exogenous gangliosides GD1b and GD1b-lactone, stably associated to rat brain P2 subcellular fraction, modulate differently the process of protein phosphorylation.

GD1b and GD1b-lactone (GD1b-L) gangliosides bind to the same extent to a P2 crude membrane preparation from rat brain. After 30 min of incubation with 10(-4), 10(-5) and 10(-6) M solutions of ganglioside, 1,800, 450, and 100 pmol of ganglioside/mg of protein, respectively, were found to be stably associated to the P2 fraction. This association modifies the phosphorylation process of the P2 membrane proteins in a dose-dependent manner, the maximal effect being reached at a ganglioside association of 1.85 nmol/mg of protein and in large part at 450 pmol/mg of protein. The effects of GD1b and GD1b-L on the phosphorylation of five proteins, showing apparent molecular masses of 17, 20, 36, 41, and 44 kDa, were different after 0.5 min of phosphorylation reaction as well as after 15 min. After 0.5 min of reaction, in the presence of stably associated GD1b, the phosphorylation of the 36-, 41-, and 44-kDa proteins was increased with reference to the control, whereas the phosphorylation of the 17- and 20-kDa proteins was decreased. GD1b-L exerted qualitatively similar effects only on the 44-, 41-, and 36-kDa proteins and to a strongly reduced degree. After 15 min of reaction, only the phosphorylation of the 36-kDa protein was stimulated by GD1b; GD1b-L exerted a similar effect, but to a low degree.

Animals↗

alpha-Peroxyachifolid and other new sensitizing sesquiterpene lactones from yarrow (Achillea millefolium L., Compositae).

Yarrow, Achillea millefolium L., is one of the commonest weeds of the Compositae family. Cases of allergic contact dermatitis have been described since 1899. Although 10 sesquiterpene lactones (SL) and 3 polyines have previously been identified, the sensitizers of yarrow have escaped detection. A reinvestigation of short ether extracts of yarrow revealed the presence of 5 unsaturated hitherto unknown guaianolides of peroxide character. The main SL, identified as a strong sensitizer in guinea pig sensitization experiments, was named alpha-peroxyachifolid. The minor SL also contribute marginally to the sensitizing capacity, while other known yarrow constituents like dehydromatricaria ester and pontica epoxide appear to play no role. A 5-year follow-up (1985-1990) of Compositae-sensitive patients showed that more than 50% reacted when tested with a short ether extract of yarrow. Exacerbation of the patch test sites by irradiation with UV light was never observed.

Animals↗

Sesquiterpene lactone contact sensitivity: clinical patterns of Compositae dermatitis and relationship to chronic actinic dermatitis.

A mix of 3 sesquiterpene lactones (SL) (SL mix 0.1%) was evaluated over a 4-year period. Of 7420 patients with eczema investigated by patch testing, 135 (68 male, 67 female) (1.8%) demonstrated positive reactions, 114 (84%) considered clinically relevant. Females outnumbered males until the age of 60, after which men were more commonly affected. The clinical patterns varied from patients presenting with generalized eczema (20%) or eczema of the hands and face (24%), to patients with hand (36%) or facial eczema (11%) alone. 48 patients were investigated for suspected photosensitivity and 29 (21 male, mean age 69 years, and 8 female, mean age 66 years) had abnormal cutaneous monochromatic irradiation tests. These results highlight the varied clinical presentation of SL contact dermatitis and its association with chronic actinic dermatitis. The SL mix proved reliable and safe, supporting its inclusion in the European standard series of contact allergens.

Adolescent↗

Sesquiterpene lactone mix contact sensitivity and its relationship to chronic actinic dermatitis: a follow-up study.

In a retrospective case note analysis over a 4-year period, 0.9% of all patients tested with a standard patch test series (65 of 7600) were demonstrated to have clinically relevant responses to a sesquiterpene lactone (SQL) mix. Of these patients, 11 (17%) also had a diagnosis of chronic actinic dermatitis. This group made up 25% of all patients diagnosed as suffering from CAD in this 4-year period. These figures differ somewhat from those reported by our group in an initial 4-year period immediately following the introduction of the mix into our standard patch test series, when 1.5% of all patients tested had a clinically relevant response to the SQL mix, including 36% of all patients with a diagnosis of CAD. It is not uncommon for the prevalence of sensitivity to an allergen to be overestimated immediately following its introduction into routine testing. Possible reasons for our findings are discussed.

Asteraceae↗

Routine patch testing with the sesquiterpene lactone mix in Europe: a 2-year experience. A multicentre study of the EECDRG.

To test the screening value of the sesquiterpene lactone (SL) mix in Europe today and describe epidemiological and clinical features of Compositae-sensitive patients, the SL mix 0.1% pet. was included in the standard patch test series in 11 European clinics. 10,695 patients were tested, and 106 (1%) had positive reactions, 74% of which were of current or old relevance. The prevalence of positive reactions varied between 0.1 and 2.7% in different centres. The median age of the 66 females was 51.5 years, and 55.2 in the 40 males. The 20 occupationally sensitized had a higher % of males and a median age of 43 years, whereas 7 UV-sensitive patients had a median age of 72 years. Garden plants were the major suspected sensitizers and the clinical patterns were partly, in accordance with plant dermatoses in general, involving hands, forearms and face, and partly widespread eczema in a large proportion of the patients. More than 1/3 were positive to perfume and/or colophony, possibly reflecting cross-reactivity. With only 1 case of active sensitization and no irritant reactions, the SL mix is a safe allergen and the overall prevalence of positive reactions supports its continued use in the standard patch test series.

Adult↗

Compositae mix is a more sensitive test for Compositae dermatitis than the sesquiterpene lactone mix.

Over the past 2 decades, Compositae dermatitis has increasingly been recognized as a cause of exposure-pattern dermatitis. The introduction of the sesquiterpene lactone (SL) mix as a screening test has contributed to this improved recognition. However, there is growing evidence that the SL mix fails to detect a substantial number of genuine Compositae allergies. We therefore investigated whether another screening reagent (the Compositae mix) might be more sensitive in detecting cases of Compositae allergy than the SL mix. Over a 1-year period, we tested 656 consecutive unselected patch test patients to both SL mix and Compositae mix. 31 patients were found to have genuine Compositae allergies. Of these, 28 had reacted to the Compositae mix but only 13 had reacted to the SL mix. The Compositae mix failed to detect only 2 genuine Compositae allergies, whereas the SL mix missed 17 such allergies. On the other hand, the Compositae mix led to 9 irritant reactions, while there was only 1 irritant reaction with the SL mix. We conclude that Compositae dermatitis is still being underdiagnosed with the current screening method, and that the Compositae mix is significantly more sensitive in detecting Compositae allergy than the SL mix.

Adolescent↗

Dependence of anticancer activity of camptothecins on maintaining their lactone function.

Camptothecins contain a lactone ring that exists in the closed form below ph 7. Above 7, the open (CPT+) and the closed (CPT) form coexist in a 50-50 ratio in mouse plasma and in a 90-10 ratio in human plasma due to the high affinity of human serum albumin (HSA) for CPT+. CPT+ is much less toxic than CPT and it is excreted much faster. In complete RPMI 1640 culture medium, the equilibrium CPT(+)-CPT is 50-50. If 4% HSA is added, it moves to 90-10 modeling for the human physiological situation.

Animals↗

Lactones as inhibitors of the fibrinolytic system.

Caprolactone, valerolactone, and butyrolactone inhibit proteolytic and fibrinolytic activities of human plasmin. In very low concentrations, they also inhibit activation of plasminogen through plasmin-streptokinase activator and human urokinase. The degree of inhibitory potency depends upon the number of carbon atoms in the lactone.

Aminocaproates↗

5-oxo-5H-benzo[e]indole, a new type of highly sarcomagenic lactone.

The title compound, which belongs to a new synthetic group of polycyclic lactones derived from isocoumarin, exhibits a remarkably high degree of carcinogenicity in situ when injected in mice. Cancer-inducing activity has also been found in similar isocoumarins, a family known to include many naturally occurring substances.

Animals↗

Reactions of alpha methylene lactone tumor inhibitors with model biological nucelophiles.

Thiols are the most reactive nucleophilic reagents among the biological models investigated. They undergo "Michael-type" addition to the polyfunctional sesquiterpene lactones. The rapid rates of reaction with L-cysteine were measured and the reaction products were characterized. Each addition of thiol successively decreased the cytotoxicity of the adducts formed.

Antineoplastic Agents↗

Branched-chain fatty acids produced by mutants of Streptomyces fradiae, putative precursors of the lactone ring of tylosin.

Three branched-chain fatty acids (7-hydroxy-4,6-dimethylnona-2,4-dienoic acid [compound 1], its 7-epimer [compound 2], and 7-keto-4,6-dimethylnona-2,4-dienoic acid [compound 3]) and a ketone (9-hydroxy-6,8-dimethylundeca-4,6-dien-3-one [compound 4]) were isolated from the culture broth of mutants of Streptomyces fradiae which were blocked in the biosynthesis of the macrolide antibiotic tylosin. Two phenotypic classes of mutants of this organism which were blocked in the addition of mycaminose to tylactone (compound 6) accumulated these compounds. These compounds were not produced by mutants which were blocked in lactone synthesis, in steps beyond mycaminose addition, or by the wild-type strain. Synthesis of these compounds, like synthesis of tylosin, was inhibited by the addition of cerulenin. Compounds 1, 2, and 3 were partially interconvertible by these mutants; but they were not produced from the degradation of tylactone and they were not directly incorporated into tylosin by intact cells. The structures of compounds 1 and 2 were equivalent to that of a predicted intermediate (S. Yue, J. S. Duncan, Y. Yamamoto, and C. R. Hutchinson, J. Am. Chem. Soc. 109:1253-1255, 1987) in the biosynthesis of tylactone. The ketone (compound 4) reported previously (N. D. Jones, M. O. Chaney, H. A. Kirst, G. M. Wild, R. H. Baltz, R. L. Hamill, and J. W. Paschal, J. Antibiot. 35:420-425, 1982) appears to be the decarboxylation product of the intermediate following that represented by compound 1. This represents the first report of the isolation of putative precursors of tylactone from tylosin-producing organisms.

Alcohols↗

Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium.

The in vitro activity of parthenolide against Leishmania amazonensis was investigated. Parthenolide is a sesquiterpene lactone purified from the hydroalcoholic extract of aerial parts of Tanacetum parthenium. This isolated compound was identified through spectral analyses by UV, infrared, (1)H and (13)C nuclear magnetic resonance imaging, DEPT (distortionless enhancement by polarization transfer), COSY (correlated spectroscopy), HMQC (heteronuclear multiple-quantum coherence), and electron spray ionization-mass spectrometry. Parthenolide showed significant activity against the promastigote form of L. amazonensis, with 50% inhibition of cell growth at a concentration of 0.37 microg/ml. For the intracellular amastigote form, parthenolide reduced by 50% the survival index of parasites in macrophages when it was used at 0.81 microg/ml. The purified compound showed no cytotoxic effects against J774G8 macrophages in culture and did not cause lysis in sheep blood when it was used at higher concentrations that inhibited promastigote forms. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis with gelatin as the substrate showed that the enzymatic activity of the enzyme cysteine protease increased following treatment of the promastigotes with the isolated compound. This finding was correlated with marked morphological changes induced by parthenolide, such as the appearance of structures similar to large lysosomes and intense exocytic activity in the region of the flagellar pocket, as seen by electron microscopy. These results provide new perspectives on the development of novel drugs with leishmanicidal activities obtained from natural products.

Animals↗

Screening, nucleotide sequence, and biochemical characterization of an esterase from Pseudomonas fluorescens with high activity towards lactones.

A genomic library of Pseudomonas fluorescens DSM 50106 in a lambdaRESIII phage vector was screened in Escherichia coli K-12 for esterase activity by using alpha-naphthyl acetate and Fast Blue RR. A 3.2-kb DNA fragment was subcloned from an esterase-positive clone and completely sequenced. Esterase EstF1 was encoded by a 999-bp open reading frame (ORF) and exhibited significant amino acid sequence identity with members of the serine hydrolase family. The deduced amino acid sequences of two other C-terminal truncated ORFs exhibited homology to a cyclohexanone monooxygenase and an alkane hydroxylase. However, esterase activity was not induced by growing of P. fluorescens DSM 50106 in the presence of several cyclic ketones. The esterase gene was fused to a His tag and expressed in E. coli. The gene product was purified by zinc ion affinity chromatography and characterized. Detergents had to be added for purification, indicating that the enzyme was membrane bound or membrane associated. The optimum pH of the purified enzyme was 7.5, and the optimum temperature was 43 degreesC. The showed highest purified enzyme activities towards lactones. The activity increased from gamma-butyrolactone (18.1 U/mg) to epsilon-caprolactone (21.8 U/mg) to delta-valerolactone (36.5 U/mg). The activities towards the aliphatic esters were significantly lower; the only exception was the activity toward ethyl caprylate, which was the preferred substrate.

Amino Acid Sequence↗

Identification and characterization of an N-acylhomoserine lactone-dependent quorum-sensing system in Pseudomonas putida strain IsoF.

Recent reports have shown that several strains of Pseudomonas putida produce N-acylhomoserine lactones (AHLs). These signal molecules enable bacteria to coordinately express certain phenotypic traits in a density-dependent manner in a process referred to as quorum sensing. In this study we have cloned a genomic region of the plant growth-promoting P. putida strain IsoF that, when present in trans, provoked induction of a bioluminescent AHL reporter plasmid. Sequence analysis identified a gene cluster consisting of four genes: ppuI and ppuR, whose predicted amino acid sequences are highly similar to proteins of the LuxI-LuxR family, an open reading frame (ORF) located in the intergenic region between ppuI and ppuR with significant homology to rsaL from Pseudomonas aeruginosa, and a gene, designated ppuA, present upstream of ppuR, the deduced amino acid sequence of which shows similarity to long-chain fatty acid coenzyme A ligases from various organisms. Using a transcriptional ppuA::luxAB fusion we demonstrate that expression of ppuA is AHL dependent. Furthermore, transcription of the AHL synthase ppuI is shown to be subject to quorum-sensing regulation, creating a positive feedback loop. Sequencing of the DNA regions flanking the ppu gene cluster indicated that the four genes form an island in the suhB-PA3819 intergenic region of the currently sequenced P. putida strain KT2440. Moreover, we provide evidence that the ppu genes are not present in other AHL-producing P. putida strains, indicating that this gene cluster is so far unique for strain IsoF. While the wild-type strain formed very homogenous biofilms, both a ppuI and a ppuA mutant formed structured biofilms with characteristic microcolonies and water-filled channels. These results suggest that the quorum-sensing system influences biofilm structural development.

Amino Acid Sequence↗

Comparison of the two isofunctional enol-lactone hydrolases from Acinetobacter calcoaceticus.

The rates of thermal denaturation and the molecular weights of the two isofunctional enol-lactone hydrolases (ELH I and ELH II) of Acinetobacter calcoaceticus were determined. The molecular weights of ELH I and ELH II were found by gel filtration to be approximately 24,000 and 21,000, respectively. In crude extract at 45 C the two enzymes showed a marked difference in rate of thermal denaturation. After chromatography on Sephadex G-100, however, the rates were nearly identical. The thermolability of ELH II in crude extract was shown to be due to its sensitivity to an unidentified component of the crude extract which modified its rate of thermal denaturation. In the light of the physical similarities of the two enzymes, it is concluded that the different regulatory patterns imposed upon the two enzymes do not provide sufficient evidence that they are the product of two different structural genes.

Alcaligenes↗