A study of the mechanism of polymyxin M inactivation

.I.NH₄OH , N N - - ,-. , .     

Butyrate-induced reactivation of the fetal globin genes: A molecular treatment for theβ-hemoglobinophaties

The inherited -hemoglobinopathies (sickle cell disease and thalassemia) are the result of a mutation in the adult () globin gene. The fetal globin chain, encoded by the globin genes, can substitute for the mutated or defective globin chain, but expression of the globin gene is developmentally inactivated prior to birth. Reinducing expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and the thalassemias. Stimulation of as little as 4–8% fetal globin synthesis in the bone marrow can produce >20% fetal hemoglobin in the peripheral circulation, due to enhanced survival of red blood cells containing both sickle and fetal hemoglobin, compared to those containing sickle hemoglobin alone. Butyric acid and butyrate derivatives are generally safe compounds which induce fetal hemoglobin production by stimulating the promoter of the fetal globin genes. An initial trial with the parent compound, delivered as Arginine Butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that have been shown to ameliorate these conditions. Phase 1 trials of an oral butyrate derivative with a long plasma half-life have just begun. These agents now provide a specific new apporach for ameliorating these classic molecular disorders and merit further investigation in larger patient populations.     

The molecular structure of the benzilic acid rearrangement product of 3α, 17β-diacetoxy-11-hydroxy-12-oxo-5β-androst-9(11)-ene

Zusammenfassung Die Struktur desp-Brombenzoates des Benzilsäureumlagerungsproduktes von 3, 17-Diacetoxy-11-hydroxy-12-oxo-5-9(11)-androsten wurde durch dreidimensionale Röntgenstrukturanalyse eines Einkristalls als 3-p-Brombenzoat des 11-Carboxy-3, 11, 17-trihydroxy-13-C-nor-5-androstan 11a, 17-Laktons erkannt.     

Metabolism in Porifera. IX. Studies on the biological conversion of cholesterol into 19-nor-cholestanol by the spongeAxinella polypoides

Summary The conversion of cholesterol into 19-nor-5-cholestan-3-ol by the spongeAxinella polypoides involves a partial loss (40%) of the 3-hydrogen atom; moreover administration to the sponge of [4-¹⁴C]cholesterol tritiated at C-4 and C-7 showed that the 4- and 7-hydrogen atoms are retained in this conversion. A competitive uptake experiment, [4-¹⁴C]cholesterol vs. [7-³H₂]5-cholestanol, showed that the sponge utilized exclusively cholesterol for the production of 19-nor-5-cholestan-3-ol.Part of this work has been presented at the Nato Conference on Marine Natural Products (Jersey, Great Britain, October, 1976).-This contribution is part of the Programma finalizzato Oceanografia e Fondi marini-sottoprogetto Risorse biologiche C.N.R. Italy.     

Defensive steroids from a carrion beetle (Silpha americana)

Summary The defensive anal effluent discharged bySilpha americana in response to disturbance contains a mixture of steroids stemming from a glandular annex of the rectum. The compounds have been characterized as 15-hydroxyprogesterone (1, principal component), 5-pregnan-15-ol-3, 20-dione (2), 5-pregnan-3, 15-diol-20-one (3), 5-pregnan-7, 15-diol-3,20-dione (4), 5-pregnan-3, 7, 15-triol-20-one (5), 5-pregnan-16-ol-3,20-dione (6), and 5-pregnan-3, 16-diol-20-one (7), none previously found in insects. Bioassays with jumping spiders showed compounds1 and6 to be feeding deterrents at the 1 g level.Paper No. 78 of the series: Defense Mechanisms of Arthropods. Study supported by NIH (Grants AI-02908, AI-12020). We thank Maura Malarcher and Maria Eisner for excellent technical help, and the Squibb Institute of Medical Research for samples of authentic reference compounds.     

Antitumor effect of β-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death

-Elemene is a novel anticancer drug, which was extracted from the ginger plant. However, the mechanism of action of -elemene in non-small-cell lung cancer (NSCLC) remains unknown. Here we show that -elemene had differential inhibitory effects on cell growth between NSCLC cell lines and lung fibroblast and bronchial epithelial cell lines. In addition, -elemene was found to arrest NSCLC cells at G2-M phase, the arrest being accompanied by decreases in the levels of cyclin B1 and phospho-Cdc2 (Thr-161) and increases in the levels of p27^kip1 and phospho-Cdc2 (Tyr-15). Moreover, -elemene reduced the expression of Cdc25C, which dephosphorylates/activates Cdc2, but enhanced the expression of the checkpoint kinase, Chk2, which phosphorylates/ inactivates Cdc25C. These findings suggest that the effect of -elemene on G2-M arrest in NSCLC cells is mediated partly by a Chk2-dependent mechanism. We also demonstrate that -elemene triggered apoptosis in NSCLC cells. Our results clearly show that -elemene induced caspase-3, –7 and –9 activities, decreased Bcl-2 expression, caused cytochrome c release and increased the levels of cleaved caspase-9 and poly(ADP-ribose) polymerase in NSCLC cells. These data indicate that the effect of -elemene on lung cancer cell death may be through a mitochondrial release of the cytochrome c-mediated apoptotic pathway.Received 12 January 2005; accepted 5 February 2005     

Isoforms of baker's yeast transketolase

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Uptake of D-glucose anomers by rat retina

Summary Uptake ofd-glucose anomers by isolated rat retina was studied. After 3 min incubation at 37°C in the presence of or anomer (750 g/ml), a significantly greater uptake (1.32 mg/g wet tissue) of -anomer was observed compared with that of -d-glucose (1.11 mg/g wet tissue). This result and other data suggest that the carrier ford-glucose transport in the retina prefers the -anomer stereospecifically.Acknowledgment. The authors are grateful to Mr S. Suzuki for his technical assistance.     

Gender- and site-related effects on lipolytic capacity of rat white adipose tissue

Gender- and site-related differences in the lipolytic capacity, at the different steps of the adrenergic pathway, in gonadal and inguinal white adipose tissue (WAT), were assessed by studying _2A-adrenergic receptor (AR), ₃-AR and hormone-sensitive lipase (HSL) protein levels, and by determining the lipolytic response to different agents. Gonadal WAT showed a lower _2A/₃-AR ratio, a greater lipolytic capacity in response to AR agonists, and higher HSL activity and protein levels than inguinal WAT. In female rats, we found greater _2A-AR protein levels and _2A/₃-AR ratio compared to their male counterparts, but, on the other hand, a higher lipolytic response to -AR agonists and a greater lipolytic capacity at the postreceptor level, including a more activated HSL protein. Thus, the lipolytic capacity was clearly higher in gonadal than in inguinal WAT, at the different steps of the adrenergic pathway studied. Moreover, in both tissues, females showed a greater inhibition of lipolysis via ₂-AR, which was counteracted by the higher lipolytic capacity at the postreceptor level.Received 1 April 2003; received after revision 11 June 2003; accepted 23 June 2003     

11β-methyl-19-norsteroids: Novel progestational hormones

Zusammenfassung Die Synthese von 3, 17-Diacetoxy-17-Äthinyl-11-Methylestr-4-en (XII) wird beschrieben. Die Substanz besitzt besonders starke Antifertilitätseigenschaften, wie sie sonst nur Mischungen von Hormonen eigen sind, welche für die Humanfertilität benutzt werden, jedoch ohne deren Nebenwirkungen.     

The participation of kinins in the pathogenesis of early disturbances in the skin capillary permeability in localβ-ray irradiation

, - Sr⁹⁰ + Y⁹⁰, , . - () . , , - .     

Age-related differences in the urinary excretion of prostaglandin F2α catabolites in the rat

Summary Tritium-labelled PGF₂ was administered i.v. into rats of varying ages (2, 4, 6 weeks and adult). Urine was collected and assayed for radioactive products by thin-layer-chromatography. Results showed a distinctly different urinary profile between the 2-week-old and the adult rat. While the urinary pattern from the 2-week-old rat gave a single less polar product than PGF₂, the pattern from the adult rat gave products more polar than PGF₂. Urine from the 4- and 6-week-old rats gave a mixture of these types of products. These results indicate that some prostaglandin catabolic pathway (likely the -oxidative system) is activated in vivo within the 4–6-week postnatal period in the rat.Supported by a grant (MT-4181) to C.P.-A. from the Medical Research Council of Canada.This study is in partial fulfillment of the requirements for a Ph.D. degree in the Department of Pharmacology, University of Toronto.     

Evidence for the extranuclear localization of thymosins in thymus

A new radioimmunoassay has been developed for thymosin ₄ by generating rabbit polyclonal antibodies against the synthetic N-terminal peptide fragment 1–15 coupled to KLH. The synthetic analogue [Tyr¹²]-thymosin ₄ (1–15) was used as tracer. This radioimmunoassay, with a useful range of 10–1000 pmoles, showed cross-reactivity with the second homologous -thymosin of man and rat (thymosin ₁₀) but not of calf (thymosin ₉). This radioimmunoassay, together with an improved radioimmunoassay for the N-terminus of parathymosin , was employed for the measurement of the levels of thymosin ₄ and parathymosin in nuclear and extranuclear extracts of calf thymus. The bulk of these polypeptides was found in the extranuclear material whereas only traces were observed in the nuclear environment, which indicates the extranuclear localisation of - and -thymosins.     

X-ray research for polycrystals. The formation geometry of instrumental width of the diffractional line at the investigation of the polycrystals in the translucent X-rays

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Changes in the lumen of coronary vessels under oligemic hypotension

Conclusions The decrease of circulating blood volume, resulting in oligemic hypotension, may evoke in anaesthetized cat the active constrictory coronary vessel responses of 2 types, one occuring immediately after start of the hypotension and the other having a significantly prolonged latency.

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The formation of androgens in human foetal liver in vitro

Zusammenfassung Nach Inkubation des homogenisierten Lebergewebes menschlicher, 7–20 Wochen alter, Foeten mit 3-Hydroxy-5-androsten-17-on wird die Bildung von Testosteron, 4-Androsten-3, 17-dion und 5-Androsten-3, 17-diol nachgewiesen.     

The effect of chloramphenicol analogs on protein biosynthesis in a cell-freeEscherichia coli B system

a aaa a aa aa a a E. coli aa, a aa aa a , a a aa - a .

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Laboratory of Biological Investigations.

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Laboratory for Chemistry of Antibiotics.     

Chromosomes and some issues of the evolution of the ground squirrel genusCitellus (Rodentia: Sciuridae)

Citellus (s. str.) relictus, C. dauricus C. pygmaeus (2=36, NF=72). . (Colobotis) erythrogenys . fulvus -. . (Urocitellus) undulatus (2n=32, NF=64) . columbianus. Citellus, , Citellus, . , .     

Effect of administration of synthetic ecdysone on the moulting ofPalamnaeus bengalensis

Summary Synthetic analogue of ecdysone, 3, 14-dihydroxy-5-cholest-7-en-6-one did not bring the scorpionPalamnaeus bengalensis to moult. It also failed completely in stimulating the scorption to produce any change related to moulting.Acknowledgment. Author is grateful to Dr Suresh C. Shrivastava for providing research facilities, Dr S.P. Tewarson for encouragement and S.C.S.T. (U.P.) for funds. Present address: Department of Zoology, Lucknow Christian College, Lucknow-226001.