Crystal and molecular structure of 3, 3′-dibromobenzophenone

Résumé La structure du cristal de 3, 3-dibromobenzophénone a été définie par l'emploi de données obtenues par rayons X dans trois dimensions. Les distances et les angles de liaison ont été obtenus et l'on a trouvé que deux anneaux de phényle de la molécule ne sont pas dans le même plan, l'angle compris entre eux étant de 39,9°.     

Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review, we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt, Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD. Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006     

Reduction of adenylylsulfate and 3′-phosphoadenylylsulfate in phototrophic bacteria

Summary Extracts of 14 species of phototrophic bacteria, partly grown with different sulfur compounds, were tested for their ability to form volatile sulfur compounds from adenylylsulfate (APS) and 3-phosphoadenylylsulfate (PAPS). The Rhodospirillum species showed marked activities with both APS and PAPS while the Rhodopseudomonas species seem to prefer PAPS. the Chromatiaceae exhibited the strongest activities with APS, whereas Chlorobium limicola had equally high activity with PAPS.We thank J. F. Imhoff for skilful assistance and the Deutsche Forschungsgemeinschaft for financial support.     

Synthesis and application of the photolabile guanosine 3′,5′-phosphoric-o-nitrobenzylester

Summary The o-nitrobenzylester of guanosine 3,5-phosphate is prepared and the photolysis studied. This photoactive form of cGMP should be an agent capable of altering the intracellular concentration of cGMP through membrane penetration and subsequent photolysis.Acknowledgments. We would like to thank the Deutsche Forschungsgemeinschaft and the Universität Konstanz for kindly supporting this research.     

C3aR and C5aR1 act as key regulators of human and mouse β-cell function

Aims

Complement components 3 and 5 (C3 and C5) play essential roles in the complement system, generating C3a and C5a peptides that are best known as chemotactic and inflammatory factors. In this study we characterised islet expression of C3 and C5 complement components, and the impact of C3aR and C5aR1 activation on islet function and viability.

Materials and methods

Human and mouse islet mRNAs encoding key elements of the complement system were quantified by qPCR and distribution of C3 and C5 proteins was determined by immunohistochemistry. Activation of C3aR and C5aR1 was determined using DiscoverX beta-arrestin assays. Insulin secretion from human and mouse islets was measured by radioimmunoassay, and intracellular calcium ([Ca²⁺]i), ATP generation and apoptosis were assessed by standard techniques.

Results

C3 and C5 proteins and C3aR and C5aR1 were expressed by human and mouse islets, and C3 and C5 were mainly localised to β- and α-cells. Conditioned media from islets exposed for 1 h to 5.5 and 20 mM glucose stimulated C3aR and C5aR1-driven beta-arrestin recruitment. Activation of C3aR and C5aR1 potentiated glucose-induced insulin secretion from human and mouse islets, increased [Ca²⁺]i and ATP generation, and protected islets against apoptosis induced by a pro-apoptotic cytokine cocktail or palmitate.

Conclusions

Our observations demonstrate a functional link between activation of components of the innate immune system and improved β-cell function, suggesting that low-level chronic inflammation may improve glucose homeostasis through direct effects on β-cells.

     

Prothoracic gland synthesis of 3-dehydroecdysone and its hemolymph 3β-reductase mediated conversion to ecdysone in representative insects

Summary The prothoracic glands of a variety of insects were tested for their ability to synthesize ecdysteroids in vitro. More specifically, they were evaluated for their ability to produce 3-dehydroecdysone and ecdysone using both radioimmunoassay and reverse phase high performance liquid chromatography. Three categories of insect prothoracic glands were noted: a) those producing much more 3-dehydroecdysone than ecdysone; b) glands synthesizing almost equivalent amounts of each of these two ecdysteroids; c) prothoracic glands that yielded more ecdysone than 3-dehydroecdysone. In addition, the 3-oxoecdysteroid 3-reductase activity of the hemolymph of these insects was evaluated for its ability to convert 3-dehydroecdysone to ecdysone. The lepidopteran species tested yielded the most potent enzyme activity, although activity was demonstrated in members of other orders. These data indicate that the dehydroecdysone-ecdysone axis is not restricted to moths and butterflies.     

Protein profiling of 3T3-L1 adipocyte differentiation and (tumor necrosis factor α-mediated) starvation

The increased incidence of obesity and related disorders in Western societies requires a thorough understanding of the adipogenic process. Data at the protein level of this process are scarce. Therefore we performed a proteome analysis of differentiating and starving 3T3-L1 cells using two-dimensional gel electrophoresis combined with mass spectrometry. Effects of different starvation conditions were examined by subjecting 3T3-L1 adipocytes to caloric restriction, either in the absence or the presence of the lipolysis inducer tumor necrosis factor-. Ninety-three differentially expressed proteins were found during differentiation and starvation of 3T3-L1 cells, 50 of which were identified. GenMAPP/MAPP-finder software revealed a non-reciprocal regulation of the glycolytic pathway during 3T3-L1 differentiation followed by starvation. Furthermore, proteins involved in growth regulation, cytoskeletal rearrangements and protein modification, 16 of which have not been described before in 3T3-L1 cells, were identified. In conclusion, our data provide valuable information for further understanding of the adipogenic process.Received 9 November 2004; received after revision 21 December 2004; accepted 28 December 2004     

GSK-3β is essential for physiological electric field-directed Golgi polarization and optimal electrotaxis

Endogenous electrical fields (EFs) at corneal and skin wounds send a powerful signal that directs cell migration during wound healing. This signal therefore may serve as a fundamental regulator directing cell polarization and migration. Very little is known of the intracellular and molecular mechanisms that mediate EF-induced cell polarization and migration. Here, we report that Chinese hamster ovary (CHO) cells show robust directional polarization and migration in a physiological EF (0.3–1 V/cm) in both dissociated cell culture and monolayer culture. An EF of 0.6 V/cm completely abolished cell migration into wounds in monolayer culture. An EF of higher strength (≥1 V/cm) is an overriding guidance cue for cell migration. Application of EF induced quick phosphorylation of glycogen synthase kinase 3β (GSK-3β) which reached a peak as early as 3 min in an EF. Inhibition of protein kinase C (PKC) significantly reduced EF-induced directedness of cell migration initially (in 1–2 h). Inhibition of GSK-3β completely abolished EF-induced GA polarization and significantly inhibited the directional cell migration, but at a later time (2–3 h in an EF). Those results suggest that GSK-3β is essential for physiological EF-induced Golgi apparatus (GA) polarization and optimal electrotactic cell migration.     

Totally synthetic (±)-13-Alkyl-3-hydroxy and methoxy-gona-1,3,5(10)-trien-17-ones and related compounds

Zusammenfassung Von mehreren (±) 3-Oxy- und (±) 3-Methoxy-13-alkylgona-1,3,5(10)trien-17-onen und verwandten Verbindungen, einschliesslich von Vertretern der (±) 13-Alkylgon-4-en-3-on-Reihe, werden Totalsynthese und biologische Wirksamkeit beschrieben.     

NHE3 phosphorylation via PKCη marks the polarity and orientation of directionally migrating cells

Endogenous electric fields (EF) may provide an overriding cue for directional cell migration during wound closure. Perceiving a constant direction requires active sodium-hydrogen exchanger (pNHE3) at the leading edge of HEK 293 cells but its activation mechanism is not yet fully understood. Because protein kinase C (PKC) is required in electrotaxis, we asked whether NHE3 is activated by PKC during wound healing. Using pharmacological (pseudosubstrate and edelfosine) inhibition, we showed that inhibition of PKCη isoform impairs directional cell migration in HEK 293 cells in the presence of a persistent directional cue (0.25–0.3 V/mm of EF for 2 h). Further, we found that pNHE3 forms complexes with both PKCη and ?-tubulin, suggesting that these molecules may regulate the microtubule-organizing center. In addition, cellular pNHE3 content was reduced significantly when PKCη was inhibited during directional cell migration. Taken together, these data suggest that PKCη-dependent phosphorylation of NHE3 and the formation of pNHE3/PKCη/?-tubulin complexes at the leading edge of the cell are required for directional cell migration in an EF.     

Correlation between 3′,5′, c-AMP levels and thyrotropin in separated rat pituitary thyrotropic cells

Summary The correlation between 3,5, c-AMP levels, TSH content and secretion of separated thyrotropic cells was studied. Incubation of the separated cells with 1, 10 and 100 ng of TRH does not change the 3,5, c-AMP levels, despite the significant rises of the TSH level. Dibutyryl c-AMP causes rise in TSH content, with no indication of its secretion. PGE₂ 10^–5 increased 3, 5, c-AMP levels with no change in the content or secretion of TSH in separated thyrotropic cells.     

3-Cyclopentyl ether of 17α-ethynylestradiol: A potent anti-gonadotrophic and contraceptive agent in rodents

Riassunto Esperienze condotte in ratti e topi parabionti hanno permesso di stabilire che il 3-ciclopentil etere del 17-etinilestradiolo, estrogeno dotato di elevatissima attività uterotrofica per via orale, è parimenti fornito di forte potere inibente sulla secrezione gonadotropa ipofisaria. Pure a dosi minime esso rivela chiare proprietà anticoncezionali nei ratti femmine. Sia come inibitore ipofisario che come inibitore della fertilità, tale composto si dimostra notevolmente più attivo del 3-metil etere del 17-etinilestradiolo.     

One-step synthesis route of the aligned and non-aligned single crystalline α-Si_3N_4 nanowires

This paper reports the bulk synthesis route of the aligned and non-aligned high-qualityα-Si 3 N4 nanowires(NWs) which were grown directly from the Si substrate by vapor phase deposition at 1050℃.The as-grown products were characterized by employing XRD,SEM,HRTEM and photoluminescence.The microscopic results revealed that the products consist of single crystalline aligned and non-alignedα-Si 3 N4 NWs having a same diameter range of 30-100 nm and different lengths of about hundreds of microns.The XRD observation revealed that the products consist ofα-phase Si 3 N4 NWs.The room temperature PL spectra indicated that the NWs have good emission property.The non-aligned NWs were formed at lower temperature as compared with aligned NWs.Our method is a simple and one-step procedure to synthesize the bulk-quantity and high-purity aligned and non-alignedα-Si 3 N4 NWs at a relatively low temperature.The possible growth mechanism was also briefly discussed.     

Mutagenicity testing of 3 hallucinogens: LSD,psilocybin and‡ 9-THC using the micronucleus test

Summary Using the micronucleus test as a screening method for mutagenic activity, no significant increase in the number of micronuclei was found when LSD, psilocybin or ⁹-THC were administered in 3 logarithmically increasing doses to mice. Azathioprine (Imuran^®), given as a positive control, caused a statistically significant increase in micronucleated cells.Acknowledgment. The expert technical assistance of Mr Joop Branger is greatfully acknowledged. We thank Prof. Dr C. A. Salemink, University of Utrecht, for the supply of the THC, and Dr J. Fokkens, National Institute of Public Health, for preparing the solutions.     

An antagonism between 3–4 dioxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP)

Riassunto Recentemente è stata formulata l'ipotesi che la 5-idrossitriptamina e la noradrenalina agiscano come mediatori a livello del S.N.C. I risultati ottenuti dall'A. dimostrano che la diossifenilalanina può antagonizzare il potenziamento della narcosi barbiturica indotto dal 5-idrossitriptafano.

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Research fellow from Keio University, Tokyo (Japan).     

Testicular Δ5-3β dehydrogenase,ascorbic acid and dehydroascorbic acid in actinomycin D-treated toads

Summary Unilaterally intratesticular injection of actionomycin D in toad inhibited ⁵-3 dehydrogenase activity with significant increase of dehydroascorbic acid and decrease of ascorbic acid level in the testis.Acknowledgments. Thanks are due to Prof. C. Deb, Department of Physiology, Calcutta University, for his suggestions and constant encouragment. Thanks are also extended to Mr R.K. Bhattacharya Microphotographer Department of Physiology, for his kind cooperation.     

A simple synthesis of (E)-3-formylbut-2-enenitrile,and its use as a precursor of isotope-labelled zeatin and (±) dihydrozeatin

Summary (E)-3-Formylbut-2-enenitrile (4) is synthesized in 2 steps by reacting pyruvaldehyde dimethylacetal and acetonitrile in the presence of sodium methoxide, followed by acid hydrolysis to give 58% overall yield on distillation. The aldehyde4 can be stepwise and selectively reduced to (E)-3-hydroxymethylbut-2-enylamine (7a) in 37% total yield or exhaustivelyb reduced in 1 step to (±)-4-hydroxy-3-methylbutylamine (6) in 46% total yield. Compound7a and6 can be condensed with 6-chloropurine to give zeatin and (±)dihydrozeatin respectively. This provides a readily accessible method for isotope-labelled zeatin and its derivatives at side chain.Contribution No. 1064, Alberta Research CouncilProcess for the Preparation oftrans-3-formylbut-2-enenitrile S. Chen and J. MacTaggart, patent applicatioin registered in Canada and the United States of America.Acknowledgment. The author thanks Mr J. M. MacTaggart and Mrs C. M. Goulet for valuable experimental assistance and Dr R. M. Elofson for helpful discussions.     

D2A sequence of the urokinase receptor induces cell growth through αvβ3 integrin and EGFR

The urokinase receptor (uPAR) stimulates cell proliferation by forming a macromolecular complex with αvβ3 integrin and the epidermal growth factor receptor (EGFR, ErbB1 or HER1) that we name the uPAR proliferasome. uPAR transactivates EGFR, which in turn mediates uPAR-initiated mitogenic signal to the cell. EGFR activation and EGFR-dependent cell growth are blocked in the absence of uPAR expression or when uPAR activity is inhibited by antibodies against either uPAR or EGFR. The mitogenic sequence of uPAR corresponds to the D2A motif present in domain 2. NMR analysis revealed that D2A synthetic peptide has a particular three-dimensional structure, which is atypical for short peptides. D2A peptide is as effective as EGF in promoting EGFR phosphorylation and cell proliferation that were inhibited by AG1478, a specific inhibitor of the tyrosine kinase activity of EGFR. Both D2A and EGF failed to induce proliferation of NR6-EGFR-K721A cells expressing a kinase-defective mutant of EGFR. Moreover, D2A peptide and EGF phosphorylate ERK demonstrating the involvement of the MAP kinase signalling pathway. Altogether, this study reveals the importance of sequence D2A of uPAR, and the interdependence of uPAR and EGFR.