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1.
Two synthetic routes to 3-deoxy-1α-hydroxyvitamin D3, an analog of 1α,25-dihydroxyvitamin D3, are described. One involved the six-step conversion of 1α,2α-epoxy-6,6-ethylenedioxy-5α-cholestan-3- one to 1α-acetoxycholest-5-ene, whereas, in the second, the same intermediate was prepared from 1α-hydroxycholesterol. Conversion of the Δ5-sterol to the required 5,7-diene was accomplished most efficiently via 7-keto and 7-tosylhydrazone intermediates. Bioassay of 3-deoxy-1α-hydroxyvitamin D3 in the rat establishes that the analog can fulfill all common vitamin D functions including stimulation of intestinal calcium transport, mobilization of calcium and phosphate from bone, stimulation of growth, and calcification of bone. Direct comparison indicates the compound to have to of the activity of 1α-hydroxyvitamin D3, but it acts with a time course indistinguishable from the latter. 相似文献
2.
Giacomino Randazzo Antonio Evidente Alberto Boccalatte Carlo Rossi 《Phytochemistry》1981,20(9):2177-2181
Measurement of isotope ratios in 1α,2α,3β-trihydroxy-p-menthane, which has been biosynthesized in Fusicoccum amygdali from 3H- and 14C-labelled mevalonate and in its degradation product diosphenol indicates that: (a) four tritium atoms arising from [5-3H2, 2-14C]MVA are retained, one more than suggested from the hydroxylation pattern, (b) menth-2-ene-1-ol is generated from an α-terpinyl cation through a 1,3-hydride shift and (c) trans-cleavage of an α-epoxide by hydrolysis gives 1α,2α,3β-trihydroxy-p-menthane. 相似文献
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Sally A. Holick Michael F. Holick Julia A. MacLaughlin 《Biochemical and biophysical research communications》1980,97(3):1031-1037
The simple three-step preparation of [1β-3H]1α,25-dihydroxyvitamin D3 and [1α-3H]1β,25-dihydroxyvitamin D3 from 1α,25-dihydroxyvitamin D3 is described. In the rat, 1β,25-dihydroxyvitamin D3, when compared with its α-epimer, did not stimulate intestinal calcium transport or bone calcium mobilization at doses 1000-fold higher than the doses of the natural hormone, 1α,25-dihydroxyvitamin D3. 相似文献
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Abstract 3′-Thio-3′-deoxyribonucleosides (U and C) have been synthesized via Vorbruggen-type glycosylation with 3-S-benzoyl-5-O-toluoyl-1,2-O-diacetylfuranose, which was obtained from 1,2-O-isopropylidene-5-O-toluoyl-3-O-trifluoromethanesulfonyl-α-D-xylofuranose. 3′-Thio-3′-deoxyuridine has been converted to its phosphoramidite. 相似文献
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The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl nucleosides of 5-fluorouracil (6a), N6-benzoyl adenine (6b), uracil (6c), thymine (6d) and N4-benzoyl cytosine (6e), is described. Monoiodination of compounds 1a,b, followed by acetylation, catalytic hydrogenation and finally regioselective 2′-O-deacylation afforded the partially acetylated dideoxynucleoside analogues of 5-fluorouracil (5a) and N6-benzoyl adenine (5b), respectively. Direct oxidation of the free hydroxyl group at the 2′-position of 5a,b, with simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl derivatives 6a,b. Compounds 1c-e were used as starting materials for the synthesis of the dideoxy unsaturated carbonyl nucleosides of uracil (6c), thymine (6d) and N4-benzoyl cytosine (6e). Similarly a protection-selective deprotection sequence followed by oxidation of the free hydroxyl group at the 2′-position of the dideoxy benzoylated analogues 9c-e with simultaneous elimination reaction of the β-benzoyl group, gave the desired nucleosides 6c-e. None of the compounds was inhibitory to a broad spectrum of DNA and RNA viruses at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 μM) than the other compounds. 相似文献
9.
Wang H Yin Y Li W Zhao X Yu Y Zhu J Qin Z Wang Q Wang K Lu W Liu J Huang L 《PloS one》2012,7(2):e30503
The proliferation, migration, and angiogenesis of endothelial progenitor cells (EPCs) play critical roles in postnatal neovascularization and re-endothelialization following vascular injury. Here we evaluated whether the over-expression of platelet-derived growth factor receptor-β (PDGFR-β) can enhance the PDGF-BB-stimulated biological functions of EPCs through the PDGFR-β/phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. We first confirmed the expression of endogenous PDGFR-β and its plasma membrane localization in spleen-derived EPCs. We then demonstrated that the PDGFR-β over-expression in EPCs enhanced the PDGF-BB-induced proliferation, migration, and angiogenesis of EPCs. Using AG1295 (a PDGFR kinase inhibitor), LY294002 (a PI3K inhibitor), and sc-221226 (an Akt inhibitor), we further showed that the PI3K/Akt signaling pathway participates in the PDGF-BB-induced proliferation, migration, and angiogenesis of EPCs. In addition, the PI3K/Akt signaling pathway is required for PDGFR-β over-expression to enhance these PDGF-BB-induced phenotypes. 相似文献
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Ohsawa N Koebis M Suo S Nishino I Ishiura S 《Biochemical and biophysical research communications》2011,409(1):484-69
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder of muscular dystrophy characterized by muscle weakness and wasting. DM1 is caused by expansion of CTG repeats in the 3′-untranslated region (3′-UTR) of DM protein kinase (DMPK) gene. Since CUG-repeat RNA transcribed from the expansion of CTG repeats traps RNA-binding proteins that regulate alternative splicing, several abnormalities of alternative splicing are detected in DM1, and the abnormal splicing of important genes results in the appearance of symptoms. In this study, we identify two abnormal splicing events for actinin-associated LIM protein 3 (PDLIM3/ALP) and fibronectin 1 (FN1) in the skeletal muscles of DM1 patients. From the analysis of the abnormal PDLIM3 splicing, we propose that ZASP-like motif-deficient PDLIM3 causes the muscular symptoms in DM. PDLIM3 binds α-actinin 2 in the Z-discs of muscle, and the ZASP-like motif is needed for this interaction. Moreover, in adult humans, PDLIM3 expression is highest in skeletal muscles, and PDLIM3 splicing in skeletal muscles is regulated during human development. 相似文献
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Patrizia Porcu Todd K. O’Buckley Sarah E. Alward Christine E. Marx Lawrence J. Shampine Susan S. Girdler A. Leslie Morrow 《Steroids》2009,74(4-5):463-473
The 3α,5α- and 3α,5β-reduced derivatives of progesterone, deoxycorticosterone, dehydroepiandrosterone and testosterone enhance GABAergic neurotransmission and produce inhibitory neurobehavioral and anti-inflammatory effects. Despite substantial information on the progesterone derivative (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone), the physiological significance of the other endogenous GABAergic neuroactive steroids has remained elusive. Here, we describe the validation of a method using gas chromatography–mass spectrometry to simultaneously identify serum levels of the eight 3α,5α- and 3α,5β-reduced derivatives of progesterone, deoxycorticosterone, dehydroepiandrosterone and testosterone. The method shows specificity, sensitivity and enhanced throughput compared to other methods already available for neuroactive steroid quantification. Administration of pregnenolone to rats and progesterone to women produced selective effects on the 3α,5α- and 3α,5β-reduced neuroactive steroids, indicating differential regulation of their biosynthetic pathways. Pregnenolone administration increased serum levels of 3α,5α-THP (+1488%, p < 0.001), (3α,5α)-3,21-dihydroxypregnan-20-one (3α,5α-THDOC, +205%, p < 0.01), (3α,5α)-3-hydroxyandrostan-17-one (3α,5α-A, +216%, p < 0.001), (3α,5α,17β)-androstane-3,17-diol (3α,5α-A-diol, +190%, p < 0.01). (3α,5β)-3-hydroxypregnan-20-one (3α,5β-THP) and (3α,5β)-3-hydroxyandrostan-17-one (3α,5β-A) were not altered, while (3α,5β)-3,21-dihydroxypregnan-20-one (3α,5β-THDOC) and (3α,5β,17β)-androstane-3,17-diol (3α,5β-A-diol) were increased from undetectable levels to 271 ± 100 and 2.4 ± 0.9 pg ± SEM, respectively (5/8 rats). Progesterone administration increased serum levels of 3α,5α-THP (+1806%, p < 0.0001), 3α,5β-THP (+575%, p < 0.001), 3α,5α-THDOC (+309%, p < 0.001). 3α,5β-THDOC levels were increased by 307%, although this increase was not significant because this steroid was detected only in 3/16 control subjects. Levels of 3α,5α-A, 3α,5β-A and pregnenolone were not altered. This method can be used to investigate the physiological and pathological role of neuroactive steroids and to develop biomarkers and new therapeutics for neurological and psychiatric disorders. 相似文献
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Background
Eicosapentaenoic acid-derived prostaglandin (PG) E3, PGF3α, and thromboxane (TX) B3 are bioactive lipid mediators which have anti-cancer and anti-inflammatory effects. To exert their effects, PGE3, PGF3α, and TXB3 must be released to the extracellular space from cells, but the release mechanism has been unclear. We therefore investigated the contribution of ATP-binding cassette transporter C4 (ABCC4), which has been known as a prostanoids efflux transporter, to the release of PGE3, PGF3α, and TXB3.Materials and Methods
ATP-dependent transport of PGE3, PGF3α, and TXB3 via ABCC4 was investigated by using inside-out membrane vesicles prepared from ABCC4-overexpressing HEK293 cells. To evaluate the contribution of ABCC4 to the release of PGE3, PGF3α, and TXB3, we measured the extracellular and intracellular levels of PGE3, PGF3α, and TXB3 in A549 cells when we used ABCC4 inhibitors (dipyridamole, MK571, and probenecid) or ABCC4 siRNAs. The quantification of PGE3, PGF3α, and TXB3 was performed by using liquid chromatography-tandem mass spectrometry.Results
The apparent Km values for ABCC4-mediated transport were 2.9±0.1 µM for PGE3, 12.1±1.3 µM for PGF3α, and 11.9±1.4 µM for TXB3 and the ATP-dependent accumulation of PGE3, PGF3α, and TXB3 into vesicles was decreased by using typical substrates and inhibitors of ABCC4. ABCC4 inhibitors and ABCC4 knockdown showed the reduction of extracellular/intracellular ratio of PGE3 (40–60% of control) and PGF3α (60–80% of control) in A549 cells.Conclusions
Our results suggest that PGE3, PGF3α, and TXB3 are substrates of ABCC4 and ABCC4 partially contributes to the release of PGE3 and PGF3α. 相似文献13.
Kadapakkam Nandabalan Sangeetha Sundaresan Sujatha Velusamy Shanmuganathan Muthusamy Singaravel Anand Nirmal Nithya Devadasan Velmurugan Arun Balakrishnan Baddireddi Subhadra Lakshmi 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010
Background
The present study focuses on identifying and developing an anti-diabetic molecule from plant sources that would effectively combat insulin resistance through proper channeling of glucose metabolism involving glucose transport and storage.Methods
Insulin-stimulated glucose uptake formed the basis for isolation of a bioactive molecule through column chromatography followed by its characterization using NMR and mass spectroscopic analysis. Mechanism of glucose transport and storage was evaluated based on the expression profiling of signaling molecules involved in the process.Results
The study reports (i) the isolation of a bioactive compound 3β-taraxerol from the ethyl acetate extract (EAE) of the leaves of Mangifera indica (ii) the bioactive compound exhibited insulin-stimulated glucose uptake through translocation and activation of the glucose transporter (GLUT4) in an IRTK and PI3K dependent fashion. (iii) the fate of glucose following insulin-stimulated glucose uptake was ascertained through glycogen synthesis assay that involved the activation of PKB and suppression of GSK3β.General significance
This study demonstrates the dual activity of 3β-taraxerol and the ethyl acetate extract of Mangifera indica as a glucose transport activator and stimulator of glycogen synthesis. 3β-taraxerol can be validated as a potent candidate for managing the hyperglycemic state. 相似文献14.
Induction of cardiac fibroblast lysyl oxidase by TGF-β1 requires PI3K/Akt, Smad3, and MAPK signaling
Lysyl oxidase (LOX) is a key extracellular enzyme responsible for the post-translational modification of collagens I and III to form mature fibrillar collagen. Increased expression of LOX is associated with fibrosis and cardiac dysfunction, yet little is known about the regulation of LOX in the heart. In this study, the cell signaling pathways responsible for the regulation of LOX expression by transforming growth factor (TGF)-β1 were assessed. Adult cardiac fibroblasts were isolated from male Sprague-Dawley rat hearts by enzymatic digestion. Fibroblasts were grown in DMEM with 10% FBS until approximately 80% confluent, growth arrested for 24h, and then treated with TGF-β1 (0-10 ng/ml), in the absence or presence of inhibitors of (1) PI3K (wortmannin), (2) Smad3 (SIS3), (3) p38-MAPK (PD169316), (4) JNK (SP600125) and (5) ERK1/2 (PD98059). TGF-β1 treatment significantly upregulated LOX mRNA and protein expression in cardiac fibroblasts, as well as activity in the cell-conditioned media. Concomitant increases in collagen types I and III, and bone morphogenic protein (BMP-1) expression were found in response to TGF-β1. The increase of LOX protein in response to TGF-β1 was prevented by inhibitors of PI3K, Smad3, p38-MAPK, JNK and ERK1/2. Blockade of PI3K also decreased TGF-β1 induced phosphorylation of Smad3, suggesting that the PI3K/Akt and Smad pathways may be integrated in TGF-β1 signaling. Further studies are warranted to address the regulation of LOX in the normal and diseased heart, and how this critical extracellular enzyme may be targeted for clinical benefit. 相似文献
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CD3 is an essential component of the CD3-TCR complex. In this report, we describe the cloning, characterization, and expression analysis of the CD3 and CD3/ chain genes from fugu, Takifugu rubripes. Two distinct CD3 homologue cDNAs, designated as CD3-1 and CD3-2, and a CD3/ homologue cDNA were isolated from the fugu thymus. The deduced amino acid sequences of these cDNAs exhibit conserved essential CD3 chain motifs and overall structures. RT-PCR analysis demonstrated that the CD3 and CD3/ genes were expressed in lymphoid organs (e.g. thymus, head kidney, trunk kidney and spleen), mucosal tissues (gill, skin, and intestine), and peripheral blood leucocytes (PBL). The CD3 and TCR genes were expressed only in the surface IgM– population, which were separated from PBL using an anti-fugu IgM monoclonal antibody. In addition, in situ hybridization confirmed that CD3-expressing cells were distributed randomly in the head kidney, trunk kidney, and spleen, but in the thymus were restricted to the lymphoid outer zone and epithelioid inner zone only. Collectively, these results suggest that CD3 molecules are useful markers for the identification of T cells in teleost fish. The present study thus provides a critical step in identifying T cells in this model organism.Nucleotide sequence data reported in this paper are available in the DBJ/EMBL/GenBank databases and have been assigned the accession numbers AB166798 (CD3-1), AB166799 (CD3-2), and AB166800 (CD3/). 相似文献
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Hydrogenolysis of benzyl penta-O-benzyl-4′,6′-O-benzylidene-β-cellobioside (4), -maltoside (5), and -allolactoside (16) with LiAlH4-AlCl3 gave only the corresponding derivatives having HO-6′ free, in yields of 55, 78, and 90%, respectively. The main product of the hydrogenolysis of benzyl penta-O-benzyl-4′,6′-O-benzylidene-β-lactoside (6) also had HO-6′ free, but the isomer having HO-4′ free was also isolated. The role of the C-1 substituent in the galactose moiety in the direction of benzylidene ring-cleavage is discussed. 相似文献
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Masahiro Ebihara 《Inorganica chimica acta》2004,357(4):1236-1242
Reactions of a benzylidyne-capped tricobalt cluster, [Co3Cp3(μ3-CPh)2] (1), with halogens (X2 = Cl2, Br2, and I2) in CH2Cl2 afforded halogen-adducts of 1. The structure of four isolated salts [Co3Cp3(μ3-CPh)2(μ-Cl)]PF6 · MeCN (2PF6 · MeCN), [Co3Cp3(μ3-CPh)2(μ-Br)]SbF6 (3SbF6), [Co3Cp3(μ3-CPh)2(μ-I)]SbF6 · CH2Cl2 (4SbF6 · CH2Cl2), and [Co3Cp3(μ3-CPh)2(μ-I)]I3 (4I3) determined by X-ray diffraction can be regarded formally as halide-adducts of 12+. The halogen atom in each structure lies in the Co3 plane. The halogen-bridged Co-Co edge was elongated (in 2PF6 · MeCN = 2.6072(4), in 3SbF6 = 2.6106(7), in 4SbF6 · CH2Cl2 = 2.622(2), and in 4I3=2.6718(9) Å), and the Co-Co distances that had no halogen-bridge remained unchanged from the Co-Co distance of 1 (2.382(8) Å), (in 2PF6=2.4037(8) and 2.3948(7), in 3SbF6=2.3888(6) and 2.4017(7), in 4SbF6 · CH2Cl2 = 2.393(2) and 2.388(1), and in 4I3 = 2.397(1) and 2.3868(9) Å). The UV-Vis absorption spectra of 2+, 3+, and 4+ had characteristic absorption peaks at 796, 819, and 844 nm, respectively. Cyclic voltammograms of 2PF6 in CH2Cl2 with 0.1 M nBu4NPF6 as the supporting electrolyte showed a chemically reversible oxidation (at a potential of 0.75 V versus Fc/Fc+), and an irreversible reduction wave at −0.57 V. The irreversible reduction resulted in the recovery of 1. The redox properties of 3+ and 4+ are very similar to that of 2+. Cyclic voltammetry of 1 in 0.1 M nBu4NCl/MeCN indicates that the formation of 2+ is a multi-step reaction. Initially, 1 is oxidized to 1+, and then, 1+ is coordinated by Cl− followed by immediate oxidation to 2+. 相似文献
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《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):923-925
Abstract Synthesis of 3′-deoxy-3′-fluoro-N 6-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A3 adenosine receptor are described. 相似文献
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In a preliminary study, autoradiography was used to localize target cells for 3Hdihydrotestosterone (DHT), a non-aromatizable androgen, in the brain of the rhesus monkey. One castrated male was injected intravenously with 2 mCi of 3HDHT (0.42 μg/kg), and was killed one hour later. Neurons that concentrated radioactivity in their nuclei were located in widespread areas of the brain, which included the medial and suprachiasmatic preoptic nuclei, bed nucleus of the stria terminalis, lateral septal nucleus, anterior hypothalamic area, ventromedial, arcuate, or dorsemedial, and paraventricular hypothalamic nuclei, ventral premammillary nucleus, and medial, cortical, basal accessory, and lateral amygdaloid nuclei. These results indicate that the topographic distribution of androgen target neurons is considerably wider than that observed in a study using 3Htestosterone (T) in the male rhesus monkey (1). However, further work is needed to elucidate these differences before attempting correlations between behavioral activity and androgen receptors in the brain. 相似文献