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791.
Harris DM Li L Chen M Lagunero FT Go VL Boros LG 《Metabolomics : Official journal of the Metabolomic Society》2012,8(2):201-210
The rationale of this dose matching/dose escalating study was to compare a panel of flavonoids—luteolin, resveratrol, and
quercetin—against the metabolite flux-controlling properties of a synthetic targeted fatty acid synthase inhibitor drug C75
on multiple macromolecule synthesis pathways in pancreatic tumor cells using [1,2-13C2]-d-glucose as the single precursor metabolic tracer. MIA PaCa-2 pancreatic adenocarcinoma cells were cultured for 48 h in the
presence of 0.1% DMSO (control), or 50 or 100 μM of each test compound, while intracellular glycogen, RNA ribose, palmitate
and cholesterol as well as extra cellular 13CO2, lactate and glutamate production patterns were measured using gas chromatography/mass spectrometry (GC/MS) and stable isotope-based
dynamic metabolic profiling (SiDMAP). The use of 50% [1,2-13C2]-d-glucose as tracer resulted in an average of 24 excess 13CO2 molecules for each 1,000 CO2 molecule in the culture media, which was decreased by 29 and 33% (P < 0.01) with 100 μM C75 and luteolin treatments, respectively. Extracellular tracer glucose-derived 13C-labeled lactate fractions (Σm) were between 45.52 and 47.49% in all cultures with a molar ratio of 2.47% M + 1/Σm lactate
produced indirectly by direct oxidation of glucose in the pentose cycle in control cultures; treatment with 100 μM C75 and
luteolin decreased this figure to 1.80 and 1.67%. The tracer glucose-derived 13C labeled fraction (Σm) of ribonucleotide ribose was 34.73% in controls, which was decreased to 20.58 and 8.45% with C75,
16.15 and 6.86% with luteolin, 27.66 and 19.25% with resveratrol, and 30.09 and 25.67% with quercetin, respectively. Luteolin
effectively decreased nucleotide precursor synthesis pentose cycle flux primarily via the oxidative branch, where we observed
a 41.74% flux (M + 1/Σm) in control cells, in comparison with only a 37.19%, 32.74%, or a 26.57%, 25.47% M + 1/Σm flux (P < 0.001) after 50 or 100 μM C75 or luteolin treatment. Intracellular de novo fatty acid palmitate (C16:0) synthesis was severely
and equally blocked by C75 and luteolin treatments indicated by the 5.49% (control), 2.29 or 2.47% (C75) and 2.21 or 2.73%
(luteolin) tracer glucose-derived 13C-labeled fractions, respectively. On the other hand there was a significant 192 and 159% (P < 0.001), and a 103 and 117% (P < 0.01) increase in tracer glucose-derived cholesterol after C75 or luteolin treatment. Only resveratrol and quercetin at
100 μM inhibited tracer glucose-derived glycogen labeling (Σm) and turnover by 34.8 and 23.8%, respectively. The flavonoid
luteolin possesses equal efficacy to inhibit fatty acid palmitate de novo synthesis as well as nucleotide RNA ribose turnover
via the oxidative branch of the pentose cycle in comparison with the targeted fatty acid synthase inhibitor synthetic compound
C75. Luteolin is also effective in stringently controlling glucose entry and anaplerosis in the TCA cycle, while it promotes
less glucose flux towards cholesterol synthesis than that of C75. In contrast, quercetin and resveratrol inhibit glycogen
synthesis and turnover as their underlying mechanism of controlling tumor cell proliferation. Therefore the flavonoid luteolin
controls fatty and nucleic acid syntheses as well as energy production with pharmacological strength, which can be explored
as a non-toxic natural treatment modality for pancreatic cancer. 相似文献
792.
The population of the world has recently passed the 7 billion milestone and as the cost of human genome sequencing is rapidly declining, sequence data of billions of people should be accessible much sooner than anyone would have predicted 10years ago. This will form the basis of personalised medicine. However it is still not clear, even in principle, whether these data, combined with data of the expression of one's genome in various cells and tissues relevant to different diseases, could be used effectively in clinical medicine and healthcare, or in predicting responses to different therapies. Therefore this is an important issue which needs to be addressed before more resources are wasted on less than informative studies and surveys simply because technologies exist. As a typical example, we have selected and summarise here key studies from the biomedical literature that focus on gene expression profiling of the response to biologic therapies in peripheral blood and biopsy samples in autoimmune diseases such as rheumatoid arthritis, spondylarthropathy, inflammatory bowel diseases and psoriasis. We also present the state of the biotechnology market from a European perspective, discuss how spin-offs leverage the power of genomic technologies and describe how they might contribute to personalised medicine. As ethical, legal and social issues are essential in the area of genomics, we analysed these aspects and present here the European situation with a special focus on Hungary. We propose that the synergy of these three issues: pharmacogenomics, biotechnology and regulatory issues should be considered a triad necessary to succeed in personalised medicine. 相似文献
793.
Reading DNA at single-nucleotide resolution with a mutant MspA nanopore and phi29 DNA polymerase 总被引:3,自引:0,他引:3
Manrao EA Derrington IM Laszlo AH Langford KW Hopper MK Gillgren N Pavlenok M Niederweis M Gundlach JH 《Nature biotechnology》2012,30(4):349-353
Nanopore technologies are being developed for fast and direct sequencing of single DNA molecules through detection of ionic current modulations as DNA passes through a pore's constriction. Here we demonstrate the ability to resolve changes in current that correspond to a known DNA sequence by combining the high sensitivity of a mutated form of the protein pore Mycobacterium smegmatis porin A (MspA) with phi29 DNA polymerase (DNAP), which controls the rate of DNA translocation through the pore. As phi29 DNAP synthesizes DNA and functions like a motor to pull a single-stranded template through MspA, we observe well-resolved and reproducible ionic current levels with median durations of ~28 ms and ionic current differences of up to 40 pA. Using six different DNA sequences with readable regions 42-53 nucleotides long, we record current traces that map to the known DNA sequences. With single-nucleotide resolution and DNA translocation control, this system integrates solutions to two long-standing hurdles to nanopore sequencing. 相似文献
794.
795.
796.
Otomycosis, also known as fungal otitis externa, has been used to describe a fungal infection of the external auditory canal, but sometimes involving the middle ear. Many fungal species have been identified as infectious agents in otomycosis, with Aspergillus and Candida species being the most common. Among aspergilli, Aspergillus niger is the most commonly described species in the literature. In this study, 14 black Aspergillus strains were analyzed, which were isolated from otomycosis cases in Hungary between 2010 and 2011. These strains were identified as A. niger according to conventional morphological methods. Species identification was based on sequencing of part of the calmodulin gene. Our results indicate that instead of A. niger, A. awamori and A. tubingensis are the predominant species that cause ear infections in Southern Hungary. Antifungal susceptibility tests were carried out against four antifungal drugs: amphotericin B, itraconazole, ketoconazole and terbinafine. All isolates were found to exhibit low in vitro MIC values to amphotericin B, terbinafine and itraconazole. However, the examined isolates exhibited high in vitro MIC values to ketoconazole. 相似文献
797.
Treves S Thurnheer R Mosca B Vukcevic M Bergamelli L Voltan R Oberhauser V Ronjat M Csernoch L Szentesi P Zorzato F 《The Biochemical journal》2012,441(2):731-741
In the present study we provide evidence that SRP-35, a protein we identified in rabbit skeletal muscle sarcoplasmic reticulum, is an all-trans-retinol dehydrogenase. Analysis of the primary structure and tryptic digestion revealed that its N-terminus encompasses a short hydrophobic sequence bound to the sarcoplasmic reticulum membrane, whereas its C-terminal catalytic domain faces the myoplasm. SRP-35 is also expressed in liver and adipocytes, where it appears in the post-microsomal supernatant; however, in skeletal muscle, SRP-35 is enriched in the longitudinal sarcoplasmic reticulum. Sequence comparison predicts that SRP-35 is a short-chain dehydrogenase/reductase belonging to the DHRS7C [dehydrogenase/reductase (short-chain dehydrogenase/reductase family) member 7C] subfamily. Retinol is the substrate of SRP-35, since its transient overexpression leads to an increased production of all-trans-retinaldehyde. Transfection of C2C12 myotubes with a fusion protein encoding SRP-35-EYFP (enhanced yellow fluorescent protein) causes a decrease of the maximal Ca2? released via RyR (ryanodine receptor) activation induced by KCl or 4-chloro-m-chresol. The latter result could be mimicked by the addition of retinoic acid to the C2C12 cell tissue culture medium, a treatment which caused a significant reduction of RyR1 expression. We propose that in skeletal muscle SRP-35 is involved in the generation of all-trans-retinaldehyde and may play an important role in the generation of intracellular signals linking Ca2+ release (i.e. muscle activity) to metabolism. 相似文献
798.
Zhang Z Kodumuru V Sviridov S Liu S Chafeev M Chowdhury S Chakka N Sun J Gauthier SJ Mattice M Ratkay LG Kwan R Thompson J Cutts AB Fu J Kamboj R Goldberg YP Cadieux JA 《Bioorganic & medicinal chemistry letters》2012,22(15):5108-5113
Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization. 相似文献
799.
Nice Liana Huang Yadong Steffenson Brian J. Gyenis Laszlo Schwarz Paul Smith Kevin P. Muehlbauer Gary J. 《Molecular breeding : new strategies in plant improvement》2019,39(8):1-10
Molecular Breeding - The brown midrib (bmr) phenotype is a recessive trait of sorghum (Sorghum bicolor L. Moench) that results in overall lignin reduction and is associated with enhanced ruminant... 相似文献
800.
Gascon E Vutskits L Jenny B Durbec P Kiss JZ 《Development (Cambridge, England)》2007,134(6):1181-1190
In the mammalian brain, ongoing neurogenesis via the rostral migratory stream (RMS) maintains neuronal replacement in the olfactory bulb throughout life. Mechanisms that regulate the final number of new neurons in this system include proliferation, migration and apoptosis. Here we show that the polysialylated isoforms of the neural cell adhesion molecule (PSA-NCAM) act as a pro-survival molecule in immature newborn neurons. Confocal microscopic analysis revealed a threefold increase in TUNEL-positive cells in the subventricular zone (SVZ) and the RMS of transgenic animals lacking the gene encoding NCAM (NCAM(-/-)), as compared with wild types. The enhanced apoptotic cell death occurred specifically in the population of mCD24-positive newborn neurons, but not in GFAP-positive astrocytes. Using in vitro cultures of purified SVZ-derived neurons, we demonstrate that the loss or inactivation of PSA on NCAM, as well as the deletion of NCAM, lead to reduced survival in response to neurotrophins including BDNF and NGF. These changes in cell survival are accompanied by an upregulation of p75 neurotrophin receptor expression in vitro as well as in vivo. Furthermore, the negative effects of PSA-NCAM inactivation on cell survival could be prevented by the pharmacological blockade of the p75 receptor-signaling pathway. We propose that PSA-NCAM may promote survival by controlling the expression of the p75 receptor in developing neurons. 相似文献