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71.
Dansette PM Bertho G Mansuy D 《Biochemical and biophysical research communications》2005,338(1):450-455
Oxidation of 2-phenylthiophene (2PT) by rat liver microsomes, in the presence of NADPH and glutathione (GSH), led to three kinds of metabolites whose structures were established by 1H NMR and mass spectrometry. The first ones were 2PT-S-oxide dimers formed by Diels-Alder type dimerization of 2PT-S-oxide, while the second ones were GSH adducts derived from the 1,4-Micha?l-type addition of GSH to 2PT-S-oxide. The third metabolites were GSH adducts resulting from a nucleophilic attack of GSH to the 4,5-epoxide of 2PT. Oxidation of 2PT by recombinant, human cytochrome P4501A1, in the presence of NADPH and GSH, also led to these three kinds of metabolites. These results provide the first evidence that cytochrome P450 may catalyze the oxidation of thiophene compounds with the simultaneous formation of two reactive intermediates, a thiophene-S-oxide and a thiophene epoxide. 相似文献
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73.
Margaux Luck Neila Talbi Laurent Gouya Cédric Caradeuc Hervé Puy Gildas Bertho Nicolas Pallet 《Metabolomics : Official journal of the Metabolomic Society》2018,14(1):10
Introduction
Metabolomic profiling combines Nuclear Magnetic Resonance spectroscopy with supervised statistical analysis that might allow to better understanding the mechanisms of a disease.Objectives
In this study, the urinary metabolic profiling of individuals with porphyrias was performed to predict different types of disease, and to propose new pathophysiological hypotheses.Methods
Urine 1H-NMR spectra of 73 patients with asymptomatic acute intermittent porphyria (aAIP) and familial or sporadic porphyria cutanea tarda (f/sPCT) were compared using a supervised rule-mining algorithm. NMR spectrum buckets bins, corresponding to rules, were extracted and a logistic regression was trained.Results
Our rule-mining algorithm generated results were consistent with those obtained using partial least square discriminant analysis (PLS-DA) and the predictive performance of the model was significant. Buckets that were identified by the algorithm corresponded to metabolites involved in glycolysis and energy-conversion pathways, notably acetate, citrate, and pyruvate, which were found in higher concentrations in the urines of aAIP compared with PCT patients. Metabolic profiling did not discriminate sPCT from fPCT patients.Conclusion
These results suggest that metabolic reprogramming occurs in aAIP individuals, even in the absence of overt symptoms, and supports the relationship that occur between heme synthesis and mitochondrial energetic metabolism.74.
AbstractThe study of dental wear was first used years ago to infer the palaeoecology of fossil mammals and in particular their diet. Results depend predominantly on the scale of the analysis used. Analyses of dental macrowear, mesowear or microwear do not provide the same type of dietary information, be it about the seasonal, annual or lifetime diet. This contribution focuses on emblematic species, cave bears (Ursidae), in particular Ursus spelaeus spelaeus. Methods used by previous researchers to infer their dietary preferences and thus their palaeoecology are reviewed and compared. This review is complemented by an analysis of several specimens of cave bears from the Goyet cave in Belgium, using dental microwear texture analysis (DMTA), a methodology widely applied for reconstructing palaeodiets. Three main conclusions are drawn here: (1) DMTA is the method that provides the most precise palaeobiological inferences; (2) during the pre-dormancy period, cave bears show dietary flexibility; (3) dental wear alone might be not sufficient to provide a complete reconstruction of the cave bear palaeodiet. 相似文献
75.
Hlne Arnould Vincent Baudouin Anne Baudry Luiz W. Ribeiro Hector Ardila-Osorio Matha Pietri Cdric Caradeuc Cynthia Soultawi Declan Williams Marjorie Alvarez Carole Crozet Fatima Djouadi Mireille Laforge Gildas Bertho Odile Kellermann Jean-Marie Launay Gerold Schmitt-Ulms Benoit Schneider 《PLoS pathogens》2021,17(10)
Corruption of cellular prion protein (PrPC) function(s) at the plasma membrane of neurons is at the root of prion diseases, such as Creutzfeldt-Jakob disease and its variant in humans, and Bovine Spongiform Encephalopathies, better known as mad cow disease, in cattle. The roles exerted by PrPC, however, remain poorly elucidated. With the perspective to grasp the molecular pathways of neurodegeneration occurring in prion diseases, and to identify therapeutic targets, achieving a better understanding of PrPC roles is a priority. Based on global approaches that compare the proteome and metabolome of the PrPC expressing 1C11 neuronal stem cell line to those of PrPnull-1C11 cells stably repressed for PrPC expression, we here unravel that PrPC contributes to the regulation of the energetic metabolism by orienting cells towards mitochondrial oxidative degradation of glucose. Through its coupling to cAMP/protein kinase A signaling, PrPC tones down the expression of the pyruvate dehydrogenase kinase 4 (PDK4). Such an event favors the transfer of pyruvate into mitochondria and its conversion into acetyl-CoA by the pyruvate dehydrogenase complex and, thereby, limits fatty acids β-oxidation and subsequent onset of oxidative stress conditions. The corruption of PrPC metabolic role by pathogenic prions PrPSc causes in the mouse hippocampus an imbalance between glucose oxidative degradation and fatty acids β-oxidation in a PDK4-dependent manner. The inhibition of PDK4 extends the survival of prion-infected mice, supporting that PrPSc-induced deregulation of PDK4 activity and subsequent metabolic derangements contribute to prion diseases. Our study posits PDK4 as a potential therapeutic target to fight against prion diseases. 相似文献
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Guillouet M Gueret G Rannou F Giroux-Metges MA Gioux M Arvieux CC Pennec JP 《Cytokine》2011,56(2):149-152
Background and aims
Our aim was to investigate the effect of TNFα on muscle resting potential (RP) and then in muscle excitability and to demonstrate another mechanism implicated in intensive care units (ICU) acquired polyneuromyopathy.Methods
Experiments were carried out on adult female Wistar rats. After isolation of muscle fibres from peroneus longus, influence of TNFα was tested on RP by using intracellular microelectrodes. Digoxin and chelerythrin were used to determine the mechanism of TNFα action.Results
First, we found that TNFα induced a concentration dependent increase of muscle RP and that this mechanism, which was blocked by digoxin, was due to an effect on the Na/K ATPase. As it was also blocked by chelerythrin it was concluded that this effect was mediated by PKC activation of the Na/K ATPase.Conclusions
We demonstrated that TNFα leads to a PKC mediated increase in muscle RP. Depolarization needed to reach the threshold voltage for muscle action potential should then be higher and this could be involved in the decrease in muscle excitability observed in acquired polyneuromyopathy. 相似文献78.
Choveau FS Rodriguez N Abderemane Ali F Labro AJ Rose T Dahimène S Boudin H Le Hénaff C Escande D Snyders DJ Charpentier F Mérot J Baró I Loussouarn G 《The Journal of biological chemistry》2011,286(1):707-716
Voltage-dependent potassium (Kv) channels are tetramers of six transmembrane domain (S1–S6) proteins. Crystallographic data demonstrate that the tetrameric pore (S5–S6) is surrounded by four voltage sensor domains (S1–S4). One key question remains: how do voltage sensors (S4) regulate pore gating? Previous mutagenesis data obtained on the Kv channel KCNQ1 highlighted the critical role of specific residues in both the S4-S5 linker (S4S5L) and S6 C terminus (S6T). From these data, we hypothesized that S4S5L behaves like a ligand specifically interacting with S6T and stabilizing the closed state. To test this hypothesis, we designed plasmid-encoded peptides corresponding to portions of S4S5L and S6T of the voltage-gated potassium channel KCNQ1 and evaluated their effects on the channel activity in the presence and absence of the ancillary subunit KCNE1. We showed that S4S5L peptides inhibit KCNQ1, in a reversible and state-dependent manner. S4S5L peptides also inhibited a voltage-independent KCNQ1 mutant. This inhibition was competitively prevented by a peptide mimicking S6T, consistent with S4S5L binding to S6T. Val254 in S4S5L is known to contact Leu353 in S6T when the channel is closed, and mutations of these residues alter the coupling between the two regions. The same mutations introduced in peptides altered their effects, further confirming S4S5L binding to S6T. Our results suggest a mechanistic model in which S4S5L acts as a voltage-dependent ligand bound to its receptor on S6 at rest. This interaction locks the channel in a closed state. Upon plasma membrane depolarization, S4 pulls S4S5L away from S6T, allowing channel opening. 相似文献
79.
Jean-Fran?ois Hamel Jean-Benoit Hardouin Tanguy Le Neel Gildas Kubis Yves Roquelaure Véronique Sébille 《PloS one》2012,7(10)
Subjective health measurements are increasingly used in clinical research, particularly for patient groups comparisons. Two main types of analytical strategies can be used for such data: so-called classical test theory (CTT), relying on observed scores and models coming from Item Response Theory (IRT) relying on a response model relating the items responses to a latent parameter, often called latent trait. Whether IRT or CTT would be the most appropriate method to compare two independent groups of patients on a patient reported outcomes measurement remains unknown and was investigated using simulations. For CTT-based analyses, groups comparison was performed using t-test on the scores. For IRT-based analyses, several methods were compared, according to whether the Rasch model was considered with random effects or with fixed effects, and the group effect was included as a covariate or not. Individual latent traits values were estimated using either a deterministic method or by stochastic approaches. Latent traits were then compared with a t-test. Finally, a two-steps method was performed to compare the latent trait distributions, and a Wald test was performed to test the group effect in the Rasch model including group covariates. The only unbiased IRT-based method was the group covariate Wald’s test, performed on the random effects Rasch model. This model displayed the highest observed power, which was similar to the power using the score t-test. These results need to be extended to the case frequently encountered in practice where data are missing and possibly informative. 相似文献
80.
Vivien Berthelot Gildas Mouta-Cardoso Nadia Hégarat Fran?ois Guillonneau Jean-Christophe Fran?ois Carine Giovannangeli Danièle Praseuth Filippo Rusconi 《Nucleic acids research》2016,44(10):4721-4733
DNA ends get exposed in cells upon either normal or dysfunctional cellular processes or molecular events. Telomeres need to be protected by the shelterin complex to avoid junctions occurring between chromosomes while failing topoisomerases or clustered DNA damage processing may produce double-strand breaks, thus requiring swift repair to avoid cell death. The rigorous study of the great many proteins involved in the maintenance of DNA integrity is a challenging task because of the innumerous unspecific electrostatic and/or hydrophobic DNA—protein interactions that arise due to the chemical nature of DNA. We devised a technique that discriminates the proteins recruited specifically at DNA ends from those that bind to DNA because of a generic affinity for the double helix. Our study shows that the DNA ends proteome comprises proteins of an unexpectedly wide functional spectrum, ranging from DNA repair to ribosome biogenesis and cytoskeleton, including novel proteins of undocumented function. A global mapping of the identified proteome on published DNA repair protein networks demonstrated the excellent specificity and functional coverage of our purification technique. Finally, the native nucleoproteic complexes that assembled specifically onto DNA ends were shown to be endowed with a highly efficient DNA repair activity. 相似文献