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Insect protein has the potential to become a sustainable feed ingredient for the rapidly growing aquaculture industry. In the European Union, insect derived protein is placed under the same legislation as processed animal proteins (PAP).... more
Insect protein has the potential to become a sustainable feed ingredient for the rapidly growing aquaculture industry. In the European Union, insect derived protein is placed under the same legislation as processed animal proteins (PAP). It is therefore of interest to develop methods for regulatory use, which unambiguously identify the species origin of insect-based ingredients. We performed (i) total protein quantification of insect samples using the traditional nitrogen-to-protein conversion factor of 6.25 and the sum of anhydrous amino acids, (ii) quantitative amino acid profiling and (iii) high-throughput tandem mass spectrometry to describe and differentiate 18 different commercial-grade insect meal samples derived from Hermetia illucens (8), Tenebrio molitor (5), Alphitobius diaperinus (3) and Acheta domesticus (2). In addition, we investigated and compared different protein extraction and digestion protocols for proteomic analysis. We found that irrespective of sample prepara...
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Food laboratories have developed methods for testing allergens in foods. The efficiency of qualitative and quantitativemethods is of prime importance in protecting allergic populations. Unfortunately, food laboratories encounter barriers... more
Food laboratories have developed methods for testing allergens in foods. The efficiency of qualitative and quantitativemethods is of prime importance in protecting allergic populations. Unfortunately, food laboratories encounter barriers to developing efficient methods. Bottlenecks include the lack of regulatory thresholds, delays in the emergence of reference materials and guidelines, and the need to detect processed allergens. In this study, ultra-HPLC coupled to tandem MS was used to illustrate difficulties encountered in determining method performances. We measured the major influences of both processing and matrix effects on the detection of egg, milk, soy, and peanut allergens in foodstuffs. The main goals of this work were to identify difficulties that food laboratories still encounter in detecting and quantifying allergens and to sensitize researchers to them.
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Obesity is characterized by an excessive triacylglycerol accumulation in white adipocytes. Various mechanisms allowing the tight regulation of triacylglycerol storage and mobilization by lipid droplet-associated proteins as well as... more
Obesity is characterized by an excessive triacylglycerol accumulation in white adipocytes. Various mechanisms allowing the tight regulation of triacylglycerol storage and mobilization by lipid droplet-associated proteins as well as lipolytic enzymes have been identified. Increasing energy expenditure by inducing a mild uncoupling of mitochondria in adipocytes might represent a putative interesting anti-obesity strategy as it reduces the adipose tissue triacylglycerol content (limiting alterations caused by cell hypertrophy) by stimulating lipolysis through yet unknown mechanisms, limiting the adverse effects of adipocyte hypertrophy. Herein, the molecular mechanisms involved in lipolysis induced by a mild uncoupling of mitochondria in white 3T3-L1 adipocytes were characterized. Mitochondrial uncoupling-induced lipolysis was found to be independent from canonical pathways that involve lipolytic enzymes such as HSL and ATGL. Finally, enhanced lipolysis in response to mitochondrial unc...
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Regulation of ROS metabolism plays a major role in cellular adaptation to oxidative stress in cancer cells, but the molecular mechanism that regulates catalase, a key antioxidant enzyme responsible for conversion of hydrogen peroxide to... more
Regulation of ROS metabolism plays a major role in cellular adaptation to oxidative stress in cancer cells, but the molecular mechanism that regulates catalase, a key antioxidant enzyme responsible for conversion of hydrogen peroxide to water and oxygen, remains to be elucidated. Therefore, we investigated the transcriptional regulatory mechanism controlling catalase expression in three human mammary cell lines: the normal mammary epithelial 250MK primary cells, the breast adenocarcinoma MCF-7 cells and an experimental model of MCF-7 cells resistant against oxidative stress resulting from chronic exposure to H2O2 (Resox), in which catalase was overexpressed. Here we identify a novel promoter region responsible for the regulation of catalase expression at -1518/-1226 locus and the key molecules that interact with this promoter and affect catalase transcription. We show that the AP-1 family member JunB and retinoic acid receptor alpha (RARα) mediate catalase transcriptional activation...
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Endoplasmic reticulum (ER) and mitochondria are not discrete intracellular organelles but establish close physical and functional interactions involved in several biological processes including mitochondrial bioenergetics, calcium... more
Endoplasmic reticulum (ER) and mitochondria are not discrete intracellular organelles but establish close physical and functional interactions involved in several biological processes including mitochondrial bioenergetics, calcium homeostasis, lipid synthesis and the regulation of apoptotic cell death pathways. As many cell types might face a transient and sublethal ER stress during their lifetime, it is thus likely that the adaptive UPR response might affect the mitochondrial population. The aim of this work was to study the putative effects of a non-lethal and transient endoplasmic reticulum stress on the mitochondrial population in HepG2 cells. The results show that thapsigargin and brefeldin A, used to induce a transient and sublethal ER stress, rapidly lead to the fragmentation of the mitochondrial network associated with a decrease in mitochondrial membrane potential, O2 (•-) production and less efficient respiration. These changes in mitochondrial function are transient and preceeded by the phosphorylation of JNK. Inhibition of JNK activation by SP600125 prevents the decrease in O2 (•-) production and the mitochondrial network fragmentation observed in cells exposed to the ER stress but has no impact on the reduction of the mitochondrial membrane potential. In conclusion, our data shows that a non-lethal and transient ER stress triggers a rapid activation of JNK without inducing apoptosis, leading to the fragmentation of the mitochondrial network and a reduction of O2 (•-) production. This article is protected by copyright. All rights reserved.
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Mitochondria-to-nucleus communication, known as retrograde signaling, is important to adjust the nuclear gene expression in response to organelle dysfunction. Among the transcription factors described to respond to mitochondrial stress,... more
Mitochondria-to-nucleus communication, known as retrograde signaling, is important to adjust the nuclear gene expression in response to organelle dysfunction. Among the transcription factors described to respond to mitochondrial stress, CHOP-10 is activated by respiratory chain inhibition, mitochondrial accumulation of unfolded proteins and mtDNA mutations. In this study, we show that altered/impaired expression of mtDNA induces CHOP-10 expression in a signaling pathway that depends on the eIF2α/ATF4 axis of the integrated stress response rather than on the mitochondrial unfolded protein response.
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NFkappaB is a ubiquitous transcription factor involved in the proinflammatory response to cytokines (such as IL-1 or TNF-alpha) and some particular stresses. The unraveling of the molecular mechanisms involved in its activation is quite... more
NFkappaB is a ubiquitous transcription factor involved in the proinflammatory response to cytokines (such as IL-1 or TNF-alpha) and some particular stresses. The unraveling of the molecular mechanisms involved in its activation is quite recent, particularly in the case of IL-1-stimulated cells, but the identification of the molecules involved in this pathway opens new prospects in both pharmacological and toxicological research.
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Cytokines such as IL-1 or TNF-alpha induce a specific cellular responses through the activation of a transcriptional factor, NF kappa B. This activation requires the phosphorylation of an inhibitory subunit, I kappa B, which relies upon... more
Cytokines such as IL-1 or TNF-alpha induce a specific cellular responses through the activation of a transcriptional factor, NF kappa B. This activation requires the phosphorylation of an inhibitory subunit, I kappa B, which relies upon an intracellular production of reactive oxygen intermediates. Peroxides, but also the increase of the GSSG/GSH ratio are assumed to play a major role in this process. There is presently a good agreement on the overall scheme of IL-1 and TNF-alpha activation and on the involvement of reactive oxygen intermediates in the corresponding signal transduction cascades. However several questions regarding the molecular mechanisms involved in particular steps of these cascades remain largely unresolved: how and at which subcellular level, do the cells produce these reactive oxygen intermediates that will contribute to NF kappa B activation in response to IL-1 or TNF-alpha? What are the kinases/phosphatases, being modulated by peroxides and what is the contrib...
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In this paper, we present various arguments supporting the hypothesis that reactive oxygen species (ROS) could be responsible for the modulation of various cellular functions, besides their well known toxic effects. We first review the... more
In this paper, we present various arguments supporting the hypothesis that reactive oxygen species (ROS) could be responsible for the modulation of various cellular functions, besides their well known toxic effects. We first review the recent evidence indicating that ROS are able to modulate genome expression through specific and precise mechanisms during cell activation. The role of the nitrogen reactive radicals such as nitric oxide is separately analyzed because of its specific role in the nervous and vascular systems. The action of the other ROS on gene activation will then be reviewed by first looking at their possible involvement in the activation of transcription factors like NF-kappa B. Arguments will then be developed in favor of the implication of the ROS in the cellular effects of PMA, TNF-alpha and other cytokines on the modulation of the genetic expression. Possible mechanisms will be presented for linking the production of the ROS with cell activation. In a general way...
Research Interests: Genetics, Thermodynamics, Regulation, Gene expression, Signal Transduction, and 14 moreFree Radical, Humans, Mutation, Reactive Oxygen Species, Nitric oxide, Animals, NF-kappa B, Nitrogen, Energy Expenditure, Transcription Factor, Tumor necrosis factor-alpha, Biological activity, Point of View, and Gene Expression Regulation
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Mitochondrial biogenesis and metabolism have recently emerged as important actors of stemness and differentiation. On the one hand, the differentiation of stem cells is associated with an induction of mitochondrial biogenesis and a shift... more
Mitochondrial biogenesis and metabolism have recently emerged as important actors of stemness and differentiation. On the one hand, the differentiation of stem cells is associated with an induction of mitochondrial biogenesis and a shift from glycolysis toward oxidative phosphorylations (OXPHOS). In addition, interfering with mitochondrial biogenesis or function impacts stem cell differentiation. On the other hand, some inverse changes in mitochondrial abundance and function are observed during the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). Yet although great promises in cell therapy might generate better knowledge of the mechanisms regulating the stemness and differentiation of somatic stem cells (SSCs)-which are preferred over embryonic stem cells (ESCs) and iPSCs because of ethical and safety considerations-little interest was given to the study of their mitochondria. This study provides a detailed characterization of the mitochondrial biogenesis occurring during the hepatogenic differentiation of bone marrow-mesenchymal stem cells (BM-MSCs). During the hepatogenic differentiation of BM-MSCs, an increased abundance of mitochondrial DNA (mtDNA) is observed, as well as an increased expression of several mitochondrial proteins and biogenesis regulators, concomitant with increased OXPHOS activity, capacity, and efficiency. In addition, opposite changes in mitochondrial morphology and in the abundance of several OXPHOS subunits were found during the spontaneous dedifferentiation of primary hepatocytes. These data support reverse mitochondrial changes in a different context from genetically-engineered reprogramming. They argue in favor of a mitochondrial involvement in hepatic differentiation and dedifferentiation.
Research Interests: Mitochondria, Adolescent, mtDNA, Cell Differentiation, Humans, and 15 moreChild, Bone marrow, PRC, Adult, Hepatocytes, Oxidative phosphorylation, iPSCs, PPAR, OXPHOS, Mesenchymal Stromal Cells, Biochemistry and cell biology, Mitochondrial Proteins, Child preschool, real time polymerase chain reaction, and reverse transcriptase polymerase chain reaction
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Hepatocellular carcinoma is one of the most frequent tumor types worldwide and oxidative stress represents a major risk factor in pathogenesis of liver diseases leading to HCC. Nuclear factor erythroid 2-related factor (Nrf2) is a... more
Hepatocellular carcinoma is one of the most frequent tumor types worldwide and oxidative stress represents a major risk factor in pathogenesis of liver diseases leading to HCC. Nuclear factor erythroid 2-related factor (Nrf2) is a transcription factor activated by oxidative stress that governs the expression of many genes which constitute the antioxidant defenses of the cell. In addition, oxidative stress activates AMP-activated protein kinase (AMPK), which has emerged in recent years as a kinase that controls the redox-state of the cell. Since both AMPK and Nrf2 are involved in redox homeostasis, we investigated whether there was a crosstalk between the both signaling systems in hepatocarcinoma cells. Here, we demonstrated that AMPK activator AICAR, in contrary to the A769662 allosteric activator, induces Nrf2 activation and concomitantly modulates the basal redox state of the hepatocarcinoma cells. When the expression of Nrf2 is knocked down, AICAR failed to induce its effect on redox state. These data highlight a major role of Nrf2 signaling pathway in mediating the AICAR effect on basal oxidative state. Furthermore, we demonstrated that AICAR metabolization by the cell is required to induce Nrf2 activation while, the silencing of AMPK does not have any effect on Nrf2 activation. This suggests that AICAR-induced Nrf2 activation is independent of AMPK activity. In conclusion, we identified AICAR as a potent modulator of the redox state of human hepatocarcinoma cells, via the Nrf2 signaling pathway and in an AMPK-independent mechanism.
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Research Interests: Electron Microscopy, Calcium, Transmission Electron Microscopy, Mitochondria, Gene expression, and 13 moreCell line, Mitochondrial DNA, Mice, Animals, Calcium Signaling, Biogenesis, Biological markers, DNA binding proteins, Protein Transport, Biochemistry and cell biology, Adenosine Triphosphate, Mitochondrial Proteins, and Medical biochemistry and metabolomics
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Research Interests: Colorimetry, Immune response, Biological Sciences, DNA, Antibodies, and 15 moreCell line, Environmental Sciences, Humans, High throughput screening, Animals, Nucleic Acids, NAR, DNA binding, Reproducibility of Results, Rabbits, Base Sequence, Protein Binding, Binding Site, Response Elements, and Dimerization
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Toll-like receptors 2 and 4 (TLR2, TLR4) are found in the membrane of skeletal muscle cells. A variety of molecular components can activate TLR2 and TLR4, among others, long-chain fatty acids. The subsequent downstream signaling triggers... more
Toll-like receptors 2 and 4 (TLR2, TLR4) are found in the membrane of skeletal muscle cells. A variety of molecular components can activate TLR2 and TLR4, among others, long-chain fatty acids. The subsequent downstream signaling triggers the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways. Therefore, the purpose of this study was to test whether an elevation of extracellular nonesterified fatty acids (NEFA) observed during endurance exercise may activate the MAPK and NF-κB pathways via TLR2 and TLR4. tlr2 and tlr4 mice and wild-type C57BL/6J animals (WT) were submitted to a standardized endurance exercise. Immediately after exercise, the phosphorylation state of p38 MAPK, c-Jun NH2-terminal kinase (JNK), and c-Jun was increased in the tibialis anterior (TA) and soleus (SOL) muscles of WT (P < 0.05). The phosphorylation state of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and IκB kinase α/β and the DNA-binding of NF-κB remained unchanged. The activation of p38 MAPK, JNK, and c-Jun was completely blunted in TA of tlr2 and tlr4 mice, whereas in SOL, it represented only 25% of the increase observed in WT mice. The causal relationship between NEFA concentration and MAPK activation was evaluated by injecting mice with heparin. A similar increase in plasma NEFA was observed after heparin injection than after endurance exercise. JNK and p38 MAPK were activated under heparin in TA and SOL of WT (P < 0.05) but not in muscles of tlr2 and tlr4 mice. The present study supports the idea that during endurance exercise, TLR2 and TLR4 mediate a signal linking the elevated plasma NEFA concentration to the activation of p38 MAPK and JNK.
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To study the effect of plyometric training on Ca2+ sensitivity and the influence of troponin T (TnT) isoforms on Ca2+ -activation properties in skinned human muscle fibers. Biopsies were obtained from the vastus lateralis of eight men... more
To study the effect of plyometric training on Ca2+ sensitivity and the influence of troponin T (TnT) isoforms on Ca2+ -activation properties in skinned human muscle fibers. Biopsies were obtained from the vastus lateralis of eight men before and after the training period. Chemically skinned fibers were evaluated regarding their Ca2+ -activation properties and were classified according to their myosin heavy chain (MHC) contents and analyzed regarding their slow and fast TnT isoforms. After training, significant improvements (P < 0.05) were found for static jump, countermovement jump, 6 x 5-m shuttle-run test, and leg-press performances. An 8% increase in the proportion of type IIa fibers (P < 0.05) was observed. Single-fiber diameters increased by 11% in type I (P < 0.01), 10% in type IIa (P < 0.001), and 15% in type IIa/IIx fibers (P < 0.001). Peak fiber force increased by 35% in type I (P < 0.001), 25% in type IIa (P < 0.001), and 57% in type IIa/IIx fibers (P < 0.01). The Ca2+ -activation threshold was not altered by training, but the Ca2+ concentration required to elicit half-maximal activation showed a decreasing trend, with significant changes in type I fibers (P < 0.001). Cooperativity at low Ca2+ concentrations was increased in type I and type IIa/IIx fibers (P < 0.05). Type I fibers exclusively expressed slow TnT isoforms, and type II fibers were always associated with fast TnT isoforms, independent of training status. Therefore, changes in Ca2+ sensitivity after training could not be explained by differential fast or slow TnT isoform expression. Plyometric training increased single-fiber Ca2+ sensitivity, especially in type I fibers. These changes could not be explained by a modified TnT isoform expression pattern.
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Research Interests: Genetics, Fluorescence Microscopy, Calcium, Enzyme Inhibitors, Confocal Microscopy, and 15 moreDNA, Adipose tissue, Cell Differentiation, Glucose, Fatty acids, Animals, Fatty Acid Oxidation, Cytochrome c oxidase, Glucose Transport, Carbohydrate metabolism, Adipocytes, Lipid, Biochemistry and cell biology, Cell Membrane, and Glycogen Synthase Kinase
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We have generated several transgenic mouse strains carrying a human immunodeficiency virus 1 (HIV-1) NEF/3' long terminal repeat (LTR) transgene under control of a T cell-specific promoter-enhancer element, showing a depletion of CD4+... more
We have generated several transgenic mouse strains carrying a human immunodeficiency virus 1 (HIV-1) NEF/3' long terminal repeat (LTR) transgene under control of a T cell-specific promoter-enhancer element, showing a depletion of CD4+ T cells in the thymus and periphery. The immunological functions of the line with the most dramatic changes in lymphocyte populations, B6/338L, were analyzed in greater detail. The presence of the transgene in the heterozygous animal is associated with a dominant severe immunodeficiency. Older animals develop lymph-adenopathy and splenomegaly. CD4+CD8+ and CD4+CD8- single positive thymocytes already are depleted in these mice at the earliest stages in ontogeny, and peripheral T cells are reduced in frequency and present cell surface marker expression, which is characteristic for memory and activated T cells. The immunological response of B6/338L mice to several viral infections is also greatly impaired. Thus, the HIV-1 NEF/3' LTR as transgene i...
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Oxygen-dependent regulation of HIF-1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF-1alpha protein expression have been most extensively analyzed but the ones modulating HIF-1 transcriptional activity remain... more
Oxygen-dependent regulation of HIF-1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF-1alpha protein expression have been most extensively analyzed but the ones modulating HIF-1 transcriptional activity remain unclear. Changes in the phosphorylation and/or redox status of HIF-1alpha certainly play a role. Here, we show that ionomycin could activate HIF-1 transcriptional activity in a way that was additive to the effect of hypoxia without affecting HIF-1alpha protein level. In addition, a calmodulin dominant negative mutant and W7, a calmodulin antagonist, as well as BAPTA, an intracellular calcium chelator, inhibited the hypoxia-induced HIF-1 activation. These results indicate that elevated calcium in hypoxia could participate in HIF-1 activation. Furthermore, ERK but not JNK phosphorylation was evidenced in both conditions, ionomycin and hypoxia. PD98059, an inhibitor of the ERK pathway as well as a ERK1 dominant negative mutant also blocked HIF-1 activation by hypoxia and by ionomycin. A MEKK1 (a kinase upstream of JNK) dominant negative mutant had no effect. In addition, BAPTA, calmidazolium, a calmodulin antagonist and PD98059 inhibited VEGF secretion by hypoxic HepG2. All together, these results suggest that calcium and calmodulin would act upstream of ERK in the hypoxia signal transduction pathway.
Research Interests: Calcium, Drug interactions, Enzyme Inhibitors, Transcription Factors, Cellular, and 12 moreHumans, Animals, Calcium Signaling, Cellular Physiology, Medical Physiology, Calmodulin, Eukaryotic Cells, Chelating Agents, DNA binding proteins, Hypoxia inducible factor, Mitogen- Activated Protein Kinases, and Vascular endothelial growth factors
Research Interests: DNA replication, Mitochondria, Autophagy, Signal Transduction, Molecular chaperones, and 11 moreCellular, Mitochondrial DNA, Humans, Animals, Cellular Physiology, Medical Physiology, Homeostasis, Physiological Stress Markers, Gene Expression Regulation, Mitochondrial Proteins, and Stress Physiological
Over the past years, knowledge and evidence about the existence of crosstalks between cellular organelles and their potential effects on survival or cell death have been constantly growing. More recently, evidence accumulated showing an... more
Over the past years, knowledge and evidence about the existence of crosstalks between cellular organelles and their potential effects on survival or cell death have been constantly growing. More recently, evidence accumulated showing an intimate relationship between endoplasmic reticulum (ER) and mitochondria. These close contacts not only establish extensive physical links allowing exchange of lipids and calcium but they can also coordinate pathways involved in cell life and death. It is now obvious that ER dysfunction/stress and unfolded protein response (UPR) as well as mitochondria play major roles in apoptosis. However, while the effects of major ER stress on cell death have been largely studied and reviewed, it becomes more and more evident that cells might regularly deal with sublethal ER stress, a condition that does not necessarily lead to cell death but might affect the function/activity of other organelles such as mitochondria. In this review, we will particularly focus on these new, interesting and intriguing metabolic and morphological events that occur during the early adaptative phase of the ER stress, before the onset of cell death, and that remain largely unknown. Relevance and implication of these mitochondrial changes in response to ER stress conditions for human diseases such as type II diabetes and Alzheimer's disease will also be considered.