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MAGE-A1 a été découvert parce qu’il produit un antigène tumoral reconnu par des lymphocytes T cytolytiques. Ce gène appartient à une vaste famille de gènes qui codent des protéines dans un domaine de 170 acides aminés est conservé dans différentes espèces. Le rôle physiologique de MAGE-A1 est encore inconnu. Cependant, des expériences récentes de notre laboratoire ont montré que cette protéine est capable de se lier au co-activateur transcriptionnel SKIP, d’inhiber la transactivation assurée par la portion intracellulaire de Notch et de fixer l’histone déacétylase, HDAC1. Ces résultats suggèrent qu’un rôle possible de MAGE-A1 est de réguler la transcription.
De manière à poursuivre ces observations pour déterminer le rôle physiologique de MAGE-A1 dans deux systèmes de cellules de mammifères en culture, les myoblastes de souris C2C12 et les cellules de rein embryonnaire humain 293.
En exprimant MAGE-A1 dans les cellules C2C12 produisant la partie intracellulaire de NOTCH2 (Notch2-IC), nous voulons étudier l’effet de MAGE-A1 sur un processus de différenciation régulé par NOTCH. Les cellules C2C12 ont la capacité de se différencier en myotubes lorsqu’elles sont cultivées dans un milieu pauvre en agents mitogènes. Ce processus de différenciation est bloqué par Notch2-IC parce qu’il active les gènes HES et HERP qui produisent des répresseurs inhibant les facteurs de différenciation. Nos résultats montrent que la présence de la protéine MAGE-A1 n’empêche pas les cellules C2C12 de se différencier si ces cellules ne produisent pas Notch2-IC. Cependant, contrairement à nos prévisions basées sur l’observation que MAGE-A1 est capable de contrecarrer la transactivation de Notch1-IC, nous avons observés que MAGE-A1 était incapable de rétablir un processus de différenciation dans des cellules C2C12 bloquées par Notch2-IC. En accord avec ces résultats, des expériences de PCR quantitative ont montré que le nombre de transcrits HES-1 et HERP-2 ne variaient pas dans ces cellules lorsque MAGE-A1 était exprimé.
Dans la deuxième partie de ce travail, nous avions tenté d’utiliser des systèmes commerciaux permettant d’induire l’expression de MAGE-A1 à l’aide de tétracyline dans les cellules de rein embryonnaire humain 293. Nous avons facilement obtenu des clones dans lesquels on pouvait induire la production de grandes quantités de transcrits MAGE-A1. Cependant, nous avons observé qu’en absence d’induction, le niveau d’expression était au moins aussi élevé que celui des cellules de mélanome humain cultivées en laboratoire. Or, nous voulions réprimer totalement l’expression de MAGE-A1 en absence d’induction de manière à éviter des phénomènes de toxicité de la protéine MAGE-A1 observés au laboratoire lorsque cette protéine est présente en grandes quantités dans des cellules humaines en culture. Nous avons dés lors construit deux nouveaux vecteurs recombinants : l’un utilise un vecteur commercial dans lequel on a modifié l’élément de réponse à la tétracycline ; l’autre est un vecteur dans lequel nous avons remplacé le promoteur minimal du virus CMV par un promoteur minimal MAGE-A1. Lorsque nous aurons mis au point des systèmes d’expression inductible de MAGE-A1 présentant un niveau d’expression négligeable en absence d’induction, nous utiliserons ces systèmes et la technologie des microdamiers (microarrays) pour identifier des gènes régulés par MAGE-A1 MAGE-A1 was discovered because it encodes a tumor antigen recognized by cytolytic T lymphocytes. It belongs to a large family of genes encoding proteins with an intra- and interspecies 170 amino acids conserved homology domain. The molecular function of this protein in thus far interacts with transcriptional adaptor protein SKIP, to counteract transactivation by the intracellular part of Notch1 and to bind to histone déacétylase 1. These data suggest that MAGE-A1 has a role in transcriptional regulation.
In order to examine the functional relevance of these observations, we expressed MAGE-A1 in two in vitro systems of mammalian cells, mouse C2C12 myoblasts and human embryonal kidney 293 cells.
Stable expression of MAGE-A1 in parental C2C12 cells and in C2C12 cells expressing the intracellular part of Notch2 (Notch2*-IC) allowed us to study the effect of MAGE-A1 on a differentiation process regulated by Notch. This model relies on the ability of C2C12 myoblasts to differentiate in myotubes when cultures in mitogen-poor medium. This process is blocked by Notch2-IC because it activates the expression of HES and HERP repressors that inhibit the required differentiation factors. According to our results, ectopic expression of MAGE-A1 in C2C12 myoblasts did not affect their capacity to differentiate. However, contrary to our expectations based on the inhibitory effect of MAGE-A1 on Notch1-IC transactivation, MAGE-A1 expression was not able to resume the differentiation process in Notch2-IC-expressing cells. This was confirmed by real-time PCR experiments showing that the amount of HES-1 and HERP-2 transcripts in C2C12 cells was not affected by MAGE-A1 expression.
In the second part of the study, we developed known tetracycline-regulated systems to express MAGE-A1 in human embryonic kidney cells. Induction by the antibiotic could be easily obtained in some selected clones. However, in the absence of induction, these inducible systems yielded a relatively high background level of expression, similar to that measured in melanoma cells cultured in our laboratory. This basal expression level should be tightly controlled in order to avoid toxic effects frequently observed in mammalian cells over expressing MAGE-A1. We therefore constructed two new MAGE-A1 expressing vectors: one is based on a commercial vector with a modified tetracycline response element; the other is a vector containing a MAGE-A1 minimal promoter instead of the current CMV minimal vector. When tightly controlled inducible systems will be available, we will use the microarray technology to identify genes that are regulated by MAGE-A1

Melanoma --- Antigens --- Kidney --- Myoblasts --- Tetracycline

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Horses --- Muscle fibers, skeletal --- Myoblasts, skeletal --- Anoxia --- Oxygen --- Reactive oxygen species --- Mitochondria, muscle --- metabolism --- veterinary --- pharmacology --- physiology

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This Special Issue on “Blood-Derived Products for Tissue Repair and Regeneration” reveals the evolution and diversity of platelet rich plasma (PRP) technologies, which includes experimental research on novel formulations, the creation of combination therapies, and the exploration of potential modifiers of PRPs, as well as efficacy of PRP therapies in clinical veterinary and human applications. Scientist and clinicians are now starting to develop different treatments based on their reinterpretation of the traditional roles of platelets and plasma, and the current Issue has provided a forum for sharing research and ways of understanding the associated medicinal benefits from different points of view. The research interest in this area has covered different medical disciplines, such as ophthalmology, dentistry, orthopedics, and sports medicine.

n/a --- biomaterial --- redifferentiation --- regenerative medicine --- skeletal muscle regeneration --- furcation defects --- Platelet-Rich Plasma (PRP) --- PRP --- fracture --- fibrin sealant --- periodontal surgery --- bone regeneration --- serum derived from plasma rich in growth factors (s-PRGF) --- cartilage repair --- myofibroblasts --- autologous platelet concentrates --- burns --- satellite cells --- articular cartilage --- stem cell niche --- wound healing --- quantification --- growth factors --- biologics --- platelet rich plasma --- meniscus --- adipose tissue --- Carprofen --- platelet-rich fibrin --- platelets --- hyperacute serum --- bone defects --- serum eye drops --- corneal epithelial defect --- fibrosis --- dog --- myoblasts --- differentiation --- chronic meniscal lesion --- horizontal meniscal tear --- PRGF --- collagen hydrogels --- periodontal defects --- bone grafting material --- composition --- cell therapy --- bone healing --- tissue healing --- trephination --- plasma rich plasma (PRP) --- bone repair --- plasma rich in growth factors --- knee arthrosis --- meniscus tear --- cornea regeneration --- wrist osteoarthritis --- periosteal sheet --- Platelet-Poor Plasma (PPP) --- platelet-rich plasma --- microfat --- bone grafting --- hyaluronic acid (NaHA) --- periodontal regeneration --- meniscus repair --- photobiomodulation therapy --- growth --- myogenesis --- blood derived products --- low-level laser therapy

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Mitochondria are the powerhouses of cells; however, mitochondrial dysfunction causes energy depletion and cell death in a variety of diseases. Altered oxidative phosphorylation and ion homeostasis are associated with ROS production resulting from the disassembly of respiratory supercomplexes and the disruption of electron transfer chains. In pathological conditions, the dysregulation of mitochondrial homeostasis promotes Ca2+ overload in the matrix and ROS accumulation, which induces the mitochondrial permeability transition pore formation responsible for mitochondrial morphological changes linked to membrane dynamics, and ultimately, cell death. Finally, studies on the impaired mitochondrial bioenergetics in pathology could provide molecular tools to counteract diseases associated with mitochondrial dysfunction.

Research & information: general --- Biology, life sciences --- Biochemistry --- aging heart --- Bcl-2 family --- mitochondria --- programmed cell death --- fatty acid oxidation --- palmitate --- oleate --- m.3243A&gt --- G mutation --- MT-ATP6 --- m.8909T&gt --- C --- ATP synthase --- nephropathy --- oxidative phosphorylation --- mitochondrial disease --- cardiolipin --- Barth syndrome --- Sengers syndrome --- respiratory chain --- Dilated Cardiomyopathy with Ataxia --- cardiomyopathy --- mammalian complex I --- NADH dehydrogenase --- complex I assembly --- complex I structure --- complex I deficiency --- supernumerary subunits --- electron transport chain --- mitochondrial dysfunction --- Leigh syndrome --- mitochondrial diseases --- yeast --- Saccharomyces cerevisiae --- pet mutants --- pancreatic endocrine cells --- mathematical model --- cellular bioenergetics --- diabetes --- glucagon --- insulin --- exercise --- immune system --- metabolic disease --- COVID-19 --- mitochondrial dynamics --- viral infections --- MAVS --- RIG-I --- MDA5 --- innate immune response --- SARS CoV-2 --- RSV --- influenza --- respiratory supercomplexes --- ROS --- ATP synthase/hydrolase --- mitochondrial permeability transition pore --- cristae --- cellular signaling --- human disease --- mitochondrial dynamic --- cell signaling --- cancer --- respiratory complexes --- oxidative stress --- mitochondrial DNA --- MTCYB mutations --- cytochrome b --- complex III --- aging --- energy metabolism --- entorhinal cortex --- lipoxidation-derived damage --- neurodegeneration --- oxidative damage --- protein import --- respiratory complex assembly --- supercomplexes --- mitochondrial proteostasis --- heart failure --- bioenergetics --- assembly factor --- atypical myopathy --- high-resolution respirometry --- toxicity assays --- cell culture --- equine primary myoblasts --- fibroblasts --- frozen tissue --- leukocytes --- oxygen consumption --- platelets --- respirometry --- skeletal muscle --- n/a

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This Special Issue of Nutrients on "Nutraceutical, Nutrition Supplements, and Human Health" provides readers with contemporary knowledge on the role of functional foods, dietary supplements, and nutraceuticals in improving overall health and preventing chronic diseases. Various renowned international scientists, physicians, and other healthcare professionals have contributed to this compendium of excellent laboratory and clinical studies. The manuscripts provide evidence-based knowledge of nutritional compounds/functional food to improve many health conditions, including metabolic disorders, cardiovascular disease, muscle metabolism, obesity, neurological disorders, infectious diseases, aging, and cancer. All contributions were thoroughly peer-reviewed by a distinguished panel of scientists, and only highly ranked manuscripts were included to ensure the quality of contents. This book is an excellent resource for academic personnel and students in nutrition research, dietitians, physicians, and consumers.

Research & information: general --- Biology, life sciences --- Food & society --- Lactobacillus salivarius --- otitis --- probiotic --- bacteriocin --- prevention --- Morus nigra L. --- black mulberry --- nutraceutical --- pharmacological properties --- coenzyme Q10 (CoQ10) --- bioavailability --- intestinal absorption --- neuroprotection --- fenugreek --- protein hydrolysate --- antiproliferative --- apoptosis --- antioxidant --- Caco2 cells --- catechins --- green tea extract --- herbal dietary supplements --- hepatotoxicity --- microbiome --- Streptococcus agalactiae --- GBS --- pregnancy --- cachexia --- plum --- cancer --- muscle wasting --- myoblasts --- protein synthesis --- graviola --- weight loss --- obesity --- blood glucose --- food composition --- metabolic syndrome --- natural products --- Carica papaya --- Bifidobacterium breve M-16V --- infant health --- clinical efficacy --- probiotics --- gut microbiota --- Autism spectrum disorder --- dietary supplements --- pediatric --- physician communication --- frankincense --- Boswellia --- boswellic acid --- lupeolic acid --- AKBA --- cytokine --- breast cancer --- pentacyclic triterpenic acid --- triterpenoid --- chorioallantoic membrane assay --- Platycodon grandiflorus root --- BMI --- body fat mass --- abdominal fat area --- wild rice --- metabolomics --- atherosclerosis --- LDL-r-KO mice --- cytokines --- 16S rDNA --- plasma --- feces --- proteins --- carbohydrates --- functional food --- curcumin --- formulated curcumin --- pharmacokinetics --- aurora kinase A --- hepatocellular carcinoma --- Dietary Supplement Label Database --- food description --- food classification --- FoodEx2 --- quelites --- supplementation --- arsenic --- vitamin K --- diet supplement --- age-related diseases --- vitamin K-dependent proteins --- pathological calcification --- inflammation --- skeletal muscles --- Bifidobacterium breve B-3 --- muscle mass --- mitochondria --- n/a