Corrélation entre l'organisation spatiale du perimysium et des domaines subcellulaires des fibres musculaires squelettiques (implication dans la transmission latérale des forces et conséquences possibles sur les adaptations du muscle à l'exercice physique)

BORDEAUX2-SCD-Sc.Sport/Educ.phys (335222105) / SudocSudocFranceF

Les troubles sémantiques au stade prodromal de la maladie d'Alzheimer [Semantic deficits in prodromal Alzheimer's disease]

International audienc

The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells.

International audienceOne of the hallmarks of cancer is resistance to apoptosis. Elucidating the mechanisms of how cancer cells evade or delay apoptosis should lead to novel therapeutic strategies. Previously, we showed that HT-29 colorectal cancer cells undergoing apoptosis overexpressed cyclooxygenase-2 (COX-2), in a p38 dependent pathway, to delay ursolic acid-induced apoptosis. Here, we focused on elucidating the upstream signaling pathways regulating this resistance mechanism. The role of ATP as an extracellular signaling molecule took a long time to be accepted. In recent years, ATP and its analogs, via the activation of specific purinergic receptors, have been implicated in many biological processes including cell proliferation, differentiation and apoptosis. In the present report, we have demonstrated a novel role involving purinergic receptors and particularly the P2Y(2) receptor in resistance to ursolic acid-induced apoptosis in both colorectal HT-29 and prostate DU145 cancer cells. We found that ursolic acid induced an increase in intracellular ATP and P2Y(2) transcript levels. Upon activation, P2Y(2) activated Src which in turn phosphorylated p38 leading to COX-2 overexpression which induced resistance to apoptosis in both HT-29 and DU145 cells. Furthermore, Ca(2+)-independent PLA(2) (iPLA(2)) and Ca(2+)-dependent secretory PLA(2) (sPLA(2)) were responsible for arachidonic acid release, the substrate of COX-2. Our findings document that apoptosis triggering was dependent on protein kinase C (PKC) activation in both cell lines after ursolic acid treatment

Perspectives of French adolescents with ADHD and child and adolescent psychiatrists regarding methylphenidate use

International audienceMany studies have demonstrated the short-term efficacy and tolerability of methylphenidate treatment adolescents with attention deficit hyperactivity disorder (ADHD). Qualitative literature on this matter focused on school outcomes, long-term side effects, family conflicts, personality changes and stigmatization. Yet, no qualitative study has crossed the perspectives of child and adolescent psychiatrists (CAPs) prescribing methylphenidate and adolescents with ADHD. This French qualitative study followed the five stages IPSE—Inductive Process to analyze the Structure of lived Experience-approach. Fifteen adolescents with ADHD and 11 CAPs were interviewed. Data collection by purposive sampling continued until data saturation was reached. Data analysis, based on a descriptive and structuring procedure to determine the structure of lived experience characterized by the central axes of experience, produced two axes: (1) The process of methylphenidate prescription, highlighting how this prescription was motivated from the exterior, experienced as passive by the adolescents and required commitment from the CAPs; and (2) the perceived effects of methylphenidate treatment, in three domains: at school, in relationships and in the sense of self. Findings raised both the issues of the epistemic position and social representation of the adolescents about ADHD and methylphenidate within this specific French context, and the self-awareness and perception of the adolescents with ADHD. We conclude that these two issues need to be regularly addressed by the CAPs prescribing methylphenidate to avoid epistemic injustice and prevent the harmful effects of stigmatization

Bioenergetics of lung tumors: Alteration of mitochondrial biogenesis and respiratory capacity

International audienceLittle is known on the metabolic profile of lung tumors and the reminiscence of embryonic features. Herein, we determined the bioenergetic profiles of human fibroblasts taken from lung epidermoid carcinoma (HLF-a) and fetal lung (MRC5). We also analysed human lung tumors and their surrounding healthy tissue from four patients with adenocarcinoma. On these different models, we measured functional parameters (cell growth rates in oxidative and glycolytic media, respiration, ATP synthesis and PDH activity) as well as compositional features (expression level of various energy proteins and upstream transcription factors). The results demonstrate that both the lung fetal and cancer cell lines produced their ATP predominantly by glycolysis, while oxidative phosphorylation was only capable of poor ATP delivery. This was explained by a decreased mitochondrial biogenesis caused by a lowered expression of PGC1␣ (as shown by RT-PCR and Western blot) and mtTFA. Consequently, the relative expression of glycolytic versus OXPHOS markers was high in these cells. Moreover, the re-activation of mitochondrial biogenesis with resveratrol induced cell death specifically in cancer cells. A consistent reduction of mitochondrial biogenesis and the subsequent alteration of respiratory capacity was also observed in lung tumors, associated with a lower expression level of bcl2. Our data give a better characterization of lung cancer cells' metabolic alterations which are essential for growth and survival. They designate mitochondrial biogenesis as a possible target for anti-cancer therapy

Physiological diversity of mitochondrial oxidative phosphorylation

International audienc

Safety, Pharmacokinetics, and Pharmacodynamics of the ADAMTS-5 Inhibitor GLPG1972/S201086 in Healthy Volunteers and Participants With Osteoarthritis of the Knee or Hip

GLPG1972/S201086 is a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5) inhibitor in development as an osteoarthritis disease-modifying therapy. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics (turnover of plasma/serum ARGS-aggrecan neoepitope fragments [ARGS]) of GLPG1972 in 3 randomized, double-blind, placebo-controlled phase 1 trials. Study A, a first-in-human trial of single (≤2100 mg [fasted] and 300 mg [fed]) and multiple (≤1050 mg once daily [fed]; 14 days) ascending oral (solution) doses, investigated GLPG1972 in healthy men (N = 41; NCT02612246). Study B investigated multiple ascending oral (tablet) doses of GLPG1972 (≤300 mg once daily [fed]; 4 weeks) in male and female participants with osteoarthritis (N = 30; NCT03311009). Study C investigated single (Japanese: ≤1500 mg; White: 300 mg [fasted]) and multiple (Japanese, ≤1050 mg once daily; White, 300 mg once daily [fed]; 14 days) ascending oral (tablet) doses of GLPG1972 in healthy Japanese and White men (N = 88). The pharmacokinetic profile of GLPG1972 was similar between healthy participants and participants with osteoarthritis, with low to moderate interindividual variability. GLPG1972 was rapidly absorbed (median time to maximum concentration, 4 hours), and eliminated with a mean apparent terminal elimination half-life of ≈10 hours. Steady state was achieved within 2 days of dosing, with minimal accumulation. Steady-state plasma exposure after 300 mg of GLPG1972 showed no or minor differences between populations. Area under the plasma concentration–time curve (56.8-67.6 μg · h/mL) and time to maximum concentration (4 hours) were similar between studies. Urinary excretion of GLPG1972 (24 hours) was low (<11%). Multiple dosing significantly reduced ARGS levels vs baseline at all time points for all doses vs placebo. GLPG1972 was generally well tolerated at all doses

Erythropoietin Protects against Local Anesthetic Myotoxicity during Continuous Regional Analgesia

International audienceBackground: Local anesthetics offer the benefits of extended analgesia with greater patient satisfaction and faster rehabilitation compared with intravenous morphine. These benefits, however, can be offset by adverse iatrogenic muscle pain caused by bupivacaine. Here, the authors describe the mechanisms of local anesthetic-induced myotoxicity and a partial protective effect of recombinant human erythropoietin (rhEPO). Methods: The authors developed a rat analgesia model with femoral nerve catheter and a cell culture model of human skeletal muscle myoblasts to study local anesthetic effects. Rats were randomly assigned to four different groups: daily intraperitoneal injection with 5,000 U/kg rhEPO or saline coupled to a perineural catheter injection with 1 ml/kg bupivacaine, 0.25%, or saline. In psoas rat muscle, oxygen consumption rates were measured using a Clark-type electrode in saponin-skinned fibers. Mitochondrial adenosine triphosphate synthesis rates were determined by bioluminescence. Enzymatic activity of mitochondrial respiratory chain complexes was measured on tissue homogenates using spectrophotometric procedures, and mitochondrial morphology was analyzed by transmission electron microscopy. In addition, the interaction between bupivacaine and rhEPO was investigated on human skeletal muscle myoblasts by fluorescence microscopy using mitotracker green and using the lipophilic cation JC-1. Results: Bupivacaine caused impairment of mitochondrial structure and bioenergetics in rats. Human myoblasts treated with bupivacaine showed a dose-dependent decrease in mitochondrial membrane potential associated with unusual morphologies. Impairment of mitochondrial bioenergetics was prevented partially by the use of rhEPO coadministered with bupivacaine. Conclusions: The authors demonstrated a dose-and timedependent protective effect of rhEPO against bupivacaine-induced myotoxicity in regional analgesia