Cellular protection by erythropoietin: new therapeutic implications

ABSTRACT Erythropoietin (EPO), the principal hematopoietic hormone produced by the kidney and the liver in fetuses, regulates mammalian erythropoiesis and exhibits diverse cellular effects in nonhematopoietic tissues. The introduction of recombinant human EPO (rhEPO) has marked a significant advance in the management of anemia associated with chronic renal failure. At the same time, experimental studies have unveiled its potential neuroprotective and cardioprotective properties, occurring independently of its hematopoietic action. As with other cytoprotective agents, administration of exogenous rhEPO can confer cerebral and myocardial protection against ischemia-reperfusion injury in terms of reduction in cellular apoptosis and necrosis, as well as improvement in functional recovery. Very recent studies even suggest that this drug could have beneficial applications in oncology, protecting against chemotherapy cardiotoxicity. The purpose of this letter is to review current information regarding the various conditions in which rhEPO and its derivates could confer cellular protection. We also address clinical perspectives and novel therapeutic strategies that could be developed based on these studies. Thus, EPO seems to be a very promising agent for protecting cellular survival during both acute and chronic diseases, and its future should be considered with enthusiasm. The hormone erythropoietin (EPO), produced by the kidney and the liver in fetuses, is well known in regulating mammalian erythropoiesis. Exogenous EPO, the recombinant human EPO (rhEPO), introduced approximately two decades ago, is presently used for the treatment of anemia resulting from a variety of conditions, such as chronic renal failure and chemotherapy. However, since the last decade, the existence of EPO and its receptor (EPOR) localized outside of the liver and the kidney, such as the brain and heart, has been shown. At the same time, several experimental studies using rhEPO have unveiled the potential neuroprotective and cardioprotective role of EPO against ischemia, occurring independently of its hematopoietic action The cell possesses a remarkable ability to adapt to stress by changing its phenotype in a manner that renders it more resistant to subsequent injury. This powerful adaptative phenomenon called preconditioning is illustrated by the fact that a sublethal stress (such as ischemia or pharmacological agent administration) applied to an organ enhances its tolerance to a subsequent lethal stress. When preventively administered, rhEPO is able to mimic ischemic preconditioning, protecting neuronal and cardiac cell against various stresses, such as lethal ischemia or cytotoxic drugs In this article, we review current information regarding the various conditions in which rhEPO and its derivates could confer cellular protection. We also report recent data concerning the mechanisms underlying the cytoprotective effects of rhEPO, such as the role of EPOR and the activation of the following cellular signaling pathways. Finally, we adArticle, publication date, and citation information can be found a

Sécurisation du circuit du médicament et son administration dans les EHPAD (formation du personnel soignant par le pharmacien)

Devant un vieillissement de la population et une espérance de vie augmentée dans un contexte polypathologique, les Établissements d Hébergement pour Personnes Agées Dépendantes (EHPAD) occupent une place de plus en plus importante dans les structures de soins et de vie pour le secteur gériatrique. Face à la complexité du circuit du médicament en son sein, notamment de par les nombreux acteurs de santé intervenant, sa sécurisation devient primordiale et représente un des objectifs de santé publique prioritaires. En effet, l iatrogénie médicamenteuse serait responsable de plus de 10 % des hospitalisations chez le sujet âgé, dont près d un tiers serait lié à une erreur d administration. Cela peut être dû à une mauvaise utilisation du médicament, plus particulièrement par la modification de la galénique des formes orales solides (comprimés et gélules) effectuée par le personnel soignant devant des patients ayant des difficultés de déglutition (plus d un tiers des résidents par établissement concerné). Mal informé des nombreux risques que cet acte comporte, ce dernier en a fait une pratique banalisée, le plus souvent sans en informer le prescripteur ou le pharmacien. Devant ce constat, un état des lieux des pratiques a été établi dans quatre EHPAD de l Isère, ainsi qu une formation du personnel soignant sur ce sujet, afin d éviter cette pratique au maximum, ou tout du moins de la contrôler.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Quelle est la place de l homéopathie dans la prise en charge de la rhinopharyngite aiguë en France ? (état des lieux en 2013)

La rhinopharyngite aiguë est une pathologie très fréquente en France. Le marché du médicament français regorge de médicaments pour la prise en charge de la rhinopharyngite aiguë. Sur prescription ou en vente libre, ces médicaments n ont pas tous montré leur efficacité ni leur innocuité. Ce mémoire fait un état des lieux des données concernant l efficacité, l innocuité et le coût, de différents médicaments utilisés en prévention ou en curatif dans la rhinopharyngite aiguë (combinaisons de décongestionnant-antihistaminiques par voie orale, décongestionnant par voie locale, préparation à base d Echinacea, vitamine C et homéopathie) afin de comprendre qu elle est la place de l homéopathie dans la prise en charge de la rhinopharyngite aiguë en France.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Le rôle du pharmacien d officine face aux inégalités de santé dans les dépistages organisés des cancers

Chaque année, 90 000 personnes sont touchées par le cancer du sein ou le cancer colorectal en France. Fort de cette constatation, le gouvernement français a mis en place le dépistage organisé du cancer du sein en 2004 (pour les femmes de 50 à 74 ans) et celui du cancer colorectal en 2008 (pour les hommes et les femmes de 50 à 74 ans). Les taux de participation ne sont cependant pas à la hauteur des objectifs fixés par les autorités compétentes. De plus, des inégalités de santé sont présentes autant sur le plan territorial (urbain/rural) que sur le niveau socio-économique des individus. Des perspectives d évolution sont donc à envisager, en impliquant par exemple de nouveaux acteurs de santé. C est dans ce contexte que le pharmacien d officine a un rôle à jouer. Pour les patients, il est un professionnel de santé en qui ils peuvent avoir confiance et demander facilement des informations du fait de sa proximité. Cette étude, réalisée à Grenoble et dans son agglomération, permet de recueillir la vision des équipes officinales sur le rôle du pharmacien d officine dans les dépistages organisés des cancers et leurs attentes en vue d une éventuelle formation. Cette étude s intéresse également aux connaissances des patients sur les dépistages organisés des cancers et à leur vision sur l implication du pharmacien d officine dans ce domaine. Les résultats obtenus ont été, dans un premier temps, comparés à une étude similaire faite en milieu rural en 2008 et, dans un deuxième temps, répartis en fonction du niveau socio-économique des zones étudiées afin d évaluer l impact de celui-ci sur les connaissances et la participation aux dépistages organisés des cancers.Every year, 90 000 people are affected by breast cancer or colorectal cancer in France. Accordingly, the French government implemented the organized screening of breast cancer in 2004 (for women between 50 and 74 years) and of colorectal cancer in 2008 (for men and women between 50 and 74 years). The turnout is far lower than expected by the relevant authorities. Moreover, health disparities are present both on a regional and socio-economic level. Evolution prospects have to be considered, involving new health factors. In this context, the pharmacist has a role to play. For patients, he is a health professional in whom they can trust and obtain information easily because of his proximity. This study, conducted in Grenoble and the local area, collected views of official teams about the role of the pharmacist in organized cancer screening and their expectations for a possible outcome. This study is also about patients views regarding organized cancer screening and the role the pharmacist has in this area. Results were, in the first instance, compared to a similar study done in a rural area in 2008, and secondly, divided further into socio-economic levels of the studied areas, to evaluate the impact on the knowledge and participation in organized cancer screening.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Dépistage du Syndrome d'Apnées Obstructives du Sommeil et évaluation du risque cardiovasculaire à l'officine (implication du pharmacien et perspectives d'application)

La loi HPST reconnaît aux pharmaciens d officine la possibilité d exercer de nouvelles missions, dont le dépistage de certaines pathologies. Le pharmacien, par son accessibilité et ses compétences, semble idéalement positionné pour mener à bien ce type d action. Cependant, la conjoncture économique étant difficile pour le secteur, la mise en place du dépistage non rémunéré présente un risque pour l entreprise officinale. C est dans ce contexte que le projet Pharma-SAS a été développé. Cette étude consiste à mettre en place le dépistage du syndrome d apnées obstructif du sommeil (SAOS) par le pharmacien, au comptoir de l officine ainsi que l évaluation du risque cardiovasculaire chez certains des sujets inclus. Le SAOS constitue le principal trouble respiratoire lié au sommeil. Il correspond à l obstruction partielle ou totale des voies respiratoires supérieures pendant le sommeil, à l origine d apnées ou d hypopnées. Cette maladie touche près de 5 % de la population, elle est responsable de nombreuses complications cardiovasculaires et d une nette dégradation de la qualité de vie. Au niveau clinique, le SAOS se caractérise par une somnolence diurne et des ronflements associés parfois à des pauses respiratoires. Ces symptômes, facilement identifiables, permettent un dépistage aisé réalisable à l aide d un simple questionnaire. 214 sujets ont été inclus dans l étude Pharma-SAS et parmi eux, 71 sujets ont été décrits à haut risque de SAOS. A notre connaissance, seulement 4 des sujets dépistés à haut risque de SAOS ont effectué l examen diagnostic. Un diagnostic de SAOS a ainsi été vérifié chez 3 de ces patients qui sont actuellement traités par pression positive continue.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Assessing Adherence to Healthy Dietary Habits Through the Urinary Food Metabolome:Results From a European Two-Center Study

BACKGROUND: Diet is one of the most important modifiable lifestyle factors in human health and in chronic disease prevention. Thus, accurate dietary assessment is essential for reliably evaluating adherence to healthy habits. OBJECTIVES: The aim of this study was to identify urinary metabolites that could serve as robust biomarkers of diet quality, as assessed through the Alternative Healthy Eating Index (AHEI-2010). DESIGN: We set up two-center samples of 160 healthy volunteers, aged between 25 and 50, living as a couple or family, with repeated urine sampling and dietary assessment at baseline, and 6 and 12 months over a year. Urine samples were subjected to large-scale metabolomics analysis for comprehensive quantitative characterization of the food-related metabolome. Then, lasso regularized regression analysis and limma univariate analysis were applied to identify those metabolites associated with the AHEI-2010, and to investigate the reproducibility of these associations over time. RESULTS: Several polyphenol microbial metabolites were found to be positively associated with the AHEI-2010 score; urinary enterolactone glucuronide showed a reproducible association at the three study time points [false discovery rate (FDR): 0.016, 0.014, 0.016]. Furthermore, other associations were found between the AHEI-2010 and various metabolites related to the intake of coffee, red meat and fish, whereas other polyphenol phase II metabolites were associated with higher AHEI-2010 scores at one of the three time points investigated (FDR < 0.05 or β ≠ 0). CONCLUSION: We have demonstrated that urinary metabolites, and particularly microbiota-derived metabolites, could serve as reliable indicators of adherence to healthy dietary habits. CLINICAL TRAIL REGISTRATION: www.ClinicalTrials.gov, Identifier: NCT03169088

Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways

Maladaptive changes in the carotid body (CB) induced by chronic intermittent hypoxia (IH) account for the pathogenesis of cardiovascular morbidity in patients with sleep-disordered breathing. We postulated that the proinflammatory cytokines, namely interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and cytokine receptors (IL-1r1, gp130 and TNFr1) locally expressed in the rat CB play a pathophysiological role in IH-induced CB inflammation. Results showed increased levels of oxidative stress (serum 8-isoprostane and nitrotyrosine in the CB) in rats with 7-day IH treatment resembling recurrent apneic conditions when compared with the normoxic control. Local inflammation shown by the amount of ED1-containing cells (macrophage infiltration) and the gene transcripts of NADPH oxidase subunits (gp91phox and p22phox) and chemokines (MCP-1, CCR2, MIP-1α, MIP-1β and ICAM-1) in the CB were significantly more in the hypoxic group than in the control. In addition, the cytokines and receptors were expressed in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase and the levels of expressions were significantly increased in the hypoxic group. Exogenous cytokines elevated the intracellular calcium ([Ca2+]i) response to acute hypoxia in the dissociated glomus cells. The effect of cytokines on the [Ca2+]i response was significantly greater in the hypoxic than in the normoxic group. Moreover, daily treatment of IH rats with anti-inflammatory drugs (dexamethasone or ibuprofen) attenuated the levels of oxidative stress, gp91phox expression and macrophage infiltration in the CB. Collectively, these results suggest that the upregulated expression of proinflammatory cytokine pathways could mediate the local inflammation and functional alteration of the CB under chronic IH conditions

The “Goldilocks Zoneâ€? from a redox perspectiveâ€â€�Adaptive vs. deleterious responses to oxidative stress in striated muscle

Consequences of oxidative stress may be beneficial or detrimental in physiological systems. An organ system's position on the “hormetic curve� is governed by the source and temporality of reactive oxygen species (ROS) production, proximity of ROS to moieties most susceptible to damage, and the capacity of the endogenous cellular ROS scavenging mechanisms. Most importantly, the resilience of the tissue (the capacity to recover from damage) is a decisive factor, and this is reflected in the disparate response to ROS in cardiac and skeletal muscle. In myocytes, a high oxidative capacity invariably results in a significant ROS burden which in homeostasis, is rapidly neutralized by the robust antioxidant network. The up-regulation of key pathways in the antioxidant network is a central component of the hormetic response to ROS. Despite such adaptations, persistent oxidative stress over an extended time-frame (e.g., months to years) inevitably leads to cumulative damages, maladaptation and ultimately the pathogenesis of chronic diseases. Indeed, persistent oxidative stress in heart and skeletal muscle has been repeatedly demonstrated to have causal roles in the etiology of heart disease and insulin resistance, respectively. Deciphering the mechanisms that underlie the divergence between adaptive and maladaptive responses to oxidative stress remains an active area of research for basic scientists and clinicians alike, as this would undoubtedly lead to novel therapeutic approaches. Here, we provide an overview of major types of ROS in striated muscle and the divergent adaptations that occur in response to them. Emphasis is placed on highlighting newly uncovered areas of research on this topic, with particular focus on the mitochondria, and the diverging roles that ROS play in muscle health (e.g., exercise or preconditioning) and disease (e.g., cardiomyopathy, ischemia, metabolic syndrome)