Exposure to manganese and lead disrupt the human placental serotonergic system

International audienc

Release kinetics of [lidocainium][ibuprofenate] as Active Pharmaceutical Ingredient-Ionic Liquid from a plasticized zein matrix in simulated digestion

International audienceAn in vitro approach is proposed to study the release of an Active Pharmaceutical Ingredient-Ionic Liquid (API-IL) from a natural biopolymer matrix based on zein, a maize storage protein. Zein can be processed in the molten state with 20 w% [Lidocainium][Ibuprofenate] added as API-IL also acting as plasticizer and potentially coplasticized by glycerol. The thermal stability of the matrix is checked, as well as the in vivo biological activity of the API-IL confirming anesthetic and anti-inflammatory activities. Model tablets are thermomolded at 130 • C (∅20 mm, 0.2 mm thick) and submitted to simulated digestion based on the INFOGEST static protocol of gastrointestinal food digestion at 37 • C (2 h under gastric conditions followed by 2 h under intestinal ones). The release of the API-IL is evaluated by HPLC-UV to dissociate lidocainium, that shows a progressive release (35 % after 2 h and 60 % after 4 h digestion), from ibuprofenate, that is mainly released under intestinal conditions due to low solubility in acidic conditions. The monitoring of the tablets reveals release mechanisms based on diffusion without noticeable erosion of the matrix. These results demonstrate the interest of this thermoplastic material to provide a relevant drug delivery system

DNA Double-Strand Breaks Induced in Human Cells by Twelve Metallic Species: Quantitative Inter-Comparisons and Influence of the ATM Protein

Despite a considerable amount of data, the molecular and cellular bases of the toxicity due to metal exposure remain unknown. Recent mechanistic models from radiobiology have emerged, pointing out that the radiation-induced nucleo-shuttling of the ATM protein (RIANS) initiates the recognition and the repair of DNA double-strand breaks (DSB) and the final response to genotoxic stress. In order to document the role of ATM-dependent DSB repair and signalling after metal exposure, we applied twelve different metal species representing nine elements (Al, Cu, Zn Ni, Pd, Cd, Pb, Cr, and Fe) to human skin, mammary, and brain cells. Our findings suggest that metals may directly or indirectly induce DSB at a rate that depends on the metal properties and concentration, and tissue type. At specific metal concentration ranges, the nucleo-shuttling of ATM can be delayed which impairs DSB recognition and repair and contributes to toxicity and carcinogenicity. Interestingly, as observed after low doses of ionizing radiation, some phenomena equivalent to the biological response observed at high metal concentrations may occur at lower concentrations. A general mechanistic model of the biological response to metal exposure based on the nucleo-shuttling of ATM is proposed to describe the metal-induced stress response and to define quantitative endpoints for toxicity and carcinogenicity

BUILDING TOGETHER : A reflection on community-based participatory research priorities in relation to hiv/aids in a remote region of Quebec

The objective of the article is to underline the importance of community-based participatory research, which involves institutional researchers and community practitioners, in establishing local and regional research priorities in relation to HIV/AIDS. We describe an 11-month-long reflection process conducted by a research collective in the Abitibi-Témiscamingue region of northern Quebec. The significant results of the joint reflection and discussion process included: the development of local capacities for research and collective action, involving academics and practitioners; the valorization of participatory research; and the increased accessibility of research-based knowledge for community actors involved in the fight against HIV/AIDS. In contrast with more traditional research methods, the participatory approach situates the balance of power within a research collective that jointly determines, throughout the course of the project, the priorities that best reflect local needs for HIV/AIDS research. This initial process of discussion resulted also in the joint validation of a forthcoming grant application to be submitted to the Canadian Institutes of Health Research (CIHR).L’objectif de l’article est de souligner l’importance de la recherche participative communautaire, impliquant des acteurs locaux et les chercheurs institutionnels, dans l’établissement des priorités de recherche locales et régionales en matière de VIH/SIDA. Les auteurs décrivent un processus de réflexion de 11 mois mené par un collectif de recherche dans la région de l’Abitibi-Témiscamingue, dans le Nord du Québec. Parmi les résultats importants du processus de réflexion et de discussion conjoint, mentionnons : le développement des capacités locales de recherche et d’action collective, impliquant des universitaires et des praticiens; la valorisation de la recherche participative; et l’accessibilité accrue des connaissances issues de la recherche pour les acteurs communautaires impliqués dans la lutte contre le VIH/SIDA. Contrairement aux méthodes de recherche plus traditionnelles, l’approche participative situe le pouvoir au sein d’un collectif de recherche qui détermine conjointement, tout au long du projet, les priorités qui reflètent le mieux les besoins locaux en matière de recherche sur le VIH/SIDA. Ce processus initial de discussion a également abouti à la validation conjointe d’une prochaine demande de subvention qui sera soumise aux Instituts de recherche en santé du Canada (IRSC)

Stat3 Controls Tubulointerstitial Communication during CKD

In CKD, tubular cells may be involved in the induction of interstitial fibrosis, which in turn, leads to loss of renal function. However, the molecular mechanisms that link tubular cells to the interstitial compartment are not clear. Activation of the Stat3 transcription factor has been reported in tubular cells after renal damage, and Stat3 has been implicated in CKD progression. Here, we combined an experimental model of nephron reduction in mice from different genetic backgrounds and genetically modified animals with in silico and in vitro experiments to determine whether the selective activation of Stat3 in tubular cells is involved in the development of interstitial fibrosis. Nephron reduction caused Stat3 phosphorylation in tubular cells of lesion-prone mice but not in resistant mice. Furthermore, specific deletion of Stat3 in tubular cells significantly reduced the extent of interstitial fibrosis, which correlated with reduced fibroblast proliferation and matrix synthesis, after nephron reduction. Mechanistically, in vitro tubular Stat3 activation triggered the expression of a specific subset of paracrine profibrotic factors, including Lcn2, Pdgfb, and Timp1. Together, our results provide a molecular link between tubular and interstitial cells during CKD progression and identify Stat3 as a central regulator of this link and a promising therapeutic target

Journée sans culture : Troubler la fête, rallumer notre joie = To Spoil the Party, To Set Our Joy Ablaze

"Composed as an extension of the conversations that took place during the 2015 Journée sans culture, To Spoil the Party, to Set Our Joy Ablaze gathers contributions from those who moderated the discussions of the day as well as those who set up its sites of rest, reflection, and play. These authors work to remain true to the spirit of what they lived, led by the desire to find a source of collective energy that exceeds the pervasive effects of tiredness and resignation. Their texts are joined by others, commissioned by the editorial team, which explore matters of concern not sufficiently addressed during the day." -- Publisher's website

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity

International audiencePURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III