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Saint-Jean-de-Luz, France

Otranto M.,University of Limoges | Otranto M.,State University of Rio de Janeiro | Sarrazy V.,University of Toronto | Bonte F.,LVMH Research | And 3 more authors.
Cell Adhesion and Migration

Since its first description in wound granulation tissue, the myofibroblast has been recognized to be a key actor in the epithelial-mesenchymal cross-talk that plays a crucial role in many physiological and pathological situations, such as regulation of prostate development, ventilation-perfusion in lung alveoli or organ fibrosis. The presence of myofibroblasts in the stroma reaction to epithelial tumors is well established and many data are accumulating which suggest that the stroma compartment is an active participant in tumor onset and/or evolution. In this review we summarize the evidence in favor of this concept, the main mechanisms that regulate myofibroblast differentiation and function, as well as the biophysical and biochemical factors possibly involved in epithelial-stroma interactions, using liver carcinoma as main model, in view of achieving a better understanding of tumor progression mechanisms and of tools directed toward stroma as eventual therapeutic target. © 2012 Landes Bioscience. Source

Desvergne A.,Paris-Sorbonne University | Desvergne A.,French National Center for Scientific Research | Desvergne A.,French Institute of Health and Medical Research | Ugarte N.,Paris-Sorbonne University | And 15 more authors.
Free Radical Biology and Medicine

The circadian system orchestrates the timing of physiological processes of an organism living in daily environmental changes. Disruption of circadian rhythmicity has been shown to result in increased oxidative stress and accelerated aging. The circadian regulation of antioxidant defenses suggests that other redox homeostasis elements such as oxidized protein degradation by the proteasome, could also be modulated by the circadian clock. Hence, we have investigated whether proteasome activities and oxidized protein levels would exhibit circadian rhythmicity in synchronized cultured mammalian cells and addressed the mechanisms underlying this process. Using synchronized human embryonic kidney HEK 293 cells and primary dermal fibroblasts, we have shown that the levels of carbonylated protein and proteasome activity vary rhythmically following a 24 h period. Such a modulation of proteasome activity is explained, at least in part, by the circadian expression of both Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the proteasome activator PA28αβ. HEK 293 cells showed an increased susceptibility to oxidative stress coincident with the circadian-dependent lower activity of the proteasome. Finally, in contrast to young fibroblasts, no circadian modulation of the proteasome activity and carbonylated protein levels was evidenced in senescent fibroblasts. This paper reports a novel role of the circadian system for regulating proteasome function. In addition, the observation that proteasome activity is modulated by the circadian clock opens new avenues for both the cancer and the aging fields, as exemplified by the rhythmic resistance of immortalized cells to oxidative stress and loss of rhythmicity of proteasome activity in senescent fibroblasts. © 2016 Elsevier Inc. Source

Zhang H.,Chinese Academy of Sciences | Zhang H.,Naval Submarine Academy | Hou W.,Chinese Academy of Sciences | Henrot L.,Sprim Advanced Life science | And 4 more authors.
Journal of the Royal Society Interface

We present a computational model to study the spatio-temporal dynamics of epidermis homoeostasis under normal and pathological conditions. The model consists of a population kinetics model of the central transition pathway of keratinocyte proliferation, differentiation and loss and an agent-based model that propagates cell movements and generates the stratified epidermis. The model recapitulates observed homoeostatic cell density distribution, the epidermal turnover time and the multilayered tissue structure. We extend the model to study the onset, recurrence and phototherapy-induced remission of psoriasis. The model considers psoriasis as a parallel homoeostasis of normal and psoriatic keratinocytes originated from a shared stem cell (SC) niche environment and predicts two homoeostatic modes of psoriasis: a disease mode and a quiescent mode. Interconversion between the two modes can be controlled by interactions between psoriatic SCs and the immune system and by normal and psoriatic SCs competing for growth niches. The prediction of a quiescent state potentially explains the efficacy of multi-episode UVB irradiation therapy and recurrence of psoriasis plaques, which can further guide designs of therapeutics that specifically target the immune system and/or the keratinocytes. © 2015 The Author(s) Published by the Royal Society.All rights reserved. Source

Demirovic D.,University of Aarhus | Nizard C.,LVMH Research | Rattan S.I.S.,University of Aarhus

Intracellular autophagy (AP) is a stress response that is enhanced under conditions of limitation of amino acids, growth factors and other nutrients, and also when macromolecules become damaged, aggregated and fibrillated. Aging is generally accompanied by an increase in intracellular stress due to all the above factors. Therefore, we have compared the basal levels of AP in serially passaged human facial skin fibroblasts undergoing aging and replicative senescence in vitro, and ex vivo in the skin biopsies from the photo-protected and photo-exposed area of the arms of 20 healthy persons of young and old ages. Immunofluorescence microscopy, employing antibodies against a specific intracellular microtubule-associated protein-1 light chain-3 (LC3) as a well established marker of AP, showed a 5-fold increase in the basal level of LC3 in near senescent human skin fibroblasts. However, no such age-related increase in LC3 fluorescence and AP could be detected in full thickness skin sections from the biopsies obtained from 10 healthy young (age 25 to 30 yr) and 10 old (age 60 to 65 yr) donors. Furthermore, there was no difference in the basal level of LC3 in the skin sections from photo-protected and photo-exposed areas of the arm. Thus, in normal conditions, the aging phenotype of the skin cells in culture and in the body appears to be different in the case of AP. © 2015 Demirovic et al. Source

Demirovic D.,University of Aarhus | de Toda I.M.,University of Aarhus | Nizard C.,LVMH Research | Rattan S.I.S.,University of Aarhus
Journal of Cell Communication and Signaling

Repeated exposure to mild heat shock (HS) has been shown to induce a wide range of health promoting hormetic effects in various biological systems, including human cells undergoing aging in vitro. In order to understand how cells distinguish between mild and severe stress, we have investigated the extent of early and immediate HS response by analyzing the nuclear translocation of the transcription factor heat shock factor-1 (HSF1), in serially passaged normal adult human facial skin fibroblasts exposed to mild (41 °C) or severe (43 °C) HS. Cells respond differently when exposed to mild and severe HS at different passage levels in terms of the extent of HSF1 translocation. In early passage young cells there was a 5-fold difference between mild and severe HS in the extent of HSF1 translocation. However, in near senescent late passage cells, the difference between mild and severe stress in terms of the extent of HSF1 translocation was reduced to less than 2-fold. One of the reasons for this age-related attenuation of heat shock response is due to the fact there was a higher basal level of HSF1 in the nuclei of late passage cells, which is indicative of increased intrinsic stress during cellular aging. These observations are consistent with previously reported data that whereas repeated mild stress given at younger ages can slow down aging and increase the lifespan, the same level of stress given at older ages may not provide the same benefits. Therefore, elucidating the early and immediate steps in the induction of stress response can be useful in deciding whether a particular level of stress is potentially hormetically beneficial or not. © 2014, The International CCN Society. Source

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