137 research outputs found
Développement d'un modèle de sénescence prématurée induite par les UVB chez des fibroblastes humains diploïdes de derme: étude des mécanismes moléculaires impliqués dans l'apparition de ce phénotype
Exploring the Communication of the SASP:Dynamic, Interactive, and Adaptive Effects on the Microenvironment
Cellular senescence is a complex cell state that can occur during physiological ageing or after exposure to stress signals, regardless of age. It is a dynamic process that continuously evolves in a context-dependent manner. Senescent cells interact with their microenvironment by producing a heterogenous and plastic secretome referred to as the senescence-associated secretory phenotype (SASP). Hence, understanding the cross-talk between SASP and the microenvironment can be challenging due to the complexity of signal exchanges. In this review, we first aim to update the definition of senescence and its associated biomarkers from its discovery to the present day. We detail the regulatory mechanisms involved in the expression of SASP at multiple levels and develop how SASP can orchestrate microenvironment modifications, by focusing on extracellular matrix modifications, neighboring cells’ fate, and intercellular communications. We present hypotheses on how these microenvironmental events may affect dynamic changes in SASP composition in return. Finally, we discuss the various existing approaches to targeting SASP and clarify what is currently known about the biological effects of these modified SASPs on the cellular environment.</p
UV, stress and aging
Skin is a model of choice in studies on aging. Indeed, skin aging can be modulated by internal and external factors, reflecting its complexity. Two types of skin aging have been identified: intrinsic, mainly genetically determined and extrinsic—also called "photo-aging"—resulting on the impact of environmental stress and more precisely of UV rays. Simplified in vitro models, based on cellular senescence, have been developed to study the relationship between UV and aging. These models vary on the cell type (fibroblasts or keratinocytes, normal or immortalized) and the type of UV used (UVA or UVB)
Unraveling the interplay between senescent dermal fibroblasts and cutaneous squamous cell carcinoma cell lines at different stages of tumorigenesis
Age-related cellular copper dynamics in the fungal ageing model Podospora anserina and in ageing human fibroblasts
In previous investigations an impact of cellular copper homeostasis on ageing of the ascomycete Podospora anserina has been demonstrated. Here we provide new data indicating that mitochondria play a major role in this process. Determination of copper in the cytosolic fraction using total reflection X-ray fluorescence spectroscopy analysis and eGfp reporter gene studies indicate an age-related increase of cytosolic copper levels. We show that components of the mitochondrial matrix (i.e. eGFP targeted to mitochondria) become released from the organelle during ageing. Decreasing the accessibility of mitochondrial copper in P. anserina via targeting a copper metallothionein to the mitochondrial matrix was found to result in a switch from a copper-dependent cytochrome-c oxidase to a copper-independent alternative oxidase type of respiration and results in lifespan extension. In addition, we demonstrate that increased copper concentrations in the culture medium lead to the appearance of senescence biomarkers in human diploid fibroblasts (HDFs). Significantly, expression of copper-regulated genes is induced during in vitro ageing in medium devoid of excess copper suggesting that cytosolic copper levels also increase during senescence of HDFs. These data suggest that the identified molecular pathway of age-dependent copper dynamics may not be restricted to P. anserina but may be conserved from lower eukaryotes to humans
Proteomic Profiling of Human Keratinocytes Undergoing UVB-Induced Alternative Differentiation Reveals TRIpartite Motif Protein 29 as a Survival Factor
BACKGROUND: Repeated exposures to UVB of human keratinocytes lacking functional p16(INK-4a) and able to differentiate induce an alternative state of differentiation rather than stress-induced premature senescence. METHODOLOGY/PRINCIPAL FINDINGS: A 2D-DIGE proteomic profiling of this alternative state of differentiation was performed herein at various times after the exposures to UVB. Sixty-nine differentially abundant protein species were identified by mass spectrometry, many of which are involved in keratinocyte differentiation and survival. Among these protein species was TRIpartite Motif Protein 29 (TRIM29). Increased abundance of TRIM29 following UVB exposures was validated by Western blot using specific antibody and was also further analysed by immunochemistry and by RT-PCR. TRIM29 was found very abundant in keratinocytes and reconstructed epidermis. Knocking down the expression of TRIM29 by short-hairpin RNA interference decreased the viability of keratinocytes after UVB exposure. The abundance of involucrin mRNA, a marker of late differentiation, increased concomitantly. In TRIM29-knocked down reconstructed epidermis, the presence of picnotic cells revealed cell injury. Increased abundance of TRIM29 was also observed upon exposure to DNA damaging agents and PKC activation. The UVB-induced increase of TRIM29 abundance was dependent on a PKC signaling pathway, likely PKCdelta. CONCLUSIONS/SIGNIFICANCE: These findings suggest that TRIM29 allows keratinocytes to enter a protective alternative differentiation process rather than die massively after stress
Genotoxicity and Gene Expression in the Rat Lung Tissue following Instillation and Inhalation of Different Variants of Amorphous Silica Nanomaterials (aSiO2 NM)
This article belongs to the Special Issue Cytotoxicity and Genotoxicity of Nanomaterials.Several reports on amorphous silica nanomaterial (aSiO2 NM) toxicity have been questioning their safety. Herein, we investigated the in vivo pulmonary toxicity of four variants of aSiO2 NM: SiO2_15_Unmod, SiO2_15_Amino, SiO2_7 and SiO2_40. We focused on alterations in lung DNA and protein integrity, and gene expression following single intratracheal instillation in rats. Additionally, a short-term inhalation study (STIS) was carried out for SiO2_7, using TiO2_NM105 as a benchmark NM. In the instillation study, a significant but slight increase in oxidative DNA damage in rats exposed to the highest instilled dose (0.36 mg/rat) of SiO2_15_Amino was observed in the recovery (R) group. Exposure to SiO2_7 or SiO2_40 markedly increased oxidative DNA lesions in rat lung cells of the exposure (E) group at every tested dose. This damage seems to be repaired, since no changes compared to controls were observed in the R groups. In STIS, a significant increase in DNA strand breaks of the lung cells exposed to 0.5 mg/m3 of SiO2_7 or 50 mg/m3 of TiO2_NM105 was observed in both groups. The detected gene expression changes suggest that oxidative stress and/or inflammation pathways are likely implicated in the induction of (oxidative) DNA damage. Overall, all tested aSiO2 NM were not associated with marked in vivo toxicity following instillation or STIS. The genotoxicity findings for SiO2_7 from instillation and STIS are concordant; however, changes in STIS animals were more permanent/difficult to revert.This work was funded by the Portuguese Foundation for Science and Technology (FCT)
through ERA-NET SIINN project NanoToxClass (SIINN/0001/2013). FB and MJB are recipients of
FCT PhD scholarships (SFRH/BD/101060/2014 and SFRH/BD/12046/2016). Thanks are due to
FCT/MCTES for the financial support through national funds to EPIUnit (UIDB/04750/2020). J.
Laloy performed STIS at the University of Namur with funding provided by BfR (grant agreement
number 1329-561). F. Debacq-Chainiaux is a research associate at FRS-FNRS (National Funds for
Scientific Research, Belgium).info:eu-repo/semantics/publishedVersio
Children's microvascular traits and ambient air pollution exposure during pregnancy and early childhood:Prospective evidence to elucidate the developmental origin of particle-induced disease
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