Ergothérapie et soins palliatifs : Soutenir la vie en attendant la fin

Sans résumé

Dose-dependent effects of morphine on lipopolysaccharide (LPS)-induced inflammation, and involvement of multixenobiotic resistance (MXR) transporters in LPS efflux in teleost fish

Opioid drugs, such as morphine (MO), detected in aquatic environments worldwide, may harm fish due to their semi-persistence and ability to potently interact with molecular targets conserved across vertebrates. Here, we established a waterborne bacterial lipopolysaccharide (LPS) challenge assay with zebrafish embryos as a model to investigate chemically-induced disruption of the innate immune system, and used it to study the effects of MO exposure. Exposure to 1 mg/L MO resulted in pronounced immunosuppression, reflected in downregulation of several inflammation-related genes, including myd88, trif, traf6, p38, nfκb2, il-1β, il-8 and ccl34a. Fish exposed to 1 mg/L MO accumulated 11.7 ng/g (wet weight) of MO, a concentration comparable to that reported in blood of chronic drug abusers subject to higher infection rates. Surprisingly, exposure to lower MO concentrations (100 ng/L–100 μg/L) led to exacerbation of LPS-induced inflammation. Two ATP-binding cassette (ABC) transporters known to be involved in the xenobiotic efflux - abcb4 and abcc2, also known as multixenobiotic resistance (MXR) transporters - were downregulated at 100 ng/L MO. We hypothesized that ABC/MXR transporters could modulate the severity of inflammation by being involved in efflux of LPS, thus regulating its accumulation in the organism. Indeed, we could demonstrate that blocking of ABC/MXR transporters by an inhibitor, cyclosporine A, results in stronger inflammation, coinciding with higher LPS accumulation, as visualized with fluorescently labeled LPS. Our work demonstrates that MO can disrupt fish innate immune responses at environmentally relevant concentrations. We also provide evidence for a role of ABC/MXR transporters in LPS efflux in fish. These finding may be applicable across other taxa, as ABC transporters are evolutionary conserved. Since diverse environmentally present chemicals are known to interfere with ABC/MXR transporters' expression or activity, our discovery raises concerns about potential adverse effects of such compounds on the immune system responses in aquatic organisms

Response of zebrafish and Japanese medaka to imidacloprid: a comparative study

International audienceNeonicotinoids are among the most produced and used insecticides and are frequently found in freshwater with concentrations ranging from ng to μg/L. These molecules are small and very soluble in water. This given, they are likely to pass the chorion and thus easily enter embryos of fish. It is known that these compounds impact on insects, including bees, in terms of toxicity and behaviour, but whether similar impacts could be observed in fish is not yet known. The aim of this study was to investigate effects of exposure to imidacloprid, one of the most used neonicotinoids, on the development and behaviour of two common fish lab species: Zebrafish (Danio rerio) and Japanese medaka (Oryzias latipes). Fish were exposed during 5 (zebrafish) and 13 days (medaka) to 0, 0.2, 2, 20, 200 and 2000 μg/L imidacloprid by aqueous exposure, matching the respective time from fertilization to emerged larvae for the two species. At similar developmental stages, survival, hatch, growth, morphology, behaviour and histology were examined. No impact on survival was found. A delay for 2 μg/L imidacloprid exposures was observed for hatch in both species. Except for the 20 mg/L exposure level, imidacloprid led to hypoactivity in both species. A striking difference was found in morphology: a high number of deformities were noticed for medaka whereas almost none were found in zebrafish. Yolk and bone oedemas started to be noticed at 20 μg/L after hatch, jaw deformity and lordosis/scoliosis increased with concentration level. An increase of haemorrhage was found at the highest concentration (2000 μg/L). In order to shed light on the observed species differences, we intend to investigate the uptake of imidacloprid into the fish embryos and its biotransformation

Les premiers stades de médaka japonais (Oryzias latipes) sont plus sensibles à l’imidaclopride que les les premiers stades de poissons zèbres (Danio rerio)

Lien vers le programme du congrès : https://cote.labex.u-bordeaux.fr/Download/News/PieceJointeInfo/fichier/1724.pdfInternational audienc

Imidacloprid induces adverse effects on fish early life stages that are more severe in Japanese medaka (Oryzias latipes) than in zebrafish (Danio rerio)

International audienceNeonicotinoids are widely used insecticides that have frequently been found in freshwater with concentrations ranging from ng to μg/L. It is known that these compounds impact non-target invertebrates, such as bees and gammaridae, in terms of toxicity and behavior, but impacts and species differences on vertebrates such as fish are little explored. The aim of this study was to investigate and compare the effects of one widely used neonicotinoid, imidacloprid, on development and behavior of two fish model species: Zebrafish (Danio rerio) and Japanese medaka (Oryzias latipes). Fish were exposed for 5 (zebrafish) and 14 (medaka) days from 0.2 to 2000 μg/L imidacloprid by aqueous exposure. Survival, development, behavior and histological features were monitored and organism-internal concentrations and biotransformation products measured. Imidacloprid caused sublethal effects in both species but the effects were much stronger in medaka with deformities, lesions and reduced growth being the most prominent impacts. Due to the overall longer time of development, time-integrated exposure of medaka was about 2-fold higher compared to zebrafish, potentially accounting for parts of the sensitivity differences. Our results underline the importance of taking species sensitivity differences into account especially when considering that medaka responded at imidacloprid concentrations that have been measured in the environment

Endothelial, but not smooth muscle, peroxisome proliferator-activated receptor β/δ regulates vascular permeability and anaphylaxis.

International audienceRemodeling of quiescent vessels with increases in permeability, vasodilatation, and edema are hallmarks of inflammatory disorders. Factors involved in this type of remodeling represent potential therapeutic targets. We investigated whether the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) β/δ, a regulator of metabolism, fibrosis, and skin homeostasis, is involved in regulation of this type of remodeling. Wild-type and various Pparb/d mutant mice were used to monitor dermal acute vascular hyperpermeability (AVH) and passive systemic anaphylaxis-induced hypothermia and edema. PPARβ/δ-dependent kinase activation and remodeling of endothelial cell-cell junctions were addressed by using human endothelial cells. AVH and dilatation of dermal microvessels stimulated by vascular endothelial growth factor A, histamine, and thrombin are severely compromised in PPARβ/δ-deficient mice. Selective deletion of the Pparb/d-encoding gene in endothelial cells in vivo similarly limits dermal AVH and vasodilatation, providing evidence that endothelial PPARβ/δ is the major player in regulating acute dermal microvessel remodeling. Furthermore, endothelial PPARβ/δ regulatory functions are not restricted to the skin vasculature because its deletion in the endothelium, but not in smooth muscle cells, also leads to reduced systemic anaphylaxis, the most severe form of allergic reaction, in which an acute vascular response plays a key role. PPARβ/δ-dependent AVH activation likely involves the activation of mitogen-activated protein kinase and Akt pathways and leads to downstream destabilization of endothelial cell-cell junctions. These results unveil not only a novel function of PPARβ/δ as a direct regulator of acute vessel permeability and dilatation but also provide evidence that antagonizing PPARβ/δ represents an important strategy to consider for moderating diseases with altered endothelial integrity, such as acute inflammatory and allergic disorders

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers