Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay. The compound 6E11, a natural product derivative, was characterized as a positive hit. Interestingly, this flavanone compound: inhibits necroptosis induced by death receptors ligands TNF-α (Tumor Necrosis Factor) or TRAIL (TNF-Related Apoptosis-Inducing Ligand); is an extremely selective inhibitor, among kinases, of human RIPK1 enzymatic activity with a nM Kd; has a non-ATP competitive mode of action and a novel putative binding site; is weakly cytotoxic towards human primary blood leukocytes or retinal pigment epithelial cells at effective concentrations; protects human aortic endothelial cells (HAEC) from cold hypoxia/reoxygenation injury more effectively than necrostatin-1 (Nec-1) and Nec-1s. Altogether, these data demonstrate that 6E11 is a novel potent small molecular inhibitor of RIPK1-driven necroptosis.
ISSN: 2045-2322

hal-01616456
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456/file/s41598-017-12788-4.pdf
DOI : 10.1038/s41598-017-12788-4

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
Introduction. - Temocillin is an alternative to treat urinary tract infections with bacteria producing extended spectrum beta-lactamase (ESBL). The objective is to evaluate the use of temocillin in urinary tract infections. Materials and methods. - A systematic review of literature was carried out according to PRISMA criteria. All national and international recommendations have been reviewed regarding the indication of the use of temocillin in urology. Data collection on the use of temocillin in urinary tract infection has been performed from the Cochrane, LILACS and the Medline database. The following keywords were used: temocillin, extended spectrum. beta-lactamase, urinary tract infections, urine, prostate, epididymis, testis, diffusion, pharmacokinetics, pharmacodynamics. The selection was based on the methodology, language of publication (English/French), relevance to the topic and date of publication of the articles collected. The endpoint was to provide exhaustive scientific information allowing urologists to use this antibiotic in febrile urinary infections. Results. - Bacteria producing ESBL has a relatively high susceptible to temocillin, ranging from 61 % to 90 %. These rates would allow its use in probabilistic. The dosage recommended is currently, in the normo-renal patient, 4 g per day by intermittent infusion or continuously after a loading dose of 2g. Some studies argue, particularly in case of difficult clinical situations or obese patients, for administration of high doses (6 g/24 h) rather continuous infusion. There is no evident relationship between high doses and side effects. With an excellent urinary and prostatic diffusion, temocilllin might be recommend for the treatment of ESBL prostatitis. Conclusion. - Temocillin is known to have good urinary and prostatic diffusion. According to our results, this antibiotics is now a reliable alternative for the treatment of documented ESBL urinary tract infections. (C) 2017 Elsevier Masson SAS. All rights reserved.
ISSN: 1166-7087

hal-01659245
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01659245
DOI : 10.1016/j.purol.2017.07.242
PUBMED : 28869169

Éditeur(s) : HAL CCSD American Society for Investigative Pathology
Résumé : International audience
Recent studies suggest that psoriasis may be more severe in patients with nonalcoholic fatty liver disease, particularly in those with the inflammatory stage of steatohepatitis [nonalcoholic steatohepatitis (NASH)]. Herein, we investigated the impact of diet-induced steatohepatitis on the severity of imiquimod-induced psoriasiform dermatitis. Mice fed with a high-fat diet developed steatohepatitis reminiscent of human NASH with ballooning hepatocytes and significant liver fibrosis. Mice with steatohepatitis also displayed moderate cutaneous inflammation characterized by erythema, dermalinfiltrates of CD45(+) leukocytes, and a local production of IL-17A. Moreover, steatohepatitis was associated with an epidermal activation of caspase-1 and cutaneous overexpression of IL-1 beta. Imiquimod-induced psoriasiform dermatitis was exacerbated in mice with steatohepatitis as compared to animals fed with a standard diet. Scale formation and acanthosis were aggravated, in correlation with increased IL-17A and IL-22 expression in inflamed skins. Finally, intradermal injection of IL-17A in standard diet-fed mice recapitulated the cutaneous pathology of mice with steatohepatitis. The results show that high-fat diet induced steatohepatitis aggravates the inflammation in psoriasiform dermatitis, via the cutaneous production of IL-17A. In agreement with clinical data, this description of a novel extrahepatic manifestation of NASH should sensitize dermatologists to the screening and the management of fatty liver in psoriatic patients.
ISSN: 0002-9440

hal-01390977
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01390977
DOI : 10.1016/j.ajpath.2016.05.012
PUBMED : 27423696

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
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ISSN: 1043-4666

hal-01485264
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01485264