Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Introduction The Latitudinal Gradient Hypothesis (LGH) foresees that specialized metabolites are overexpressed under low latitudes, where organisms are subjected to higher herbivory pressure. The widespread macroalga Asparagopsis taxiformis is composed of six distinct genetic lineages, some of them being introduced in many regions. Objectives To study (i) metabolic fingerprints of the macroalga and (ii) its bioactivity in space and time, both as proxies of its investment in defensive traits, in order to assess links between bioactivities and metabotypes with macroalgal invasiveness. Methods 289 macroalgal individuals, from four tropical and three temperate regions, were analyzed using untargeted metabolomics and the standardized Microtox (R) assay. Results Metabotypes showed a low divergence between tropical and temperate populations, while bioactivities were higher in temperate populations. However, these phenotypes varied significantly in time, with a higher variability in tropical regions. Bioactivities were high and stable in temperate regions, whereas they were low and much variable in tropical regions. Although the introduced lineage two exhibited the highest bioactivities, this lineage could also present variable proliferation fates. Conclusion The metabolomic approach partly discriminates macroalgal populations from various geographic origins. The production of chemical defenses assessed by the bioactivity assay does not match the macroalgal genetic lineage and seems more driven by the environment. The higher content of chemical defenses in temperate versus tropical populations is not in accordance with the LGH and cannot be related to the invasiveness of the macroalgae.
ISSN: 1573-3882

hal-01681538
https://hal.archives-ouvertes.fr/hal-01681538
DOI : 10.1007/s11306-017-1169-z

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Basal cell carcinoma (BCC) is the commonest tumor in human. About 70% sporadic BCCs bear somatic mutations in the PATCHED1 tumor suppressor gene which encodes the receptor for the Sonic Hedgehog morphogen (SHH). PATCHED1 germinal mutations are associated with the dominant Nevoid Basal Cell Carcinoma Syndrome (NBCCS), a major hallmark of which is a high susceptibility to BCCs. Although the vast majority of sporadic BCCs arises exclusively in sun exposed skin areas, 40 to 50% BCCs from NBCCS patients develop in non photo-exposed skin. Since overwhelming evidences indicate that microenvironment may both be modified by- and influence the- epithelial tumor, we hypothesized that NBCCS fibroblasts could contribute to BCCs in NBCCS patients, notably those developing in non photo-exposed skin areas. The functional impact of NBCCS fibroblasts was then assessed in organotypic skin cultures with control keratinocytes. Onset of epidermal differentiation was delayed in the presence of primary NBCCS fibroblasts. Unexpectedly, keratinocyte proliferation was severely reduced and showed high levels of nuclear P53 in both organotypic skin cultures and in fibroblast-led conditioning experiments. However, in spite of increased levels of senescence associated β-galactosidase activity in keratinocytes cultured in the presence of medium conditioned by NBCCS fibroblasts, we failed to observe activation of P16 and P21 and then of bona fide features of senescence. Constitutive extinction of P53 in WT keratinocytes resulted in an invasive phenotype in the presence of NBCCS fibroblasts. Finally, we found that expression of SHH was limited to fibroblasts but was dependent on the presence of keratinocytes. Inhibition of SHH binding resulted in improved epidermal morphogenesis. Altogether, these data suggest that the repertoire of diffusible factors (including SHH) expressed by primary NBCCS fibroblasts generate a stress affecting keratinocytes behavior and epidermal homeostasis. Our findings suggest that defects in dermo/epidermal interactions could contribute to BCC susceptibility in NBCCS patients.
ISSN: 1932-6203

Droits : http://creativecommons.org/licenses/by/
hal-01257867
http://hal.upmc.fr/hal-01257867
http://hal.upmc.fr/hal-01257867/document
http://hal.upmc.fr/hal-01257867/file/journal.pone.0145369.pdf
DOI : 10.1371/journal.pone.0145369

Éditeur(s) : HAL CCSD Wiley Open Access
Résumé : International audience
Estetrol (E4) is a natural estrogen with a long half-life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand-binding domain bound to 17β-estradiol (E2) and E4 are very similar, as well as their capacity to activate the two activation functions AF-1 and AF-2 and to recruit the coactivator SRC3. In vivo administration of high doses of E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane-initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS-dependent effects in endothelium but also in MCF-7 breast cancer cell line. This profile of ERα activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further.
ISSN: 1757-4676

hal-01118028
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118028
PUBMED : 25214462
PUBMEDCENTRAL : PMC4287935
DOI : 10.15252/emmm.201404112