The Thyroid Hormone Receptors Modulate the Skin Response to Retinoids

[Background]: Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice. [Methodology/Principal Findings]: We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA) induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced. [Conclusions/significance]: Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to these compounds could have not only physiological but also therapeutic implications.This work was supported by grants BFU2007-62402 and SAF2008-00121 from Ministerio de Ciencia e Innovación, RD06/0020/0036 and RD06/0020/0029 from the Fondo de Investigaciones Sanitarias and by the European Grant CRESCENDO (FP-018652).Peer reviewe

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide

The relevance of a point mutation at the C-terminal end of the S6 helix (F468) and the introduction of C-type inactivation in the blockage of hEag1 channels by astemizole, imipramine and dofetilide was tested. C-type inactivation decreased block by asternizole and dofetilide but not imipramine, suggesting different binding sites in the channel. F468C mutation increased IC50 for asternizole and imipramine but in contrast to HERG channels, only slightly for dofetilide. Together with measurements on recovery of blocking, our observations indicate that the mechanism of hEag1 blockage by each of these drugs is different, and suggest relevant structural differences between hEag1 and HERG channels. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved

Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide.

6The relevance of a point mutation at the C-terminal end of the S6 helix (F468) and the introduction of C-type inactivation in the blockage of hEag1 channels by astemizole, imipramine and dofetilide was tested. C-type inactivation decreased block by astemizole and dofetilide but not imipramine, suggesting different binding sites in the channel. F468C mutation increased IC(50) for astemizole and imipramine but in contrast to HERG channels, only slightly for dofetilide. Together with measurements on recovery of blocking, our observations indicate that the mechanism of hEag1 blockage by each of these drugs is different, and suggest relevant structural differences between hEag1 and HERG channels.reservedmixedD. GOMEZ-VARELA; C. CONTRERAS-JURADO; S. FURINI; R. GARCA-FERREIRO; W. STÜHMER; L. PARDOD., GOMEZ VARELA; C., CONTRERAS JURADO; Furini, Simone; R., GARCA FERREIRO; W., Stühmer; L., Pard

Assessment of seasonal and annual patterns in phosphorus content in a monitored catchment through a partitioning approach based on hydrometeorological data

High amounts of phosphorus (P) in rivers come mainly from two sources: fertilizers washed off from agricultural and urban areas by runoff water (non-point sources) and urban and industrial development which are translated in P discharges from wastewater treatment plants (WWTP). This work analyses the content of P in water for nearly 40 years inquiring into the origin of the sources, based on the hypothesis of runoff generation from the detection of river streamflow increases during the P contribution episode and the previous precipitation. For this purpose, the Guadaira River, which is located in the South of Spain and has a drainage surface of 1524 km2 , was selected. In this watershed agricultural land use converges with numerous human activities resulting in high pressures on water quality. We found 40% of the P contribution episodes found seem to come from the runoff generated after the heaviest rainfall events, which normally occur between November and May. The remaining 60% of the P contribution episodes were found to be linked to point sources, which become more relevant from June to September, reaching the highest concentration values (6–17 mg/L). The results highlight that the target phosphate concentration value of 0.34 mg PO4/L imposed by the national legislation for a good state following the Water Framework Directive 2000/60/EC is exceeded by 96% of the measurements during the period from 1981 to 2022. On a monthly basis, PO4 loads showed a linear relationship with river streamflow (R2 = 0.94). However, on field measurements scale, a potential relationship between both variables was found, which changed according to the improvement in the wastewater treatment and facilities for 1982–1994, 1995–2017 and 2018–2022. In these three periods, different significant decreasing trends of the P content were found, mainly marked by the setup of each individual WWTP.Consejería de Economía, Conocimiento, Empresa y Universidad de la Junta de Andalucía - SGUIT/DGITC/SVAT/TAN19/UPO CEI CambioFondos europeos FEDER - FEDER 2014-202