Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation

BACKGROUND: Psoriasis is a frequent inflammatory skin disease that is mainly mediated by IL-23, IL-1β, and IL-17 cytokines. Although psoriasis is a hyperproliferative skin disorder, the possible role of amino acid transporters has remained unexplored. OBJECTIVE: We sought to investigate the role of the essential amino acid transporter L-type amino acid transporter (LAT) 1 (SLC7A5) in psoriasis. METHODS: LAT1 floxed mice were crossed to Cre-expressing mouse strains under the control of keratin 5, CD4, and retinoic acid receptor-related orphan receptor γ. We produced models of skin inflammation induced by imiquimod (IMQ) and IL-23 and tested the effect of inhibiting LAT1 (JPH203) and mammalian target of rapamycin (mTOR [rapamycin]). RESULTS: LAT1 expression is increased in keratinocytes and skin-infiltrating lymphocytes of psoriatic lesions in human subjects and mice. LAT1 deletion in keratinocytes does not dampen the inflammatory response or their proliferation, which could be maintained by increased expression of the alternative amino acid transporters LAT2 and LAT3. Specific deletion of LAT1 in γδ and CD4 T cells controls the inflammatory response induced by IMQ. LAT1 deletion or inhibition blocks expansion of IL-17-secreting γ4+δ4+ and CD4 T cells and dampens the release of IL-1β, IL-17, and IL-22 in the IMQ-induced model. Moreover, inhibition of LAT1 blocks expansion of human γδ T cells and IL-17 secretion by human CD4 T cells. IL-23 and IL-1β stimulation upregulates LAT1 expression and induces mTOR activation in IL-17+ γδ and TH17 cells. Deletion or inhibition of LAT1 efficiently controls IL-23- and IL-1β-induced phosphatidylinositol 3-kinase/AKT/mTOR activation independent of T-cell receptor signaling. CONCLUSION: Targeting LAT1-mediated amino acid uptake is a potentially useful immunosuppressive strategy to control skin inflammation mediated by the IL-23/IL-1β/IL-17 axis.Funding This manuscript has been funded by grants SAF 2017-82886-R (FS-M) and SAF 2013-42850-R (MF) from the Spanish Ministry of Economy and Competitiveness; CAM (S2017/BMD-3671-INFLAMUNE-CM) from the Comunidad de Madrid (FS-M); CIBERCV, BIOIMID PIE13/041 from Instituto de Salud Carlos III and Fundación La Marató TV3 (20152330 31). The project leading to these results has also received funding from FUNDACIÓN BBVA A EQUIPOS DE INVESTIGACIÓN CIENTÍFICA 2018 and from “la Caixa” Banking Foundation under the project code HR17-00016 (FS-M), and from Agencia Estatal de Investigación, Fondo Europeo de Desarrollo Regional PI17/01972 (E.D).S

Multiteide Project: Multiparametric characterization of the activity of Teide-Pico Viejo volcanic system

European Geosciences Union General Assembly (2017. Viena)Teide-Pico Viejo complex stands for one of the major natural volcanic hazards in the Canary Islands, due to the expected types of eruptions in the area and the high number of inhabitants in Tenerife Island. Therefore, it is necessary to have a volcanic alert system able to afford a precise assessment of the current state of the complex. For this purpose, the knowledge of the expected signals at each volcanic activity level is required. Moreover, the external effects that can affect the measurements shall be distinguished, external influences as the atmosphere are qualitatively known but have not been quantified yetCentro Geofísico de Canarias, Instituto Geográfico Nacional, EspañaObservatorio Geofísico Central, Instituto Geográfico Nacional, EspañaInstituto Geológico y Minero de España, EspañaLaboratoire GéoSciences Réunion, Institut de Physique du Globe de Paris, Centre National de la Recherche Scientifique, EspañaPeer reviewe

Ligandos PPAR, líquidos iónicos y adamantanos como analgésicos y fármacos para el tratamiento del síndrome metabólico

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica, leída el 22/10/2013Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEunpu

The reaction of NH-indazoles with 1-fluoro-2,4-dinitrobenzene: the unusual formation of benzotriazole-N-oxides

15 páginas, 19 figuras, 7 tablas.When N-unsubstituted indazoles, like indazole itself, reacted with 1-fluoro-2,4-dinitrobenzene or 1-chloro-2,4,6-trinitrobenzene, three products were obtained whose structures were determined by X-ray diffraction. Besides the two N-substituted nitroaryl derivatives, a third compound was obtained with the same molecular formula (C13H8N4O4) to which was assigned the structure of a derivative of benzotriazole N-oxide. With the combined use of crystallography, NMR and DFT calculations this reaction was studied with special stress on the mechanism of formation of the benzotriazole-N-oxide.This work was supported by the Spanish Ministerio de Economía y Competitividad (MAT2010-15094, Factoría de Cristalización–Consolider Ingenio 2010) and FEDER funding. We also thank the Ministerio de Ciencia e Innovación (Project No. CTQ 2009-13129-C02-02) and the Comunidad Autónoma de Madrid (Project MADRISOLAR2, ref. S2009/PPQ-1533) for continuing support. F. P. C. thanks the Spanish MICINN (Grants CTQ2010-16959 and Ingenio-Consolider CSD2007-00006) and the Basque Government (GV-EJ, Grant IT-324-07) for financial support.Peer reviewe

Galectin-1 expression in CD8+ T lymphocytes controls inflammation in contact hypersensitivity

Allergic contact dermatitis, also known as contact hypersensitivity, is a frequent T-cell‒mediated inflammatory skin disease characterized by red, itchy, swollen, and cracked skin. It is caused by the direct contact with an allergen and/or irritant hapten. Galectin-1 (Gal-1) is a β-galactoside‒binding lectin, which is highly expressed in several types of immune cells. The role of endogenous Gal-1 in contact hypersensitivity is not known. We found that Gal-1‒deficient mice display more sustained and prolonged skin inflammation than wild-type mice after oxazolone treatment. Gal-1‒deficient mice have increased CD8 T cells and neutrophilic infiltration in the skin. After the sensitization phase, Gal-1‒depleted mice showed an increased frequency of central memory CD8 T cells and IFN-γ secretion by CD8 T cells. The absence of Gal-1 does not affect the migration of transferred CD4 and CD8 T cells from the blood to the lymph nodes or to the skin. The depletion of CD4 T lymphocytes as well as adoptive transfer experiments demonstrated that endogenous expression of Gal-1 on CD8 T lymphocytes exerts a major role in the control of contact hypersensitivity model. These data underscore the protective role of endogenous Gal-1 in CD8 but not CD4 T cells in the development of allergic contact dermatitis.Spanish Ministry of Economy and Competitiveness, grant S2017/BMD-3671-INFLAMUNE-CM from the Comunidad de Madrid, a grant from the Ramón Areces Foundation Ciencias de la Vida y la Salud (XIX Concurso-2018), and a grant from Ayudas Fundación BBVA a Equipos de Investigación Científica (BIOMEDICINA-2018), the Fundacio´ Marato´ TV3 (grant 122/C/2015), and La Caixa Banking Foundation (HR17-00016

Structure and thermodynamical properties of metformin salicylate

The behavior under thermal conditions of the cocrystal formed by metformin and salicylic acid was studied by DSC, crystallography (single-crystal), and powder diffraction (WAXS). Metformin salicylate crystallizes in space group P21/c, with the salicylate anion showing a planar structure, stabilized by strong intramolecular hydrogen bonds. The more flexible metformin cations link through the oxygen atoms of salicylate, forming a dense hydrogen-bonding network. The compound exists initially as a salt, metformin salicylate, but after melting and cooling, it is transformed into a glass form that crystallizes and melts again, showing different behaviors depending on the heating rate. © 2013 American Chemical Society.This work was supported by SAF2009-12422-C02-02 and RTA (RED Trastornos Adictivos RD06/001/0014) as well as by FEDER funding and the Spanish Ministerio de Economía y Competitividad MAT2006-01997, MAT2010-15094, and the Factoría de Crystalización (Consolider Ingenio 2010).Peer Reviewe

Multinuclear NMR characterization of cyanuric Fluoride (2,4,6-Trifluoro-1, 3,5-triazine)

Although 2,4,6-trifluoro-1,3,5-triazine, C 3F 3N 3, is a highly symmetrical molecule, its NMR parameters can be obtained by reducing its symmetry through the introduction of 14N/ 15N and 12C/ 13C isotopomers. Experimental and computed chemical shifts of cyanuric fluoride have been obtained for 13C, 15N, and 19F. Spin-spin coupling constants have been measured and compared with previous experimental data and with the complete set of computed EOM-CCSD coupling constants. © 2012 HeteroCorporation.Peer Reviewe

Oxazolidinone cross-alkylation during Evans' asymmetric alkylation reaction

Starting from Evans’ imidazolidin-2-one (1) two compounds were obtained by trans-N-acylation: the expected one 3 with S,R configuration and a second compound 5, that is, related to 3 by the loss of a CH(CH3)C]O fragment. The stereochemistry of 3 was established by NMR spectroscopy, mainly NOE experiments, as expected, the new center has an S configuration, the compound being thus S,R. The structure of compound 5 was determined by X-ray crystallography. A mechanism of formation of 5 was proposed.This work was supported by the Ministerio de Ciencia e Innovación (Project No. CTQ2009-13129-C02-02), Comunidad Autónoma de Madrid (Project MADRISOLAR, ref. S-0505/PPQ/ 0225), SAF2009-12422-C02-02, and RTA (RED Trastornos Adictivos RD06/001/0014). The authors thank the CTI (CSIC) for allocation of computer time and the Departamento de Química Orgánica y Bio- orgánica (UNED) for recording the CPMAS NMR spectra. Financial support from Spanish Ministerio de Ciencia e Innovación (MAT2006-01997, MAT2010-15094 and ‘Factoría de Cristalización Consolider Ingenio 2010), and FEDER funding is acknowledged.Peer reviewe

Brønsted acid-base pairs of drugs as dual ionic liquids: NMR ionicity studies

Twenty-eight protic ionic liquids (PILs) have been prepared from Active Pharmaceutical Ingredients (APIs). They have been characterized by TGA, DSC and NMR. An important property of Ionic Liquids (ILs) such as the 'degree of ionicity' has been estimated from quantitative determinations by 1H NMR in DMSO-d6 solutions.Peer Reviewe