-
1دورية أكاديمية
المؤلفون: Natalia Reglero-Real (11435653), Lorena Pérez-Gutiérrez (11435656), Azumi Yoshimura (10746250), Loïc Rolas (11435659), José Garrido-Mesa (11435662), Anna Barkaway (11032859), Catherine Pickworth (11435665), Rebeca S Saleeb (11435668), Maria Gonzalez-Nuñez (11435671), Shani N Austin-Williams (11435674), Dianne Cooper (381398), Laura Vázquez-Martínez (11435677), Tao Fu (477112), Giulia De Rossi (493891), Matthew Golding (8960975), Mathieu Benoit-Voisin (11435680), Chantal M Boulanger (11435683), Yoshiaki Kubota (3390908), William A Muller (11435686), Sharon A Tooze (8114291), Thomas D Nightingale (11435689), Lucy Collinson (3507032), Mauro Perretti (241694), Ezra Aksoy (11435692), Sussan Nourshargh (157725)
مصطلحات موضوعية: Model organisms, Biochemistry & Proteomics, Imaging, Signalling & Oncogenes, Cell Biology, Chemical Biology & High Throughput, ATG16L1, ATG5, autophagy, diapedesis, endothelium, extravasation, inflammation, junctions, neutrophils, PECAM-1, Tooze FC001187, EM, 1107 Immunology, Immunology
الوصف: The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.
-
2دورية أكاديمية
المؤلفون: Beatriz Marcos-Ramiro (6858824), Ana Gil-Ordóñez (6858821), Nagore I. Marín-Ramos (11032850), Francisco J. Ortega-Nogales (1600546), Moisés Balabasquer (1600540), Pilar Gonzalo (11032853), Nora Khiar-Fernández (8130210), Loïc Rolas (11032856), Anna Barkaway (11032859), Sussan Nourshargh (157725), Vicente Andrés (11032862), Mar Martín-Fontecha (1600552), María L. López-Rodríguez (1600543), Silvia Ortega-Gutiérrez (1600525)
مصطلحات موضوعية: Biochemistry, Medicine, Cell Biology, Genetics, Molecular Biology, Pharmacology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, compound UCM -13207, enzyme, Isoprenylcysteine Carboxylmethyltra., FDA, hallmark, UCM -13207 treatment, progeria, ICMT, HGPS, lonafarnib, strategy, VSMC, DNA, Hutchinson, tissue, UCM -13207, Lmna G 609G progeroid mouse model, UCM -13207 delocalized progerin
الوصف: Hutchinson–Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.
