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http://hdl.handle.net/10668/19505
Title: | Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis. |
Authors: | Herranz, Carmen Mateo, Francesca Baiges, Alexandra Ruiz de Garibay, Gorka Junza, Alexandra Johnson, Simon R Miller, Suzanne García, Nadia Capellades, Jordi Gómez, Antonio Vidal, August Palomero, Luis Espín, Roderic Extremera, Ana I Blommaert, Eline Revilla-López, Eva Saez, Berta Gómez-Ollés, Susana Ancochea, Julio Valenzuela, Claudia Alonso, Tamara Ussetti, Piedad Laporta, Rosalía Xaubet, Antoni Rodríguez-Portal, José A Montes-Worboys, Ana Machahua, Carlos Bordas, Jaume Menendez, Javier A Cruzado, Josep M Guiteras, Roser Bontoux, Christophe La Motta, Concettina Noguera-Castells, Aleix Mancino, Mario Lastra, Enrique Rigo-Bonnin, Raúl Perales, Jose C Viñals, Francesc Lahiguera, Alvaro Zhang, Xiaohu Cuadras, Daniel van Moorsel, Coline H M van der Vis, Joanne J Quanjel, Marian J R Filippakis, Harilaos Hakem, Razq Gorrini, Chiara Ferrer, Marc Ugun-Klusek, Aslihan Billett, Ellen Radzikowska, Elżbieta Casanova, Álvaro Molina-Molina, María Roman, Antonio Yanes, Oscar Pujana, Miquel A |
Keywords: | biomarker;histamine;lymphangioleiomyomatosis;mTOR;therapy |
metadata.dc.subject.mesh: | Biomarkers Histamine Humans Lung Neoplasms Lymphangioleiomyomatosis Signal Transduction |
Issue Date: | 11-Aug-2021 |
Abstract: | Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management. |
URI: | http://hdl.handle.net/10668/19505 |
metadata.dc.identifier.doi: | 10.15252/emmm.202113929 |
Appears in Collections: | Producción 2020 |
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PMC8422079.pdf | 7,25 MB | Adobe PDF | View/Open |
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