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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
Lung Neoplasms
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.
metadata.dc.identifier.doi: 10.15252/emmm.202113929
Appears in Collections:Producción 2020

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