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Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

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.

SUBMITTER: Dr. Carmen Herranz

PROVIDER: S-SCDT-EMM-2021-13929 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:PurposeIncreasing evidence suggests myopia is not a simple refractive error, many other factors might also be involved. Here, we assessed myopic and normal corneas' gene expression profiles to identify possible diagnostic and therapeutic biomarkers for myopia.Materials and methodsWe obtained the expression profile of ten patients and seven normal control samples from the GSE112155 and GSE151631 datasets based on the Gene Expression Omnibus (GEO) database. We used the "limma" R package to determine the differentially expressed genes (DEGs) between myopic and normal corneas. Weighted gene co-expression network analysis (WGCNA) was used to identify critical co-expressed modules related to myopia, and enrichment analyses were used to annotate the function of genes encompassed in the compulsory module. We also validated these findings in two external datasets (GSE24641 and GSE136701).ResultsWe identified that the DEGs were significantly enriched in ultraviolet (UV) response, TNF-α signaling via NFκB, Angiogenesis, Myogenesis pathways, etc. We used 2095 genes to construct the co-expression gene modules and found five interesting modules because the eigengene expression of these modules was significantly differentially expressed between myopic and normal corneas. Notably, the enrichment analysis found that the genes encompassed in lightgreen module were significantly enriched in immune-related pathways. These findings were proved by subsequent analysis based on Xcell software. We found the component of B cells, CD4+ memory T cells, CD8+ central memory T cells, plasmacytoid dendritic cells, T helper 2 (Th2) cells, regulatory T cells (Tregs), etc. were significantly increased in myopic corneas, while CD8+ T cells, CD4+ T central memory cells, natural killer T (NKT) cells, and T helper 1 (Th1) cells were significantly decreased.ConclusionOur findings identified some markers that might detect diagnosis and treatment for myopia from cornea aspect. Future studies are warranted to verify the functional role of immune-related pathways in cornea during the pathogenesis or progression of myopia.

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Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

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