Combining monoamine oxidase B and semicarbazide-sensitive amine oxidase enzyme inhibition to address inflammatory disease

Foot, Jonathan S.; Buson, Alberto; Deodhar, Mandar; Findlay, Alison D.; Robertson, Alan D.; Turner, Catherine; Yow, Tin T; Zhou, Wenbin; Jarolimek, Wolfgang

doi:10.1016/j.bmcl.2022.128942

Cited by 2 publications

(1 citation statement)

References 28 publications

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“…PXS-5131 was provided by Pharmaxis Ltd. (Sydney, NSW, Australia), which has recently described its design and synthesis [ 18 ]. Unless otherwise stated, all other chemicals used were purchased from Sigma, Merck Life Science, Milan, Italy.…”

Section: Methodsmentioning

confidence: 99%

A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice

Gasparella,

Nogara,

Germinario

et al. 2024

Antioxidants

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Duchenne muscular dystrophy (DMD) is one of the most frequent and severe childhood muscle diseases. Its pathophysiology is multifaceted and still incompletely understood, but we and others have previously shown that oxidative stress plays an important role. In particular, we have demonstrated that inhibition of mitochondrial monoamine oxidases could improve some functional and biohumoral markers of the pathology. In the present study we report the use of dystrophic mdx mice to evaluate the efficacy of a dual monoamine oxidase B (MAO-B)/semicarbazide-sensitive amine oxidase (SSAO) inhibitor, PXS-5131, in reducing inflammation and fibrosis and improving muscle function. We found that a one-month treatment starting at three months of age was able to decrease reactive oxygen species (ROS) production, fibrosis, and inflammatory infiltrate in the tibialis anterior (TA) and diaphragm muscles. Importantly, we also observed a marked improvement in the capacity of the gastrocnemius muscle to maintain its force when challenged with eccentric contractions. Upon performing a bulk RNA-seq analysis, PXS-5131 treatment affected the expression of genes involved in inflammatory processes and tissue remodeling. We also studied the effect of prolonged treatment in older dystrophic mice, and found that a three-month administration of PXS-5131 was able to greatly reduce the progression of fibrosis not only in the diaphragm but also in the heart. Taken together, these results suggest that PXS-5131 is an effective inhibitor of fibrosis and inflammation in dystrophic muscles, a finding that could open a new therapeutic avenue for DMD patients.

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Section: Methodsmentioning

confidence: 99%

A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice

Gasparella,

Nogara,

Germinario

et al. 2024

Antioxidants

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Vascular-adhesion protein 1 in giant cell arteritis and polymyalgia rheumatica

Petzinna,

Bauer,

Schäfer

2024

Front. Med.

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Vascular adhesion protein-1 (VAP-1) is a type 2 transmembrane sialoglycoprotein with oxidative deamination functionality, encoded by the amine oxidase copper-containing 3 (AOC3) gene. VAP-1 is widely expressed across various tissues, particularly in highly vascularized tissues and organs essential for lymphocyte circulation. In the vascular system, VAP-1 is predominantly found in vascular smooth muscle cells and endothelial cells, with higher expression levels in vascular smooth muscle cells. Under inflammatory conditions, VAP-1 rapidly translocates to the endothelial cell surface, facilitating leukocyte adhesion and migration through interactions with specific ligands, such as sialic acid-binding immunoglobulin-type lectins (Siglec)-9 on neutrophils and monocytes, and Siglec-10 on B cells, monocytes, and eosinophils. This interaction is crucial for leukocyte transmigration into inflamed tissues. Furthermore, VAP-1’s enzymatic activity generates hydrogen peroxide and advanced glycation end-products, contributing to cytotoxic damage and vascular inflammation. In this context, the soluble form of VAP-1 (sVAP-1), produced by matrix metalloproteinase cleavage from its membrane-bound counterpart, also significantly influences leukocyte migration. This review aims to elucidate the multifaceted pathophysiological roles of VAP-1 in vascular inflammation, particularly in giant cell arteritis (GCA) and associated polymyalgia rheumatica (PMR). By exploring its involvement in immune cell adhesion, migration, and its enzymatic contributions to oxidative stress and tissue damage, we investigate the importance of VAP-1 in GCA. Additionally, we discuss recent advancements in imaging techniques targeting VAP-1, such as [68Ga]Ga-DOTA-Siglec-9 PET/CT, which have provided new insights into VAP-1’s role in GCA and PMR. Overall, understanding VAP-1’s comprehensive roles could pave the way for improved strategies in managing these conditions.

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Combining monoamine oxidase B and semicarbazide-sensitive amine oxidase enzyme inhibition to address inflammatory disease

Cited by 2 publications

References 28 publications

A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice

A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice

Vascular-adhesion protein 1 in giant cell arteritis and polymyalgia rheumatica

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