A New Use for an Old Drug: Carmofur Attenuates Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Inhibition of FAAH and NAAA Activities

Frontiers in Pharmacology
Kangni WuYuhang Li

Abstract

Acute lung injury (ALI), characterized by a severe inflammatory process, is a complex syndrome that can lead to multisystem organ failure. Fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA) are two potential therapeutic targets for inflammation-related diseases. Herein, we identified carmofur, a 5-fluorouracil-releasing drug and clinically used as a chemotherapeutic agent, as a dual FAAH and NAAA inhibitor. In Raw264.7 macrophages, carmofur effectively reduced the mRNA expression of pro-inflammatory factors, including IL-1β, IL-6, iNOS, and TNF-α, and down-regulated signaling proteins of the nuclear transcription factor κB (NF-κB) pathway. Furthermore, carmofur significantly ameliorated the inflammatory responses and promoted resolution of pulmonary injury in lipopolysaccharide (LPS)-induced ALI mice. The pharmacological effects of carmofur were partially blocked by peroxisome proliferator-activated receptor-α (PPARα) antagonist MK886 and cannabinoid receptor 2 (CB2) antagonist SR144528, indicating that carmofur attenuated LPS-induced ALI in a PPARα- and CB2-dependent mechanism. Our study suggested that carmofur might be a novel therapeutic agent for ALI, and drug repurposing may provide us effective t...Continue Reading

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Citations

Dec 11, 2020·International Immunopharmacology·Joshua Adedeji BolarinAdenike Bernice-Eloise Adeoye
Nov 26, 2019·Bioorganic & Medicinal Chemistry·Michael S MalamasAlexandros Makriyannis
Dec 22, 2020·Frontiers in Molecular Biosciences·Wen CuiHaitao Yang
Jan 28, 2021·International Journal of Molecular Sciences·Ana Lago-FernandezPaula Morales
Oct 30, 2020·Frontiers in Pharmacology·Longhe YangYan Qiu
Mar 20, 2020·Journal of Medicinal Chemistry·Daniele PiomelliMarco Mor
Jun 15, 2021·Biochemical and Biophysical Research Communications·Dequan KongYaping Xu

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Methods Mentioned

BETA
PCR
protein assay
Bronchoalveolar Lavage
ELISA
nuclear translocation

Software Mentioned

Image J
Image Pro Plus
GraphPad Prism

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