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

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 therapeutic strategies for ALI.

Chronic Oleoylethanolamide Treatment Decreases Hepatic Triacylglycerol Level in Rat Liver by a PPARγ/SREBP-Mediated Suppression of Fatty Acid and Triacylglycerol Synthesis

“…The suppressive effect of OEA on PPAγ expression was also demonstrated in vitro by incubating HLF hepatic cells for 2 h with 10 µM OEA ( Figure 5 d,e). Moreover, the ceramidase inhibitor Carmofur, which increases OEA cell level by inhibiting fatty acid hydrolases [ 56 ], induced both alone and in association with OEA, a strong decrease in PPARγ expression ( Figure 5 d,e).…”

“…In our study, we observed that OEA-induced a significant decrease of PPARγ expression both in vivo and in vitro. In this latter system the link between OEA and PPARγ was reinforced by using Carmofur, a fatty acid hydrolase inhibitor that can block OEA degradation and, thus, increase OEA level in the cell [ 56 ].…”

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

“…Western blot assay and RT-qPCR were performed as descriptions. 24,25 Cell Apoptosis Assay T cells were isolated from BALB/c mice spleens by nylon wool-elution, as described previously. 23 T cells were cultured with RPMI 1640 medium, HSC-CM, or shC3 HSC-CM in 12-well plates, respectively, and then stimulated with 1 μg/mL of anti-CD3 mAb and CD28 (R&D Systems, Minneapolis, MN, USA).…”

Natural Potent NAAA Inhibitor Atractylodin Counteracts LPS-Induced Microglial Activation

“…These chemicals showed selective inhibitory potency but with a poor plasma stability, which restricted its systematic administration (Bandiera et al, 2014;Petracca et al, 2017). Based on the structure of pyrrolidine derivatives, our research group identified a class of novel inhibitors with oxazolidone moiety, represented by F96 and F215, with nanomolar potency against NAAA (Yang et al, 2015;Li et al, 2017;Ren et al, 2017;Wu et al, 2019;Zhou et al, 2019). Migliore et al reported third-generation NAAA inhibitors based on a benzothiazole-piperazine scaffold that is stable in mouse plasma and liver microsomes (Migliore et al, 2016).…”