N-Acetyldopamine Dimer Attenuates DSS-Induced Ulcerative Colitis by Suppressing NF-κB and MAPK Pathways

Abstract

Ulcerative Colitis (UC) is a major form of chronic inflammatory bowel disease of the colonic mucosa and exhibits progressive morbidity. There is still a substantial need of small molecules with greater efficacy and safety for UC treatment. Here, we report a N-acetyldopamine dimer (NADD) elucidated (2R,3S)-2-(3′,4′-dihydroxyphenyl)-3-acetylamino-7-(N-acetyl-2″-aminoethyl)-1,4-benzodioxane, which is derived from traditional Chinese medicine Isaria cicadae, exhibits significant therapeutic efficacy against dextran sulfate sodium (DSS)-induced UC. Functionally, NADD treatment effectively relieves UC symptoms, including weight loss, colon length shortening, colonic tissue damage and expression of pro-inflammatory factors in pre-clinical models. Mechanistically, NADD treatment significantly inhibits the expression of genes in inflammation related NF-κB and MAPK signaling pathways by transcriptome analysis and western blot, which indicates that NADD inhibits the inflammation in UC might through these two pathways. Overall, this study identifies an effective small molecule for UC therapy.

Investigation of the Anti-Inflammatory Activity of Fusaproliferin Analogues Guided by Transcriptome Analysis

“…To investigate the potential inflammation-related mechanism of 1 , K-means clustering was adopted to assign genes to 2 clusters (A and B) ( Ge et al, 2018 ). After GO analysis, cluster B, which contains 7885 genes, was thought to be closely associated with inflammation ( Supplementary Figure S13 ), and GO analysis and KEGG analysis based on gene set enrichment analysis (GSEA) were performed ( Subramanian et al, 2005 ; Huang et al, 2022 ). The results of GO_GSEA indicated that 1 could reverse the LPS-induced upregulation of three biological processes, including cellular response to molecules of bacterial origin, cellular response to lipopolysaccharide, and lipopolysaccharide-mediated signaling pathway.…”

N-acetyldopamine dimer inhibits neuroinflammation through the TLR4/NF-κB and NLRP3/Caspase-1 pathways

“…The primary antibodies were as follows: TLR4 (1:4000; Proteintech, Rosemont, USA), NF-κB (1:1000; CST, Beverly, USA), NLRP3 (1:1000; CST), Caspase-1 (1:1000; Proteintech), ASC/TMS1 (1:1000; Proteintech), iNOS (1:1000; NOVUS, Littleton, USA), COX-2 (1:1000; Abcam, Cambridge, UK), and β-Actin (1:20,000; Proteintech). Then, the PVDF membranes were incubated with the corresponding HRP-conjugated secondary antibodies at room temperature for 2 h. Finally, the membranes were washed 3 times with PBS, the target proteins were visualized using Immobilon western chemiluminescent HRP substrate (Millipore, Billerica, USA), and the blot images were captured and analyzed with the Chemiluminescent Imaging System (SAGECREATION, Beijing, China ) [16] .…”

“…N-acetyldopamine dimer (NADD) is a natural compound and has been elucidated as (2R,3S)-2-(3′,4′-dihydroxyphenyl)-3- acetylamino-7-(N-acetyl-2″-aminoethyl)-1,4-benzodioxane. In our previous study, NADD extracted from the traditional Chinese medicine Isaria cicada was found to suppress inflammation in DSS-induced ulcerative colitis by inhibiting the NF-κB and MAPK signaling pathways [16] . In addition, NADD has been reported to possess antioxidant and anti-inflammatory activities [17] .…”

Berberine Depresses Inflammation and Adjusts Smooth Muscle to Ameliorate Ulcerative Colitis of Cats by Regulating Gut Microbiota

“…Dextran sulfate sodium (DSS) has been used widely to generate an experimental model of UC disease. The clinical phenotype of the animal model shares a high similarity with that of patients with UC ( 5 , 29 – 31 ).…”