ABSTRACT
Artemisia argyi and Artemisia indica are edible medicinal plants belonging to the genus Artemisia in the Asteraceae. There are many similarities in their morphology, traditional curative effect, and modern pharmacological treatment. In this study, we built distribution maps of A. argyi and A. indica in China and a phylogenetic tree of common medicinal plants in Asteraceae. Then, we verified the chemical composition changes of A. argyi and A. indica via their metabolome. Traditional efficacy and modern pharmacological action were verified by network pharmacology and in vitro using RAW264.7 cells. The results showed that A. argyi and A. indica are widely distributed in China, and they shared pharmaphylogeny, which provides theoretical support for the mixed use of A. argyi and A. indica in most regions of China. Furthermore, there were both similarities and differences in volatile oil and flavonoid composition between A. argyi and A. indica. The network pharmacology results showed that A. argyi and A. indica had 23 common active compounds and that both had pharmacological effects on chronic gastritis (CG). Molecular docking analyses showed that quercetin, luteolin, and kaempferol have strong binding affinities with the target proteins JUN, TP53, AKT1, MAPK3, TNF, MAPK, and IL6. The cell experiment results further demonstrated that A. argyi and A. indica treat CG via the NOD-like receptor pathway. Based on the theory of pharmaphylogeny, this study explored the pharmaphylogeny between A. argyi and A. indica from various perspectives to provide a basis for the substitution of A. argyi and A. indica.
ABSTRACT
BACKGROUND: Colitis-associated cancer (CAC) is known to be a complex combination of tumor cells, non-tumor cells and a large intestinal flora. The increasing role of intestinal flora in CAC may represent a new approach to improving CAC treatment. Berberine can reduce colorectal adenoma recurrence and inhibit colorectal carcinogenesis. PURPOSE: Berberine has demonstrated efficacy for the control and suppression of CAC. Given the low oral absorption into the blood and large intestinal excretion of berberine, intestinal flora may be one of the important targets of berberine inhibiting the occurrence of colorectal cancer (CRC). The purpose of this study was to investigate the effects of berberine on intestinal flora in CAC mice and its ability to remodel intestinal flora to improve short-chain fatty acid metabolism. STUDY DESIGN AND METHODS: The CAC model in mice was induced by Azoxymethane/Dextran sodium sulfate (AOM/DSS). Berberine was administered daily at doses of 50 and 100 mg/kg, and aspirin was used as the positive control. The effect of berberine on colitis-associated colorectal tumorigenesis was assessed by general imaging, tumor counting, and Ki67 staining. Intestinal flora changes were detected by 16S rDNA sequencing technology. Targeted short-chain fatty acid detection was performed by GC-MS/MS, and Lipopolysaccharide (LPS) levels in feces were quantified with an ELISA kit. The signaling pathway of TLR4/NF-κB P65/IL-6/p-STAT3 was evaluated by Western blotting and immunofluorescence. The expression levels of intestinal barrier functional biomarkers Occludin and ZO-1 were detected by immunohistochemistry. Fecal flora transplantation (FMT) was used to evaluate the effect of intestinal flora in inhibiting inflammatory cancer transformation by berberine. RESULTS: Berberine reduced the number and load of tumors in CAC mice. Berberine remodeled the composition of pathogenic and beneficial bacteria in mice with colitis-associated colorectal tumorigenesis. Berberine treatment resulted in increases in fecal butyric acid, acetic acid and propionic acid levels, but did not alter isobutyric acid, isovaleric acid, valeric acid and caproic acid. In addition, berberine reduced LPS content in feces in mice with colitis-associated colorectal tumorigenesis. Occludin and ZO-1 were upregulated, and the TLR4/p-NF-κB p65/IL-6/p-STAT3 inflammatory-cancer transformation pathway was inhibited with berberine. The FMT results further verified that the berberine-treated intestinal flora was sufficient to alleviate the occurrence of colonic tumors associated with colitis in mice. CONCLUSION: Our study showed that berberine alleviated the colitis-associated colorectal tumorigenesis from three equilibrium levels: (1) Pathogenic and beneficial bacteria; (2) Short-chain fatty acids and LPS produced by intestinal flora; and (3) Inflammatory cancer transformation signaling and intestinal barrier function. This study provided a new approach and experimental basis for the application of berberine in the treatment of CAC in clinical practice.