Integrated systematic pharmacology analysis and experimental validation to reveal the mechanism of action of Semen aesculi on inflammatory bowel diseases

Semen aesculi (SA), a traditional Chinese herb, has been used in the treatment of gastrointestinal disease for thousands of years. The escin was the main components of SA. A growing number of research showed that escin has a wide range of pharmacological activities in intestinal barrier dysfunction.Inflammatory bowel diseases (IBD) are an idiopathic disease of the intestinal tract with the hallmark features of mucosal inflammation and loss of barrier function. The theory of traditional Chinese medicine (TCM) suggests that SA plays a potential role in protecting the gastrointestinal diseases. The present study aimed to explore the effects of SA on the intestinal barrier under existing inflammatory conditions and elucidate underlying mechanisms.The bioactive components of SA and their predicted biological targets were combined to develop a compound target pathway network. It is used to predict the bioactive components, molecular targets, and molecular pathways of SA in improving IBD. The ingredients of SA were extracted by decoction either in water and ethanol and separated into four fractions (AE, EE, PEE and PCE). The effects of extractions were evaluated in the lipopolysaccharide (LPS)-induced RAW264.7 macrophages cell model, LPS-induced intestinal barrier injury model and imodium-induced constipation model. The high-performance liquid chromatography (HPLC) analysis was performed to identify the bioactive components.The compound-target pathway network was identified with 10 bioactive compounds, 166 IBD-related targets, and 52 IBD-related pathways. In LPS-induced RAW264.7 cells, PEE and PCE significantly decreased nitric oxide (NO) production and TNF-α level. In mice, PEE and PCE administration improved intestinal barrier damage, increased intestinal motility, reduced levels of TNF-α and diamine oxidase (DAO). Furthermore, PEE and PCE administration not only decreased expression of p-Akt, p-IκBα, nuclear p-p65, and TNF-α level, but also increased expression of the zonula occludin-1 (ZO-1) in LPS-induced intestinal barrier injury model. The escin content of AE, EE, PEE and PCE gradually increased with an increase of the bioactivity.Escin was the main bioactive components of SA. The effects of SA on IBD were mediated by repairing the intestinal barrier and promoting intestinal motility. The mechanism of action of SA is related to inhibiting the Akt/NF-κB signaling pathway in intestinal tissue, at least, in part. Our results provide a scientific basis for further exploring the mechanisms involved in the beneficial effects of SA in IBD.