Network Pharmacology-Based Validation of the Efficacy of Huiyangjiuji Decoction in the Treatment of Experimental Colitis

Abstract

Ulcerative colitis (UC) is the major type of inflammatory bowel disease (IBD) characterized by an overactive immune responses and destruction of the colorectal epithelium with intricate pathological factors. In China, Huiyangjiuji decoction (HYJJ) has been widely administered against inflammation, but the underlying mechanical mechanisms are not known. A murine model of colitis was established by orally feeding 4% dextran sodium sulfate for 5 days. Intestinal organoids (IOs) were treated with TNFα (Tumor necrosis factor-α) as an ex-vivo UC model. A scratch assay combined with a co-culture system that incubated murine epithelial cell line (IEC-6) with macrophages (Mφs) was utilized to assess epithelial recovery under inflammatory conditions. Network pharmacology analysis was performed to elucidate the mechanism of HYJJ decoction. In the present study, we confirmed that HYJJ considerably alleviated of DSS-induced colitis, as evidenced by the improved intestinal injury and fecal albumin, as well as feces blood. Network pharmacology analysis identified the active components in HYJJ formula, and KEGG enrichment analysis indicated that HYJJ-target genes were enriched in pathogen-induced infections, cancer-related as well as inflammatory pathways. Consistently, RNA-sequencing demonstrated that HYJJ treated inhibited cytokine-cytokine interaction, IBD as well as TNF signaling pathways, confirming the anti-inflammatory and anti-neoplastic role of HYJJ decoction. In-vitro experimental evidence confirmed the suppression of pro-interleukins by HYJJ, including IL-2, IL-10 and IL-12. Moreover, the contribution of HYJJ to mucosal healing was corroborated by ex-vivo experiments, in which HYJJ rescued TNFα-compromised IOs functions, i.e., elevated mitochondrial stress (MOS) and impaired regeneration capacity. IEC-6 cells co-culture with Mφs from HYJJ-treated experimental colitis mice showed an improved migration capacity as compared to those incubated with Mφs from untreated colitis mice. We conclude that HYJJ re-establishes homeostasis of the gut epithelium during colitis by suppressing inflammation and orchestrating cytokines interaction.

Network Pharmacology and Molecular Docking Analysis on Molecular Mechanism of Qingzi Zhitong Decoction in the Treatment of Ulcerative Colitis

“…Furthermore, QZZTD inhibited PI3K-AKt pathway activation, reduced inflammation, and alleviated UC. The aforementioned study also yielded the same results, revealing that TCM treatment of UC may mainly produce efficacy by regulating the PI3K-Akt signaling pathway ( Liu J. et al, 2021 ; Liu X. et al, 2021 ; Song et al, 2021 ; Yu et al, 2021 ).…”

“…It revealed that Gegen Qinlian Decoction ameliorates inflammation via downregulating the epidermal growth factor receptor (EGFR)/PI3K/AKT signaling pathway and pro-inflammatory cytokines ( Liu X. et al, 2021 ). Studies using network pharmacology combined with in vivo and ex vivo experiments and RNA-sequencing methods have similarly confirmed that genes downregulated by drugs were enriched in inflammation-related pathways ( Yu et al, 2021 ). Additionally, there are research studies that use the same approach to study drugs for different diseases, such as resveratrol, which can alleviate COVID-19–related inflammation ( Xiao et al, 2021 ).…”

The pharmacological evidence of the chang-yan-ning formula in the treatment of colitis

“…When it comes to the regulation of ROS, we observed that macrophages isolated from the DSS group aggravated the ROS production in intestinal stem cells due to the release of inflammation-promoting cytokines by macrophages ( Yan et al, 2021 ; Yu et al, 2021 ). Since intestinal stem cells are responsible for epithelial replenishment, excessive ROS-induced cell death would exacerbate the compromised epithelial integrity during colitis.…”

Application of network pharmacology in the study of mechanism of Chinese medicine in the treatment of ulcerative colitis: A review

“…The experimental results also show that Zuojin pill is effective in the treatment of chronic atrophic gastritis ( Tong et al, 2021 ). In the Huiyangjiuji decoction on the molecular mechanism of the UC treatment study, the target genes of the validation pathway were found, induced by pathogen infection and tumor-related enrichment in frontal pathways, in vitro experiments also confirmed Huiyangjiuji decoction of IL-2, IL-10, and IL-12 interleukins have an obvious inhibitory effect, thus inhibiting the further development of intestinal inflammation ( Yu et al, 2021 ). In other studies, nine active components of Xianglian pill that may have anti-inflammatory effects which were identified through the literature review, and the treatment of ulcerative colitis was mainly through regulating key pathways of the immune system, reducing mucosal inflammation, and achieving anti-inflammatory effects ( Liu et al, 2021b ).…”