Current therapeutics for ulcerative colitis (UC) have limitations. Classical Formula Gegen Qinlian decoction (GQD) is derived from Shang Han Lun and has a long history of treating gastrointestinal diseases such as diarrhea and UC. Nevertheless, the exact mechanism of it needs to be further clarified. We aimed to investigate the treatment effects of modified GQD (MGQD) on dextran sodium sulfate (DSS)-induced chronic colitis in mice and conduct further exploration of its underlying mechanisms. The protective effect of MGQD was estimated in a DSS-induced chronic colitis mouse model. Model evaluation included body weight, disease activity index (DAI) score, colon length and histopathology. Alcian Blue/Phosphoric Acid Schiff (AB/PAS) staining, transmission electron microscopy (TEM), immunofluorescence and real time‒PCR (RT-PCR) were used to assess goblet cell function. ELISA, flow cytometry and immunofluorescence were applied to estimate the immunoinflammatory status. Western blot was performed to test the protein expression levels of relevant pathways and related receptors. All experiments were conducted in duplicate. MGQD alleviated DSS‑induced chronic colitis symptoms in mice, protected goblet cell function and restored the intestinal mucus barrier. Furthermore, MGQD efficiently suppressed the abnormal immune inflammatory response and the activate of γδT17 cells and NLRP3 inflammasome. The mechanisms by which MGQD protects against DSS-induced chronic colitis may involve restoring goblet cell function, repairing the intestinal mucus barrier, and modulating the immune inflammatory response. More importantly, MGQD inhibited NLRP3 inflammasome-associated signaling pathway activation, which consequently reduced the activation of γδT17 cells.

Ulcerative colitis (UC) is a recurrent and persistent nonspecific inflammatory bowel disease (IBD) that greatly affects human survival and social wealth. Despite the advances in the treatment of UC, there is still a high demand for novel therapeutic strategies for UC patients. Cell death is critical to the development and progression of UC. Understanding how intestinal cells die and how to prevent damage to intestinal cells is of great interest for the diagnosis and early treatment of UC. Ferroptosis, a novel form of regulated cell death (RCD) manifested by iron accumulation, lipid peroxidation, and excessive reactive oxygen species (ROS) production, has been shown to contribute to the development and progression of UC. Inhibitors of ferroptosis have been validated in models of UC. Here, we reviewed the mechanisms of initiation and control of ferroptosis and summarize the therapeutic activity of ferroptosis inhibitors in models of UC. We further discussed the possibility of inhibiting ferroptosis as a novel therapeutic target for UC. These findings revealed novel mechanisms to protect the colonic mucosa and highlighted the importance of ferroptosis in the disease process.

Xiang Sha Liu Junzi decoction (XSLJZD) is a famous traditional Chinese medicinal prescription for the treatment of functional dyspepsia (FD) in spleen deficiency. However, its therapeutic mechanism has not been fully clarified. The present study aimed to determine the role of mitochondrial quality control (MQC)-mediated gastrointestinal motility disorder in FD treated with XSLJZD by using spleen-deficient FD rats and gastrointestinal smooth muscle cells (GSMCs). In vivo, an FD with spleen deficiency syndrome model was established by gastric perfusion with iodoacetamide solution combined with the modified multiple platform method (MMPM), followed by intragastric gavage with XSLJZD for 4 weeks. Improvement of pathological symptoms was evaluated based on food intake, water intake, grip strength, gastric histopathological changes, gastric emptying rate, small intestinal propulsion rate, and average amplitude and frequency of smooth muscle strips. The mitochondrial ultrastructure was observed by transmission electron microscopy. The colocalization of LC3 and Parkin with mitochondria was detected by immunofluorescence. The expression and localization of Drp1 proteins were detected by immunohistochemistry. In vitro, GSMCs were treated with different concentrations of XSLJZD-CS for 24 h, followed by treatment with 20 μM carbon cyanide 3-chlorophenylhydrazone (CCCP) for 4 h. Cell viability, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS), cellular ATP generation and mitochondrial Keima (mtKeima) expression were examined. Both in vivo and in vitro, gene expression was assessed by Western blotting. All experiments were performed in duplicate. Disorders of the mitochondrial quality control system existed in gastric smooth muscle in FD spleen deficiency syndrome. XSLJZD administration promoted the contraction of gastric smooth muscle and restored mitochondrial function by downregulating the colocalization of LC3 or Parkin with mitochondria, reducing the ratio of LC3II/LC3I, decreasing the expression of PINK1, Parkin and Drp1 and increasing the expression of p62 to restore mitochondrial morphology and function. In vitro studies showed that the improvement in mitochondrial function by XSLJZD was related to PINK1-parkin-mediated mitochondrial quality control. We demonstrated that XSLJZD can improve gastrointestinal motility disorder in functional dyspepsia with spleen deficiency syndrome, which was related to reconstruction of the mitochondrial quality control system by restraining PINK1/Parkin-mediated mitophagy and division. This study illustrates a novel clinical significance of herbal medicine in the treatment of FD and clarifies the important role of MQC in treating gastrointestinal motility disorder.

Background: Ge-Gen-Qin-Lian Decoction (GGQLD), a traditional Chinese medicine (TCM) formula, has been widely used for ulcerative colitis (UC) in China, but the pharmacological mechanisms remain unclear. This research was designed to clarify the underlying pharmacological mechanism of GGQLD against UC.Method: In this research, a GGQLD-compound-target-UC network was constructed based on public databases to clarify the relationship between active compounds in GGQLD and potential targets. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed to investigate biological functions associated with potential targets. A protein–protein interaction network was constructed to screen and evaluate hub genes and key active ingredients. Molecular docking was used to verify the activities of binding between hub targets and ingredients.Results: Finally, 83 potential therapeutic targets and 118 corresponding active ingredients were obtained by network pharmacology. Quercetin, kaempferol, wogonin, baicalein, and naringenin were identified as potential candidate ingredients. GO and KEGG enrichment analyses revealed that GGQLD had anti-inflammatory, antioxidative, and immunomodulatory effects. The effect of GGQLD on UC might be achieved by regulating the balance of cytokines (e.g., IL-6, TNF, IL-1β, CXCL8, CCL2) in the immune system and inflammation-related pathways, such as the IL-17 pathway and the Th17 cell differentiation pathway. In addition, molecular docking results demonstrated that the main active ingredient, quercetin, exhibited good affinity to hub targets.Conclusion: This research fully reflects the multicomponent and multitarget characteristics of GGQLD in the treatment of UC. Furthermore, the present study provided new insight into the mechanisms of GGQLD against UC.