The Pharmacological Mechanism of Guchangzhixie Capsule Against Experimental Colitis

Abstract

Ulcerative colitis (UC) is the major type of inflammatory bowel disease (IBD) characterized by an overactive immune response and destruction of colorectal epithelium with intricate pathological factors. Guchangzhixie (GCZX) capsule, included in the Chinese Pharmacopoeia 2020, has been widely utilized against UC. However, the underlying molecular mechanisms have not been elucidated. In the present study, a murine model of experimental colitis was established by orally feeding 4% dextran sodium sulfate (DSS) for 5 days and subsequently subjecting to GCZX treatment for another 15 days. Network pharmacology analysis was performed to predict the pertinent mechanisms of GCZX capsule. Cellular experiments examining the functional changes of intestinal organoids (IOs), macrophages (Mφs), and human colon epithelial cell cells (NCM460 cell line) after GCZX therapy were performed. Sequencing of 16S rRNA was conducted on the stools from the mouse model. Liquid chromatography-mass spectrometry (LC–MS) was utilized to detect serum metabolites. As a result, DSS induced experimental colitis, and this induction was alleviated by GCZX treatment, as evidenced by rescued pathological symptoms in UC mouse models, such as rectal bleeding stopping, decreased levels of albumin, interleukin-17, as well as chemokine (C-X-C motif) ligand 1 (CXCL1), and reduction in colon length. Network pharmacology analysis showed that GCZX-target genes were enriched in pathogen-induced infections, inflammatory pathways, as well as neoplastic processes. DSS treatment decreased microbial diversity and led to the accumulation of pathological bacterial, which was reversed by GCZX capsule. PICRUSt2 (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) based on profiles of microbiota composition demonstrated a decreased incidence of infectious disease and cancers after GCZX therapy. In full accordance with these data, GCZX administration suppressed Mφ transition to pro-inflammatory phenotype, alleviated tumor necrosis factor-α (TNFα)-compromised IOs functions, and decreased the recruitment of Mφs by epithelial cells. We conclude that GCZX capsule is an effective drug for UC and its pharmacological mechanisms involve re-establishing an anti-inflammatory milieu and favoring mucosal healing.

HucMSC-Exo Promote Mucosal Healing in Experimental Colitis by Accelerating Intestinal Stem Cells and Epithelium Regeneration via Wnt Signaling Pathway

“…27 Substantial traditional Chinese medicine and other bioactive substances were also verified to be efficacious for intestinal organoids to resist injury induced by pro-inflammatory cytokines TNF-α or INF-γ. 25,[54][55][56] In our present study, great effort was devoted to showcase the enormous potential role of hucMSC-exo in ISCs regeneration vividly, characterized by the increased growth rate, budding rate and average buddings number.…”

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.…”

“…Precessed 660 g DJ, 900 g EC, 660 g ZS, 330 g XR, and 330g FX powder were extracted with water at 95°C for 2 h, and approximately 280 g extraction was obtained. 0.2 g extraction was subjected to LC-30 (Shimadzu)-Hybrid Quadruple time-of-flight mass spectrometer (TOF-MS) with electrospray ionization source (ESI) was utilized to identify the components of CYN as the previous protocol ( Yan et al, 2021 ).…”

“…Every 8 mice were grouped. The disease active index (DAI) were calculated with the following criteria: weight loss (weight gain or no loss-0; 1∼2 g: 1; 2∼4 g: 2; 4∼5 g:3; >5 g: 4); feces (healthy: 0; soft: 1; watery: 2; liquid: 3); bloody stool test (no blood within 2 min: 0; positive in 10 s: 1; light purple within 10 s: 2; heavy purple within 10 s: 3)(Leagene, China); ( Yan et al, 2021 ).…”

A potential therapeutic target in traditional Chinese medicine for ulcerative colitis: Macrophage polarization

“…The Guchangzhixie capsule is composed of Mume Fructus , Corydalis rhizome , Papaveris pericarpium , Zingiberis rhizoma , Coptidis rhizoma , and Aucklandiae radix , which has been widely utilized against UC. In a murine model of experimental colitis, Guchangzhixie capsule could inhibit experimental colitis progression including alleviating the severity of fecal blood and albumin, shortening colon length, relieving the epithelial structural collapse, and reversing the levels of IL-17 and CXCL1 in mouse serum by hampering macrophage infiltration and suppressing its transition to M1 macrophage polarization ( Yan J. et al, 2021 ). Xian-He-Cao-Chang-Yan formula is composed of Platycodonis Radix , Agrimoniae Herba , Cicadae Periostracum , Acori Tatarinowii Rhizoma , Aucklandiae Radix , and Coptidis Rhizoma , which attenuated the increase of DAI score and the colon shortening, reduced the levels of inflammation in colon tissues and improved DSS-induced acute colitis in mice by suppressing the M1 polarization of macrophages and promoting the M2 polarization of macrophages ( Li J. et al, 2021 ).…”