Ulcerative colitis (UC) is a chronic inflammatory disorder with a complex etiology, characterized by intestinal inflammation and barrier dysfunction. Platycodon grandiflorus polysaccharides (PGP), the primary component of Platycodon grandiflorus, and hesperidin (Hesp), a prominent active component in Citrus aurantium L. (CAL), have both demonstrated anti-inflammatory properties. This study aims to elucidate the underlying mechanism of the synergistic effect of PGP combined with Hesp on UC, focusing on the coordinated interaction between the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. A mouse model of UC induced by dextran sulfate sodium (DSS) and a cell model using lipopolysaccharide (LPS)-induced RAW264.7/IEC6 cells were employed to investigate the in vitro and in vivo anti-inflammatory effects of PGP combined with Hesp on UC and its potential mechanism of action. The results indicated that compared to the effects of either drug alone, the combination of PGP and Hesp significantly modulated inflammatory factor levels, inhibited oxidative stress, regulated colonic mucosal immunity, suppressed apoptosis, and restored intestinal barrier function in vitro and in vivo. Further in vitro studies revealed that PGP significantly inhibited the PI3K/AKT signaling pathway, while Hesp significantly inhibited the JAK2/STAT3 signaling pathway. The use of inhibitors and activators targeting both pathways validated the synergistic effects of PGP combined with Hesp on the PI3K/AKT and JAK2/STAT3 signaling pathways. These findings suggest that PGP combined with Hesp exhibits a synergistic effect on DSS-induced colitis, potentially mediated through the phosphatase and tensin homolog (PTEN)/PI3K/AKT and interleukin-6 (IL-6)/JAK2/STAT3 signaling pathways.
Animals ; STAT3 Transcription Factor/genetics* ; Janus Kinase 2/genetics* ; Polysaccharides/administration & dosage* ; Colitis, Ulcerative/chemically induced* ; Mice ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/genetics* ; Drug Synergism ; Male ; Hesperidin/administration & dosage* ; Platycodon/chemistry* ; Phosphatidylinositol 3-Kinases/genetics* ; Disease Models, Animal ; RAW 264.7 Cells ; Mice, Inbred C57BL

Objective To investigate the expression of dermatopontin(DPT)in abdominal aortic aneurysm(AAA)and to explore the mechanism in promoting AAA progression.Methods Differential gene expression(DEG)and GO-KEGG pathway enrichment were used to assess DPT expression level and related pathways in AAA.AAA tissue samples were collected from patients undergoing open surgical repair at Beijing Hospital(experimental group,n=3),while control aortic tissues were collected from kidney transplant donors(n=3).Immun-ohistochemistry and immuno-fluorescence staining were performed to validate DPT protein expression differences in AAA tissues.Masson staining microscopy was used to evaluate fibrosis level.Human aortic smooth muscle cells(HASMCs)were divided into control(Ctrl)and lipopolysaccharide(LPS)-treated groups(n=3).RT-qPCR,ELISA,and immu-nocytochemistry(ICC)were used to measure DPT expression level.HASMCs were further divided into control(Ctrl)and recombinant human DPT-treated groups with 3 cases in each.RT-qPCR was performed to detect the ex-pression of interleukin-1α(IL-1α),interleukin-1β(IL-1β),collagen type Ⅰ alpha 1 chain(COL1A1),matrix metalloproteinase-2(MMP2),and matrix metalloproteinase-9(MMP9).Cell adhesion assays were conducted to ex-amine the role of integrin α3 and integrin β1 in HASMC adhesion.Results DPT was highly expressed in human AAA tissues(P＜0.01).LPS induced DPT expression and secretion in HASMCs(P＜0.05).DPT promoted IL-1α(P＜0.001)and IL-1β(P＜0.01)expression through a positive feedback mechanism while suppressed COL1A1(P＜0.001)production.DPT enhanced HASMC adhesion via the integrin α3β1 receptor(P＜0.001).Conclusions DPT promotes AAA progression by activating IL-1α/IL-1β inflammatory cytokines and inhibits COL1A1-mediated extra cellular matrix(ECM)remodeling.Integrin α3β1 is potentially involved in the regulation process.