peoniflorin and Colitis

Ulcerative colitis (UC) is a chronic and immune-mediated inflammatory disorder characterized by abdominal pain, diarrhoea, and haematochezia. The goal of clinical therapy for UC is mucosal healing, accomplished by regenerating and repairing the intestinal epithelium. Paeoniflorin (PF) is a natural ingredient extracted from Paeonia lactiflora that has significant anti-inflammatory and immunoregulatory efficacy. In this study, we investigated how PF could regulate the renewal and differentiation of intestinal stem cells (ISCs) to improve the regeneration and repair of the intestinal epithelium in UC. Our experimental results showed that PF significantly alleviated colitis induced by dextran sulfate sodium (DSS) and ameliorated intestinal mucosal injury by regulating the renewal and differentiation of ISCs. The mechanism by which PF regulates ISCs was confirmed to be through PI3K-AKT-mTOR signalling. In vitro, we found that PF not only improved the growth of TNF-α-induced colon organoids but also increased the expression of genes and proteins related to the differentiation and regeneration of ISCs. Furthermore, PF promoted the repair ability of lipopolysaccharide (LPS)-induced IEC-6 cells. The mechanism by which PF regulates ISCs was further confirmed and was consistent with the in vivo results. Overall, these findings demonstrate that PF accelerates epithelial regeneration and repair by promoting the renewal and differentiation of ISCs, suggesting that PF treatment may be beneficial to mucosal healing in UC patients.

Topics: Animals; Colitis; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Humans; Intestinal Mucosa; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Regeneration; Stem Cells; TOR Serine-Threonine Kinases

Topics: Animals; Cell Proliferation; Colitis; Complement C1q; Dextran Sulfate; Disease Models, Animal; Glucosides; Inflammation; Interleukin-10; Intestinal Mucosa; Macrophages; Mice; Mice, Inbred C57BL; Monoterpenes; Stem Cells

Inflammatory bowel disease (IBD) is an autoimmune disease. The pathogenesis of IBD is complicated and intestinal mucosal barrier damage is considered as the trigger factor for the initiation and recurrence of IBD. Total Glucosides of Paeony (TGP) has shown good inhibitory effects on immune-inflammation in clinic studies. However, its effect and mechanism on IBD are largely unknown.. The purpose of this study is to evaluate the effect and mechanism of TGP on IBD.. DSS-induced colitis mouse model was used. TGP was given by gavage. Caco-2 cells were stimulated by outer membrane vesicles (OMV) to establish an in vitro model.. C57BL/6 mice were divided into normal control group, model group, mesalazine group, paeoniflorin (PA) group, high-dose group of TGP, and low-dose group of TGP. The model was induced with 2.5% DSS for 7 days, and TGP was intragastrically administered for 10 days. The therapeutic effect of TGP was evaluated by symptoms, histochemical analysis, RT-qPCR and ELISA. The mechanism was explored by intestinal permeability, Western blot and immunofluorescence in vivo and in vitro.. Our results showed that TGP could significantly improve the symptoms and pathological changes, with reduced levels of TNF-α, IL-17A, IL-23 and IFN-γ in the colon tissues and serum under a dose-dependent manner. TGP also reduced the intestinal permeability and restored the protein expression of tight junction and adherens junction proteins of intestinal epithelial cells in vivo and in vitro. Furthermore, TGP could inhibit the expression of p-Lyn and Snail and prevent Snail nuclear localization, thereby maintaining tight and adherens junctions.. TGP effectively improves the symptoms of DSS-induced colitis in mice, protects the intestinal epithelial barrier by inhibiting the Lyn/Snail signaling pathway, and maybe a promise therapeutic agent for IBD treatment.

Topics: Animals; Caco-2 Cells; Colitis; Dextran Sulfate; Disease Models, Animal; Glucosides; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mice, Inbred C57BL; Monoterpenes; Paeonia; Permeability; Snail Family Transcription Factors; src-Family Kinases; Tight Junction Proteins; Tight Junctions

Total glucosides of peony (TGP), extracted from the root and rhizome of Paeonia lactiflora Pall, has well-confirmed immunomodulatory efficacy in the clinic. However, the mechanism and active ingredients remain largely unclear.. Our previous study revealed a low systemic exposure but predominant gut distribution of TGP components. The aim of this study was to investigate involvement of the gut microbiota in the immunoregulatory effects and identify the active component.. Mice received 3% DSS to establish a model of colitis. The treatment group received TGP or single paeoniflorin (PF) or albiflorin (AF). Body weight, colon length, inflammatory and histological changes were assessed. Gut microbiota structure was profiled by 16s rRNA sequencing. Antibiotic treatment and fecal transplantation were used to explore the involvement of gut microbiota. Metabolomic assay of host and microbial metabolites in colon was performed.. TGP improved colonic injury and gut microbial dysbiosis in colitis mice, and PF was responsible for the protective effects. Fecal microbiota transfer from TGP-treated mice conferred resilience to colitis, while antibiotic treatment abrogated the protective effects. Both TGP and PF decreased colonic indole-3-lactate (ILA), a microbial tryptophan metabolite. ILA was further identified as an inhibitor of epithelial autophagy and ILA supplementation compromised the benefits of TGP.. Our findings suggest that TGP acts in part through a gut microbiota-ILA-epithelial autophagy axis to alleviate colitis.

Topics: Animals; Autophagy; Bridged-Ring Compounds; Colitis; Drugs, Chinese Herbal; Dysbiosis; Feces; Gastrointestinal Microbiome; Glucosides; HCT116 Cells; Humans; Immunologic Factors; Indoles; Male; Mice, Inbred BALB C; Monoterpenes; Paeonia; RNA, Ribosomal, 16S

Paeonia lactiflora Pall is one of the most well-known herbs in China, Korea, and Japan for more than 1,200 years. Paeoniflorin, the major bioactive component of peony root, has recently been reported to have anticolitic activity. However, the underlying molecular mechanism is unclear. The present study was to explore the possible mechanism of paeoniflorin in attenuating dextran sulfate sodium (DSS)-induced colitis. Pre- and coadministration of paeoniflorin significantly reduced the severity of colitis and resulted in downregulation of several inflammatory parameters in the colon, including the activity of myeloperoxidase (MPO), the levels of TNF-α and IL-6, and the mRNA expression of proinflammatory mediators (MCP-1, Cox2, IFN-γ, TNF-α, IL-6, and IL-17). The decline in the activation of NF-κB p65, ERK, JNK, and p38 MAPK correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) but not TLR2 or TLR5 expression. In accordance with the in vivo results, paeoniflorin downregulated TLR4 expression, blocked nuclear translocation of NF-κB p65, and reduced the production of IL-6 in LPS-stimulated mouse macrophage RAW264.7 cells. Transient transfection assay performed in LPS-stimulated human colon cancer HT-29 cells indicated that paeoniflorin inhibits NF-κB transcriptional activity in a dose-dependent manner. TLR4 knockdown and overexpression experiments demonstrated a requirement for TLR4 in paeoniflorin-mediated downregulation of inflammatory cytokines. Thus, for the first time, the present study indicates that paeoniflorin abrogates DSS-induced colitis via decreasing the expression of TLR4 and suppressing the activation of NF-κB and MAPK pathways.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Biological Availability; Bridged-Ring Compounds; Colitis; Dextran Sulfate; Drugs, Chinese Herbal; Gene Expression Profiling; Glucosides; HT29 Cells; Humans; Inflammation; Interleukin-6; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Models, Animal; Monoterpenes; NF-kappa B; Paeonia; Peroxidase; Protein Biosynthesis; Toll-Like Receptor 4; Transcriptional Activation; Tumor Necrosis Factor-alpha

Previous studies have demonstrated that the Chinese medicine paeoniflorin, derived from the Ranunculaceae plant peony, peony, purple peony root, was able to have anti-inflammatory, anti-ulcer, anti-hypersusceptibility and anti-oxidation activity. In order to elucidate the pesticide effect and the mechanisms by which paeoniflorin exerts its effect of anti-inflammation and immunoregulation on oxazolone-induced colitic mice, disease activity index (DAI) and histological grading of colitis (HGC) were evaluated in animal model. Moreover, the expressions of HBD-2, IL-6 and IL-10 of mice with experimental colitis were observed with immunohistochemistry and RT-PCR in this study. Results showed that DAI and HGC of oxazolone control group was significantly higher than that of normal control group, and that paeoniflorin groups and 5-ASA group, compared with oxazolone control group, could alleviate the symptoms and histological damages of colitic mice (P < 0.05, P < 0.01). The expression of HBD-2 and IL-6 cytokine on the colon of colitic mice was higher than that of normal control, paeoniflorin and 5-ASA groups (P < 0.05, P < 0.01), but the expression of IL-10 is lower than that of normal control, paeoniflorin and 5-ASA groups (P < 0.05, P < 0.01). The positive correlations were demonstrated between the expression of (HBD-2 and IL-6) and DAI (Pearson r = 0.728, Pearson r = 0.758, P < 0.01, respectively), (HBD-2 and IL-6) and HGC (Pearson r = 0.819, Pearson r = 0.825, P < 0.01, respectively), whereas, the negative correlations were demonstrated between the expression of IL-10 and DAI (Pearson r = -0.789, P < 0.01), IL-10 and HGC (Pearson r = -0.725, P < 0.01). It can be concluded that to some extent paeoniflorin effectively alleviate the symptoms of oxazolone-induced colitis through regulating the expression of HBD-2, IL-6 and IL-10.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; beta-Defensins; Bridged-Ring Compounds; Colitis; Colon; Female; Glucosides; Interleukin-10; Interleukin-6; Intestinal Mucosa; Mesalamine; Mice; Mice, Inbred BALB C; Monoterpenes; Oxazolone; Paeonia; Random Allocation; RNA, Messenger

Water extract of Geijigajakyak-Tang (GJT) consisting of five crude drugs [dried root of P. lactiflora Peony (Paeoniaceae), dried trunk bark of C. cassia Blume (Lauraceae), seed of Z. jujube var. inermis Mill (Rhamnaceae), fresh root of Z. officinale Rocoe (Zingiberaceae) and dried trunk bark of G. uralensis Fish (Leguminosae)] is a folk medicine used for the treatment of chronic colitis. This study was designed to further elucidate the effect of GJT on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats.. GJT orally given to mice before and after TNBS intoxication, and their clinical and morphological changes, myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels in colon tissues, were evaluated on Day 8 post-TNBS. Furthermore, the effect of six major constituents of individual herbs on ileum smooth muscle contraction and neutrophil chemotaxis was studied.. GJT had a significant anti-inflammatory effect based on clinical and morphologic changes, MPO activity and MDA levels in colon tissues as compared with sham control. GJT and 5 major active constituents of individual herbs, paeoniflorin, cinnamaldehyde, jujuboside A, jujubogenin, and diammonium glycyrhhizinate significantly inhibited neutrophil chemotaxis. GJT significantly inhibited muscle contraction (IC(50); 2.10 +/- 0.11 mg/ml), and 1,8-cineol has the most spasmolytic activity (IC(50); 0.10 +/- 0.03 mg/ml).. GJT has significant anti-inflammatory effects on TNBS-induced colitis via inhibitions of smooth muscle contraction and neutrophil chemotaxis.

Topics: Acrolein; Animals; Anti-Inflammatory Agents; Antioxidants; Benzoates; Bridged-Ring Compounds; Chemotaxis; Colitis; Cyclohexanols; Eucalyptol; Female; Glucosides; Glycyrrhizic Acid; Ileum; Lipid Peroxidation; Magnoliopsida; Malondialdehyde; Mice; Mice, Inbred BALB C; Models, Animal; Monoterpenes; Muscle Contraction; Muscle, Smooth; Neutrophils; Parasympatholytics; Peroxidase; Phytotherapy; Plant Extracts; Saponins; Trinitrobenzenesulfonic Acid; Triterpenes