lignans and Colitis

The study investigates the positive effects of phillygenin on intestinal tight junction via the let-7b signaling pathway and the regulation of intestinal microbiota. The expression levels of tight junction proteins are determined through PCR and Western blot. DSS-induced mice colitis is used to verify the protective effects of phillygenin on intestinal barrier and tight junction. Fecal microbiota transplantation is used to verify the role intestinal microbiota. let-7b is detected in the colon tissues of patients with acute stercoral obstruction. Phillygenin could promote the expression of occludin, which might be inhibited by let-7b inhibitor. DSS-induced mice colitis showed that phillygenin could lower the colonic permeability and maintain the tight junction-associated proteins. The effects of phillygenin could be deprived by anti-let-7b and rescued by FMT of normal intestinal microbiota. Clinical samples verified a lower level of let-7b in stercoral obstruction patients. Phillygenin could protect the intestinal barrier from dysfunction via the signaling pathway of let-7b by regulating intestinal microbiota.

Topics: Animals; Colitis; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Humans; Lignans; Mice; Signal Transduction

Intestinal mucus barrier dysfunction is closely involved in the pathogenesis of inflammatory bowel diseases (IBD). To investigate the protective effect and underlying mechanism of arctigenin, a phytoestrogen isolated from the fruits of Arctium lappa L., on the intestinal mucus barrier under colitis condition. The role of arctigenin on the intestinal mucus barrier and the apoptosis of goblet cells were examined by using both in vitro and in vivo assays. Arctigenin was demonstrated to promote the mucus secretion and maintain the integrity of mucus barrier, which might be achieved by an increase in the number of goblet cells via inhibiting apoptosis. Arctigenin selectively inhibited the mitochondrial pathway-mediated apoptosis. Moreover, arctigenin elevated the protein level of prohibitin 1 (PHB1) through blocking the ubiquitination via activation of estrogen receptor β (ERβ) to competitively interact with PHB1 and disrupt the binding of tripartite motif 21 (TRIM21) with PHB1. ERβ knock down in the colons of mice with DSS-induced colitis resulted in significant reduction of the protection of arctigenin and DPN against the mucosal barrier. Arctigenin can maintain the integrity of the mucus barrier by inhibiting the apoptosis of goblet cells through the ERβ/TRIM21/PHB1 pathway.

Topics: Animals; Apoptosis; Colitis; Estrogen Receptor beta; Furans; Goblet Cells; Inflammatory Bowel Diseases; Lignans; Mice; Mice, Inbred C57BL; Mucus; Phytoestrogens; Prohibitins

Chronic consumption of excess ethanol is one of the major risk factors for colorectal cancer (CRC), and the pathogenesis of ethanol-related CRC (ER-CRC) involves ethanol-induced oxidative-stress and inflammation in the colon and rectum, as well as gut leakiness. In this study, we hypothesised that oral administration of sesaminol, a sesame lignan, lowers the risk of ER-CRC because we found that it is a strong antioxidant with very low prooxidant activity. This hypothesis was examined using a mouse model, in which 2.0% v/v ethanol was administered

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Chemokine CCL2; Colitis; Cytochrome P-450 CYP2E1; Dioxoles; Endotoxins; Ethanol; Furans; Heme Oxygenase-1; Inflammation; Interleukin-6; Lignans; Malondialdehyde; Mice; Nitric Oxide Synthase Type II; Oxidative Stress; Tight Junction Proteins; Tumor Necrosis Factor-alpha

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Colitis; Cyclooctanes; Epithelial Cells; HCT116 Cells; Humans; Inflammasomes; Lignans; Mice; Mice, Inbred C57BL; Mitochondria; Network Pharmacology; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Polycyclic Compounds; Pyroptosis

To investigate the protective effects and mechanisms of sesamin (SES) on dextran sulfate sodium (DSS)-induced experimental colitis in mice.. SES (50, 100, and 200 mg kg-1) were orally administered to C57BL/6 male mice after DSS instillation. The anti-inflammatory effect of SES on colonic damage was assessed by clinical, macroscopic, microscopic, and inflammatory signaling pathways.. It could be found that bodyweight and colon length of mice treated with DSS was significantly decreased while that were increased by SES treatment. SES treatment reduced the DAI values and improved the histopathology of the colon in the DSS-treated mice. SES also reduced TNF-α, IL-1β and IL-6 production caused by DSS. We also measured the expression of the phosphorylation of p65, IκB, p38, ERK and JNK protein and found that SES can alleviate colon damage via the NF-κB and MAPK signaling pathways. The findings of this study suggested that SES had anti-inflammatory effects on intestinal inflammation and can be used as a new therapeutic candidate for inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Dextran Sulfate; Dioxoles; Lignans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NF-kappa B; Protective Agents

Honokiol (HNK) is a biphenolic compound that has been used in traditional medicine for treating various ailments, including cancers. In this study, we determined the effect of HNK on colon cancer cells in culture and in a colitis-associated cancer model. HNK treatment inhibited proliferation and colony formation while inducing apoptosis. In addition, HNK suppressed colonosphere formation. Molecular docking suggests that HNK interacts with reserve stem cell marker protein DCLK1, with a binding energy of -7.0 Kcal/mol. In vitro kinase assays demonstrated that HNK suppressed the DCLK1 kinase activity. HNK also suppressed the expression of additional cancer stem cell marker proteins LGR5 and CD44. The Hippo signaling pathway is active in intestinal stem cells. In the canonical pathway, YAP1 is phosphorylated at Ser127 by upstream Mst1/2 and Lats1/2. This results in the sequestration of YAP1 in the cytoplasm, thereby not allowing YAP1 to translocate to the nucleus and interact with TEAD1-4 transcription factors to induce gene expression. However, HNK suppressed Ser127 phosphorylation in YAP1, but the protein remains sequestered in the cytoplasm. We further determined that this occurs by YAP1 interacting with PUMA. To determine if this also occurs in vivo, we performed studies in an AOM/DSS induced colitis-associated cancer model. HNK administered by oral gavage at a dose of 5mg/kg bw for 24 weeks demonstrated a significant reduction in the expression of YAP1 and TEAD1 and in the stem marker proteins. Together, these data suggest that HNK prevents colon tumorigenesis in part by inducing PUMA-YAP1 interaction and cytoplasmic sequestration, thereby suppressing the oncogenic YAP1 activity.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Biphenyl Compounds; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colitis; Colonic Neoplasms; Doublecortin-Like Kinases; Down-Regulation; Hippo Signaling Pathway; Humans; Intracellular Signaling Peptides and Proteins; Lignans; Male; Mice, Inbred ICR; Models, Biological; Neoplastic Stem Cells; Protein Binding; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Signal Transduction; Transcription Factors; Tumor Stem Cell Assay; YAP-Signaling Proteins

Topics: Animals; Antioxidants; Caco-2 Cells; Colitis; Dioxoles; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; HEK293 Cells; Humans; Lignans; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Transcriptional Activation

Topics: Animals; Anti-Inflammatory Agents; Colitis; Dextran Sulfate; Flowers; Forsythia; Gene Expression Regulation; Glycosides; Janus Kinase 1; Lignans; Lipopolysaccharides; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Plant Extracts; RAW 264.7 Cells; Signal Transduction; STAT Transcription Factors; Transcription Factor AP-1

The present study aimed to investigate the protective effects of magnolol on acute 2,4,6-trinitrobenzene sulfonic acid (TNBS)‑induced colitis, and its underlying mechanisms. Experimental colitis was induced by intracolonic administration of TNBS/ethanol into rats. The model rats were randomly assigned into groups: TNBS, magnolol (high, medium and low doses), and salazosulfapyridine (positive control). All intervention regimens were administered by oral gavage, once a day for 7 consecutive days, 24 h after colitis induction. Histological and biochemical changes in colonic inflammation were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. Rats treated with all doses of magnolol exhibited decreased colonic myeloperoxidase activity (P<0.05 vs. TNBS), reduced serum levels of proinflammatory cytokines [including interleukin (IL)‑6 and IL‑17], and downregulated Toll‑like receptor-4 (TLR‑4) mRNA expression. Histological analysis revealed that medium and high doses of magnolol conferred an anti‑inflammatory effect, which was indicated by a decrease in disease activity index, an increase in thymus index, and downregulation of nuclear factor (NF)‑κB p65 mRNA and TLR‑4 protein expression. However, only high‑dose magnolol significantly ameliorated the elevated colon weight/length ratio. The results of the present study indicate that magnolol exerts protective effects against acute TNBS‑induced colitis in rats, and the TLR‑4/NF‑κB signaling pathway‑mediated inhibitory effect on inflammatory cascades may contribute to the protective activity of magnolol.

Topics: Acute Disease; Animals; Biphenyl Compounds; Colitis; Cyclooxygenase 2; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Interleukin-17; Interleukin-6; Lignans; Male; Nitric Oxide Synthase Type II; Peroxidase; Protective Agents; Rats; Rats, Wistar; Spleen; Thymus Gland; Toll-Like Receptor 4; Transcription Factor RelA; Trinitrobenzenesulfonic Acid

Topics: Animals; Biphenyl Compounds; Colitis; Dextran Sulfate; Indoleacetic Acids; Indoles; Interleukin-1beta; Interleukin-6; Kynurenic Acid; Lignans; Male; Mice; Mice, Inbred C57BL; Polyphenols; Tumor Necrosis Factor-alpha

Arctigenin was previously proven to inhibit Th17 cell differentiation and thereby attenuate colitis in mice by down-regulating the activation of mechanistic target of rapamycin complex 1 (mTORC1). The present study was performed to address its underlying mechanism in view of estrogen receptor (ER). The specific antagonist PHTPP or siRNA of ERβ largely diminished the inhibitory effect of arctigenin on the mTORC1 activation in T cell lines and primary CD4+ T cells under Th17-polarization condition, suggesting that arctigenin functioned in an ERβ-dependent manner. Moreover, arctigenin was recognized to be an agonist of ERβ, which could bind to ERβ with a moderate affinity, promote dissociation of ERβ/HSP90 complex and nuclear translocation and phosphorylation of ERβ, and increase the transcription activity. Following activation of ERβ, arctigenin inhibited the activity of mTORC1 by disruption of ERβ-raptor-mTOR complex assembly. Deficiency of ERβ markedly abolished arctigenin-mediated inhibition of Th17 cell differentiation. In colitis mice, the activation of ERβ, inhibition of mTORC1 activation and Th17 response by arctigenin were abolished by PHTPP treatment. In conclusion, ERβ might be the target protein of arctigenin responsible for inhibition of mTORC1 activation and resultant prevention of Th17 cell differentiation and colitis development.

Topics: Animals; Cell Differentiation; Colitis; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Estrogen Receptor Antagonists; Estrogen Receptor beta; Female; Furans; HSP90 Heat-Shock Proteins; Humans; Jurkat Cells; Lignans; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Ovariectomy; Phosphorylation; Regulatory-Associated Protein of mTOR; Selective Estrogen Receptor Modulators; Signal Transduction; Th17 Cells; Time Factors; Transcription, Genetic

Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway.

Topics: Animals; Anti-Inflammatory Agents; Cell Differentiation; Colitis; Dextran Sulfate; Furans; Humans; Jurkat Cells; Lignans; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Multiprotein Complexes; Signal Transduction; Th1 Cells; Th17 Cells; TOR Serine-Threonine Kinases

Schisandrin B (Sch B), the most abundant dibenzocyclooctadiene lignan isolated from the traditional Chinese medicinal herb Schisandra chinensis (Turcz.) Baill, possesses various biological activities, such as hepatic protection, anti-tumor, anti-inflammatory and anti-cardiovascular properties. However, the effect of Sch B on inflammatory bowel disease (IBD) is not yet known. The aim of this study was to investigate whether Sch B has protective effect against dextran sulfate sodium (DSS)-induced colitis in a mouse model. The acute mouse model of IBD was induced by drinking 2.5% DSS water for 5 days. Sch B was administered orally in doses of 10, 40, and 100 mg/kg respectively. It significantly reduced concentration of TNF-α, IL-1β, INF-γ and IL-6 in colon tissue as well as the mRNA expression levels. In addition, we demonstrated that Sch B blocked the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, and extracellular signal regulated kinase in DSS-induced acute colitis. In conclusion, these results indicated that Sch B could exert beneficial effects on experimental IBD induced by DSS and may represent a novel treatment strategy for IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Cyclooctanes; Cytokines; Dextran Sulfate; Female; Inflammatory Bowel Diseases; Lignans; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; NF-kappa B; Polycyclic Compounds; Signal Transduction

The crude powder of the fruit of Arctium lappa L. (ALF) has previously been reported to attenuate experimental colitis in mice. But, its main effective ingredient and underlying mechanisms remain to be identified. In this study, ALF was extracted with ethanol, and then successively fractionated into petroleum ether, ethyl acetate, n-butanol and water fraction. Experimental colitis was induced by dextran sulfate sodium (DSS) in mice. Among the four fractions of ALF, the ethyl acetate fraction showed the most significant inhibition of DSS-induced colitis in mice. The comparative studies of arctigenin and arctiin (the two main ingredients of ethyl acetate fraction) indicated that arctigenin rather than arctiin could reduce the loss of body weight, disease activity index and histological damage in the colon. Arctigenin markedly recovered the loss of intestinal epithelial cells (E-cadherin-positive cells) and decreased the infiltration of neutrophils (MPO-positive cells) and macrophages (CD68-positive cells). Arctigenin could down-regulate the expressions of TNF-α, IL-6, MIP-2, MCP-1, MAdCAM-1, ICAM-1 and VCAM-1 at both protein and mRNA levels in colonic tissues. Also, it markedly decreased the MDA level, but increased SOD activity and the GSH level. Of note, the efficacy of arctigenin was comparable or even superior to that of the positive control mesalazine. Moreover, it significantly suppressed the phosphorylation of MAPKs and the activation of NF-κB, including phosphorylation of IκBα and p65, p65 translocation and DNA binding activity. In conclusion, arctigenin but not arctiin is the main active ingredient of ALF for attenuating colitis via down-regulating the activation of MAPK and NF-κB pathways.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arctium; Colitis; Dextran Sulfate; Dose-Response Relationship, Drug; Fruit; Furans; Glucosides; Lignans; Male; Mesalamine; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Molecular Structure; NF-kappa B; Oxidative Stress; Plant Extracts

Seeds of Arctium lappa, containing arctigenin and its glycoside arctiin as main constituents, have been used as a diuretic, anti-inflammatory and detoxifying agent in Chinese traditional medicine. In our preliminary study, arctigenin inhibited IKKβ and NF-κB activation in peptidoglycan (PGN)- or lipopolysaccharide (LPS)-induced peritoneal macrophages. To understand the anti-inflammatory effect of arctigenin, we investigated its anti-inflammatory effect in LPS-stimulated peritoneal macrophages and on LPS-induced systemic inflammation as well as 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Arctigenin inhibited LPS-increased IL-1β, IL-6 and TNF-α expression in LPS-stimulated peritoneal macrophages, but increased LPS-reduced IL-10 and CD204 expression. Arctigenin inhibited LPS-induced PI3K, AKT and IKKβ phosphorylation, but did not suppress LPS-induced IRAK-1 phosphorylation. However, arctigenin did not inhibit NF-κB activation in LPS-stimulated PI3K siRNA-treated peritoneal macrophages. Arctigenin suppressed the binding of p-PI3K antibody and the nucleus translocation of NF-κB p65 in LPS-stimulated peritoneal macrophages. Arctigenin suppressed blood IL-1β and TNF-α level in mice systemically inflamed by intraperitoneal injection of LPS. Arctigenin also inhibited colon shortening, macroscopic scores and myeloperoxidase activity in TNBS-induced colitic mice. Arctigenin inhibited TNBS-induced IL-1β, TNF-α and IL-6 expression, as well as PI3K, AKT and IKKβ phosphorylation and NF-κB activation in mice, but increased IL-10 and CD204 expression. However, it did not affect IRAK-1 phosphorylation. Based on these findings, arctigenin may ameliorate inflammatory diseases, such as colitis, by inhibiting PI3K and polarizing M1 macrophages to M2-like macrophages.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Cytokines; Furans; Lignans; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Peroxidase; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Trinitrobenzenesulfonic Acid