Activation of PXR by alantolactone ameliorates DSS-induced experimental colitis via suppressing NF-κB signaling pathway

Abstract Alantolactone (ALA) is a sesquiterpene lactone with potent anti-inflammatory activity. However, the effect of ALA on intestinal inflammation remains largely unknown. The present study demonstrated that ALA significantly ameliorated the clinical symptoms of dextran sulfate sodium (DSS)-induced mice colitis as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration and histological injury. In mice exposed to DSS, ALA treatment significantly lowered pro-inflammatory mediators, including nuclear factor-kappa B (NF-κB) activation. In vitro, ALA inhibited NF-κB nuclear translocation and dose-dependently activated human/mouse pregnane X receptor (PXR), a key regulator gene in inflammatory bowel disease (IBD) pathogenesis. However, the pocket occluding mutants of the ligand-binding domain (LBD) of hPXR, abrogated ALA-mediated activation of the receptor. Overexpression of hPXR inhibited NF-κB-reporter activity and in this setting, ALA further enhanced the hPXR-mediated inhibition of NF-κB-reporter activity. Furthermore, silencing hPXR gene demonstrated the necessity for hPXR in downregulation of NF-κB activation by ALA. Finally, molecular docking studies confirmed the binding affinity between hPXR-LBD and ALA. Collectively, the current study indicates a beneficial effect of ALA on experimental IBD possibly via PXR-mediated suppression of the NF-κB inflammatory signaling.

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Acacetin Ameliorates Experimental Colitis in Mice via Inhibiting Macrophage Inflammatory Response and Regulating the Composition of Gut Microbiota

Frontiers in Physiology ◽

10.3389/fphys.2020.577237 ◽

2021 ◽

Vol 11 ◽

Author(s):

Junyu Ren ◽

Bei Yue ◽

Hao Wang ◽

Beibei Zhang ◽

Xiaoping Luo ◽

...

Keyword(s):

Inflammatory Response ◽

Gut Microbiota ◽

Intestinal Inflammation ◽

Clinical Symptoms ◽

Biological Effects ◽

Body Weight Loss ◽

Experimental Colitis ◽

Inflammatory Infiltration ◽

Acacia Honey

Acacetin, a natural dietary flavonoid abundantly found in acacia honey and citrus fruits, reportedly exerts several biological effects, such as anti-tumor, anti-inflammatory, and anti-oxidative effects. However, the effects of acacetin on intestinal inflammation remain unclear. We sought to investigate whether acacetin ameliorates inflammatory bowel disease (IBD) in mice with dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Our results suggest that acacetin alleviates the clinical symptoms of DSS-induced colitis, as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration, and histological injury. Further studies showed that acacetin remarkably inhibited both the macrophage inflammatory response in vitro and levels of inflammatory mediators in mice with colitis. In addition, some features of the gut microbiota were disordered in mice with DSS-induced colitis, as evidenced by a significant reduction in microbiota diversity and a marked shift in bacterial profiles. However, acacetin treatment improved this imbalance and restored gut microbiota to levels that were similar to those in normal mice. In conclusion, our work presents evidence that acacetin attenuates DSS-induced colitis in mice, at least in part, by inhibiting inflammation and regulating the intestinal microbiota.

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RETRACTED ARTICLE:Deficiency in intestinal epithelial Reg4 ameliorates intestinal inflammation and alters the colonic bacterial composition

Mucosal Immunology ◽

10.1038/s41385-019-0161-5 ◽

2019 ◽

Vol 12 (4) ◽

pp. 919-929 ◽

Cited By ~ 5

Author(s):

Yongtao Xiao ◽

Ying Lu ◽

Ying Wang ◽

Weihui Yan ◽

Wei Cai

Keyword(s):

Intestinal Inflammation ◽

Elevated Serum ◽

Intestinal Failure ◽

Experimental Colitis ◽

Mucosal Injury ◽

Intestinal Epithelial ◽

Bacterial Composition ◽

Novel Target

AbstractThe regenerating islet-derived family member 4 (Reg4) in the gastrointestinal tract is up-regulated during intestinal inflammation. However, the physiological function of Reg4 in the inflammation is largely unknown. In the current study, the functional roles and involved mechanisms of intestinal epithelial Reg4 in intestinal inflammation were studied in healthy and inflamed states using human intestinal specimens, an intestinal conditional Reg4 knockout mouse (Reg4ΔIEC) model and dextran sulfate sodium (DSS)-induced colitis model. We showed that the elevated serum Reg4 in pediatric intestinal failure (IF) patients were positively correlated with the serum concentrations of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In inflamed intestine of IF patients, the crypt base Reg4 protein was increased and highly expressed towards the luminal face. The Reg4 was indicated as a novel target of activating transcription factor 2 (ATF2) that enhanced Reg4 expression during the intestinal inflammation. In vivo, the DSS-induced colitis was significantly ameliorated in Reg4ΔIEC mice. Reg4ΔIEC mice altered the colonic bacterial composition and reduced the bacteria adhere to the colonic epithelium. In vitro, Reg4 was showed to promote the growth of colonic organoids, and that this occurs through a mechanism involving activation of signal transducer and activator of transcription 3 (STAT3). In conclusion, our findings demonstrated intestinal-epithelial Reg4 deficiency protects against experimental colitis and mucosal injury via a mechanism involving alteration of bacterial homeostasis and STAT3 activation.

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Lactobacillus paracaseiReduces Intestinal Inflammation in Adoptive Transfer Mouse Model of Experimental Colitis

Clinical and Developmental Immunology ◽

10.1155/2011/807483 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 18

Author(s):

Manuel Oliveira ◽

Nabil Bosco ◽

Genevieve Perruisseau ◽

Jeanne Nicolas ◽

Iris Segura-Roggero ◽

...

Keyword(s):

Mouse Model ◽

Adoptive Transfer ◽

Immune Modulation ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Neutrophil Infiltration ◽

Lactobacillus Paracasei ◽

Therapeutic Benefits

Studies showed that specific probiotics provide therapeutic benefits in inflammatory bowel disease.In vitroevidence suggested thatLactobacillus paracaseialso called ST11 (CNCM I-2116) is a potent strain with immune modulation properties. However, little is known about its capacity to alleviate inflammatory symptomsin vivoIn this context, the main objective of this study was to investigate the role of ST11 on intestinal inflammation using the adoptive transfer mouse model of experimental colitis. Rag2-/-recipient mice were fed with ST11 (109CFU/day)a month prior toinduce colitis by adoptive transfer of naive T cells. One month later, in clear contrast to nonfed mice, weight loss was significantly reduced by 50% in ST11-fed mice. Further analysis of colon specimens revealed a significant reduction neutrophil infiltration and mucosal expression of IL1β, IL-6, and IL12 proinflammatory cytokines, whereas no consistent differences in expression of antibacterial peptides or tight junction proteins were observed between PBS and ST11-fed mice. All together, our results demonstrate that oral administration of ST11 was safe and had a significant preventive effect on colitis. We conclude that probiotics such asLactobacillus paracaseiharbor worthwhilein vivoimmunomodulatory properties to prevent intestinal inflammation by nutritional approaches.

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Somatostatin does not attenuate intestinal injury in dextran sodium sulphate-induced subacute colitis

Mediators of Inflammation ◽

10.1080/09629359891108 ◽

1998 ◽

Vol 7 (3) ◽

pp. 169-173 ◽

Cited By ~ 5

Author(s):

J. D. van Bergeijk ◽

M. E. van Meeteren ◽

C. J. A. M. Tak ◽

A. P. M. van Dijk ◽

M. A. C. Meijssen ◽

...

Keyword(s):

Intestinal Inflammation ◽

Experimental Colitis ◽

Sodium Sulphate ◽

Dextran Sodium Sulphate ◽

Acute Colitis ◽

Inflammatory Score ◽

Long Acting ◽

Intestinal Macrophage

From severalin vitroandin vivostudies involvement of som atostatin (SMS) in intestinal inflammation emerge. Acute colitis induced in rats is attenuated by the long-acting SMS analogue octreotide. We studied the potential beneficial effect of SMS on non-acute experimental colitis. BALB/c mice received either saline, SMS-14 (36 or 120 μg daily) or octreotide (3 μg daily) subcutaneously delivered by implant osmotic pumps. A non-acute colitis was induced by administration of dextran sodium sulphate (DSS) 10% in drinking water during 7 days. DSS evoked a mild, superficial pancolitis, most characterized by mucosal ulceration and submucosal influx of neutrophils. Neither SMS-14 nor octreotide reduced mucosal inflammatory score or macroscopical disease activity, although reduction of intestinal levels of interleukin1 β (IL-1 β), IL-6 and IL-10 during DSS was augmented both by SMS and octreotide. A slight increase of neutrophil influx was seen during SMS administration in animals not exposed to DSS. In conclusion, SMS or its long-acting analogue did not reduce intestinal inflammation in non-acute DSS-induced colitis. According to the cytokine profile observed, SMS-14 and octreotide further diminished the reduction of intestinal macrophage and Th2 lymphocyte activity.

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Echinochrome A Reduces Colitis in Mice and Induces In Vitro Generation of Regulatory Immune Cells

Marine Drugs ◽

10.3390/md17110622 ◽

2019 ◽

Vol 17 (11) ◽

pp. 622 ◽

Cited By ~ 1

Author(s):

Su-Jeong Oh ◽

Yoojin Seo ◽

Ji-Su Ahn ◽

Ye Young Shin ◽

Ji Won Yang ◽

...

Keyword(s):

Therapeutic Potential ◽

Sea Urchins ◽

Biological Activities ◽

Cardiac Injury ◽

Body Weight Loss ◽

Experimental Colitis ◽

Treg Cells ◽

Echinochrome A ◽

Intestinal Immune System

Echinochrome A (Ech A), a natural pigment extracted from sea urchins, is the active ingredient of a marine-derived pharmaceutical called ‘histochrome’. Since it exhibits several biological activities including anti-oxidative and anti-inflammatory effects, it has been applied to the management of cardiac injury and ocular degenerative disorders in Russia and its protective role has been studied for other pathologic conditions. In the present study, we sought to investigate the therapeutic potential of Ech A for inflammatory bowel disease (IBD) using a murine model of experimental colitis. We found that intravenous injection of Ech A significantly prevented body weight loss and subsequent lethality in colitis-induced mice. Interestingly, T cell proliferation was significantly inhibited upon Ech A treatment in vitro. During the helper T (Th) cell differentiation process, Ech A stimulated the generation regulatory T (Treg) cells that modulate the inflammatory response and immune homeostasis. Moreover, Ech A treatment suppressed the in vitro activation of pro-inflammatory M1 type macrophages, while inducing the production of M2 type macrophages that promote the resolution of inflammation and initiate tissue repair. Based on these results, we suggest that Ech A could provide a beneficial impact on IBD by correcting the imbalance in the intestinal immune system.

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Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation

Science ◽

10.1126/science.aar2641 ◽

2018 ◽

Vol 361 (6404) ◽

pp. 810-813 ◽

Cited By ~ 70

Author(s):

Delphine Cuchet-Lourenço ◽

Davide Eletto ◽

Changxin Wu ◽

Vincent Plagnol ◽

Olivier Papapietro ◽

...

Keyword(s):

Intestinal Inflammation ◽

Clinical Symptoms ◽

Critical Role ◽

Mitogen Activated Protein Kinase ◽

Human Immune System ◽

Hematopoietic Stem ◽

Kinase Activation ◽

Protein Kinase Activation ◽

Mitogen Activated Protein

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.

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Effects of Guchang Capsule on Dextran Sulphate Sodium-Induced Experimental Ulcerative Colitis in Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/3150651 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Baoshan Liu ◽

Tong Liu ◽

Xiaohong Wang ◽

Xin Zheng ◽

Hong Wang ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Body Weight Loss ◽

Experimental Colitis ◽

Intestinal Disease ◽

Therapeutic Effects ◽

Dextran Sulphate ◽

Chinese Materia Medica ◽

Dextran Sulphate Sodium ◽

Underlying Mechanisms

Guchang capsule (GC) is a Chinese materia medica standardized product extracted from 15 Chinese traditional medical herbs and it has been clinically used in the treatment of intestinal disease. In this study, in order to extend the research of GC in intestinal disease, we were aiming to evaluate potential effects of GC on dextran sulphate sodium- (DSS-) induced murine experimental colitis and to elucidate the underlying mechanisms. GC treatment attenuated DSS-induced body weight loss and reduced the mortality. Moreover, GC treatment prevented DSS-induced colonic pathological damage; meanwhile it inhibited proinflammatory cytokines production in colon tissues.In vitro, GC significantly reduced LPS-induced proinflammatory cytokines production via inhibiting the activation of NF-κB in macrophage cells, and the expressions of several long noncoding RNAs (lncRNAs) which were reported in regulating NF-κB signaling pathway were obviously affected by adding GC into culture medium. In conclusion, our data suggested that administration of GC exhibits therapeutic effects on DSS-induced colitis partially through regulating the expression of NF-κB related lncRNAs in infiltrating immune cells.

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The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro185 and Ala185 Variants Repress both AHR and Hypoxia-Inducible Factor

Molecular and Cellular Biology ◽

10.1128/mcb.00206-09 ◽

2009 ◽

Vol 29 (13) ◽

pp. 3465-3477 ◽

Cited By ~ 32

Author(s):

Sibel I. Karchner ◽

Matthew J. Jenny ◽

Ann M. Tarrant ◽

Brad R. Evans ◽

Hyo Jin Kang ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Nuclear Translocation ◽

Active Form ◽

Hypoxia Inducible Factor ◽

Pregnane X Receptor ◽

Estrogen Receptor Α ◽

Aryl Hydrocarbon ◽

Human Reproductive ◽

Factor Specificity

ABSTRACT The aryl hydrocarbon receptor (AHR) repressor (AHRR) inhibits AHR-mediated transcription and has been associated with reproductive dysfunction and tumorigenesis in humans. Previous studies have characterized the repressor function of AHRRs from mice and fish, but the human AHRR ortholog (AHRR715) appeared to be nonfunctional in vitro. Here, we report a novel human AHRR cDNA (AHRRΔ8) that lacks exon 8 of AHRR715. AHRRΔ8 was the predominant AHRR form expressed in human tissues and cell lines. AHRRΔ8 effectively repressed AHR-dependent transactivation, whereas AHRR715 was much less active. Similarly, AHRRΔ8, but not AHRR715, formed a complex with AHR nuclear translocator (ARNT). Repression of AHR by AHRRΔ8 was not relieved by overexpression of ARNT or AHR coactivators, suggesting that competition for these cofactors is not the mechanism of repression. AHRRΔ8 interacted weakly with AHR but did not inhibit its nuclear translocation. In a survey of transcription factor specificity, AHRRΔ8 did not repress the nuclear receptor pregnane X receptor or estrogen receptor α but did repress hypoxia-inducible factor (HIF)-dependent signaling. AHRRΔ8-Pro185 and -Ala185 variants, which have been linked to human reproductive disorders, both were capable of repressing AHR or HIF. Together, these results identify AHRRΔ8 as the active form of human AHRR and reveal novel aspects of its function and specificity as a repressor.

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Cornelian Cherry Iridoid-Polyphenolic Extract Improves Mucosal Epithelial Barrier Integrity in Rat Experimental Colitis and Exerts Antimicrobial and Antiadhesive Activities In Vitro

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7697851 ◽

2020 ◽

Vol 2020 ◽

pp. 1-19

Author(s):

Marta Szandruk-Bender ◽

Maria Rutkowska ◽

Anna Merwid-Ląd ◽

Benita Wiatrak ◽

Adam Szeląg ◽

...

Keyword(s):

Mrna Expression ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Epithelial Barrier ◽

Trinitrobenzenesulfonic Acid ◽

Cornelian Cherry ◽

Polyphenolic Extract ◽

Tnf Α ◽

The Impact

Background and Aims. Inflammatory bowel disease pharmacotherapy, despite substantial progress, is still not satisfactory for both patients and clinicians. In view of the chronic and relapsing disease course and not always effective treatment with adverse effects, attempts to search for new, more efficient, and safer substances are essential and reasonable. This study was designed to elucidate the impact of cornelian cherry iridoid-polyphenolic extract (CE) and loganic acid (LA) on adherent-invasive E. coli growth and adhesion in vitro and to assess the effect of pretreatment with CE or LA on the course of intestinal inflammation in rat experimental colitis compared with sulfasalazine. Methods. Antibacterial and antiadhesive activities of CE and LA were assessed using microdilution, Int407 cell adherence, and yeast agglutination assays. The colitis model was induced by 2,4,6-trinitrobenzenesulfonic acid. Studied substances were administered intragastrically for 16 days prior to colitis induction. Body weight loss; colon index; histological injuries; IL-23, IL-17, TNF-α, and chemerin levels; and STAT3, Muc2, and TFF3 mRNA expression were evaluated. Results. Only CE exerted antimicrobial and antiadhesive activities in vitro and alleviated colonic symptoms. CE coadministrated with sulfasalazine was more effective than single compounds in reversing increased concentrations of TNF-α, IL-17, and chemerin and decreased Muc2 mRNA expression. Conclusions. CE exerted a protective effect against experimental colitis via impaired mucosal epithelial barrier restoration and intestinal inflammatory response attenuation and given concomitantly with sulfasalazine counteracted colitis in a more effective way than sulfasalazine alone, which indicates their synergistic interaction. The beneficial effect of CE may also be due to its bacteriostatic and antiadhesive activities.

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PYK2 controls intestinal inflammation via activation of IRF5 in macrophages

10.1101/2020.05.24.113076 ◽

2020 ◽

Author(s):

Grigory Ryzhakov ◽

Hannah Almuttaqi ◽

Alastair L. Corbin ◽

Tariq Khoyratty ◽

Dorothee Berthold ◽

...

Keyword(s):

Risk Factor ◽

Genetic Risk ◽

Protein Tyrosine Kinase ◽

Target Genes ◽

Intestinal Inflammation ◽

Nuclear Translocation ◽

Kinase Inhibitor ◽

Genetic Risk Factor ◽

Tyrosine Kinase 2

AbstractInflammatory bowel disease (IBD) is a group of inflammatory disorders of the gastro-intestinal tract caused by a complex combination of genetic and environmental factors. Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, which plays a key pathogenic role in mouse colitis models and is a genetic risk factor for IBD. A screen of a protein kinase inhibitor library in macrophages revealed a list of putative IRF5 kinases. Among the top hits validated in multiple in vitro assays, protein-tyrosine kinase 2-beta (PTK2B or PYK2) was identified as the only IBD genetic risk factor, known to impact gene expression in myeloid cells1,2. Phospho-proteomics and mutagenesis analyses established that PYK2 directly phosphorylates and activates IRF5 at tyrosine (Y) 171. IRF5 nuclear translocation and recruitment to target genes was impaired in PYK2-deficient cells or in cells treated with PYK2 inhibitors. Importantly, macrophage transcriptomic signature under PYK2 inhibition phenocopied IRF5 deficiency. Treatment with a PYK2 inhibitor reduced pathology and inflammatory cytokine production in Helicobacter hepaticus + anti-IL-10R antibody induced colitis model. It also decreased levels of pro-inflammatory cytokines in human colon biopsies taken from patients with ulcerative colitis. Thus, we have identified a major role for PYK2 in regulating the inflammatory response and mapped its activity to the IRF5 innate sensing pathway, opening opportunities for therapeutic interference with it in IBD and other inflammatory conditions.

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