RÉSUMÉ
Background: Ulcerative colitis (UC) is an intestinal inflammatory disease that is strongly associated with mitochondrial damage and dysfunction as well as mitophagy and lacks of satisfactory treatments. Hair follicle mesenchymal stem cell (HF-MSC)-derived exosomes owe benefit effectiveness on inflammatory therapies. Hypoxia-preconditioned HF-MSCs exhibit enhanced proliferation and migration abilities, and their exosomes exert stronger effects than normal exosomes. However, the therapeutic function of Hy-Exos in UC is unknown. Methods: The inflammation model was established with LPS-treated MODE-K cells, and the mouse UC model was established by dextran sulfate sodium (DSS) administration. The therapeutic effects of HF-MSC-derived exosomes (Exos) and hypoxia-preconditioned HF-MSC-derived exosomes (Hy-Exos) were compared in vitro and in vivo. Immunofluorescence staining and western blotting were used to explore the effects of Hy-Exos on mitochondrial function, mitochondrial fission and fusion and mitophagy. MiRNA sequencing analysis was applied to investigate the differences in components between Exos and Hy-Exos. Results: Hy-Exos had a better therapeutic effect on LPS-treated MODE-K cells and DSS-induced UC mice. Hy-Exos promoted colonic tight junction proteins expression, suppressed the oxidative stress response, and reduced UC-related inflammatory injury. Hy-Exos may exert these effects via miR-214-3p-mediated inhibition of the PI3K/AKT/mTOR signaling pathway, maintenance of mitochondrial dynamic stability, alleviation of mitochondrial dysfunction and enhancement of mitophagy. Conclusion: This study revealed a vital role for Hy-Exos in suppressing inflammatory progression in UC and suggested that miR-214-3p is a potential critical target for Hy-Exos in alleviating UC.
Sujet(s)
Rectocolite hémorragique , Modèles animaux de maladie humaine , Exosomes , Follicule pileux , Cellules souches mésenchymateuses , Mitophagie , Phosphatidylinositol 3-kinases , Protéines proto-oncogènes c-akt , Transduction du signal , Sérine-thréonine kinases TOR , Animaux , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/thérapie , Rectocolite hémorragique/anatomopathologie , Cellules souches mésenchymateuses/métabolisme , Exosomes/métabolisme , Souris , Protéines proto-oncogènes c-akt/métabolisme , Sérine-thréonine kinases TOR/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Follicule pileux/métabolisme , Sulfate dextran , Mâle , Mitochondries/métabolisme , Souris de lignée C57BL , microARN/métabolisme , microARN/génétique , HumainsRÉSUMÉ
Inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), is a complicated illness whose exact cause is yet unknown. Necroptosis is associated with IBD pathogenesis, leading to intestinal barrier abnormalities and uncontrolled inflammation. Molecules involved in necroptosis, however, exhibit different expression levels in IBD and its associated colorectal cancer. Multiple studies have shown that inhibiting these molecules alleviates necroptosis-induced IBD. Moreover, due to the severe scarcity of clinical medications for treating IBD caused by necroptosis, we review the various functions of crucial necroptosis molecules in IBD, the stimuli regulating necroptosis, and the current emerging therapeutic strategies for treating IBD-associated necroptosis. Eventually, understanding the pathogenesis of necroptosis in IBD will enable the development of additional therapeutic approaches for the illness.
Sujet(s)
Maladies inflammatoires intestinales , Nécroptose , Humains , Maladies inflammatoires intestinales/métabolisme , Maladies inflammatoires intestinales/anatomopathologie , Animaux , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/anatomopathologie , Maladie de Crohn/métabolisme , Maladie de Crohn/anatomopathologieRÉSUMÉ
The utility of spatial omics in leveraging cellular interactions in normal and diseased states for precision medicine is hampered by a lack of strategies for matching disease states with spatial heterogeneity-guided cellular annotations. Here we use a spatial context-dependent approach that matches spatial pattern detection to cell annotation. Using this approach in existing datasets from ulcerative colitis patient colonic biopsies, we identified architectural complexities and associated difficult-to-detect rare cell types in ulcerative colitis germinal-center B cell follicles. Our approach deepens our understanding of health and disease pathogenesis, illustrates a strategy for automating nested architecture detection for highly multiplexed spatial biology data, and informs precision diagnosis and therapeutic strategies.
Sujet(s)
Rectocolite hémorragique , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/génétique , Humains , Côlon/anatomopathologie , Côlon/métabolisme , BiopsieRÉSUMÉ
Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease affecting the gastrointestinal tract. Although paeonol has been used for treating UC due to its anti-inflammatory and antioxidant effects, the underlying mechanisms remain unclear. In this study, we investigated the mechanisms of paeonol's action on UC by conducting in-vitro and in-vivo studies using NCM460 cells and RAW264.7 cells, and the DSS-induced mice colitis model. The in vitro studies demonstrate that paeonol exerts inhibitory effects on the activation of the NF-κB signaling pathway through upregulating PPARγ expression, thereby attenuating pro-inflammatory cytokine production, reducing reactive oxygen species levels, and promoting M2 macrophage polarization. These effects are significantly abrogated upon addition of the PPARγ inhibitor GW9662. Moreover, UC mice treated with paeonol showed increased PPARγ expression, which reduced inflammation and apoptosis to maintain intestinal epithelial barrier integrity. In conclusion, our findings suggest that paeonol inhibits the NF-κB signaling pathway by activating PPARγ, reducing inflammation and oxidative stress and improving Dss-induced colitis. This study provides a new insight into the mechanism of treating UC by paeonol.
Sujet(s)
Acétophénones , Rectocolite hémorragique , Facteur de transcription NF-kappa B , Récepteur PPAR gamma , Transduction du signal , Acétophénones/pharmacologie , Acétophénones/usage thérapeutique , Récepteur PPAR gamma/métabolisme , Animaux , Rectocolite hémorragique/traitement médicamenteux , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/induit chimiquement , Rectocolite hémorragique/anatomopathologie , Facteur de transcription NF-kappa B/métabolisme , Souris , Transduction du signal/effets des médicaments et des substances chimiques , Humains , Cellules RAW 264.7 , Modèles animaux de maladie humaine , Mâle , Espèces réactives de l'oxygène/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Anti-inflammatoires/pharmacologie , Sulfate dextran/toxicité , Souris de lignée C57BLRÉSUMÉ
Neutrophils (polymorphonuclear leukocytes, PMNs) comprise a major component of the immune cell infiltrate during acute mucosal inflammation and have an important role in molding the inflammatory tissue environment. While PMNs are essential to clearance of invading microbes, the major PMN antimicrobial enzyme myeloperoxidase (MPO) can also promote bystander tissue damage. We hypothesized that blocking MPO would attenuate acute colitis and prevent the development of chronic colitis by limiting bystander tissue damage. Using the acute and chronic dextran sodium sulfate model of murine colitis, we demonstrated that MPO-deficient mice experienced less inflammation and more rapidly resolved colitis relative to wild-type controls. Mechanistic studies demonstrated that activated MPO disrupted intestinal epithelial barrier function through the dysregulation of the epithelial tight junction proteins. Our findings revealed that activated MPO chlorinates tyrosine within several tight junction proteins, thereby promoting tight junction mislocalization and dysfunction. These observations in cell models and in murine colitis were validated in human intestinal biopsies from individuals with ulcerative colitis and revealed a strong correlation between disease severity (Mayo score) and tissue chlorinated tyrosine levels. In summary, these findings implicate MPO as a viable therapeutic target to limit bystander tissue damage and preserve mucosal barrier function during inflammation.
Sujet(s)
Modèles animaux de maladie humaine , Muqueuse intestinale , Granulocytes neutrophiles , Myeloperoxidase , Protéines de la jonction serrée , Myeloperoxidase/métabolisme , Animaux , Souris , Humains , Muqueuse intestinale/anatomopathologie , Muqueuse intestinale/métabolisme , Granulocytes neutrophiles/métabolisme , Granulocytes neutrophiles/immunologie , Protéines de la jonction serrée/métabolisme , Colite/anatomopathologie , Colite/métabolisme , Colite/induit chimiquement , Halogénation , Inflammation/métabolisme , Inflammation/anatomopathologie , Mâle , Souris knockout , Sulfate dextran/toxicité , Jonctions serrées/métabolisme , Femelle , Souris de lignée C57BL , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/métabolismeRÉSUMÉ
PURPOSE: The aim of this study was to explore whether MAF bZIP transcription factor B (MAFB) might alleviate ulcerative colitis (UC) in dextran sulfate sodium (DSS)-induced mice and LPS-induced IEC-6 cells. METHODS: UC in vivo and in vitro model was established by using DSS and LPS, respectively. The mice body weight and disease activity index (DAI) score were recorded daily, and colon length was measured. Moreover, the permeability was evaluated utilizing a fluorescein isothiocyanate dextran (FITC-Dextran) probe. Histopathological changes of DSS-induced colitis mice was assessed utilizing H&E staining. Next, qRT-PCR was performed to detect IL-1ß, IL-6, TNF-α, and IL-10 level in in vivo and in vitro. Furthermore, the level of MDA, SOD, CAT, and GSH were evaluated in colon tissues. Besides, the expressions of tight junction proteins and NF-κB pathway relative proteins were examined in colitis mice and IEC-6 cells using western blot, immunohistochemistry and immunofluorescence. RESULTS: MAFB level was downregulated in DSS-induced colitis mice. Moreover, the upregulation of MAFB protected mice from DSS-induced colitis by suppressing DSS-induced inflammation, oxidative stress, and intestinal barrier impairment. We also demonstrated that the upregulation of MAFB inactivated NF-κB pathway in DSS-caused colitis mice. Subsequently, we observed that MAFB upregulation could inhibit LPS-caused epithelial barrier impairment and inflammation in IEC-6 cells. Additionally, MAFB overexpression could suppress the activation of NF-κB pathway in IEC-6 cells. CONCLUSION: The upregulation of MAFB could protect against UC via the suppression of inflammation and the intestinal barrier impairment through inhibiting the NF-κB pathway.
Sujet(s)
Rectocolite hémorragique , Sulfate dextran , Facteur de transcription MafB , Facteur de transcription NF-kappa B , Transduction du signal , Animaux , Mâle , Souris , Lignée cellulaire , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/induit chimiquement , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/prévention et contrôle , Cytokines/métabolisme , Sulfate dextran/toxicité , Modèles animaux de maladie humaine , Lipopolysaccharides/toxicité , Facteur de transcription MafB/génétique , Facteur de transcription MafB/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Stress oxydatifRÉSUMÉ
Ulcerative colitis (UC) is a chronic non-specific inflammatory disease involving the mucosa and submucosa of the rectum and colon. Lindera aggregate (Sims) Kosterm is a traditional Chinese herb used for thousands of years in the treatment of gastrointestinal diseases. Previously, we have demonstrated that the extracts of Lindera aggregate have good anti-UC effects, but their pharmacodynamic active components have not been fully clarified. Therefore, we explored the therapeutic effect of Linderanine C (LDC), a characteristic component of Lindera aggregata, on UC and its mechanism in this study. Firstly, we found that LDC could significantly reduce the disease activity index of UC and improve shortened colon and pathological changes in vivo. Colon tissue transcriptomics suggested that the anti-UC effect of LDC might be related to its anti-inflammatory activity. Cellular experiments revealed that LDC could inhibit the expression of the M1 cell marker CD86 in RAW264.7 cells, reduce the production of inflammatory mediators such as IL-6 and TNF-α, and have good anti-inflammatory activity in vitro. Cellular transcriptomics reveal the potential involvement of the MAPK signaling pathway in the anti-inflammatory effect of LDC. The co-culture assay confirmed that LDC could significantly reduce inflammation-mediated intestinal epithelial cell injury. In conclusion, LDC was able to inhibit macrophage M1 polarization and reduce inflammatory mediator production by inhibiting the MAPK signaling pathway, effectively improving UC.
Sujet(s)
Anti-inflammatoires , Rectocolite hémorragique , Système de signalisation des MAP kinases , Macrophages , Animaux , Rectocolite hémorragique/traitement médicamenteux , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/métabolisme , Souris , Cellules RAW 264.7 , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Mâle , Anti-inflammatoires/pharmacologie , Côlon/effets des médicaments et des substances chimiques , Côlon/anatomopathologie , Côlon/métabolisme , Souris de lignée C57BL , Humains , Polarité de la cellule/effets des médicaments et des substances chimiques , Médiateurs de l'inflammation/métabolisme , Modèles animaux de maladie humaineRÉSUMÉ
Ulcerative colitis (UC) is characterized by chronic non-recessive inflammation of the intestinal mucosa involving both innate and adaptive immune responses. Currently, new targeted therapies are urgently needed for UC, and neutrophil extracellular traps (NETs) are new therapeutic options. NETs are DNA-based networks released from neutrophils into the extracellular space after stimulation, in which a variety of granule proteins, proteolytic enzymes, antibacterial peptides, histones, and other network structures are embedded. With the deepening of the studies on NETs, their regulatory role in the development of autoimmune and autoinflammatory diseases has received extensive attention in recent years. Increasing evidence indicates that excess NETs exacerbate the inflammatory response in UC, disrupting the structure and function of the intestinal mucosal barrier and increasing the risk of thrombosis. Although NETs are usually assigned a deleterious role in promoting the pathological process of UC, they also appear to have a protective role in some models. Despite such progress, comprehensive reviews describing the therapeutic promise of NETs in UC remain limited. In this review, we discuss the latest evidence for the formation and degradation of NETs, focusing on their double-edged role in UC. Finally, the potential implications of NETs as therapeutic targets for UC will be discussed. This review aims to provide novel insights into the pathogenesis and therapeutic options for UC.
Sujet(s)
Rectocolite hémorragique , Pièges extracellulaires , Granulocytes neutrophiles , Pièges extracellulaires/immunologie , Pièges extracellulaires/métabolisme , Humains , Rectocolite hémorragique/immunologie , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/thérapie , Animaux , Granulocytes neutrophiles/immunologie , Granulocytes neutrophiles/métabolisme , Muqueuse intestinale/immunologie , Muqueuse intestinale/anatomopathologie , Muqueuse intestinale/métabolismeRÉSUMÉ
Rationale: The treatment of ulcerative colitis (UC) presents an ongoing clinical challenge. Emerging research has implicated that the cGAS-STING pathway promotes the progression of UC, but conflicting results have hindered the development of STING as a therapeutic target. In the current study, we aim to comprehensively elucidate the origins, downstream signaling and pathogenic roles of myeloid STING in colitis and colitis-associated carcinoma (CAC). Methods: Tmem173 fl/fl Lyz2-Cre ert2 mice were constructed for inducible myeloid-specific deletion of STING. RNA-sequencing, flow cytometry, and multiplex immunohistochemistry were employed to investigate immune responses in DSS-induced colitis or AOM/DSS-induced carcinogenesis. Colonic organoids, primary bone marrow derived macrophages and dendritic cells, and splenic T cells were used for in vitro studies. Results: We observed that myeloid STING knockout in adult mice inhibited macrophage maturation, reduced DC cell activation, and suppressed pro-inflammatory Th1 and Th17 cells, thereby protecting against both acute and chronic colitis and CAC. However, myeloid STING deletion in neonatal or tumor-present mice exhibited impaired immune tolerance and anti-tumor immunity. Furthermore, we found that TFAM-associated mtDNA released from damaged colonic organoids, rather than bacterial products, activates STING in dendritic cells in an extracellular vesicle-independent yet endocytosis-dependent manner. Both IRF3 and NF-κB are required for STING-mediated expression of IL-12 family cytokines, promoting Th1 and Th17 differentiation and contributing to excessive inflammation in colitis. Conclusions: Detection of the TFAM-mtDNA complex from damaged intestinal epithelium by myeloid STING exacerbates colitis through IL-12 cytokines, providing new evidence to support the development of STING as a therapeutic target for UC and CAC.
Sujet(s)
ADN mitochondrial , Cellules dendritiques , Interleukine-12 , Muqueuse intestinale , Protéines membranaires , Souris knockout , Animaux , Cellules dendritiques/immunologie , Cellules dendritiques/métabolisme , Protéines membranaires/métabolisme , Protéines membranaires/génétique , Souris , Interleukine-12/métabolisme , Interleukine-12/génétique , ADN mitochondrial/génétique , ADN mitochondrial/métabolisme , Muqueuse intestinale/métabolisme , Muqueuse intestinale/anatomopathologie , Muqueuse intestinale/immunologie , Souris de lignée C57BL , Colite/anatomopathologie , Colite/induit chimiquement , Colite/métabolisme , Colite/génétique , Transduction du signal , Rectocolite hémorragique/génétique , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/immunologie , Néoplasmes associés aux colites/anatomopathologie , Néoplasmes associés aux colites/génétique , Néoplasmes associés aux colites/métabolisme , Néoplasmes associés aux colites/immunologie , Macrophages/métabolisme , Macrophages/immunologie , Modèles animaux de maladie humaine , Sulfate dextranRÉSUMÉ
Objective: To investigate the value of histological evaluation in predicting endoscopic relapse among patients with ulcerative colitis (UC) who were in endoscopic remission, and to compare the usefulness of various histological scoring systems. Methods: Histological sections from 61 patients with UC who were in endoscopic remission were retrospectively analyzed, at Peking University Third Hospital, Beijing, China from January 2015 to June 2021. They were subdivided into endoscopic persistent remission group (remission group, n=31, Mayo endoscopic score 0) and endoscopic relapse group (relapse group, n=30, Mayo endoscopic score≥1) according to the results of the first endoscopic reexamination after the biopsy. Histological evaluation was performed using the Geboes score (GS) and its simplified version (SGS), the Nancy index (NI) and the Robarts histopathological index (RHI). The median and maximum histological scores for each case in all biopsies were recorded. Univariate comparisons were performed using chi-squares and multivariate analysis using binary logistic regression. The values of four histological evaluation systems for predicting endoscopic relapse among UC patients in endoscopic remission were analyzed using receiver operating characteristic (ROC) curves. Results: Significant differences were observed between the remission and relapse groups. The differences were more pronounced in the maximum histological scores; the mean and highest results of area under the ROC curve scores (AUC) for GS, SGS, NI, and RHI were 0.657, 0.668, 0.682, 0.691, and 0.866, 0.863, 0.864, 0.869, respectively. The differences were statistically significant (P<0.05). The corresponding best cut-offs were GS≥2B.1, SGS≥2B.1, NI≥2, and RHI≥2.5, respectively, which meant mild active inflammation histologically, while there was no statistical difference of AUC among the four histological scoring indices (P>0.05). Univariate and multivariate analyses revealed statistically significant differences in the number of neutrophils in the epithelium and lamina propria (P<0.05). Conclusions: Biopsies from UC patients in endoscopic remission may still have histological active inflammation which appears to correlate with endoscopic relapse. Four commonly used histological scoring systems can be used to assess the risk of endoscopic relapse among UC patients in endoscopic remission. The patients who more likely have endoscopic relapse seem to have a histological score greater than the cut-off value (i.e., mild histological activity). The maximum histological scores can accurately predict the risk of endoscopic relapse, while the presence of epithelial and laminar propria neutrophil infiltrates can independently predict the endoscopic relapse in these patients. Considering the utility and convenience in routine practice, NI is recommended for evaluating histological inflammatory activity.
Sujet(s)
Rectocolite hémorragique , Récidive , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/chirurgie , Humains , Études rétrospectives , Biopsie , Coloscopie , Induction de rémission , Courbe ROC , Valeur prédictive des tests , Indice de gravité de la maladie , Femelle , Mâle , AdulteRÉSUMÉ
Purpose: This study aimed to delineate the molecular processes underlying the therapeutic effects of berberine on UC by employing network pharmacology tactics, molecular docking, and dynamic simulations supported by empirical validations both in vivo and in vitro. Patients and Methods: We systematically screened potential targets and relevant pathways affected by berberine for UC treatment from comprehensive databases, including GeneCards, DisGeNET, and GEO. Molecular docking and simulation protocols were used to assess the interaction stability between berberine and its principal targets. The predictions were validated using both a DSS-induced UC mouse model and a lipopolysaccharide (LPS)-stimulated NCM460 cellular inflammation model. Results: Network pharmacology analysis revealed the regulatory effect of the TLR4/NF-κB/HIF-1α pathway in the ameliorative action of berberine in UC. Docking and simulation studies predicted the high-affinity interactions of berberine with pivotal targets: TLR4, NF-κB, HIF-1α, and the HIF inhibitor KC7F2. Moreover, in vivo analyses demonstrated that berberine attenuates clinical severity, as reflected by decreased disease activity index (DAI) scores, reduced weight loss, and mitigated intestinal inflammation in DSS-challenged mice. These outcomes include suppression of the proinflammatory cytokines IL-6 and TNF-α and downregulation of TLR4/NF-κB/HIF-1α mRNA and protein levels. Correspondingly, in vitro findings indicate that berberine decreases cellular inflammatory injury and suppresses TLR4/NF-κB/HIF-1α signaling, with notable effectiveness similar to that of the HIF-1α inhibitor KC7F2. Conclusion: Through network pharmacology analysis and experimental substantiation, this study confirmed that berberine enhances UC treatment outcomes by inhibiting the TLR4/NF-κB/HIF-1α axis, thereby mitigating inflammatory reactions and improving colonic pathology.
Sujet(s)
Berbérine , Rectocolite hémorragique , Biologie informatique , Sous-unité alpha du facteur-1 induit par l'hypoxie , Facteur de transcription NF-kappa B , Récepteur de type Toll-4 , Berbérine/pharmacologie , Berbérine/composition chimique , Récepteur de type Toll-4/métabolisme , Récepteur de type Toll-4/antagonistes et inhibiteurs , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Sous-unité alpha du facteur-1 induit par l'hypoxie/antagonistes et inhibiteurs , Facteur de transcription NF-kappa B/métabolisme , Facteur de transcription NF-kappa B/antagonistes et inhibiteurs , Animaux , Souris , Humains , Rectocolite hémorragique/traitement médicamenteux , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/induit chimiquement , Rectocolite hémorragique/anatomopathologie , Simulation de docking moléculaire , Lipopolysaccharides/pharmacologie , Lipopolysaccharides/antagonistes et inhibiteurs , Mâle , Sulfate dextran , Souris de lignée C57BL , Modèles animaux de maladie humaine , Pharmacologie des réseauxRÉSUMÉ
Purpose: To clarify the significance of mitochondria-related differentially expressed genes (MTDEGs) in UC carcinogenesis through a bioinformatics analysis and provide potential therapeutic targets for patients with UC associated colorectal cancer. Methods: Microarray GSE37283 was utilized to investigate differentially expressed genes (DEGs) in UC and UC with neoplasia (UCN). MTDEGs were identified by intersecting DEGs with human mitochondrial genes. Utilizing LASSO and random forest analyses, we identified three crucial genes. Subsequently, using ROC curve to investigate the predictive ability of three key genes. Following, three key genes were confirmed in AOM/DSS mice model by Real-time PCR. Finally, single-sample gene set enrichment analysis (ssGSEA) was employed to explore the correlation between the hub genes and immune cells infiltration in UC carcinogenesis. Results: The three identified hub MTDEGs (HMGCS2, MAVS, RDH13) may exhibit significant diagnostic specificity in the transition from UC to UCN. Real-time PCR assay further confirmed that the expressions of HMGCS2 and RDH13 were significantly downregulated in UCN mice than that in UC mice. ssGSEA analysis revealed the hub genes were highly associated with CD56dim natural killer cells. Conclusion: RDH13, HMGCS2, and MAVS may become diagnostic indicators and potential biomarkers for UCN. Our research has the potential to enhance our understanding of the mechanisms underlying carcinogenesis in UC.
Sujet(s)
Rectocolite hémorragique , Tumeurs colorectales , Rectocolite hémorragique/génétique , Rectocolite hémorragique/anatomopathologie , Tumeurs colorectales/génétique , Tumeurs colorectales/anatomopathologie , Animaux , Souris , Humains , Mitochondries/métabolisme , Mitochondries/génétique , Souris de lignée C57BL , Modèles animaux de maladie humaine , Mâle , Biologie informatiqueRÉSUMÉ
Dihydromyricetin (DHM), which has various biological functions, possesses therapeutic potential for ulcerative colitis (UC). Neutrophil extracellular traps (NETs) and their components play a crucial role in several pathological processes in UC. However, whether DHM alleviates UC by regulating NETs remains unclear. Mice with dextran sulfate sodium (DSS)-induced acute colitis were treated with DHM at different concentrations, and the severity of colitis was evaluated by assessing body weight, colon length, histological scores, cytokine production, and epithelial barrier integrity. To quantify and visualize NETs, the expression of cell free-DNA (cf-DNA) in serum and Cit-H3 in colonic tissue was analyzed via western blotting and immunofluorescence analysis. HL-60 cells and mouse bone marrow-derived neutrophils (BMDNs) were used to evaluate the effects of DHM on NETs in vitro. NETs were treated with DHM at varying concentrations or DNase I and used to repair the intestinal epithelial barrier in a Caco-2/HIEC-6 cell monolayer model. Furthermore, the genes targeted by DHM through neutrophils for alleviating UC were identified by screening online databases, and the results of network pharmacological analysis were verified via western blotting and quantitative real-time polymerase chain reaction. DHM alleviated DSS-induced colitis in mice by reversing weight loss, increased DAI score, colon length shortening, enhanced spleen index, colonic pathological damage, cytokine production, and epithelial barrier loss in a dose-dependent manner. In addition, it inhibited the formation of NETs both in vivo and in vitro. Based on the results of network pharmacological analysis, DHM may target HIF-1α and VEGFA through neutrophils to alleviate UC. Treatment with PMA increased the expression of HIF-1α and VEGFA in D-HL-60 cells and BMDNs, whereas treatment with DHM or DNase I reversed this effect. Treatment with DMOG, an inhibitor of HIF prolyl hydroxylase (HIF-PH), counteracted the suppressive effects of DHM on NETs formation in D-HL-60 cells and BMDNs. Accordingly, it partially counteracted the protective effects of DHM on the intestinal epithelial barrier in Caco-2 and HIEC-6 cells. These results indicated that DHM alleviated DSS-induced UC by regulating NETs formation via the HIF-1α/VEGFA signaling pathway, suggesting that DHM is a promising therapeutic candidate for UC.
Sujet(s)
Rectocolite hémorragique , Pièges extracellulaires , Flavonols , Sous-unité alpha du facteur-1 induit par l'hypoxie , Transduction du signal , Animaux , Humains , Mâle , Souris , Anti-inflammatoires/pharmacologie , Cellules Caco-2 , Rectocolite hémorragique/traitement médicamenteux , Rectocolite hémorragique/induit chimiquement , Rectocolite hémorragique/anatomopathologie , Côlon/effets des médicaments et des substances chimiques , Côlon/anatomopathologie , Sulfate dextran , Modèles animaux de maladie humaine , Pièges extracellulaires/effets des médicaments et des substances chimiques , Pièges extracellulaires/métabolisme , Flavonols/pharmacologie , Cellules HL-60 , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Souris de lignée C57BL , Granulocytes neutrophiles/effets des médicaments et des substances chimiques , Granulocytes neutrophiles/immunologie , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Sinomenine hydrochloride (SH) has anti-inflammatory and immunosuppressive effects, and its effectiveness in inflammatory diseases, such as rheumatoid arthritis, has been demonstrated. However, whether SH has a therapeutic effect on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in mice and its mechanism of action have not been clarified. This study aimed to investigate the therapeutic effects and mechanism of action of SH on UC. METHODS: Twenty-four mice were randomly divided into control, model, SH low-dose (SH-L, 20mg/kg), and SH high-dose (SH-H, 60mg/kg) groups with six mice in each group. Disease activity index (DAI), colonic mucosal damage index, and colonic histopathology scores were calculated. The expression levels of related proteins, genes, and downstream inflammatory factors in the Toll-like receptor 2/NF-κB (TLR2/NF-κB) signaling pathway were quantified. RESULTS: SH inhibited weight loss, decreased DAI and histopathological scores, decreased the expression levels of TLR2, MyD88, P-P65, P65 proteins, and TLR2 genes, and also suppressed the expression of inflammatory factors TNF-α, IL-1 ß, and IL-6 in the peripheral blood of mice. CONCLUSION: The therapeutic effect of SH on DSS-induced UC in mice may be related to the inhibition of the TLR2/NF-κB signaling pathway.
Sujet(s)
Sulfate dextran , Morphinanes , Facteur de transcription NF-kappa B , Transduction du signal , Récepteur de type Toll-2 , Animaux , Morphinanes/pharmacologie , Morphinanes/usage thérapeutique , Transduction du signal/effets des médicaments et des substances chimiques , Facteur de transcription NF-kappa B/métabolisme , Souris , Mâle , Rectocolite hémorragique/traitement médicamenteux , Rectocolite hémorragique/induit chimiquement , Rectocolite hémorragique/anatomopathologie , Modèles animaux de maladie humaine , Répartition aléatoire , Colite/traitement médicamenteux , Colite/induit chimiquement , Colite/anatomopathologieRÉSUMÉ
Abnormalities in mucosal immunity are involved in the onset and progression of ulcerative colitis (UC), resulting in a high incidence of colorectal cancer (CRC). While high-mobility group box-1 (HMGB1) is overexpressed during colorectal carcinogenesis, its role in UC-related carcinogenesis remains unclear. In the present study, we investigated the role of HMGB1 in UC-related carcinogenesis and sporadic CRC. Both the azoxymethane colon carcinogenesis and dextran sulfate sodium colitis carcinogenesis models demonstrated temporal increases in mucosal HMGB1 levels. Activated CD8+ cells initially increased and then decreased, whereas exhausted CD8+ cells increased. Additionally, we observed increased regulatory CD8+ cells, decreased naïve CD8+ cells, and decreased mucosal epithelial differentiation. In the in vitro study, HMGB1 induced energy reprogramming from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. Furthermore, in UC dysplasia, UC-related CRC, and hyperplastic mucosa surrounding human sporadic CRC, we found increased mucosal HMGB1, decreased activated CD8+ cells, and suppressed mucosal epithelial differentiation. However, we observed increased activated CD8+ cells in active UC mucosa. These findings indicate that HMGB1 plays an important role in modulating mucosal immunity and epithelial dedifferentiation in both UC-related carcinogenesis and sporadic CRC.
Sujet(s)
Lymphocytes T CD8+ , Différenciation cellulaire , Rectocolite hémorragique , Protéine HMGB1 , Immunité muqueuse , Muqueuse intestinale , Protéine HMGB1/métabolisme , Humains , Muqueuse intestinale/métabolisme , Muqueuse intestinale/immunologie , Muqueuse intestinale/anatomopathologie , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/immunologie , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/induit chimiquement , Animaux , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Souris , Mâle , Cellules épithéliales/métabolisme , Cellules épithéliales/anatomopathologie , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/métabolisme , Tumeurs colorectales/immunologie , Souris de lignée C57BL , Carcinogenèse/immunologie , Carcinogenèse/anatomopathologie , Carcinogenèse/métabolismeRÉSUMÉ
SMARCA5, a protein in the SWI/SNF family, has been previously implicated in the development of ulcerative colitis (UC) through methylation. However, the specific molecular mechanisms by which SMARCA5 contributes to colonic inflammation and the imbalance between Th17 and Treg cells remain unclear. This study was designed to explore these molecular mechanisms. A UC mouse model was established using dextran sulfate sodium induction, followed by measurements of mouse weight, disease activity index (DAI) score, colon length, pathological changes in the colon, and FITC-dextran concentration. The levels of IL-17a, IFN-γ, IL-6, TNF-α, TGF-ß, and IL-10 were measured, along with the protein expression of ZO-1 and Occludin. Flow cytometry was used to assess the presence of IL-17 + CD4 + (Th17 +) cells and FOXP3 + CD25 + CD4 + (Treg +) cells in the spleen and mesenteric lymph nodes of UC mice. We observed that SMARCA5 and RNF180 were increased, while ALKBH5 was downregulated in UC mouse colon tissue. SMARCA5 or RNF180 knockdown or ALKBH5 overexpression ameliorated the colon inflammation and Th17/Treg cell imbalance in UC mice, shown by increased body weight, colon length, FOXP3 + CD25 + CD4 + T cells, and the levels of ZO-1, Occludin, TGF-ß, IL-10, and FOXP3. It decreased DAI scores, IL-17 + CD4 + T cells, and levels of IL-17a, IFN-γ, IL-6, TNF-α, and ROR-γt. ALKBH5 inhibited SMARCA5 expression via m6A modification, while RNF180 reduced ALKBH5 expression via ubiquitination. Our findings indicate that RNF180 aggravated the colon inflammation and Th17/Treg cell imbalance in UC mice by regulating the ALKBH5/SMARCA5 axis.
Sujet(s)
Rectocolite hémorragique , Lymphocytes T régulateurs , Cellules Th17 , Ubiquitin-protein ligases , Animaux , Cellules Th17/immunologie , Cellules Th17/métabolisme , Rectocolite hémorragique/immunologie , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/induit chimiquement , Rectocolite hémorragique/métabolisme , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Souris , Ubiquitin-protein ligases/métabolisme , Ubiquitin-protein ligases/génétique , Mâle , AlkB Homolog 5, RNA demethylase/métabolisme , Sulfate dextran/toxicité , Modèles animaux de maladie humaine , Protéines chromosomiques nonhistones/métabolisme , Protéines chromosomiques nonhistones/génétique , Souris de lignée C57BL , Inflammation/métabolisme , Inflammation/anatomopathologie , Inflammation/immunologie , Souris de lignée BALB CRÉSUMÉ
Ulcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract. Various programmed cell death pathways in the intestinal mucosa are crucial to the pathogenesis of UC. Disulfidptosis, a recently identified form of programmed cell death, has not been extensively reported in the context of UC. This study evaluated the expression of disulfidptosis-related genes (DRGs) in UC through public databases and assessed disulfide accumulation in the intestinal mucosal tissues of UC patients and dextran sulfate sodium (DSS)-induced colitis mice via targeted metabolomics. We utilized various bioinformatics techniques to identify UC-specific disulfidptosis signature genes, analyze their potential functions, and investigate their association with immune cell infiltration in UC. The mRNA and protein expression levels of these signature genes were confirmed in the intestinal mucosa of DSS-induced colitis mice and UC patients. A total of 24 DRGs showed differential expression in UC. Our findings underscore the role of disulfide stress in UC. Four UC-related disulfidptosis signature genes-SLC7A11, LRPPRC, NDUFS1, and CD2AP-were identified. Their relationships with immune infiltration in UC were analyzed using CIBERSORT, and their expression levels were validated by quantitative real-time PCR and western blotting. This study provides further insights into their potential functions and explores their links to immune infiltration in UC. In summary, disulfidptosis, as a type of programmed cell death, may significantly influence the pathogenesis of UC by modulating the homeostasis of the intestinal mucosal barrier.
Sujet(s)
Rectocolite hémorragique , Muqueuse intestinale , Rectocolite hémorragique/génétique , Rectocolite hémorragique/induit chimiquement , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/anatomopathologie , Animaux , Humains , Souris , Muqueuse intestinale/métabolisme , Muqueuse intestinale/anatomopathologie , Sulfate dextran , Apoptose/génétique , Mâle , Modèles animaux de maladie humaine , Femelle , Analyse de profil d'expression de gènes , Souris de lignée C57BL , Biologie informatique/méthodesRÉSUMÉ
Objective To explore the relationship between the expression levels of microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS1) in the colonic mucosal tissue of patients with ulcerative colitis (UC) and the severity of the disease.Methods A total of 130 UC patients admitted to the Second Affiliated Hospital of Hebei North University from September 2021 to June 2023 were selected.According to the modified Mayo score system,the patients were assigned into an active stage group (n=85) and a remission stage group (n=45).According to the modified Truelove and Witts classification criteria,the UC patients at the active stage were assigned into a mild group (n=35),a moderate group (n=30),and a severe group (n=20).A total of 90 healthy individuals who underwent colonoscopy for physical examination or those who had normal colonoscopy results after single polypectomy and excluded other diseases were selected as the control group.The colonic mucosal tissues of UC patients with obvious lesions and the colonic mucosal tissue 20 cm away from the anus of the control group were collected.The levels of miR-155 and SOCS1 mRNA in tissues were determined by fluorescence quantitative PCR,and the expression of SOCS1 protein in tissues was determined by immunohistochemistry.The correlations of the levels of miR-155 and SOCS1 mRNA in the colonic mucosal tissue with the modified Mayo score of UC patients were analyzed.The values of the levels of miR-155 and SOCS1 mRNA in predicting the occurrence of severe illness in the UC patients at the active stage were evaluated.Results Compared with the control group and the remission stage group,the active stage group showed up-regulated expression level of miR-155,down-regulated level of SOCS1 mRNA,and decreased positive rate of SOCS1 protein in the colonic mucosal tissue (all P<0.001).The expression level of miR-155 and modified Mayo score in colonic mucosal tissues of UC patients at the active stage increased,while the mRNA level of SOCS1 was down-regulated as the disease evolved from being mild to severe (all P<0.001).The modified Mayo score was positively correlated with the miR-155 level and negative correlated with the mRNA level of SOCS1 in colonic mucosal tissues of UC patients (all P<0.001).The high miR-155 level (OR=2.762,95%CI=1.284-5.944,P=0.009),low mRNA level of SOCS1 (OR=2.617,95%CI=1.302-5.258,P=0.007),and modified Mayo score≥12 points (OR=3.232,95%CI=1.450-7.204,P=0.004) were all risk factors for severe disease in the UC patients at the active stage.The area under curve of miR-155 combined with SOCS1 mRNA in predicting severe illness in the UC patients at the active stage was 0.920.Conclusions The expression levels of miR-155 and SOCS1 mRNA were correlated with the disease severity in the UC patients at the active stage.The combination of the two indicators demonstrates good performance in predicting the occurrence of severe illness in UC patients at the active stage.
Sujet(s)
Rectocolite hémorragique , Muqueuse intestinale , microARN , Protéine-1 suppressive de la signalisation des cytokines , Adulte , Femelle , Humains , Mâle , Adulte d'âge moyen , Rectocolite hémorragique/génétique , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/physiopathologie , Côlon/métabolisme , Côlon/anatomopathologie , Muqueuse intestinale/métabolisme , Muqueuse intestinale/anatomopathologie , microARN/génétique , microARN/métabolisme , Indice de gravité de la maladie , Protéine-1 suppressive de la signalisation des cytokines/génétique , Protéine-1 suppressive de la signalisation des cytokines/métabolismeRÉSUMÉ
Ulcerative colitis (UC) is a persistent inflammatory condition affecting the bowels. Gegen Qinlian decoction (GQD) has been widely used in the therapy of gastrointestinal diseases. We investigated the protective impacts and mechanism of GQD against UC. To establish the UC model, dextran sulfate sodium (DSS) was utilized. The disease activity index (DAI), colon length and colonic pathology were assessed to examine the impacts of GQD on UC. The level of pan-lysine lactylation (Pan kla) and specific sites were detected using western blot. Then, the inflammatory factors and the oxidative stress parameters were measured via the corresponding kits, respectively. Our findings demonstrated that GQD suppressed the lactate generation and LDH activity. The western blot revealed that GQD inhibited the expression of Pan kla and specific sites of H3K18la, H3K23la, H4K8la, and H4K12la. Furthermore, the suppressive effects on inflammation and oxidative stress caused by GQD were counteracted upon the exogenous lactate. GQD suppressed the phenotypic differentiation of M1 macrophages by reducing the expression of M1 markers, which was also reversed by exogenous lactate. In conclusion, GQD effectively suppressed UC progression through histone lactylation. Our results broadened the theoretical basis for the clinical use of GQD.
Sujet(s)
Rectocolite hémorragique , Médicaments issus de plantes chinoises , Histone , Macrophages , Rectocolite hémorragique/métabolisme , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/traitement médicamenteux , Animaux , Histone/métabolisme , Souris , Macrophages/métabolisme , Macrophages/effets des médicaments et des substances chimiques , Médicaments issus de plantes chinoises/pharmacologie , Évolution de la maladie , Stress oxydatif/effets des médicaments et des substances chimiques , Mâle , Souris de lignée C57BL , Activation des macrophages/effets des médicaments et des substances chimiquesRÉSUMÉ
The polysaccharide glucan was extracted from Gastrodia elata Blume, and its structural characterizations and beneficial effects against acute dextran sulfate sodium (DSS)-induced ulcerative colitis were investigated. The results showed that a polysaccharide GP with a molecular weight of 811.0 kDa was isolated from G. elata Blume. It had a backbone of α-D-1,4-linked glucan with branches of α-d-glucose linked to the C-6 position. GP exhibited protective effects against DSS-induced ulcerative colitis, and reflected in ameliorating weight loss and pathological damages in mice, increasing colon length, inhibiting the expression of inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), decreasing the levels of inflammatory related proteins NLRP3 and ASC, and elevating the anti-inflammatory cytokine interleukin-10 (IL-10) level in mouse colon tissues. GP supplementation also reinforced the intestinal barrier by promoting the expression of ZO-1, Occludin, and MUC2 of colon tissues, and positively regulated intestinal microbiota. Thus, GP treatment possessed a significant improvement in ulcerative colitis in mice, and it was expected to be developed as a functional food.