Mechanisms Of Ulcerative Colitis Research Articles

Hesperetin Alleviated Experimental Colitis via Regulating Ferroptosis and Gut Microbiota.

Hesperetin (HT) is a type of citrus flavonoid with various pharmacological activities, including anti-tumor, anti-inflammation, antioxidant, and neuroprotective properties. However, the role and mechanism of HT in ulcerative colitis (UC) have been rarely studied. Our study aimed to uncover the beneficial effects of HT and its detailed mechanism in UC. Experimental colitis was induced by 2.5% dextran sodium sulfate (DSS) for seven days. HT ameliorated DSS-induced colitis in mice, showing marked improvement in weight loss, colon length, colonic pathological severity, and the levels of TNFα and IL6 in serum. A combination of informatics, network pharmacology, and molecular docking identified eight key targets and multi-pathways influenced by HT in UC. As a highlight, the experimental validation demonstrated that PTGS2, a marker of ferroptosis, along with other indicators of ferroptosis (such as ACSL4, Gpx4, and lipid peroxidation), were regulated by HT in vivo and in vitro. Additionally, the supplement of HT increased the diversity of gut microbiota, decreased the relative abundance of Proteobacteria and Gammaproteobacteria, and restored beneficial bacteria (Lachnospiraceae_NK4A136_group and Prevotellaceae_UCG-001). In conclusion, HT is an effective nutritional supplement against experimental colitis by suppressing ferroptosis and modulating gut microbiota.

Niga-ichigoside F1 alleviates DSS-induced ulcerative colitis by inhibiting the NF-κB pathway

Niga-ichigoside F1, an ursolic acid-type pentacyclic triterpenoid, possesses various pharmacological properties, including anti-tumor, anti-inflammatory, and antinociceptive potentials. However, its function and underlying mechanism in ulcerative colitis (UC) remain unknown. Hence, this study aimed to explore the effect of Niga-ichigoside F1 on dextran sulfate sodium (DSS)-induced colitis. The predictive results of network pharmacology identified 311 common targets of Niga-ichigoside F1 and ulcerative colitis. The 4 highest-scoring genes were screened by the BottleNeck method and they were, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor (TNF), protein kinase B gamma (AKT3), and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta (PIK3CB). KEGG pathway analysis indicated that Niga-ichigoside F1 probably exerted a protective effect on UC through the nuclear factor-kappa B (NF-κB) pathways. Molecular docking results showed that Niga-ichigoside F1 had a high affinity for nuclear factor-kappa B-inhibitor of nuclear factor-kappa B (NF-κB-IκB) complex, with the lowest binding energy. Furthermore, our results in vivo showed that Niga-ichigoside F1 alleviated weight loss, colon shortening, disease activity index (DAI), and histological scoring in DSS-induced colitis mice. Moreover, Niga-ichigoside F1 decreased the levels of inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) and the expression of oxidative stress markers nitric oxide (NO), myeloperoxidase (MPO), and malonaldehyde (MDA) to mitigate inflammation and intestinal damage. Western blotting results evidenced that Niga-ichigoside F1 intervention significantly regulated the NF-κB pathway. In conclusion, this study highlighted the potential of Niga-ichigoside F1 in ameliorating colitis, indicating its potential application as a functional food.

L.acidophilus HSCC LA042 and HKL suspension ameliorate DSS-induced ulcerative colitis in mice by improving the intestinal barrier inhibiting the NLRP3 inflammasome and pathogenic bacteria

Ulcerative Colitis(UC) is a chronic intestinal inflammation affecting the intestines, yet its underlying causes remain unclear. In recent decades, the global prevalence of UC has been on the rise, leading to an increasing demand for therapeutic drugs with minimal side effects. Huan Kui Le (HKL), a traditional Chinese medicine compound, has demonstrated promising efficacy when combined with Lactobacillus acidophilus (Lac.) for UC intervention. However, the precise therapeutic mechanism of this combination remains unknown. The study focused on understanding the mechanisms of UC by examining the effects of Lac. and HKL (LH) treatment. The outcomes discovered that the disruption of gut microbiota, triggered by the activation of the NLRP3 inflammasome, plays a crucial role in UC development. This disruption exacerbates UC symptoms by causing disturbances in inflammatory cytokines and mucosal permeability. We investigated the dynamic changes following the application of this treatment using 16S rRNA sequencing, HE, WB, IHC, and ELISA. Compared with the UC group, LH treatment reduced colon pathological injury, improved colon length, and decreased IL-1 β serum levels. Furthermore, it restored the expression of TJs and preserved mucosal barrier integrity. LH treatment also mitigated colon injury by attenuating the expression of pyroptosis-related genes and proteins, such as NLRP3 and Caspase-1. Additionally, LH treatment altered the gut microbiota's microecology, characterized by a reduction in pathogenic bacteria abundance like Escherichia-shigella and an increase in beneficial bacteria abundance like Akkermansia and Erysipelatoclostridium. Overall, our findings indicate that LH therapy may be associated with intestinal barrier repair, inflammasome inhibition, and gut microbiota regulation, suggesting its potential as a UC treatment.

Dual targeting total saponins of Pulsatilla of natural polymer crosslinked gel beads with multiple therapeutic effects for ulcerative colitis

Oral colon targeted drug delivery system (OCTDDS) is desirable for the treatment of ulcerative colitis (UC). In this study, we designed a partially oxidized sodium alginate-chitosan crosslinked microsphere for UC treatment. Dissipative particle dynamics (DPD) was used to study the formation and enzyme response of gel beads from a molecular perspective. The formed gel beads have a narrow particle size distribution, a compact structure, low cytotoxicity and great colon targeting in vitro and in vivo. Animal experiments demonstrated that gel beads promoted colonic epithelial barrier integrity, decreased the level of pro-inflammatory factors, accelerated the recovery of intestinal microbial homeostasis in UC rats and restored the intestinal metabolic disorders. In conclusion, our gel bead is a promising approach for the treatment of UC and significant for the researches on the pathogenesis and treatment mechanism of UC.

Ruscogenin Attenuates Ulcerative Colitis in Mice by Inhibiting Caspase-1-Dependent Pyroptosis via the TLR4/NF-κB Signaling Pathway.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders affecting the digestive tract, including ulcerative colitis and Crohn's disease. Ruscogenin, a prominent steroidal sapogenin present in radix ophiopogon japonicus, has shown a protective effect on attenuating the inflammatory response associated with inflammatory diseases, but the efficacy of ruscogenin in IBD remains unclear. The aim of this study is to explore the effect of ruscogenin on intestinal barrier dysfunction and inflammatory responses as well as the underlying mechanism in ulcerative colitis. A dextran sulfate sodium salt (DSS)-induced C57BL/6 mouse colitis model was employed for the in vivo studies, while in vitro experiments were performed in THP-1 cells and human intestinal epithelial cells involved in inducing inflammatory responses and pyroptosis using LPS/nigericin. The results indicated that ruscogenin treatment attenuated the symptoms of ulcerative colitis, reduced the release of inflammatory cytokines and the expression of pyroptosis-associated proteins, and restored the integrity of the intestinal epithelial barrier in colon tissue in mice. Moreover, ruscogenin inhibited LPS/nigericin-induced pyroptosis in THP-1 cells. Mechanically, ruscogenin inhibited NLRP3 inflammasome activation and canonical pyroptosis, at least in part, through the suppression of the TLR4/NF-κB signaling pathway. These findings might provide new insights and a solid foundation for further exploration into the therapeutic potential of ruscogenin in the treatment of IBD.

Exploring Pyroptosis-related Signature Genes and Potential Drugs in Ulcerative Colitis by Transcriptome Data and Animal ExperimentalValidation.

Ulcerative colitis (UC) is an idiopathic, relapsing inflammatory disorder of the colonic mucosa. Pyroptosis contributes significantly to UC. However, the molecular mechanisms of UC remain unexplained. Herein, using transcriptome data and animal experimentalvalidation, we sought to explore pyroptosis-related molecular mechanisms, signature genes, and potential drugs in UC.Gene profiles (GSE48959, GSE59071, GSE53306, and GSE94648) were selected from the Gene Expression Omnibus (GEO) database, which contained samples derived from patients with active and inactive UC, as well as health controls. Gene Set Enrichment Analysis (GSEA), Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on microarrays to unravel the association between UC and pyroptosis. Then, differential expressed genes (DEGs) and pyroptosis-related DEGs were obtained by differential expression analyses and the public database. Subsequently, pyroptosis-related DEGs and their association with the immune infiltration landscape were analyzed using the CIBERSORT method. Besides, potential signature genes were selected by machine learning (ML) algorithms, and then validated by testing datasets which included samples of colonic mucosal tissue and peripheral blood. More importantly, the potential drug was screened based on this. And these signature genes and the drug effect were finally observed in the animal experiment.GSEA and KEGG enrichment analyses on key module genes derived from WGCNA revealed a close association between UC and pyroptosis. Then, a total of 20 pyroptosis-related DEGs of UC and 27 pyroptosis-related DEGs of active UC were screened. Next, 6 candidate genes (ZBP1, AIM2, IL1β, CASP1, TLR4, CASP11) in UC and 2 candidate genes (TLR4, CASP11) in active UC were respectively identified using the binary logistic regression(BLR), least absolute shrinkage and selection operator (LASSO), random forest (RF) analysis and artificial neural network (ANN), and these genes also showed high diagnostic specificity for UC in testing sets. Specially, TLR4 was elevated in UC and further elevated in active UC. The results of the drug screen revealed that six compounds (quercetin, cyclosporine, resveratrol, cisplatin, paclitaxel, rosiglitazone) could target TLR4, among which the effect of quercetin on intestinal pathology, pyroptosis and the expression of TLR4 in UC and active UC was further determined by the murine model.These findings demonstrated that pyroptosis may promote UC, and especially contributes to the activation of UC. Pyroptosis-related DEGs offer new ideas for the diagnosis of UC. Besides, quercetin was verified as an effective treatment for pyroptosis and intestinal inflammation. This study might enhance our comprehension on the pathogenic mechanism and diagnosis of UC and offer a treatment option for UC.

Rauwolfia polysaccharide can inhibit the progress of ulcerative colitis through NOS2-mediated JAK2/STAT3 pathway.

Ulcerative colitis (UC) is an inflammatory disease of the digestive tract. Rauwolfia polysaccharide (Rau) has therapeutic effects on colitis in mice, but its mechanism of action needs to be further clarified. In the study, we explored the effect of Rau on the UC cell model induced by Lipopolysaccharide (LPS). We constructed a UC cell model by stimulating HT-29 cells with LPS. Dextran sodium sulfate (DSS) was used to induce mice to construct an animal model of UC. Subsequently, we performed Rau administration on the UC cell model. Then, the therapeutic effect of Rau on UC cell model and was validated through methods such as Cell Counting Kit-8 (CCK8), Muse, Quantitative real‑time polymerase chain reaction (RT-qPCR), Western blotting, and Enzyme-linked immunosorbent assay (ELISA). The results showed that Rau can promote the proliferation and inhibit the apoptosis of the HT-29 cells-induced by LPS. Moreover, we observed that Rau can inhibit the expression of NOS2/JAK2/STAT3 in LPS-induced HT-29 cells. To further explore the role of NOS2 in UC progression, we used siRNA technology to knock down NOS2 and search for its mechanism in UC. The results illustrated that NOS2 knockdown can promote proliferation and inhibit the apoptosis of LPS-induced HT-29 cells by JAK2/STAT3 pathway. In addition, in vitro and in vivo experiments, we observed that the activation of the JAK2/STAT3 pathway can inhibit the effect of Rau on DSS-induced UC model. In short, Rauwolfia polysaccharide can inhibit the progress of ulcerative colitis through NOS2-mediated JAK2/STAT3 pathway. This study provides a theoretical clue for the treatment of UC by Rau.

Abstract LB360: Establishment of predictive biomarkers for carcinogenesis in ulcerative colitis using RNA editing analyses

Abstract Background: Ulcerative colitis (UC) is a chronic inflammatory disease continuous from the rectum. We previously reported that chronic inflammation may induce the RNA-editing enzyme ADAR1 and promote carcinogenesis (Journal of Crohn's and Colitis, 2023). However, the relationship between RNA editing and carcinogenesis in UC remains unresolved because we could not identify specific RNA editing sites. Therefore, in this study, we performed a new comprehensive RNA analysis using RNA sequencing to clarify the role of RNA editing in the carcinogenesis process in UC and to construct a prediction model of carcinogenic risk. Methods: We performed immunostaining of ADAR1, an RNA-editing enzyme, in 139 cases of ulcerative colitis. In addition, normal colorectal tissue, UC inflammatory phase, normal rectal mucosa of UC carcinoma cases, and UC carcinoma sites were submitted to RNA-Seq testing in 6 cases each (24 cases total). Bioinformatics analysis was performed to compare RNA editing sites in each group. Results: RNA-seq analysis showed a significant increase in global RNA editing sites in the inflammatory phase compared to normal colon tissue (p = 0.02). This phenomenon was due to increased ADAR1 expression associated with type 1 interferon. We hypothesized that global RNA editing was decreased in normal colonic mucosa during the remission phase but that some sites of prolonged RNA editing might promote carcinogenesis. We attempted to identify carcinogenesis-specific RNA editing sites. We identified 72 cancer-specific RNA editing sites, mainly in long noncoding RNAs such as NEAT1 and in the 3'UTR region of mRNAs such as CTSS. Assuming that the accumulation of these RNA editing leads to carcinogenesis, pathway analysis revealed that pathways promoting cancer invasion and stemness are activated. When ROC curves were generated using these editing sites as markers, the AUC was 0.935, suggesting that analysis of RNA editing in the colonic mucosa of UC patients may be able to predict the risk of carcinogenesis. Conclusions: We identified potential editing sites for carcinogenesis in UC, allowing the identification of carcinogenic mechanisms in UC and the establishment of predictive markers for carcinogenic risk. Citation Format: Toshiaki Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Hibiki Umeda, Kazuya Moriwake, Masashi Kayano, Kaori Nitta, Fuminori Teraishi, Yuzo Umeda, Hiroshi Tazawa, Toshiyoshi Fujiwara. Establishment of predictive biomarkers for carcinogenesis in ulcerative colitis using RNA editing analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB360.

Lizhong decoction ameliorates ulcerative colitis by inhibiting ferroptosis of enterocytes via the Nrf2/SLC7A11/GPX4 pathway

Ethnopharmacology relevanceTraditional herbal medicines have been considered as a novel and effective way to treat many diseases. Lizhong decoction (LZD), a classical prescription composed of Zingiber officinale Rosc., Panax ginseng C. A. Mey., Atractylodes macrocephala Koidz., and Glycyrrhiza uralensis Fisch., has been used to treat gastrointestinal disorders in clinical practices for thousands of years. However, the mechanism of LZD in alleviating ulcerative colitis (UC) is still unclear. Aim of the studyThe purpose of this study was to clarify the potential molecular mechanism of LZD in improving UC. Materials and methodsThe amelioration of LZD on dextran sodium sulfate (DSS)-induced UC mice was evaluated by body weight, colon length, pathology of colon tissues, pro-inflammatory cytokines, and intestinal tight junction (TJ) proteins. Moreover, the gene expression profiles of UC patients were extracted to investigate potential pathological mechanisms of UC. The influence of LZD on ferroptosis was analyzed by iron load, malondialdehyde (MDA), and the expression of ferroptosis-associated proteins. Meanwhile, the inhibition of LZD on oxidative stress (OS) was assessed by the superoxide dismutase (SOD) activity, as well as the expression levels of glutathione (GSH) and glutathione disulfide (GSSG). Furthermore, the influence of LZD on ferroptosis was assessed by inhibiting nuclear factor (erythroid-derived-2)-like 2 (Nrf2). ResultsLZD showed significant therapeutic effects in UC mice, including reduction of intestinal injury and inflammation. Moreover, LZD treatment notably upregulated the expression of TJ proteins. Further investigation indicated that LZD significantly inhibited the ferroptosis of enterocytes by decreasing iron load and MDA, and increasing the expression levels of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in colon tissues. Furthermore, the decreased activity of SOD, reduced level of GSH, and increased content of GSSG in UC mice were notably reversed by LZD. Consistent with in vivo results, LZD could markedly inhibit ferroptosis and OS in RSL3-induced Caco-2 cells. Mechanistically, LZD alleviated ferroptosis by suppressing OS through the activation of Nrf2 signaling. ConclusionsCollectively, LZD remarkably improved intestinal pathological injury in UC mice, and its potential mechanism was the suppression of ferroptosis in enterocytes by the Nrf2/SLC7A11/GPX4 pathway.

Effects of folate-chicory acid liposome on macrophage polarization and TLR4/NF-κB signaling pathway in ulcerative colitis mouse

BackgroundChichoric acid (CA) is a major active ingredient found in chicory and Echinacea. As a derivative of caffeic acid, it has various pharmacological effects. PurposeDue to the unclear etiology and disease mechanisms, effective treatment methods for ulcerative colitis (UC) are currently lacking. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and dextran sulfate sodium (DSS)-induced mouse UC models. MethodsFolate-chicory acid liposome was prepared using the double emulsion ultrasonic method with the aim of targeting folate receptors specifically expressed on macrophages. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and DSS -induced mouse UC models. Furthermore, the effects of the liposomes on macrophage polarization and their underlying mechanisms in UC were explored. ResultsThe average particle size of folate-chicory acid liposome was 120.4 ± 0.46 nm, with an encapsulation efficiency of 77.32 ± 3.19 %. The folate-chicory acid liposome could alleviate macrophage apoptosis induced by LPS, decrease the expression of inflammatory factors in macrophages, enhance the expression of anti-inflammatory factors, inhibit macrophage polarization towards the M1 phenotype, and mitigate cellular inflammation in vetro. In vivo test, folate-chicory acid liposome could attenuate clinical symptoms, increased colon length, reduced DAI scores, CMDI scores, and alleviated the severity of colonic histopathological damage in UC mice. Furthermore, it inhibited the polarization of macrophages towards the M1 phenotype in the colon and downregulated the TLR4/NF-κB signaling pathway, thereby ameliorating UC in mice. ConclusionFolate-chicory acid liposome exhibited a uniform particle size distribution and high encapsulation efficiency. It effectively treated UC mice by inhibiting the polarization of macrophages towards the M1 phenotype in the colon and downregulating the TLR4/NF-κB signaling pathway.

Sea bass (Lateolabrax maculatus) exerts anti‐ulcerative colitis effects through gut microbiota modulation

AbstractTraditional Chinese medicinal books have noted that sea bass (Lateolabrax maculatus) may effectively manage inflammation‐linked conditions. The folk use of sea bass during pregnancy as nutritional care is also popular in China. However, scientific verification of health benefits of sea bass remains a lack of report. Our previous studies have proven that sea bass has therapeutic benefits for ulcerative colitis (UC). However, a further investigation on the interacted mechanism among sea bass, UC, and gut microbiota has still not been fully explored and clarified. Hence, gut microbiota as the crucial mechanism of UC was evaluated. Gut ecosystem was analyzed by 16sRNA sequencing. The potential microbial biomarker was found through LEfSe analysis. Flow cytometry was then further applied to verify the identified biomarker. Results revealed that sea bass could effectively recover the abundance of UC‐mediated microbiota. LEfSe analysis found that Christensenellaceae could be identified as the potential biomarker for sea bass‐mediated gut microbiota in UC. Further in vitro study conjointly confirmed that the identified bioactive constituent of sea bass could significantly promote the growth of Christensenella minuta. Sufficient results derived that sea bass could ameliorate UC through gut microbiota modulation. C. minuta was identified as the promising microbial biomarker for the mechanism of sea bass in treating intestinal inflammation. It provided further elucidation on the pharmacological mechanism of sea bass in alleviating UC through gut microbiota modulation. It is a crucial driving force for the progress of scientific research on the dietary therapy of sea bass.

Network pharmacology and molecular docking reveal potential mechanism of esculetin in the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of the colonic mucosa. Esculetin is a type of natural coumarin that has many pharmacological activities such as antioxidant, anticancer, anti-inflammatory, etc. A previous study showed that esculetin improved intestinal inflammation and reduced serum proinflammatory cytokines in UC. The present study aimed to utilize network pharmacology and molecular docking to explore the potential mechanism of esculetin against UC. The potential gene targets of esculetin were predicted through SwissTargetPrediction and Super-PRED web servers. UC-related genes were obtained from DisGeNet, OMIM, and GeneCards databases. The overlap between gene targets of esculetin and UC-related genes were identified as the potential targets of esculetin against UC. The interaction between these overlapping genes was analyzed by the STRING database and the core genes were identified by Cytoscape platform. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the core genes were then performed. And the results of these analyses were further confirmed through molecular docking. A total of 50 overlapping genes were identified as the potential action targets of esculetin against UC. Among them, 10 genes (AKT1, STAT1, CCND1, SRC, PTGS2, EGFR, NFKB1, ESR1, MMP9, SERPINE1) were finally identified as the core genes. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis results showed that the top signaling pathway associated with the core genes of esculetin against UC was the prolactin (PRL) signaling pathway. Molecular docking results showed that esculetin has a strong binding affinity to the core genes, as well as PRL and prolactin receptor. This study suggests that esculetin may have a crucial impact on UC through the PRL signaling pathway and provides insights into the potential mechanism of esculetin in the treatment of UC, which may shed light on the mechanism and treatment of UC.

Single-Cell RNA-Sequencing Analysis of Colonic Lamina Propria Immune Cells Reveals the Key Immune Cell-Related Genes of Ulcerative Colitis.

Ulcerative colitis (UC) is a severe threat to humans worldwide. Single-cell RNA sequencing (scRNA-seq) can be used to screen gene expression patterns of each cell in the intestine, provide new insights into the potential mechanism of UC, and analyze the development of immune cell changes. These findings can provide new ideas for the diagnosis and treatment of intestinal diseases. In this study, bioinformatics analysis combined with experiments applied in dextran sulfate sodium (DSS)-induced colitis mice was used to explore new diagnostic genes for UC and their potential relationship with immune cells. We downloaded microarray datasets (GSE75214, GSE87473, GSE92415) from the Gene Expression Omnibus and used these datasets to screen differentially expressed genes (DEGs) and conduct Weighted Gene Co-expression Network Analysis (WGCNA) after quality control. The hub genes were screened, and ROC curves were drawn to verify the reliability of the results in both training set (GSE75214, GSE87473, GSE92415) and validation cohort (GSE87466). Also, we explored the relation of diagnostic genes and immune cells by CIBERSORT algorithm and single-cell analysis. Finally, the expression of hub genes and their relation with immune cells were verified in DSS-induced colitis mice. Diagnostic genes (ANXA5, MMP7, NR1H4, CYP3A4, ABCG2) were identified. In addition, we found these five genes firmly related to immune infiltration. The DSS-induced colitis mice confirm that the expression of ANXA5 mainly increased in the intestinal macrophages and had a strong negative correlation with M2 macrophages, which indicated its possible influence on the polarization of macrophages in UC patients. We identified ANXA5, MMP7, NR1H4, CYP3A4, and ABCG2 as diagnostic genes of UC that are closely related to immune infiltration and ANXA5 maintains a negative correlation with M2 macrophages which indicated its possible influence on the polarization of macrophage in UC patients.

Inhibition of IEC-6 Cell Proliferation and the Mechanism of Ulcerative Colitis in C57BL/6 Mice by Dandelion Root Polysaccharides.

An exploration was conducted on the potential therapeutic properties of dandelion polysaccharide (DP) in addressing 3% dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in murine models. Subsequent assessments focused on DP's influence on inflammation, oxidative stress, and ferroptosis in IEC-6 cells damaged by H2O2. Results highlighted the efficacy of DP in mitigating weight loss, improving disease activity index scores, normalizing colon length, and alleviating histological abnormalities in the affected mice. DP repaired colonic mitochondrial damage by enhancing iron transport and inhibited iron death in colonic cells. Moreover, DP played a pivotal role in enhancing the antioxidant potential. This was evident from the increased expression levels of Nrf2, HO-1, NQO-1, and GSH, coupled with a decrease in MDA and 4-HNE markers in the UC-afflicted mice. Concurrently, DP manifested inhibitory effects on MPO activation and transcription levels of inflammatory mediators such as IL-1β, IL-6, TNF-α, and iNOS. An upsurge in the expression of occludin and ZO-1 was also observed. Restoration of intestinal tightness resulted in decreased serum LPS and LDH levels. Thereafter, administration of DP by gavage increased fecal flora diversity and relative abundance of probiotics in UC mice. Analysis of metabolites indicated that DP counteracted metabolic disturbances and augmented the levels of short-chain fatty acids in ulcerative colitis-affected mice. In vitro studies underscored the role of DP in triggering Nrf2 activation, which in turn exhibited anti-inflammatory, antioxidant, and anti-ferroptotic properties. Summarily, DP's capacity to activate Nrf2 contributes to the suppression of ferroptotic processes in intestinal epithelial cells of UC-affected mice, enhancing the intestinal barrier's integrity. Beyond that, DP possesses the ability to modulate the gut microbiome, rectify metabolic imbalances, rejuvenate short-chain fatty acid levels, and bolster the intestinal barrier as a therapeutic approach to UC.

Endoplasmic reticulum stress related genome-wide Mendelian randomization identifies therapeutic genes for ulcerative colitis and Crohn's disease.

Background: Endoplasmic reticulum stress (ERS) is an important pathophysiological mechanism in ulcerative colitis (UC) and Crohn's disease (CD). ERS-related genes may be influenced by genetic factors and intestinal inflammation. However, the role of ERS as a trigger or potential etiological factor for UC and CD is unclear, as the expression of ERS-related genes in UC and CD may be the cause or subsequent changes in intestinal inflammation. Here, we used a three-step summary data-based Mendelian randomization (SMR) approach integrating multi-omics data to identify putative causal effects of ERS-related genes in UC and CD. Methods: Genome-wide association study (GWAS) summary data for UC (6,968 cases and 20,464 controls) and CD (5,956 cases and 14,927 controls) were extracted as outcome, and DNA methylation quantitative trait loci (mQTL, 1,980 participants) data and expression QTL data (eQTL, 31,684 participants) from the blood were obtained as exposure. The ERS-related genes were extracted from the GeneCards database, and then the GWAS summary data were integrated with the mQTL and eQTL data associated with ERS genes by SMR. Sensitivity analysis included two-sample MR analysis, power calculations, Bayesian co-localization analysis, and phenotype scanning were performed to evaluate the robustness of the results. Results: A total of 1,193 ERS-related genes were obtained. The three-step SMR analysis showed that cg24011261 CpG site regulating GPX1 expression was associated with a low risk of UC, whereas GPX1 expression regulated by a combination of cg05055782, cg24011261, and cg05551922 CpG sites was associated with a low risk of CD. Sensitivity analysis further supports these findings. Conclusion: This multi-omics integration study identifies a causal relationship between the role of ERS in UC and CD and suggests potential new therapeutic targets for clinical practice.

Acalypha australis L. Extract Attenuates DSS-Induced Ulcerative Colitis in Mice by Regulating Inflammatory Factor Release and Blocking NF-κB Activation.

Ulcerative colitis (UC) is a chronic gastroenteric inflammatory disease that may cause life-threatening complications. Currently available therapeutic drugs are not as effective as expected, necessitating the development of new targets and drugs. The etiology and pathogenetic mechanisms of UC are largely unclear; thus, the treatment effects are limited. The aqueous extract of Acalypha australis L. (AAL) has shown good therapeutic efficacy in treating UC. AAL is used in traditional Chinese medicine owing to its hemostasis, detoxification, and heat clearance effects. Although astragalus has such broad-spectrum biological activities closely related to inflammation, its therapeutic efficacy for UC treatment has not been reported, the underlying mechanism remains unknown. We studied the therapeutic effect of AAL on UC in mice and explored its potential mechanism. Mice were treated with AAL aqueous extract for 7 days (20 mg/kg), after which the colon tissue was assessed for damage (colon mucosal damage index [CMDI]), apoptosis (immunohistochemistry), and release of cytokines (enzyme-linked immunosorbent assay). The concentration of AAL aqueous extract at 20 mg/kg significantly improved the CMDI score and colon injury of UC model. It also reduced the serum levels of IL-2, IL-8, IL-17A, IL-22, IFN-γ, and TNF-α, and decreased apoptosis in the colon. AAL water extract also significantly reduced the expression level of NF-κB pathway-related proteins. In conclusion, AAL can protect against UC mainly by inhibiting the expression level of NF-κB pathway-related proteins and reducing the release of inflammatory factors.

Oxysophocarpine suppresses TRAF6 level to ameliorate oxidative stress and inflammatory factors secretion in mice with dextran sulphate sodium (DSS) induced-ulcerative colitis

PurposeUlcerative colitis is an inflammation-related disease with a high recurrence risk. Oxysophocarpine (OSC) is a traditional Chinese medicine isolated from legumes and exerts vital functions on many human diseases. However, the OSC's role in ulcerative colitis has not been fully elucidated. This research aimed to investigate the OSC's impact on ulcerative colitis and its mechanisms. MethodsA mouse model of ulcerative colitis was induced by dextran sulphate sodium (DSS). The effect of OSC on ulcerative colitis was examined using Disease Activity Index detection, hematoxylin-eosin (HE) staining, and enzyme-linked immunosorbent assay (ELISA). Meanwhile, the mechanism of OSC in ulcerative colitis was assessed by immunohistochemistry assay, Western blot, HE staining, and ELISA. ResultsFor the OSC's function in ulcerative colitis, OSC increased the mice weight, decreased Disease Activity Index scores, and alleviated colitis cell infiltration and epithelial cell destruction in DSS-induced ulcerative colitis. Also, OSC mitigated oxidative stress (decreased PGE2, MPO levels, and increased SOD levels) and inflammation (decreased IL-6, TNF-α and IL-1β levels) in DSS-induced ulcerative colitis. For the OSC's mechanism in ulcerative colitis, OSC inhibited the level of tumor necrosis factor receptor-associated Factor 6 (TRAF6) and the phosphorylation of nuclear factor-κB (NF-κB). TRAF6 overexpression abolished the effect of OSC on DSS-induced colon injury and its associated oxidative stress and inflammatory properties in ulcerative colitis. ConclusionOSC decreased the TRAF6 level to reduce oxidative stress and inflammatory factors secretion in mice with DSS induced-ulcerative colitis.

Levetiracetam attenuates experimental ulcerative colitis through promoting Nrf2/HO-1 antioxidant and inhibiting NF-κB, proinflammatory cytokines and iNOS/NO pathways

Ulcerative colitis (UC) is a serious inflammatory disease of the colon. The pathogenic mechanisms of UC involve the activation of inflammatory and oxidative stress responses in the colon. Levetiracetam is an antiepileptic drug with anti-inflammatory and antioxidant effects. The aim of this study was to investigate the potential protective effect of levetiracetam against UC in a mouse model. UC was induced in mice by intrarectal administration of acetic acid and then mice were treated with levetiracetam (50 or 100mg/kg/day, i.p.) for three days. The colonic tissue samples were dissected for biochemical, RT-PCR and immunofluorescence analysis. Results showed that levetiracetam treatment significantly decreased colonic mucosal injury as evidenced by the macroscopic and histopathological analysis. Levetiracetam induced Nrf2/HO-1 and antioxidants while reduced lipid peroxidation and myeloperoxidase activity in colon tissue. Levetiracetam treatment decreased NF-κB activity and the expression of proinflammatory mediators TNF-α, IL-6, IL-1β, IFN-γ, MCP-1 and ICAM-1. The colonic levels of anti-inflammatory cytokines IL-10 and TGF-β1 were increased by levetiracetam treatment. Furthermore, levetiracetam significantly diminished iNOS expression and NO production in colon tissue. These findings suggest that levetiracetam ameliorates the severity of UC in mice through the regulation of inflammatory and oxidative responses.

Exploring the common diagnostic gene KCNJ15 and shared pathway of ankylosing spondylitis and ulcerative colitis through integrated bioinformatics.

Introduction: The similarity between ankylosing spondylitis (AS) and ulcerative colitis (UC) in incidence rate and pathogenesis has been revealed. But the common pathogenesis that explains the relationship between AS and UC is still lacked, and the related genetic research is limited. We purposed to explore shared biomarkers and pathways of AS and UC through integrated bioinformatics. Methods: Gene expression data of AS and UC were obtained in the GEO database. We applied weighted gene co-expression network analysis (WGCNA) to identify AS-related and UC-related co-expression gene modules. Subsequently, machine learning algorithm was used to further screen hub genes. We validated the expression level and diagnostic efficiency of the shared diagnostic gene of AS and UC in external datasets. Gene set enrichment analysis (GSEA) was applied to analyze pathway-level changes between disease group and normal group. Finally, we analyzed the relationship between hub biomarker and immune microenvironment by using the CIBERSORT deconvolution algorithm. Results: 203 genes were obtained by overlapping AS-related gene module and UC-related gene module. Through SVM-RFE algorithm, 19 hub diagnostic genes were selected for AS in GSE25101 and 6 hub diagnostic genes were selected for UC in GSE94648. KCNJ15 was obtained as a common diagnostic gene of AS and UC. The expression of KCNJ15 was validated in independent datasets, and the results showed that KCNJ15 were similarly upregulated in AS samples and UC samples. Besides, ROC analysis also revealed that KCNJ15 had good diagnostic efficacy. The GSEA analysis revealed that oxidative phosphorylation pathway was the shared pathway of AS and UC. In addition, CIBERSORT results revealed the correlation between KCNJ15 gene and immune microenvironment in AS and UC. Conclusion: We have explored a common diagnostic gene KCNJ15 and a shared oxidative phosphorylation pathway of AS and UC through integrated bioinformatics, which may provide a potential diagnostic biomarker and novel insight for studying the mechanism of AS-related UC.

Progress on Regulation of NLRP3 Inflammasome by Chinese Medicine in Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic, non-specific intestinal disease that not only affects the quality of life of patients and their families but also increases the risk of colorectal cancer. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is an important component of inflammatory response system, and its activation induces an inflammatory cascade response that is involved in the development and progression of UC by releasing inflammatory cytokines, damaging intestinal epithelial cells, and disrupting the intestinal mucosal barrier. Chinese medicine (CM) plays a vital role in the prevention and treatment of UC and is able to regulate NLRP3 inflammasome. Many experimental studies on the regulation of NLRP3 inflammasome mediated by CM have been carried out, demonstrating that CM formulae with main effects of clearing heat, detoxifying toxicity, drying dampness, and activating blood circulation. Flavonoids and phenylpropanoids can effectively regulate NLRP3 inflammasome. Other active components of CM can interfere with the process of NLRP3 inflammasome assembly and activation, leading to a reduction in inflammation and UC symptoms. However, the reports are relatively scattered and lack systematic reviews. This paper reviews the latest findings regarding the NLRP3 inflammasome activation-related pathways associated with UC and the potential of CM in treating UC through modulation of NLRP3 inflammasome. The purpose of this review is to explore the possible pathological mechanisms of UC and suggest new directions for development of therapeutic tools.