Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising global prevalence.Histological healing (HH) is a key treatment target associated with better long-term outcomes. Although endoscopic ultrasound (EUS) is known to be related to both clinical and endoscopic activity in UC, its role in defining HH remains unclear. Therefore, this study was aimed at investigating the association between EUS and histological activity (HA), as well as the predictive potential of EUS for HH.

In this cross-sectional analysis, 68 UC adults underwent EUS and colonoscopy with biopsies. We used the Mayo Endoscopic Score (MES) for endoscopic activity, the Nancy Index (NI) for biopsy grading, and the Endoscopic Ultrasound-Ulcerative Colitis (EUS-UC) score for EUS analysis, defining endoscopic remission as MES ≤ 1 and HH as NI ≤ 1.A receiver operating characteristic (ROC) curve was employed to evaluate the ability of the indices to predict HH.

Totally 23 patients (33.80%) achieved HH, while 45 (66.20%) showed HA. The EUS-UC scores were significantly lower in the HH group (p < 0.001) and correlated strongly with NI (ρ = 0.73). EUS-UC score was an independent risk factor for HH (adjusted OR = 1.918, 95% CI: 1.195-3.080, p = 0.007). The EUS-UC score demonstrated a strong predictive value for HH, with an AUC of 0.840, a sensitivity of 75.56%, and a specificity of 78.26%.

The EUS-UC score has a significant correlation with histological outcomes and shows strong potential as a reliable, invasive predictor of HH in UC, with implications for improved disease monitoring.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which remission is dependent on corticosteroid (CS) treatment. The diversity of disease pathophysiology necessitates optimal case-specific treatment selection. This study aimed to identify prognostic factors for refractory UC using a machine learning model based on nationwide registry data.

The study included 4003 patients with UC with a Mayo score of ≥3 at the time of registration who had been using CS since their entry out of 79,096 newly registered UC cases in a nationwide registry from April 2003 to March 2012 (before the widespread use of biologic agents in Japan) with 3-year data. A pointwise linear (PWL) model was used for machine learning.

A PWL model, which was developed to predict long-term remission (lasting >3 years), had an area-under-the-curve (AUC), precision rate, recall rate, and F-value of 0.774, 0.55, 0.70, 0.62, respectively, in the test dataset from the time of registration to 2 years later. Furthermore, the presence of pseudopolyps at the time of registration was significantly and negatively correlated with remission, highlighting its importance as a prognostic factor.

In this study, we constructed a highly accurate prognosis prediction model for UC, in which inflammation persists for an extensive period, by training a machine learning model for long-term disease progression. The results showed that machine learning can be used to determine the factors affecting remission during the treatment of refractory UC.

Scutellaria baicalensis Georgi (HQ) and Rubia cordifolia L. (QC) are clinically effective against ulcerative colitis (UC), but their synergistic mechanisms remain unclear. This study evaluated the therapeutic effects of HQ, QC, and their combination (HQ-QC) in dextran sulfate sodium (DSS)-induced colitis and explored underlying mechanisms. Mice were divided into normal, model, HQ, QC, HQ-QC, and 5-ASA groups. Colon tissue metabolomics was performed using UPLC-Q-TOF-MS, while network pharmacology and molecular docking identified potential anti-UC targets. The HQ-QC combination significantly alleviated weight loss, colon shortening, and histopathological damage, and improved intestinal barrier function and inflammation compared to single herbs. Metabolomics revealed xanthine, cytosine, and N-octanoylsphingosine-1-phosphate as key metabolites enriched in vascular smooth muscle contraction and fatty acid metabolism pathways. Network pharmacology identified 62 potential targets, with wogonin and xyloidone as major active compounds. KEGG analysis highlighted platelet activation as a key pathway, and molecular docking confirmed strong binding of wogonin and xyloidone to platelet activation-related targets including PIK3CG, NOS3, PTGS1, and MAPK14. These findings suggest HQ-QC exerts synergistic effects in treating DSS-induced UC by regulating vascular smooth muscle contraction and platelet activation, providing mechanistic insight into its clinical potential.

Inflammatory bowel disease (IBD) causes damage to patients, and therapy remains a crucial challenge owing to the presence of excessive reactive oxygen species (ROS) and hydrogen sulfide (H2S) in colonic inflammatory circulation. Herein, we report a shikonin (SK) and zinc (Zn) driven coordination nanozyme (SK-Zn, S-Z), which effectively scavenged ROS and H2S. Furthermore, a pH responsive targeted polymer nanoplatform (S-Z@ChF), consisting of S-Z, chitosan, hyaluronic acid and poly ferulic acid, was developed for the oral treatment of colitis. In vivo experiments revealed that the nanoplatform could target colonic inflammatory lesions, relieve inflammatory index and restore the colonic mechanical barrier. The transcriptomics and pharmacodynamic mechanism analysis revealed that S-Z@ChF scavenged ROS, inhibited nuclear factor kappa-B (NF-κB) and pyruvate kinase isozyme type M2 (PKM2) and signal transducer and activator of transcription 3 (STAT3) pathways, balancing the level of macrophage polarization and pro-inflammatory enzyme. Additionally, S-Z@ChF reliably regulated the gut microbiota during H2S scavenging. In conclusion, S-Z@ChF, which provides multiple anti-inflammatory pathways and microenvironment reprogramming support for blocking inflammatory circulation, was found to be biologically safe, with significant potential for clinical application in IBD.

Tumor necrosis factor-alpha (TNF-α) is an important target for the treatment of inflammatory diseases. Targeting TNF-α inhibition, such as antibody drug infliximab and adalimumab, has emerged as an effective therapeutic strategy for managing the most difficult-to-treat chronic ulcerative colitis (UC). So far, there are no small molecule TNF-α inhibitors available on the market for the treatment of UC. Previously, we reported an indanone analogue (R)-STU104 showed considerable inhibitory activity on TNF-α production in both acute and chronic mouse models of UC with a favorable safety profile. However, further development potential of this compound was greatly limited due to its poor metabolic stability in human liver microsomes and suboptimal pharmacokinetic profiles in mice. Herein, we discovered a deuterated TNF-α small molecule modulator (R)-104-6D-01, which demonstrated promising clinical potential for the treatment of UC. This new compound exhibited enhanced oral bioavailability and exposure in pharmacokinetic studies, as well as superior anti-UC efficacy in a DSS-induced mouse UC model, compared with (R)-STU104 at a dosage of 30 mg/kg/d. Collectively, (R)-104-6D-01 proves to be a promising candidate of potential use in treating UC as an oral TNF-α small molecule modulator.

Eleven undescribed withanolides, phyminimolides I-XI (1-11), along with eight known derivatives (12-19), were isolated from the whole plant of Physalis minima Linn. Their structures were elucidated by extensive spectroscopic methods, including 1D-NMR, 2D-NMR, HRESIMS, IR, experimental electronic circular dichroism, quantum chemical calculation, and X-ray crystallography. The anti-inflammatory potential of these compounds was assessed in vitro via their capacity to inhibit nuclear factor kappa-B signaling in lipopolysaccharide-stimulated 293T/NF-κB-luciferase reporter cells, revealing IC50 values of 9.95, 3.15, 1.16, 9.73, and 11.74 μM for compounds 4-6, 13, and 15, respectively. Notably, compounds 4 and 13 also demonstrated inhibitory effects on interleukin-6 pathway activation, with IC50 values of 1.61 and 7.56 μM, further evidencing their anti-inflammatory mechanism. In vivo assessment using dextran sulfate sodium-induced mice model of ulcerative colitis confirmed the translational efficacy of these findings. Compound 15, administered at a dose of 25 mg/kg, significantly ameliorated disease symptoms, as evidenced by a decreased Disease Activity Index score (P < 0.05).

Exochorda racemosa is a member of the genus Exochorda in the Rosaceae family. Its tender leaves and buds are favored as a unique wild vegetable by people in central China.

This study systematically evaluated the pharmacological safety and anti-inflammatory efficacy of E. racemosa extracts, with concurrent identification and characterization of their primary bioactive components.

The chemical composition of E. racemosa extract (ERE) was analyzed using HPLC and LC-MS techniques. The safety and in vivo anti-inflammatory effects of ERE were evaluated using the maximum tolerated dose (MTD) in ICR mice and a dextran sodium sulfate-induced ulcerative colitis model in C57BL/6 J mice.

HPLC and LC-MS analyses revealed that ERE contained abundant flavonoid active ingredients. MTD study confirmed that ERE exhibited good safety. The symptoms of persistent weight loss, DAI, and shortened colon length in UC mice were suppressed by ERE. Pathological damage in colon tissues was attenuated by ERE, with a considerable reduction in histopathological scores and a substantial increase in the number of goblet cells. The levels of IL-6, IL-1β, and TNF-α in serum were significantly decreased following ERE treatment. Moreover, nitric oxide (NO) levels and myeloperoxidase (MPO) activity in colon tissues decreased, whereas glutathione (GSH) levels and superoxide dismutase (SOD) activity in colon tissues increased after ERE treatment. Furthermore, ERE could regulate the intestinal microbial composition and maintain intestinal flora homeostasis, thereby inhibiting inflammatory responses.

ERE exhibited a favorable safety profile and alleviated UC through multiple mechanisms. It is expected to serve as a promising low-toxicity natural product for adjuvant treatment in UC.

Geniposide (GE) has potential efficacy in treating ulcerative colitis (UC). However, its reactivity can be affected by rapid degradation after oral administration. Furthermore, increasing oral doses may lead to hepatotoxicity. Thus, We used enema administration, characterized by smaller dose and higher localized concentration in the lesion, to improve the above situation.

We aimed to confirm that enema administration is a better modality than oral administration for GE against UC and to explore its mechanism.

We established UC mouse model, monitoring Disease Activity Index (DAI), inflammatory cytokines levels, and histopathology. Macrogenomics and bile acid (BAs) metabolomics analysed the major intestinal flora and BAs. Simultaneouslly, we conducted quantitative proteomics analysis and screened core proteins and pathway. In vitro validation was taken by qPCR, immunofluorescence and immunoblotting experiments.

GE via enema alleviate UC by inhibiting inflammatory factor production through downregulating S100A8/S100A9/NF-κB pathway. Analysis of the intestinal flora and BAs revealed that the enhanced abundance of Lachnospiraceae, which improves the ratio of primary to secondary BAs, and the reduced abundance of Provocaceae, which increases intestinal permeability and promotes inflammation, favored the restoration of the intestinal barrier. In addition, in vitro experiments confirmed that the key BA metabolites (mainly UDCA, DCA, and LCA) stimulated TGR5 signal to inhibit the assembly of the NLRP3 inflammasome and alleviated inflammation.

We firstly confirmed that GE alleviates UC via the enema route in a better manner than the oral route, through enhancing the intestinal barrier, restoring intestinal flora and BAs homeostasis, and inhibiting inflammatory injury. This study initially revealed that GE can alleviate UC through elevating UDCA, DCA, and LCA levels at the colonic site to activate TGR5 receptor for inhibiting the NLRP3 inflammasome, in addition to downregulating the S100A8/S100A9/-TLR4-NF-κB pathway related inflammatory response directly. The evidences offer a promising strategy and profround meaning for UC treatment.

Impairment of the intestinal mucosal barrier is a prevalent feature of acute colitis, and untreated acute colitis can lead to extra-intestinal manifestations, including hepatic injury. Previous research has demonstrated that large-leaf yellow tea residue protein-derived oligopeptides (TPP) can alleviate ulcerative colitis symptoms and hepatic injury in mice. However, the underlying regulatory mechanisms by which TPP improves colitis complicated with liver injury are unknown.

To explore the potential mechanism by which TPP alleviates acute colitis complicated with hepatic injury.

Acute colitis with hepatic injury was induced in mice using 3.5 % dextran sodium sulfate. Both 16S rRNA sequencing and transcriptomic analyses were utilized to investigate the impact of TPP on mitigating symptoms in mice.

It indicated that TPP administration effectively reduced inflammatory symptoms in the colon and liver, enhanced the secretion of mucin occluding, claudin-1, ZO-1, and MUC-2, decreased intestinal mucosal permeability, and restored homeostasis within the gut microbiome of mice. Moreover, transcriptomic analysis has evidenced the effectiveness of TPP in mitigating liver-related effects. RNA-seq KEGG enrichment and RT-qPCR analyses validated TPP could modulate the "gut-microbiome-liver" axis, and participate in signaling pathways related to inflammatory regulation, as well as bile acid metabolism and synthesis.

These findings suggest that TPP administration is a promising novel approach for preventing and treating acute colitis complicated with hepatic injury.

Lizhong decoction (LZD), a Traditional Chinese Medicine formula, is widely utilized to treat gastrointestinal diseases, including ulcerative colitis in China for thousands of years.

To investigate whether the protective effect of LZD on ulcerative colitis is dependent on gut microbiota and T-cell immune homeostasis.

The preventive effects of LZD on dextran sodium sulfate (DSS)-induced colitis mice were evaluated through the measurement of body weight, disease activity index, colon length and hematoxylin-eosin staining. Flow cytometry was used to detect the ratio of Th17/Treg cells. Pseudo sterile mice and fecal transplantation experiments were used to investigate whether the preventive effect of LZD was dependent on the gut microbiota. The alterations of gut microbiota were identified by the 16S rDNA sequencing. The content of intestinal short-chain fatty acids (SCFAs) was detected by LC-MS/MS analysis. The downstream signal pathways of SCFAs were detected by the immunoblotting.

LZD administration significantly alleviated weight loss and intestinal injury in DSS-induced colitis mice. LZD administration also promotes the balance of Th17/Treg cells. Moreover, LZD administration relies on gut microbiota to alleviate ulcerative colitis and regulate Th17/Treg cell balance. LZD administration significantly improves gut microbial composition in colitis mice, elevating the abundance of SCFAs producing bacterium such as lachnospiraceae_nk4a136_group and Akkermansia. LZD treatment further increases the abundance of SCFAs and promotes activation of free fatty acid activated receptor 2 (FFAR2).

LZD administration promotes Th17/Treg cell balance in a gut microbiota-SCFAs dependent manner, which in turn ameliorates ulcerative colitis.

Inflammatory bowel disease (IBD) is characterized by recurring gastrointestinal inflammation, accompanied by a significant rise in global prevalence and disease severity. The overaccumulation of reactive oxygen and nitrogen species (RONS) in the intestinal environment disrupts redox homeostasis and drives pathological overgrowth of Escherichia coli, which are central to IBD pathogenesis. Herein, we designed a multifunctional nanozyme (W-PB) to enable sustained and targeted regulation of intestinal homeostasis through dual mechanisms: specific inhibition of E. coli overgrowth during colitis and efficient RONS clearance. To ensure colon-specific delivery, W-PB was encapsulated in an electrostatically crosslinked hydrogel composed of alginate and chitosan. This formulation protects W-PB from degradation in harsh gastrointestinal conditions and releases the nanoparticles selectively under weakly alkaline intestinal pH. The released tungsten ions suppress E. coli growth via competitive displacement of molybdenum in the molybdopterin cofactor, while W-PB simultaneously neutralizes excess RONS to shield intestinal cells from oxidative damage. In DSS-induced colitis models, the W-PB gel demonstrated significant therapeutic efficacy, achieved through intestinal microbiota remodeling and oxidative stress mitigation.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC), is a chronic inflammatory disorder with a rising incidence in pediatric populations. Immune factors play important roles in the pathogenesis of UC. This study aimed to explore the relationships of intestinal immune molecules CD27, CD20 and myeloperoxidase (MPO) with pediatric UC and their diagnostic values. In this study, gene expression data of 206 new-onset UC children and 20 non-IBD controls obtained from the NCBI Gene Expression Omnibus public database and immunohistochemistry analysis were used to evaluate CD27, CD20 and MPO expression in diseased intestinal tissues of UC children. And the diagnostic potentials of them for UC were analyzed using receiver operating characteristic curve and area under the curve (AUC). We found that CD27, CD20 and MPO mRNA and protein expressions were increased in the diseased intestinal tissues of UC children. CD27, CD20 and MPO showed good diagnostic potential for UC in children, with an AUC of 0.95 for CD27, 0.79 for CD20 and 0.92 for MPO, and combination of them had better diagnostic performance with an AUC of 0.98. Besides, they were associated with immune-related biological processes and pathways, and correlated with genes related to immune factors, intestinal epithelial barrier function, and intestinal fibrosis. In conclusion, our findings demonstrated that CD27, CD20 and MPO were increased in diseased intestinal tissues of UC children, and had good diagnostic performance for UC in children.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease in the colon and rectum. Mesenchymal stem cell-derived extracellular vesicles (MSCs-EVs) have emerged as promising cell-free therapeutics for UC, leveraging their immunomodulatory and tissue-protective properties. However, the specific epigenetic mechanisms by which EVs regulate pyroptosis (an inflammatory cell death pathway) remain poorly understood. This study explores how EVs derived from induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) regulate pyroptosis in colonic epithelial cells of UC by targeting the histone-modifying protein KDM6B, aiming to provide new therapeutic insights for UC. iPSCs were differentiated into MSCs, and their EVs were isolated and characterized. EVs were engineered to carry the circular RNA circ-CCND1 and co-cultured with UC model cells induced by DSS. Cell viability, inflammatory cytokine levels, and key molecular markers related to pyroptosis (NLRP3, cleaved Caspase-1, GSDMD-N) were measured. The molecular mechanism was dissected using RNA-protein binding assays and gene expression analysis, focusing on the circ-CCND1/KDM6B/ELF3/miR-342-3p signaling axis. EV treatment reduced pyroptosis in UC model cells, with enhanced efficacy when EVs carried circ-CCND1. Mechanistically, circ-CCND1 in EVs entered cells and bound to KDM6B, inhibiting its activation of the ELF3 gene, leading to increased miR-342-3p, which in turn suppressed KDM6B expression, forming a feedback loop that dampened pyroptosis. In conclusions, iPSC-MSC-derived EVs inhibit inflammatory cell death in colonic epithelial cells by regulating histone modification-related pathways, highlighting their potential as a novel therapeutic strategy for UC.

Colitis is an inflammatory disorder of the gastrointestinal tract. A widely consumed dietary nutrient, α-ketoglutarate (α-KG) is known to play a crucial role in cellular metabolism and provide protection to intestinal epithelium under various pathophysiological conditions. In this study, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used to induce colitis in Wistar rats. After 36 hours of TNBS administration, the rats were orally treated with a solution of α-KG at 1 g/kg body weight for 5 days. Development of colitis was confirmed by observable physical symptoms of repeated loose blood-mixed stool, apathy for food and weight loss. Macroscopic inspection revealed an inflamed colonic surface with ulcerations. Histopathological observations included alterations in crypts-structure and disruption in both epithelial and mucosal layers of colon in colitis induced rats. Colitis resulted in elevated levels of pro-inflammatory cytokines, ER stress-mediated cell death and intrinsic apoptosis pathway. The ameliorative effects of α-KG against TNBS-mediated toxicity were confirmed through molecular technics and docking analysis. Additionally, there were no instances of toxicity of α-KG. Therefore, α-KG can be considered as a valuable therapeutic agent for further comprehensive research.

The U-ACTIVATE long-term extension study aims to evaluate the long-term efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis. Here, we report interim results after 3 years of total treatment.

U-ACTIVATE is an ongoing, 288-week, phase 3, long-term extension study done at 307 centres across 43 countries (active sites on Dec 31, 2021, are presented as part of this interim analysis) and began on Jan 31, 2017. In brief, patients aged 16-75 years with a confirmed diagnosis of moderately to severely active ulcerative colitis for 90 days or more, an adapted Mayo score of 5-9, and an endoscopic subscore of 2 or 3 were eligible for the upadacitinib induction studies; patients who had a clinical response in the induction studies were eligible to enter the U-ACHIEVE maintenance study. Individuals who completed the U-ACHIEVE maintenance study were subsequently eligible for inclusion in the efficacy population of this long-term extension study. Patients in clinical remission per adapted Mayo score at week 52 of the maintenance study could continue their double-masked treatment upon entering the long-term extension study. Patients not in clinical remission originally randomly assigned to upadacitinib 15 mg were eligible to escalate to upadacitinib 30 mg, those originally randomly assigned to upadacitinib 30 mg continued on upadacitinib 30 mg, and those originally assigned to placebo were eligible to escalate to upadacitinib 15 mg in a masked way. We present data from weeks 48 and 96 of the long-term extension period. Key efficacy outcomes were clinical remission (per adapted Mayo score), endoscopic remission, maintenance of clinical remission, and maintenance of endoscopic remission, and are presented for those patients who had a clinical response after 8 weeks of upadacitinib 45 mg induction, completed 52 weeks of maintenance (U-ACHIEVE maintenance), and subsequently entered the long-term extension. Safety outcomes were treatment-emergent adverse events and adverse events of special interest, which were prespecified and were recorded in two populations: one comprising patients who received at least one dose of study drug in the long-term extension study and the other comprising all patients in the maintenance or long-term extension studies. Our primary approach for efficacy analysis was as-observed (ie, all observed data were used without imputation for missing data until patients switched to a different dose during the long-term extension study). This study is registered with ClinicalTrials.gov (NCT03006068).

414 patients from the phase 3 upadacitinib U-ACHIEVE maintenance study were eligible to enter this long-term extension study for assessment of efficacy endpoints following treatment with upadacitinib. Of these individuals, 369 patients (231 [63%] male individuals and 138 [37%] female individuals) were treated with upadacitinib in the long-term extension study: 142 patients with upadacitinib 15 mg and 227 with upadacitinib 30 mg. In the as-observed population, 84 (71%) of 118 patients receiving upadacitinib 15 mg were in clinical remission at week 48, as were 130 (67%) of 193 receiving upadacitinib 30 mg; by week 96, 69 (76%) of 91 patients receiving upadacitinib 15 mg and 104 (74%) of 141 of those receiving upadacitinib 30 mg were in clinical remission. Most patients who entered the long-term extension in clinical remission maintained it in the as-observed analysis (week 48 upadacitinib 15 mg 62 [81%] of 77 and upadacitinib 30 mg 90 [81%] of 111; week 96 upadacitinib 15 mg 50 [78%] of 64 and upadacitinib 30 mg 69 [84%] of 82). In the as-observed population, 60 (49%) of 123 patients receiving upadacitinib 15 mg and 93 (46%) of 202 receiving upadacitinib 30 mg were in endoscopic remission at week 48; by week 96, 45 (47%) of 95 patients receiving upadacitinib 15 mg and 69 (45%) of 153 receiving upadacitinib 30 mg were in endoscopic remission. Most patients who entered the long-term extension in endoscopic remission maintained it in the as-observed analysis (week 48 upadacitinib 15 mg 28 [70%] of 40 and upadacitinib 30 mg 51 [76%] of 67; week 96 upadacitinib 15 mg 20 [65%] of 31 and upadacitinib 30 mg 37 [73%] of 51). In the long-term extension-only safety analysis, we assessed data from 467 patients, representing 1027·9 patient-years of continuous long-term extension exposure on a consistent upadacitinib dose. Treatment-emergent adverse events were recorded at 238·5 events per 100 patient-years for upadacitinib 15 mg and 233·4 events per 100 patient-years for upadacitinib 30 mg. Event rates of serious treatment-emergent adverse events were 11·7 events per 100 patient-years for upadacitinib 15 mg and 12·4 events per 100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest were hepatic disorder, lymphopenia, creatine phosphokinase elevation, serious infection, neutropenia, and herpes zoster. Three treatment-emergent adverse events leading to death were reported in the long-term extension-only safety population.

This interim analysis supports the positive long-term risk-benefit profile for upadacitinib 15 mg and 30 mg among patients with moderately to severely active ulcerative colitis.

AbbVie.

The appendix might have an immunomodulatory role in ulcerative colitis. Appendicectomy has been suggested as a potentially therapeutic intervention to maintain remission in ulcerative colitis. We aimed to evaluate the clinical effectiveness of laparoscopic appendicectomy in maintaining remission in patients with ulcerative colitis.

We did a pragmatic, open-label, international, randomised controlled superiority trial in 22 centres across the Netherlands, Ireland, and the UK. Patients with established ulcerative colitis who were in remission but had been treated for disease relapse within the preceding 12 months were randomly assigned (1:1) to undergo appendicectomy plus continued maintenance medical therapy (intervention group) or to continue maintenance medical therapy alone (control group). Randomisation was done with a central, computer-generated allocation concealment, stratified by disease extent. Patients and treating physicians were unmasked to group allocation. The prespecified primary outcome was the proportion of patients with a disease relapse within 1 year, predefined as a total Mayo score of 5 or higher with an endoscopic subscore of 2 or 3, or, in absence of endoscopy, based on a centrally independent masked review by a critical event committee as an exacerbation of abdominal symptoms (eg, elevated stool frequency subscore of ≥1 point from baseline) with a rectal bleeding subscore of ≥1 or faecal calprotectin level above 150 μg/g or necessitating treatment intensification other than mesalazine. Analyses were done on an intention-to-treat principle. This trial is complete and was registered with the Netherlands Trial Register (NTR2883) and ISRCTN (ISRCTN60945764).

Between Sept 20, 2012, and Sept 21, 2022, 1386 patients were screened. 201 patients were randomly assigned to the appendicectomy group (n=101) or the control group (n=100). After exclusion of four patients due to eligibility violations (three had active disease and one received biological agents at time of randomisation), 99 patients in the appendicectomy group and 98 patients in the control group were included in the intention-to-treat analyses. The 1-year relapse rate was significantly lower in the appendicectomy group than in the control group (36 [36%] of 99 patients vs 55 [56%] of 98 patients; relative risk 0·65 [95% CI 0·47-0·89]; p=0·005; adjusted p=0·002). Adverse events occurred in 11 (11%) of 96 patients in the appendicectomy group and 10 (10%) of 101 patients in the control group. The most frequently reported adverse events were postoperative temporary self-limiting abdominal pain in the appendicectomy group (three [3%] patients) and skin rash in the control group (three [3%] patients). Two cases (2%) of low-grade appendiceal mucinous neoplasm were incidentally found in resected appendix specimens in the appendicectomy group. Serious adverse events occurred in two (2%) of 96 patients who underwent appendicectomy and none in the control group. There were no deaths.

Appendicectomy is superior to standard medical therapy alone in maintaining remission in patients with ulcerative colitis.

Fonds Nuts-Ohra and National Institute for Health Research Efficacy and Mechanism Evaluation.

Polypharmacology is an emerging approach to drug design and development that involves the use of multi-target-directed ligands (MTDLs), agents capable of interacting with multiple biological targets simultaneously. The effective treatment of chronic and multifactorial conditions, driven by the dysregulation of multiple interconnected pathways, such as cancer, autoimmune and metabolic disorders, cardiovascular and neurodegenerative diseases, is one of the most substantial challenges in contemporary pharmacology. 'Traditional' single-target-based treatment frequently shows limited effectiveness, as resistance to therapy develops or relapses occur. The rational use of MTDLs seems therefore a promising way to address the complexity of biological systems, feedback mechanisms, crosstalk, and molecular pathways. Many MTDLs have been successfully marketed to date. Moreover, plenty of them offer an additional benefit in comparison to 'traditional' treatment approaches. To assess whether the polypharmacological trend remains prevalent, we thoroughly analysed drugs approved in the years of 2023-2024 in Germany. Among 73 newly introduced substances, 18 are in line with the polypharmacology concept, including 10 antitumor agents, 5 drugs indicated for autoimmune disorders, 1 indicated for hand eczema, 1 antidiabetic (and anti-obesity) drug, and 1 modified corticosteroid.

Ulcerative colitis (UC) is a lifelong autoimmune disease associated with a high prevalence of mental disorders. An abnormal gut-brain axis plays a key role in UC. Low-intensity pulsed ultrasound (LIPUS) has been reported to alleviate neuroinflammation. This study aimed to evaluate the therapeutic effects of LIPUS in an experimental colitis model. A mouse model of colitis induced by dextran sulfate sodium (DSS) was established to evaluate the therapeutic effects of LIPUS irradiation. Intestinal inflammation and the mucosal barrier were detected using reverse transcriptase polymerase chain reaction and immunofluorescence staining. The key proteins of the NLRP3 inflammatory pathway in different groups were measured by western blotting. 16S rRNA sequencing and ultra-performance liquid-chromatography tandem mass spectrometry were applied for the detection of bacteria, metabolites, and neurotransmitters. LIPUS irradiation significantly improved the mucosal barrier in DSS-induced colitis mice and relieved intestinal inflammation and neuroinflammation by downregulating the NLRP3 inflammatory pathway. 16S rRNA sequencing showed that LIPUS irradiation significantly upregulated the abundance of Bacteroides and glutamate metabolism. Metabolic analysis revealed that the most significant metabolites between the DSS + LIPUS and DSS groups were mostly involved in alanine, aspartate, and glutamate metabolism. The detection of neurotransmitters revealed that the levels of gamma-amino butyric acid (GABA) were significantly upregulated in DSS-induced colitis mice after LIPUS irradiation, and correlation analysis revealed a positive correlation between GABA and Bacteroides. LIPUS irradiation not only alleviated gut inflammation and neuroinflammation by regulating the NLRP3 inflammatory pathway in DSS-induced colitis mice but also increased GABA levels by upregulating Bacteroides, indicating that LIPUS might be a promising therapeutic technology for UC treatment.

Total glucosides of paeony (TGP), an active ingredient extracted from the dried root of Paeonia lactiflora Pall., has been approved in China for the treatment of various autoimmune diseases. However, the role and mechanism of TGP in UC have yet to be fully elucidated. This study aims to investigate the regulatory effects and underlying mechanisms of TGP on intestinal homeostasis disruption and immune imbalance in a mouse model of dextran sulfate sodium (DSS)-induced colitis. The results showed that TGP alleviated DSS induced body weight loss, colonic shortening and histopathological changes in mice, and also enhanced the integrity of the intestinal barrier by up-regulating the expression of ZO-1, Occludin and tight junction protein in the colon. The results of 16S and antibiotic cocktail (ABX) experiments showed that TGP alleviated colitis by inhibiting Th17 cell differentiation by correcting intestinal microbial imbalance in UC mice. Mechanism studies showed that TGP inhibited the activation of JAK2/STAT3 signaling pathway in UC mice, and decreased the levels of inflammatory factors in colon supernatant and serum. Importantly, TGP regulates JAK2/STAT3 to inhibit Th17 cell differentiation depending on gut flora. In addition, TGP can also improve the metabolic imbalance in UC mice, especially purine metabolism. In conclusion, TGP promotes the normalization of purine metabolism and relies on gut microbiota to regulate JAK2/STAT3 pathway, inhibit Th17 cell differentiation, and alleviate colitis. Our findings highlight TGP as a promising treatment candidate for ulcerative colitis.

The inflammatory response is the core mechanism of the pathogenesis and symptoms of ulcerative colitis (UC), and inhibiting inflammation is a promising therapeutic approach to improving UC. Curcumin is considered a potential treatment for UC due to its significant anti-inflammatory and antioxidant effects. However, its bioavailability in the post-oral administration is limited. Therefore, the stability, sustained release, and colon targeting of curcumin in the treatment of UC have become a challenge. Herein, curcumin was efficiently filled in the porous structure of University of Oslo 66 (UiO-66). Amino-functionalized UiO-66 (MOF) was bound to hyaluronic acid (HA) via chemical crosslinking and electrostatic interactions. Polydopamine (PDA) layer was then applied to form Cur@MOF@HA-PDA NPs for colon targeting for UC treatment. Cur@MOF@HA-PDA NPs not only enhanced the stability of curcumin but also possessed acid resistance and reactive oxygen species (ROS) responsive properties, enabling it to be effectively delivered to the UC lesion site for curcumin release after oral administration, thereby enhancing the therapeutic effect. In vitro studies revealed that Cur@MOF@HA-PDA NPs possessed the ability to eliminate intracellular ROS, inhibit inflammatory (M1) polarization, and promote anti-inflammatory (M2) polarization. Additionally, in vivo experiments demonstrated that Cur@MOF@HA-PDA NPs could effectively alleviate the intestinal inflammatory symptoms of UC mice, promoting intestinal tissue repair. Furthermore, it was also confirmed that Cur@MOF@HA-PDA NPs achieved the treatment of UC by inhibiting inflammatory responses, modulating intestinal immune functions, and promoting the polarization of M2 macrophages. In short, Cur@MOF@HA-PDA NPs, as colon-targeted drug delivery nanosystems, offer a promising therapeutic strategy for the treatment of UC.

Background: Baicalin is considered to be able to alleviate the progression of ulcerative colitis (UC), but the underlying molecular mechanism needs to be further elucidated. Methods: TNF-α-induced human normal colorectal mucosa cells (FHC) were used to mimic UC models in vitro , and trinitrobenzene sulfonic acid (TNBS)-injected rats were used to construct UC models in vivo . Cell proliferation and apoptosis were determined by CCK8 assay, EdU assay and flow cytometry. Inflammation factors were examined by ELISA, and ferroptosis-related markers were detected by corresponding kit. The mRNA and protein levels of solute carrier family 6 member 14 (SLC6A14) and specific protein 1 (SP1) were analyzed by qRT-PCR and western blot. The interaction between SP1 and SLC6A14 promoter was verified by ChIP assay and dual-luciferase reporter assay. Results: Baicalin enhanced proliferation, while repressed apoptosis, inflammation, and ferroptosis in TNF-α-induced FHC cells. SLC6A14 was upregulated in UC patients, and baicalin could decrease SLC6A14 expression. SLC6A14 overexpression reversed the inhibitory effect of baicalin on TNF-α-induced FHC cell injury. SP1 could bind to SLC6A14 promoter region to upregulate its expression, and ectopic expression of SLC6A14 also abolished the suppressive effect of SP1 knockdown on TNF-α-induced FHC cell injury. Baicalin reduced SP1 expression to downregulate SLC6A14. In addition, baicalin alleviated UC process in vivo via repressing inflammation, and ferroptosis. Conclusion: Baicalin repressed SP1-mediated transcription of SLC6A14 to restrain cell apoptosis, inflammation, and ferroptosis, thus alleviating UC progression.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by intestinal barrier dysfunction, oxidative stress, and inflammation. Biochanin A (BCA) is a natural flavonoid found in various plants, known for its anti-inflammatory, antioxidant, and anticancer properties, while its therapeutic role in UC and potential mechanism remains unexplored.

To explores the therapeutic potential of BCA in alleviating UC, focusing on its effects on ferroptosis and the JAK2/STAT3 signaling pathway.

The BCA's therapeutic effects on Dextran sulfate sodium (DSS)-induced colitis model in C57BL/6J mice was investigated. Subsequently, a comprehensive range of techniques was performed to investigate the impact of BCA on intestinal barrier integrity, oxidative stress, inflammation. Besides, the RNA sequencing was performed to explore the potential mechanism. The role of ferroptosis inhibition in BCA's effects in vitro and in vivo was explored by co-treating with the ferroptosis activator Erastin.

Treatment of colitis mice with BCA significantly improved DAI scores and histopathological damage scores, reduced oxidative stress, enhanced intestinal barrier function, and suppress inflammatory responses. RNA sequencing result found that BCA could lead to the inhibition of ferroptosis in mice colon tissue. Moreover, erastin co-treatment negated BCA's effects in vitro and vivo. Mechanistically, BCA exerts these effects by suppressing the JAK2/STAT3 pathway, which plays a pivotal role in ferroptosis and inflammation. Molecular docking studies further confirm the direct binding of BCA to both GPX4 and STAT3.

These results establish BCA as a promising natural compound for UC treatment, offering a novel therapeutic strategy by specifically targeting ferroptosis and its associated molecular pathways, thereby addressing key gaps in current UC management and advancing potential clinical applications.

The destruction of intestinal mucosal mechanical barrier homeostasis caused by excessive apoptosis of intestinal epithelial cells (IECs) is an important reason for the occurrence and development of ulcerative colitis (UC). The increase in mitochondrial membrane permeability caused by the opening of the mitochondrial membrane permeability transition pore (mPTP) is a key link in the initiation of mitochondrial pathway apoptosis. Our previous studies revealed that heat shock transcription factor 2 (HSF2), which is highly expressed in the intestinal mucosa of UC patients, can inhibit the expression of the cytochrome C (Cyto-C)/Caspase-9/Caspase-3 proteins in the mitochondrial pathway of apoptosis, but the regulatory mechanism is unknown. It has been reported that heat shock proteins regulated by heat shock transcription factors are closely related to mPTP opening. Therefore, we hypothesized that HSF2 affects mitochondrial pathway apoptosis in IECs by regulating mPTP opening. In this study, we altered the level of HSF2 in Caco-2 cells by lentivirus transfection to explore the changes in the mitochondrial membrane permeability of Caco-2 cells in an inflammatory environment. Subsequently, the mPTP agonist atractylorhizin (Atr) and inhibitor cyclosporine A (CsA) were used to clarify the regulatory effects of HSF2 on mPTP and the Cyto-C/Caspase-9/Caspase-3 pathways. Our study confirmed for the first time that HSF2 plays a protective role in UC by inhibiting mPTP opening, the increase in mitochondrial membrane permeability and the activation of the mitochondrial-mediated apoptosis pathway in IECs.

Ulcerative colitis (UC) is an inflammatory bowel disease with an unknown cause. Previous studies have shown that Group 3 innate lymphoid cells (ILC3s) are crucial for maintaining intestinal mucosal immune homeostasis by producing key cytokines such as IL-22 and IL-17 A. While the RNA-binding protein Musashi-2 (MSI2) is recognized as essential for promoting intestinal epithelial regeneration post-injury, its impact on immune regulation remains unclear. Therefore, we aim to investigate the protective mechanisms associated with ILC3s-specific MSI2 deletion in a mouse model of ulcerative colitis.

Dextran sulfate sodium (DSS) was used to induce a mouse colitis model. Colitis severity was evaluated through weight loss, diarrhea, fecal traits, colon length, and pathological scoring. Transcriptome sequencing was utilized to identify differentially expressed genes in colon tissues. Flow cytometry was employed to measure the quantity and functionality of ILC3s. Western blot was conducted to analyze protein expression, while real-time polymerase chain reaction and enzyme-linked immunosorbent assay were employed to quantify inflammatory factors. Additionally, immunofluorescence, AB-PAS staining, and immunohistochemistry were employed to evaluate the integrity of the intestinal barrier.

Following DSS treatment, colon damage was milder in Msi2∆Rorc mice than in Msi2fl/fl mice. Transcriptomic analysis revealed the down-regulation of cytokines and pro-inflammatory factors in the colon tissue of Msi2∆Rorc mice. Flow cytometry showed that specific deletion of MSI2 reduced the infiltration of ILC3s in the intestinal lamina propria of Msi2∆Rorc mice and decreased IL-17 A production. The reduction of IL-17 A-mediated immune responses lessened inflammatory damage to the intestinal barrier, thereby reducing colitis severity.

Specific deletion of MSI2 alleviates DSS-induced colitis in mice by reducing ILC3s infiltration and IL-17 A secretion in the lamina propria of the colon. This decrease in inflammatory mediators and cell infiltration dampens the inflammatory response in the intestinal mucosa, helping to maintain the integrity of the intestinal barrier in mice with colitis. These findings enhance our understanding of UC pathogenesis and offer novel avenues for clinical diagnosis and treatment.

The effectiveness and safety of polyphenols in treating ulcerative colitis remain controversial. This study aimed to evaluate the efficacy and safety of polyphenols in the treatment of ulcerative colitis.

This study followed the preferred reporting items for systematic reviews and meta-analyses 2020 guidelines. A systematic search was conducted across PubMed, Embase, Web of Science, and Cochrane databases to identify relevant articles. The random-effects model was employed to calculate the odds ratio (OR) and corresponding 95% confidence intervals (CIs).

A total of 13 trials involving 742 participants were included in the meta-analysis. The clinical remission rates were higher in the polyphenol group compared to the control group, as demonstrated by both the intention-to-treat (ITT) (OR: 4.71; 95% CI: 2.02-10.99; P = .000) and per-protocol (PP) analysis (OR: 7.14; 95% CI: 3.11-16.39; P = .000). Similarly, the clinical response rate was higher in the polyphenol group compared to the control group, according to the ITT (OR: 5.40; 95% CI: 2.60-11.24; P = .000) and PP analysis (OR: 9.14; 95% CI: 4.25-19.64; P = .000). Moreover, the total endoscopic remission rate was superior in the polyphenol group, as indicated by the ITT (OR: 3.16; 95% CI: 1.20-8.37; P = .020) and PP analysis (OR: 4.92; 95% CI: 2.03-11.93; P = .000). No significant differences were observed regarding side effects between the 2 groups, according to the ITT (OR: 0.99; 95% CI: 0.56-1.76; P = .973) and PP analysis (OR: 0.99; 95% CI: 0.54-1.80; P = .971).

Polyphenols demonstrated effectiveness in inducing clinical remission, clinical response, and endoscopic remission in patients with ulcerative colitis. Furthermore, there was no evidence of a higher incidence of adverse effects associated with their use.

Aims/Background Endoscopic scoring systems are recommended internationally for assessing disease activity, response to therapy and mucosal healing. However, their real-world application remains inconsistent. This study aimed to evaluate the impact of an educational intervention on endoscopic scoring documentation and identify factors influencing its use. Methods A retrospective observational study was conducted at four hospital sites in Greater Manchester, UK. Data from endoscopies performed on ulcerative colitis (UC) patients were compared before and after an educational intervention. Logistic regression was used to analyse factors affecting documentation rates. Results Endoscopic score documentation increased from 39% (pre-intervention) to 46% (post-intervention) (p = 0.162). Nurse endoscopists had the highest documentation rates (83%), while surgeons had the lowest (8%). Attendance at educational sessions significantly increased documentation rates (29% vs. 74-80%, p < 0.001). Conclusion Educational interventions modestly improved endoscopic scoring documentation. Further targeted training and standardised reporting templates are needed to enhance adherence and patient outcomes in UC management.

Ulcerative colitis (UC) includes a dysregulated immune response. The conventional therapy includes immunosuppressants, and biologics targeting inflammatory mediators, but these are often inadequate, or subjects become unable to tolerate them.

QUASAR: the induction and maintenance components of the phase 3 trial of guselkumab, which inhibits IL-23 by dual mechanisms, in subjects with moderate-to-severe UC. QUASAR enrolled those that had an inadequate response and/or intolerance to corticosteroids, immunosuppressants, biologics, or Janus kinase (JAK) inhibitors. In both parts of the trial, guselkumab improved clinical remission with no excess of adverse events.

For those enrolled throughout, after the maintenance part, the benefit with guselkumab on clinical remission was 24% percentage points (45 vs 21%), which is relatively small. There is no direct comparison of guselkumab with other IL-23 inhibitors in UC. Indirectly comparing trials suggests the clinical remission rates at the end of the trials was higher with guselkumab than with the other approved IL-23, inhibitors, mirikizumab or risankizumab (17 or 15% points, respectively). Thus, guselkumab may be more efficacious than the other 1 L-23 antagonists, possibly due to its additional action to block the CD64 receptor. However, this needs to be tested in a direct comparison trial.

Inflammatory bowel disease was linked to an increased risk for conduction defects and ventricular arrhythmia. It coincides with dysregulation of gut microbiota, increased inflammation, and deregulation of the renin-angiotensin system. In this study, we aimed to determine the mechanism of colitis-induced electrophysiological remodeling that increases the risk for ventricular arrhythmia. In a mouse model of dextran sulfate sodium induced active colitis (3.5 %, 7 days) cardiac electrophysiological properties were quantified during active inflammation. Electrocardiographic recordings exhibited a prolonged QT duration in mice with active colitis compared to control. Field potential (FP) recordings of Langendorff perfused colitis-hearts exhibited increased FP dispersion, a reduced threshold for ventricular alternans, and an increased propensity for spatially discordant alternans. The increased propensity for alternans was also reflected in isolated ventricular myocytes where Ca2+ transient alternans occurred at lower pacing frequencies and increased alternans ratios. The action potential was unchanged during colitis but myocytes exhibited a prolonged Ca2+ transient duration that corresponded with attenuated phospholamban phosphorylation. Stimulating cellular SERCA activity (Istaroxime), normalized the propensity for alternans. Serum levels of Angiotensin II (AngII) were increased during colitis and Angiotensin-converting enzyme (ACE) inhibitor or AngII receptor type 1 blocker prevented the increased alternans inducibility in isolated myocytes and hearts. Our data demonstrate that active colitis promotes reversible remodeling of ventricular Ca2+ handling properties and increases the propensity for alternans and arrythmia. The changes can be prevented by ACE or AT1R inhibition supporting a cardiac benefit for controlling RAS signaling in patients with active colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon. The specific cause of UC is still not fully understood, but this condition is believed to arise from a combination of environmental, genetic, microbial, and immune factors. This study aimed to explore the specific roles of macrophages and fibroblasts in UC pathogenesis, focusing on their interactions and contributions to disease progression.

We utilized single-cell RNA sequencing (scRNA-seq) to analyze macrophages and fibroblasts in peripheral blood and colon biopsy samples from UC patients. Bulk RNA sequencing and spatial transcriptomic data from the Gene Expression Omnibus (GEO) database and flow cytometry and multiplex immunohistochemistry (mIHC) data were used for validation. Statistical analyses were performed to assess the correlation between cell abundance and disease severity.

Macrophages and fibroblasts were identified as key communication hubs in UC; specifically, SPP1 + macrophages and CHI3L1 + fibroblasts were significantly enriched at the sites of inflammation. These cells are strongly correlated with disease severity and orchestrate inflammatory responses within the intestinal immune microenvironment, contributing to UC-associated colorectal cancer.

Our study identified SPP1 + macrophages and CHI3L1 + fibroblasts as key contributors to UC pathogenesis. These cells are enriched in inflammatory sites, are correlated with disease severity, and play a role in UC-associated colorectal cancer, providing new insights into UC mechanisms.

JiuLiWan (JLW), as a classic traditional Chinese medicine formula, has been clinically used against ulcerative colitis (UC). However, the exact mechanism of its therapeutic effect remains unclear. This study aims to explore and validate the main components and pharmacological mechanism of JLW in the treatment of UC through network pharmacology, molecular docking, and cell experiments. Network pharmacology analyses indicated a total of 107 main components and 286 core targets of JLW against UC. Pathway enrichment analysis demonstrated the involvement of PI3K-AKT, MAPK, Ras, Rap1, TNF, T cell receptor, HIF-1, C-type lectin receptor, VEGF, and Th17 cell differentiation signal pathways in the efficacy of the formula. The molecular docking results indicated that the prominent components (ailanthone (AIL), butylidenephthalide, honokiol, dehydrocostuslactone, ganoderic acid A, atractylenolide I, neokurarinol, glycyrrhetinic acid, palmatine, tangeretin, and bruceine A) could bind to core targets AKT1, P53, STAT3, c-JUN, and ERK1. Subsequently, AIL was used as a representative compound to conduct cell experiments to verify its role and mechanism in anti-inflammation and immunomodulation. Interestingly, AIL could switch Jurkat T cells into a quiescence state without activating the inflammatory and immune status. However, AIL could significantly decrease the levels of interleukin-2 (IL-2) and interferon-gamma (IFN-γ), as well as the expression of surface activation markers CD69 and CD25, in PMA/ionomycin-activated Jurkat T cells by suppressing the RAF/ERK/STAT3 signaling pathway and increasing the phosphorylation of p53. This study combines network pharmacology prediction with experimental verification in vitro to demonstrate the mechanism of JLW in treating UC and provides an effective, safe, and inexpensive strategy for UC treatment.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic inflammation and ulcerative erosion of the colonic mucosa. Because of the complex causes, UC is often difficult to completely cure, greatly increasing the risk of bowel cancer and other diseases. In the UC environment, excessive production of reactive oxygen species (ROS) and high levels of inflammatory factors lead to the continuous deterioration of inflammation. We developed Mn-PEGCG nanoparticles (NPs) based on the metal-polyphenol network for the preventive treatment of UC. Mn-PEGCG NPs were synthesized by the polymerization of epigallocatechin gallate (EGCG) and further complexation with Mn2+. After oral administration, Mn-PEGCG NPs are more likely to reach the inflammation site of the colon through electrostatic interaction, effectively clear ROS, reduce the production of pro-inflammatory cytokines, exert antioxidant and anti-inflammatory effects, and protect colon cells from oxidative stress damage. In addition, it can play the role of EGCG in promoting the expression of tight junction protein and enhancing the intestinal epithelial barrier. In a mouse model of UC, oral administration of Mn-PEGCG NPs reduced intestinal inflammation, alleviated pathological structural damage in mice, and promoted mucus secretion and tight junction protein expression, thereby strengthening the intestinal barrier. Mn-PEGCG NPs can effectively alleviate inflammation and repair the intestinal barrier to maintain the stability of the intestinal environment, which is an ideal treatment strategy for UC.

Pediatric inflammatory bowel disease (IBD), encompassing Crohn's disease, ulcerative colitis, and indeterminate colitis, often necessitates surgical intervention in cases of severe or refractory disease. Although biologic therapies have significantly reduced the need for surgery, operative management remains essential for certain patients. The choice between laparoscopic (laparoscopy group [LG]) and open conventional surgery (open group [OG]) continues to be a subject of debate. This meta-analysis aimed to compare the postoperative outcomes of LG and OG in pediatric patients with IBD.

We conducted a meta-analysis of observational studies comparing LG and OG outcomes in pediatric patients with IBD. Key outcomes analyzed included major and minor postoperative complications, reoperations, readmissions, operative time, and length of hospital stay.

Seven studies met the inclusion criteria, analyzing 3417 patients, with 1399 (41%) undergoing OG and 2018 (59%) undergoing LG. Our analysis revealed no significant differences in major postoperative complications, reoperation, and readmissions between LG and OG (P = .114, P = .082, and P = .641, respectively). However, LG was associated with shorter hospital stays (6.04 vs 8.35 days; P < .05). Conversions from LG to open surgery amounted to a total of 153 (7.57%). Open surgery had a significantly shorter operative time (173.8 vs 195.5 min; P = .005).

Both laparoscopic and open conventional surgeries are safe, effective, and reliable in managing pediatric IBD. Although open surgery offers shorter operative times, laparoscopy reduces hospital stay and minor postoperative complications. The choice of approach depends on the surgeon's experience and patient-specific factors.

Intestinal inflammation and increased permeability have been linked to metabolic dysregulation in patients with compromised intestinal barrier function. Among the pathways, garnering attention is the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Upon binding to double-stranded DNA (dsDNA), cGAS catalyzes the conversion of ATP and GTP into cyclic GMP-AMP (cGAMP). Subsequently, cGAMP binds to STING, triggering the activation of tank-binding kinase 1 (TBK1), which activates interferon regulatory factor 3 (IRF3), thus inducing the production of type I interferon. Activated TBK1 can also induce the activation of nuclear factor κB (NF-κB), thus mediating the production of proinflammatory cytokines. The effects of this process vary among innate and adaptive immune cells, as well as intestinal epithelial cells (IECs). This review aims to elucidate the impact and role of the cGAS-STING pathway on intestinal barrier function.

Systemic lupus erythematosus (SLE) and ulcerative colitis (UC) are both chronic autoimmune diseases with unclear shared mechanisms, largely due to limited mechanistic studies and clinical research cohorts. Transcriptome datasets from the Gene Expression Omnibus (GEO) database were analyzed for SLE and UC, identifying differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) identified significant module genes, including PLEKHA1. The diagnostic potential of PLEKHA1 was confirmed using machine-learning algorithms and real-time fluorescence quantitative PCR (RT-PCR) in clinical samples. Additionally, the study explored the link between PLEKHA1 and neutrophil extracellular trap (NET) formation. Our analyses identified transcriptional signatures associated with neutrophil degranulation and NET formation pathways in the peripheral blood of both SLE and UC, a perspective not previously explored. PLEKHA1 was identified as a promising biomarker that may impact NET formation. Pathway enrichment analyses indicated that PLEKHA1 plays a regulatory role in NET formation in both diseases. This study provides novel transcriptional evidence by proposing neutrophil degranulation and NET formation as common pathways in SLE and UC, with PLEKHA1 acting as a shared diagnostic gene. PLEKHA1 may regulate neutrophil activation and immune response, influencing NET formation and neutrophil degranulation in SLE patients' peripheral blood.

Antioxidative nanomaterials with reactive oxygen species (ROS) scavenging capabilities hold promise for the treatment of ulcerative colitis (UC). However, their clinical application is limited by rapid diffusion, susceptibility to inactivation, and insufficient targeting of inflammatory sites. This study focuses on developing a nanoplatform by integrating iron oxide nanoparticles (IONPs) into zeolitic imidazolate frameworks-8 (ZIF-8), termed as ZIF-8@IONPs. ZIF-8@IONPs exhibited good biocompatibility and effective ROS scavenging capabilities in RAW 264.7 cells. To enhance inflammatory targeting, HA@ZIF-8@IONPs were generated through hyaluronic acid (HA) surface modification. HA@ZIF-8@IONPs effectively reduced damage to intestinal tissues in the UC mouse model. Mechanistic revealed that HA@ZIF-8@IONPs exhibited antioxidant and anti-inflammatory activities by eliminating endogenous ROS, activating the Nrf2 signaling pathway, and inhibiting the NF-κB signaling pathway. This study highlights the nanoplatform's potential as a promising candidate for UC treatment due to its great targeting of inflammatory microenvironments and efficient ROS scavenging.

Ulcerative colitis (UC) has demonstrated an escalating global incidence and prevalence, thereby posing substantial challenges to public health. Despite recent advancements in therapeutic interventions, the clinical management of UC remains suboptimal, underscoring the urgent need for novel treatment strategies. Saikosaponin A (SSa), a bioactive compound derived from the traditional Chinese herb Radix Bupleuri (RB), exhibits potent anti-inflammatory and immunomodulatory effects. However, its effects on UC and the underlying molecular mechanisms remain to be thoroughly explored.

This study aims to elucidate the underlying mechanisms of SSa in ameliorating UC and establish a pharmacological foundation for developing novel treatment modalities to address unmet clinical needs in UC treatment.

The protective effects of SSa against DSS-induced acute colitis were evaluated in a 3 % DSS-treated mouse model. Histological (H&E staining) and molecular analyses (RT-qPCR, ELISA, Western blotting, and flow cytometry) were performed to assess colonic tissue damage and inflammatory responses. Macrophage depletion via tail vein injection of clodronate liposomes confirmed the pivotal role of macrophages in UC pathogenesis and SSa's anti-inflammatory effects. The inhibitory effects of SSa on NLRP3 inflammasome activation were analyzed in vivo and in LPS/ATP-stimulated bone marrow-derived macrophages (BMDMs) using RT-qPCR, ELISA, and Western blotting. Bioinformatics analysis, targeted LC-MS/MS, and molecular docking were employed to identify potential molecular targets and mechanisms of SSa. Drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and CH25H siRNA knockdown assays were used to validate CH25H as the direct target of SSa.

SSa effectively attenuated DSS-induced colitis in mice by alleviating colonic inflammation, preserving intestinal barrier integrity, reducing LPS translocation, and mitigating systemic organ injury in the liver and spleen. The inflammatory response of macrophages and the production of IL-1β were identified as key pathogenic components in colitis, and the clearance of macrophages significantly ameliorated colitis progression while SSa administration post-macrophage clearance did not further alter the disease phenotype. Mechanistically, SSa inhibited the NLRP3 inflammasome activation-mediated IL-1β secretion in macrophages. The sterol metabolism played a crucial role in the activation of the NLRP3 inflammasome. SSa also restored the disturbed sterol homeostasis in the colon under inflammatory conditions, especially promoted the synthesis of 25-hydroxycholesterol (25-OHC). Further investigation revealed that SSa primarily exerts its therapeutic effects by directly targeting cholesterol 25-hydroxylase (CH25H), which promotes the production of 25-OHC and inhibits macrophage NLRP3 inflammasome activation.

This pioneering study demonstrated the therapeutic effect of SSa on DSS-induced colitis by targeting CH25H to enhance 25-OHC biosynthesis, which subsequently inhibited NLRP3 inflammasome activation in IL-1β-producing macrophages. These findings reveal a novel mechanism of SSa in UC treatment through cholesterol metabolism-regulated cascade immune modulation, providing strong pharmacological support for its development as a potential UC therapy.

Ulcerative colitis (UC) is a non-specific inflammatory bowel disease. Unlike any single form of cell death reported previously, macrophage PANoptosis, a unique programmed cell death characterized by inflammation and necrosis, plays a crucial role in the pathogenesis of colitis. Changdiqing Decoction (CDQD), an empirical hospital prescription enema, has been used to treat UC for decades. This study aimed to investigate the multi-target anti-colitic effects of CDQD by examining its impact on intestinal homeostasis and its anti-inflammatory properties.

A dextran sulfate sodium (DSS)-induced mouse model of acute colitis was employed. Interferon-gamma (IFN-γ) and KPT-330 were used to induce macrophage PANoptosis. Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLCHRMS) was utilized to identify the chemical constituents of CDQD. Multi-omics analysis and fecal microbiota transplantation (FMT) were used to explore the therapeutic targets and gut microbiota alterations induced by CDQD.

CDQD treatment significantly alleviated colitis symptoms in mice, with a dose-dependent therapeutic effect. The decoction mitigated PANoptosis in colon tissues and bone marrow-derived macrophages (BMDMs). 16S rRNA sequencing analysis and metabonomics revealed that CDQD administration significantly altered the gut microbiota composition and metabolite profiles. Notably, CDQD-modulated gut microbiota exhibited anti-colitic effects through FMT. Integrated transcriptomics and network pharmacology analysis revealed that CDQD significantly downregulated the PI3K/Akt signaling pathway in colitis. This finding was further validated using the inhibitors LY294002 and MK2206.

CDQD alleviates colitis by suppressing inflammatory macrophage activation and modulating the gut microbiota. Our research provides a novel traditional Chinese medicine strategy for the treatment of UC via enema administration.