Search Results (890)

The objective of this study was to compare the protective effects of native and nanostructured quercetin on the initiation of oxidative stress in human keratinocytes exposed to tert-butyl hydroperoxide (tBHP). Quercetin was encapsulated within gelatin-based nanocontainers, forming nanoparticles with diameters ranging from 140 to 180 nm. Two formulations were prepared: uncoated gelatin nanoparticles (NP1) and gelatin nanoparticles coated with a shell composed of dextran sulfate and a chitosan–dextran copolymer (NP2). Cell viability was assessed using PrestoBlue™ reagent. Apoptotic and necrotic cell populations were identified via flow cytometry using an Annexin V-FITC/PI staining kit. DNA damage was evaluated using the comet assay. The results demonstrate that gelatin nanoparticles effectively encapsulate quercetin, and the nanostructured form enables its application in aqueous suspensions without compromising its antioxidant, gene-protective, and cytoprotective effects under conditions of cellular oxidative stress. These findings suggest that gelatin nanoparticles are suitable carriers for quercetin, owing to their high aqueous solubility, which may improve its potential for oral or topical delivery. Full article

Dysregulation of the immune system, gut microbiota alteration, and epithelial dynamics in the colon contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the role of epithelial dynamics, particularly epithelial regeneration, remains incompletely understood. CADM1 encodes an immunoglobulin-superfamily cell adhesion molecule involved in epithelial adhesion, immune cell interactions, and tumor suppression in colon and various cancers. Here, we investigated the role of CADM1 in IBD using a murine model of colitis induced by dextran sulfate sodium in both wild-type and conventional Cadm1-deficient (Cadm1^−/−) mice. Cadm1^−/− mice exhibited more severe colitis than wild-type mice with increased mortality (64% vs. 10%) and delayed recovery. Cadm1^−/− mice showed reduced numbers of Ki-67-positive cells in colonic crypts and delayed epithelial regeneration, whereas no significant differences were observed in epithelial apoptosis, intestinal permeability, or immune responses. Immunohistochemistry revealed that CADM1 expression was restricted to regenerative crypt cells in wild-type mice with nuclear accumulation of β-catenin and phospho-Akt. Furthermore, CADM1 overexpression in colon epithelial cells enhanced Tcf-transcriptional activity in a β-catenin-dependent manner. Immunohistochemistry of human IBD materials revealed that CADM1 expression also correlated with nuclear β-catenin accumulation in crypt epithelial cells. Collectively, CADM1 appears to promote colonic epithelial regeneration through the PI3K/Akt/β-catenin axis to protect against severe epithelial injury in IBD. Full article

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent mucosal inflammation and dysregulated immune–metabolic responses. Koumiss, a traditional fermented mare’s milk, has long been used in ethnomedicine for gastrointestinal disorders; however, its molecular mechanisms in UC remain unclear. In this study, an integrated multi-omics approach combining network pharmacology, quantitative proteomics, and molecular docking was employed to elucidate the therapeutic mechanism of koumiss powder (KP) in a dextran sulfate sodium (DSS)-induced murine colitis model. Network pharmacology identified twelve bioactive compounds targeting fourteen UC-associated proteins, predominantly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In vivo experiments demonstrated that high-dose KP significantly alleviated disease activity, improved colon shortening and histopathological injury, reduced serum TNF-α and IL-6 levels, and restored anti-inflammatory cytokines IL-4 and IL-10. Proteomic analysis further revealed activation of the PPAR signaling pathway, with significant upregulation of Plin4 and Sorbs1. Immunofluorescence staining further confirmed that KP restored the expression of PPARA and increased the levels of Plin4 and Sorbs1 in colonic tissues. Molecular docking confirmed strong binding affinities between key koumiss-derived lipid metabolites, including 13(S)-HOTrE and stearoyl ethanolamide, and PPAR-related target proteins. Collectively, these findings demonstrate that koumiss exerts protective effects against experimental UC primarily through activation of PPAR-mediated lipid metabolic and anti-inflammatory pathways. This study provides mechanistic insight into the biological activity of koumiss and highlights the value of multi-omics integration in natural product research. Full article

Background/Objectives: The worldwide occurrence of ulcerative colitis (UC) is increasing, but existing treatments frequently suffer from limited effectiveness and notable side effects. walnut green husk polysaccharide (WGHP) has been shown to exhibit anti-inflammatory and immunomodulatory activities; however, its specific potential and mechanisms of action against colitis remain unclear. This study aimed to evaluate the effectiveness of purified WGHP on (dextran sulfate sodium) DSS-induced UC and elucidate the underlying mechanisms. Methods: WGHP-2-2, a primary acidic polysaccharide fraction, was extracted from crude WGHP and analyzed through chromatography and spectroscopy. The therapeutic efficacy of WGHP-2 was assessed using a murine model of DSS-induced UC. Assessments included disease severity (DAI, colon length, histopathology), inflammatory markers (tissue IL-6, TNF-α, IL-10), and intestinal barrier integrity (Claudin-5, Occludin, ZO-1). Results: WGHP-2-2 is an acidic polysaccharide with a molecular weight of 15.29 kDa. Its composition includes glucosamine, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose, and arabinose, with respective molar ratios of 0.55, 8.48, 3.06, 65.99, 4.49, 10.86, and 6.57. Methylation and NMR analyses revealed a backbone mainly composed of →4)-α-D-GalpA-(1→ and →2)-α-D-Rhap-(1→ linkages, with side chains or terminal residues such as T-Rhap, T-Galp, T-Glcp, and T-Araf. In vivo, WGHP-2 significantly mitigated DSS-induced UC symptoms in a dose-dependent manner. Specifically, the high-dose group (123 mg/kg) markedly attenuated colon shortening and improved histological architecture, including the restoration of colonic crypts. WGHP-2 effectively reduced pro-inflammatory cytokines IL-6 and TNF-α in colon tissues, while increasing the anti-inflammatory cytokine IL-10. Conclusions: WGHP-2 mitigates DSS-induced UC by inhibiting pro-inflammatory cytokines (IL-6, TNF-α), increasing IL-10 levels, and improving intestinal barrier integrity through the upregulation of tight junction proteins. These results position WGHP-2 as a promising lead compound for developing functional foods for UC. Full article

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon characterized by dysregulated mucosal immunity and progressive epithelial injury. Upadacitinib (UPA), a selective Janus kinase 1 (JAK1) inhibitor, has demonstrated clinical efficacy in UC, but its therapeutic application is often constrained by adverse effects arising from systemic drug exposure. This underscores the need for advanced, site-specific delivery systems that enhance local efficacy while minimizing systemic toxicity. Here, we developed a colon-targeted natural lipid nanoparticle formulation of UPA (UPA-nLNP) to improve therapeutic performance and safety. UPA-nLNP was prepared by thin-film hydration using digalactosyldiacylglycerol (DGDG), monogalactosyldiacylglycerol (MGDG), and phosphatidic acid (PA), mimicking the lipid composition of ginger-derived exosomal particles, and was characterized for particle size, surface charge, and encapsulation efficiency. The formulation exhibited excellent mucus-penetrating capability and was evaluated in a dextran sulfate sodium (DSS)-induced acute colitis model in C57BL/6 mice following oral administration (5 mg/kg). Pharmacokinetic analysis demonstrated increased colonic accumulation with reduced systemic exposure compared to free UPA. Treatment with UPA-nLNP improved body weight recovery, reduced disease biomarkers, and suppressed key proinflammatory cytokines in the colon, with no evidence of systemic toxicity. This innovative strategy holds strong potential to enhance the clinical utility of JAK1 inhibitors by providing a safer and more effective therapeutic approach for ulcerative colitis. Full article

Background: Colorectal intraepithelial neoplasia (CR-EN) is a precursor lesion of colitis-associated colorectal cancer (CAC). This study investigated the interventional effects and molecular mechanisms of Rhapontici Radix extract on CR-EN. Methods: An azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model of colonic intraepithelial neoplasia, bioinformatics analysis, organoid models, and HCT116 cell experiments were employed, coupled with histopathological examination, inflammatory cytokine detection, Western blot, immunofluorescence, and HPLC-MS/MS. Results: The results showed that the YAP/AKT-PI3K signaling pathway is aberrantly activated in CRC. Rhapontici Radix extract ameliorated colonic pathology, suppressed inflammatory responses, and remodeled gut microbiota composition in model mice. The extract selectively inhibited the proliferation of CR-EN organoids by downregulating Ki67 and β-catenin while upregulating p53, and suppressed the proliferation, colony formation, and migration of HCT116 cells. Mechanistically, the extract modulated the YAP/PI3K/AKT pathway by upregulating phosphorylated YAP (p-YAP) and downregulating phosphorylated AKT (p-AKT), phosphorylated PI3K (p-PI3K), and their downstream targets p-SRC and c-MYC. Conclusions: This study suggests that Rhapontici Radix extract intervenes in inflammation-associated carcinogenesis through a multi-pathway, multi-target strategy, offering potential therapeutic targets for CAC prevention and treatment. Full article

Background: Inflammatory bowel disease (IBD) is a gut-based idiopathic disease characterized by chronic and relapsing inflammatory progression and intricate pathophysiology. It is now known that the key etiologies of IBD include immune dysregulation, imbalances in the gut microbiota, and metabolic disruptions. Probiotics are now the potential treatment for IBD, due to their ability to regulate the host immune system and microbiota of the gut. Methods: The current study analytically tested the preventive benefit of Bacillus licheniformis BL-01 on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) and also expounded on its molecular pathogenesis. Results: Our results demonstrate that supplementation with BL-01 effectively mitigates DSS-induced weight loss, an elevated disease activity index (DAI), and colonic tissue injury in mice. Concomitantly, BL-01 rectifies dysregulated inflammatory cytokine profiles, attenuates oxidative stress, and restores the expression of colonic tight junction proteins as well as the number of goblet cells. Furthermore, BL-01 modulates the gut microbiota diversity by increasing the abundance of beneficial bacterial genera such as Duncaniella and decreasing the abundance of pathogenic genera such as Helicobacter. Notably, BL-01 restores DSS-induced microbial metabolic dysregulation, modulates key metabolic pathways including arachidonic acid metabolism and steroid hormone biosynthesis, and regulates associated metabolites to ameliorate UC. Finally, Bacillus licheniformis BL-01 mitigates oxidative stress, reverses gut dysbiosis and metabolic disorders, and has a protective effect on UC. Conclusions: The findings give new information on the development of probiotic-based therapeutics in the prevention and treatment of IBD. Full article

The dextran sodium sulfate (DSS) colitis model is the most widely used experimental model of inflammatory bowel disease (IBD) due to its simplicity and versatility, with over 7000 PubMed entries in the last decade and an exponential rise in recent years. Since its initial description in 1985, DSS colitis has been extensively evaluated across species, most notably in mice and rats, and has yielded substantial insights into IBD pathogenesis. However, the model’s multifactorial nature poses a dual challenge: it offers an opportunity but complicates study design, interpretation, and translational relevance. This complexity is worsened by inconsistent reporting, which hampers reproducibility and comparability across studies. The broad use of the DSS-induced colitis model yields numerous insights about the model, which help better understand its complexity, characteristics and limitations. Although DSS colitis is induced locally, inflammation in the colon and gut barrier destruction may also affect other organs (such as the liver and brain) and their metabolism and molecular responses, which, in turn, may interfere with colitis-underlying mechanisms and drug response, and may influence the interpretation of results. These intrinsic (intra-experimental) characteristics of the DSS model are summarised in the paper (colitis, gut–brain axis, gut–liver axis). In addition, the DSS model is heavily influenced by numerous extrinsic (inter-experimental) factors (environmental, microbiological, genetic), which may further complicate the colitis model, the study outcomes, and data interpretation, and these are also discussed in the paper. As science advances and new data accumulate, understanding the intricate interplay among internal mechanisms, external factors, and technical variables becomes increasingly essential for the accurate interpretation of DSS outcomes. This review synthesises the complexity and interdependence of factors shaping the DSS model, emphasising the need for meticulous reporting and consideration of methodological nuances to enhance reproducibility, interpretation, and translational value in DSS colitis research. In addition, the review provides practical guidance through a “traps and tricks” subsection and checklist table designed to provide a framework and practical recommendations to better understand, apply, and interpret DSS model results in the context of broader systemic and methodological considerations. Full article

Background: Ulcerative colitis, a chronic inflammatory disorder of the intestine, represents a major health concern worldwide. This study aimed to explore the in vivo efficacy of rice bran protein hydrolysates in mitigating UC. Methods: Rice bran protein hydrolysates with enhanced antioxidant activity were prepared via co-treatment with Alcalase and Lactiplantibacillus plantarum 13110. Results: Compared with hydrolysates obtained using Alcalase in isolation (RHP), the co-treated rice bran (CRB) protein hydrolysates exhibited significantly higher antioxidant capacity. Structural characterization revealed marked alterations in molecular weight distribution, amino acid composition, and RHP spectral features, based on Fourier transform infrared spectroscopy, during fermentation with L. plantarum 13110. The 500 mg/kg·bw CRB intervention effectively attenuated oxidative stress and inflammatory responses in dextran sulfate sodium (DSS)-induced colitic mice, as evidenced by significantly reduced colonic levels (p < 0.05) of pro-inflammatory mediators (TNF-α, IL-1β, IL-6, and LPS), decreased serum concentrations of fatty acid-binding protein 2 (FABP2), diamine oxidase (DAO), and D-lactic acid (D-LA), and increased colonic IL-10 content (p < 0.05). These changes were associated with ulcerative colitis amelioration and improved intestinal barrier function. Conclusions: Thus, CRB exhibits promising prophylactic effects against ulcerative colitis, suggesting its potential for therapeutic application. Full article

Background: Astragalus membranaceus Fisch. ex Bunge has long been used in East Asian medicine for gastrointestinal disorders and immune modulation. Astragaloside IV (AS-IV), a major bioactive saponin from its roots, exhibits potent anti-inflammatory and antioxidant activities, yet its protective effects against inflammatory bowel disease (IBD)-associated multi-organ damage via the gut–liver–brain axis remain unclear. Methods: Experimental colitis was induced in C57BL/6N mice by administering 5% dextran sulfate sodium (DSS) in drinking water for seven days. AS-IV (100 mg/kg/day) was orally administered during DSS exposure. Disease severity was evaluated using body weight, colon length, disease activity index, and histopathology. Inflammatory cytokines and oxidative stress markers were measured using ELISA, and NF-κB and MAPK signaling were analyzed through Western blotting and immunohistochemistry in colonic, hepatic, and brain tissues. Results: AS-IV significantly alleviated DSS-induced weight loss, disease activity, and colon shortening, while improving intestinal histopathological damage. AS-IV also reduced systemic pro-inflammatory cytokine levels and oxidative stress. Mechanistically, AS-IV was associated with a reduced expression of phosphorylated NF-κB and MAPK proteins, including p-NF-κB, p-IκBα, p-ERK, p-JNK, and p-p38, across the colon, liver, and brain. Conclusions: AS-IV attenuates DSS-induced multi-organ inflammation via gut–liver–brain axis modulation through NF-κB and MAPK pathway inhibition in experimental colitis models. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, yet the association between folic acid (FA) intake and CRC risk remains controversial. This study investigated the effects of varying dietary FA levels on colorectal carcinogenesis and the underlying mechanisms. Methods: BALB/c mice were fed diets containing FA at <0.1, 2.0, 6.0, 8.0, or 20.0 mg/kg for 14 weeks. After 4 weeks, colorectal tumorigenesis was induced using the azoxymethane/dextran sulfate sodium (AOM/DSS) protocol. Tumor multiplicity, maximum tumor diameter, tumor volume, colorectal length, histopathology, and cell proliferation were assessed. Mechanistic assessments included uracil misincorporation, thymidylate synthase (TS), telomere attrition, genome-wide DNA methylation, RAP1 signaling, immune-related markers, and inflammatory cytokines in colorectal tissues. Results: Both FA deficiency (<0.1 mg/kg) and excess (8.0/20.0 mg/kg) increased colorectal tumor burden, with increased tumor number, larger maximum diameter, greater tumor volume, shortened colorectal length, and enhanced cell proliferation, whereas the 6.0 mg/kg diet group showed the lowest tumor burden. FA deficiency reduced TS expression, elevated deoxyuridine monophosphate (dUMP) levels, decreased deoxythymidine monophosphate (dTMP) levels, increased uracil misincorporation, and exacerbated telomere attrition, as evidenced by shortened telomeres and increased damage. In contrast, excessive FA intake induced Rap1 GTPase-activating protein (RAP1GAP) hypermethylation, reduced Rap1GAP expression, enhanced RAP1 activity, and upregulated programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) expression. Conclusions: Dietary FA can exhibit a U-shaped association with colorectal carcinogenesis, with protective effects observed within an optimal range. FA deficiency and excess may drive tumor development through distinct molecular pathways involving uracil misincorporation-induced telomere attrition and DNA methylation-mediated immunosuppression, respectively. Full article

Background/Objectives: Ulcerative colitis (UC) involves inflammatory response, oxidative stress, changes in metabolites, and the gut microbiota. Jingangteng capsule (JGTC) has been utilized clinically for the treatment of inflammatory diseases for many years. However, the efficacy of JGTC in ameliorating UC remains unclear, and the underlying mechanisms have not yet been elucidated. This study aims to investigate the effect and mechanism of JGTC on UC. Methods: The chemical compositions of JGTC were examined using ultra-high-performance liquid chromatography with quadrupole time-of-fight mass spectrometry. The anti-UC effect of JGTC was evaluated by assessing the disease activity index (DAI), colon length, intestinal barrier recovery, and inflammatory factors in a dextran sulfate sodium (DSS)-induced colitis model. Mechanisms were investigated through fecal 16S rDNA sequencing, metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), Western blotting, and network pharmacology analysis. Results: JGTC significantly reduced the DAI scores in UC mice, increased their body weight and colon length (p < 0.001), repairing damaged intestinal tissue. It decreased the levels of inflammatory cytokines TNF-α, IL-6, IL-1β, and LPS (p < 0.01, p < 0.001), alleviating intestinal inflammation. It also raised the expression of tight junction proteins ZO-1, Claudin-1, and Occludin (p < 0.05, p < 0.001), thereby enhancing intestinal barrier function. Fecal metabolomic analysis revealed that the favorable alterations in amino acid and lipid metabolites were more pronounced. Heat maps showed strong correlations between pharmacological indicators and gut microbiota, as well as between the main differential metabolites and gut microbial communities. UPLC-QTOF-MS detection yielded 33 components of JGTC, and network pharmacology analysis based on these components predicted pathways of action of JGTC in UC. Functional pathways closely associated with significantly differential metabolites and metabolic pathways were also investigated. The PI3K-AKT-mTOR pathway was one of them, which is consistent with the conclusions drawn from network pharmacology. JGTC significantly modulated key factors in this pathway, inhibiting the expression of PI3K, Akt, PDK1, and mTOR, while augmenting the expression of PTEN (p < 0.05, p < 0.01, p < 0.001). It also mitigated the levels of related oxidative stress factors MDA, MPO, and D-LA, and raised SOD levels (p < 0.01, p < 0.001). Conclusions: JGTC improved the excessive inflammatory response in UC by regulating intestinal flora and metabolic disorders, affecting the PI3K-AKT-mTOR signaling pathway, restoring intestinal tissue damage and intestinal barrier, and inhibiting inflammatory and oxidative stress factors. Full article

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder with a high incidence of anxiety and depression. However, the underlying mechanisms of these symptoms remain to be fully elucidated. This study investigated the effects and mechanisms of a 20% ethanolic extract of Petasites japonicus leaves (EPJ) on dextran sulfate sodium (DSS)-induced colitis and depression-like behaviors. The physiological compounds identified in the EPJ were citric acid, chlorogenic acid, caffeic acid, fukinolic acid, 3,5-dicaffeoylquinic acid, quercetin 3-O-β-D-glucose-6″-acetate, 4,5-dicaffeoylquinic acid, kaempferol-3-O-(6″-acetyl)-β-glucopyranoside, and pedunculoside. EPJ significantly alleviated DSS-induced colitis, as evidenced by improvements in body weight loss (87.41% vs. 76.02% in the DSS group), colon length (5.75 vs. 4.34 cm), intestinal permeability (52.80 vs. 163.01 μg/mL), and myeloperoxidase (MPO) activity (0.24 vs. 0.67 U/mg) (p < 0.05). Histological analysis further confirmed recovery of goblet cells and attenuation of muscle layer thickening. EPJ also reversed DSS-induced gut microbiota dysbiosis and contributed to the restoration of microbial homeostasis. Behavioral assessments showed that EPJ effectively ameliorated depression-like behaviors. EPJ improved antioxidant systems in colon and brain tissues by modulating malondialdehyde (MDA) levels and reduced glutathione (GSH) and superoxide dismutase (SOD) activity. EPJ further upregulated tight junction protein expression and suppressed TLR4/NF-κB inflammatory pathway activation in both colon and brain tissues. Moreover, EPJ modulated serum stress-related hormones, normalized hypothalamic–pituitary–adrenal (HPA) axis dysregulation, regulated the BDNF/TrkB signaling pathway, and modulated tryptophan–kynurenine metabolism. Collectively, these findings suggest that EPJ exerts protective effects against DSS-induced colitis and depression-like behaviors. Full article