Dextran Sulfate Sodium Research Articles

Ninjurin1 deficiency differentially mitigates colorectal cancer induced by azoxymethane and dextran sulfate sodium in male and female mice.

This study investigated the role of Ninjurin1 (Ninj1), encoding a small transmembrane protein, in colitis-associated colon tumorigenesis in relation to sex hormones. Male and female wild-type (WT) and Ninj1 knockout (KO) mice were treated with azoxymethane (AOM) and dextran sulfate sodium (DSS), with or without testosterone propionate (TP). At week 2 (acute colitis stage), Ninj1 KO exhibited an alleviation in the colitis symptoms in both male and female mice. The M2 macrophage population increased and CD8+ T cell population decreased only in the female Ninj1 KO than in the female WT AOM/DSS group. In the female AOM/DSS group, TP treatment exacerbated colon shortening in the Ninj1 KO than in the WT. At week 13 (tumorigenesis stage), male Ninj1 KO mice had fewer tumors, but females showed similar tumors. In the WT AOM/DSS group, females had more M2 macrophages and fewer M1 macrophages than males, but this difference was absent in Ninj1 KO mice. In the Ninj1 KO versus WT group, the expression of pro-inflammatory mediators and Ho-1 and CD8+ T cell populations decreased in both female and male Ninj1 KO mice. In the WT group, M2 macrophage populations were increased by AOM/DSS treatment and decreased by TP treatment. However, neither treatment changed the cell populations in the Ninj1 KO group. These results suggest that Ninj1 is involved in colorectal cancer development in a testosterone-dependent manner, which was different in male and female. This highlights the importance of considering sex disparities in understanding Ninj1's role in cancer pathogenesis.

Therapeutic Effects of Zanthoxyli Pericarpium on Intestinal Inflammation and Network Pharmacological Mechanism Analysis in a Dextran Sodium Sulfate-Induced Colitis Mouse Model.

(1) Background: IBD (inflammatory bowel disease) is characterized by chronic intestinal inflammation leading to persistent symptoms and a lack of effective treatments. ZP (Zanthoxyli Pericarpium) has been used in traditional Chinese medicine for its anti-inflammatory and antioxidant properties for the management of intestinal disorders. (2) Methods: This study aimed to investigate the components of ZP, their specific targets, and associated diseases using the TCMSP (Traditional Chinese Medicine Systems Pharmacology) analysis platform, TCMBank database, and ETCM2.0 (Encyclopedia of Traditional Chinese Medicine 2.0) database. Additionally, we explored the protective effects of ZP on the colon and the underlying molecular mechanisms in the treatment of IBD. (3) Results: We identified 59 compounds in ZP that target 38 genes related to IBD, including PTGS2, PPARG, and GPBAR1. In a mice model of DSS (dextran sodium sulfate)-induced colitis, ZP significantly reduced colonic epithelial damage and oxidative stress markers, such as iNOS and nitrotyrosine, demonstrating its antioxidant properties. (4) Conclusions: These findings suggest that ZP has protective effects against DSS-induced colonic damage owing to its anti-inflammatory and antioxidant properties, making it a potential candidate for IBD treatment. However, further research and clinical trials are required to confirm its therapeutic potential and safety in humans.

Bioinspired core-shell microparticle for dual-delivery of prebiotic and probiotic for the treatment of ulcerative colitis

Lactiplantibacillus plantarum (LP) is a well-known probiotic strain that has a beneficial effect in preventing ulcerative colitis. However, delivering a sufficient number of viable LP to the colon still face challenges due to its vulnerability to the highly complex intestinal flora ecosystem. Herein, we present a centrifuge-driven micronozzle system designed for double-layered core-shell alginate microcapsules (DAM), which can serve as an effective carrier for dual delivery of resistant starch nanoparticles (RSNP, prebiotic) and LP (probiotics) for the treatment of colitis. This system enables precise loading of LP and RSNP within the core and shell regions of DAM, respectively. The resulting LP/RS@DAM exhibited a high encapsulation efficiency of LP (108 CFU per bead), in which the dense distribution of RSNP in the shell effectively protected LP against acidic conditions (pH 2) and maintained the cell viability up to 52 % even after long-term storage for 30 days. Furthermore, LP/RS@DAM effectively enhances the production of short-chain fatty acids, leading to a reduction in inflammatory cytokines and restoration of intestinal microbial diversity in dextran sulfate sodium (DSS)-induced colitis. We believe that this innovative approach would offer a potential solution for improving colitis management and paving the way for tailored therapeutic interventions in gastrointestinal disorders.

Dextran Sulfate Sodium as Multifunctional Aqueous Binder Stabilizes Spinel LiMn2O4 for Lithium Ion Batteries

AbstractSpinel LiMn2O4 (LMO) has several beneficial properties for utilization as a cathode material for lithium‐ion batteries, including a high operating voltage, thermal stability, low cost, and eco‐friendliness. However, its application is limited by capacity fading due to structural transformation and manganese dissolution upon cycling. A method is proposed to resolve these two issues, using dextran sulfate sodium (DSS) as an aqueous binder to coat the LMO surface. DSS stabilizes the surface/interface structure of LMO by incorporating Na into the interstitial 16c sites, creating a uniform surface coating layer and promoting the formation of a homogeneous and stable cathode‐electrolyte interphase derived from the sulfate groups in DSS and enriched with LiF/LiSOxF. The aqueous DSS binder effectively suppresses the surface degradation and Mn dissolution of spinel LMO. The LMO electrode based on DSS exhibits superior cycling stability and rate performance compared with those of electrodes using the conventional poly(vinylidene difluoride) binder. These findings demonstrate the potential value of DSS as a multifunctional aqueous binder in stabilizing spinel LMO for lithium‐ion batteries.

Immunomodulatory effect of Dicrocoelium dendriticum ova on DSS-induced experimental colitis in C57BL/6 mouse

Inflammatory bowel disease (IBD) significantly diminishes an individual’s quality of life and increases the risk of colorectal cancer. Recent clinical and experimental findings suggest that infection with parasitic helminths may suppress the development of certain inflammatory conditions. The objective of this study was to evaluate the immunoregulatory effects of Dicrocoelium eggs on experimentally induced colitis in C57BL/6 mice using dextran sulfate sodium (DSS). C57BL/6 mice received 3.5% DSS orally for 7 days to induce colitis, during which they were treated intraperitoneally with Dicrocoelium eggs. The severity of colitis was assessed through parameters such as body weight, stool consistency or bleeding, disease activity index (DAI), colon lengths, macroscopic scores, histopathological findings, colon gene expression levels, and serum cytokine levels. Our results indicated that Dicrocoelium eggs administration significantly reduced the severity of colitis and disease activity. Histopathological scores improved, correlating with downregulation of IFN-γ and upregulation of IL-4 expression. This findings suggest the therapeutic potential of Dicrocoelium eggs in treating colitis. Immunotherapy involving Dicrocoelium eggs primarily induces a Th2 response and modulates IFN-γ, contributing to reduced inflammation in colitis. Thus, this approach could be a promising therapeutic strategy for alleviating inflammation in IBD.

Kui-Jie-Ling capsule inhibits ulcerative colitis by modulating inflammation and gut microbiota.

Kui-Jie-Ling capsule (Kui-Jie-Ling) is a hospital preparation for ulcerative colitis (UC) in China. This study aimed at evaluating the protective effects and mechanisms of Kui-Jie-Ling and Kui-Jie-Ling combined with adalimumab on UC induced by dextran sulfate sodium (DSS). Network pharmacology was combined with an animal experiment to reveal the targets of Kui-Jie-Ling alleviating UC. The UC model was established by drinking 2.5% DSS solution for 7days. On the second day, the mice in the Kui-Jie-Ling group were orally administered with Kui-Jie-Ling (1.5 and 3.0g/kg) daily for seven consecutive days, and the mice in the combination group were orally administered with Kui-Jie-Ling (3.0g/kg) once a day for seven consecutive days and received one subcutaneous injection of adalimumab. The disease activity index, the colon length, the spleen index, the cytokines, the colon, the short-chain fatty acid content, and the gut microbiota in the colon were analyzed. The role of gut microbiota against UC was verified by fecal microbiota transplantation experiments. The animal study's results were consistent with the network pharmacology analysis, which reflected that Kui-Jie-Ling alleviated UC via multi-pathway. Kui-Jie-Ling ameliorated UC by inhibiting the formation of neutrophil extracellular traps (NETs), regulating inflammatory factors through the lipopolysaccharide-toll-like receptor 4/nuclear factor kappa B and interleukin-23-Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway, and restoring intestinal homeostasis. These studies provided the experimental basis for the clinical administration of Kui-Jie-Ling and Kui-Jie-Ling combined with adalimumab against UC.

Scutellarin alleviated ulcerative colitis through gut microbiota-mediated cAMP/PKA/NF-κB pathway

PurposeUlcerative colitis (UC) is a chronic, non-specific inflammatory condition of the colon, characterized by recurrent episodes and a notable lack of effective pharmacological treatments. Scutellarin, a natural component, exhibits appreciable pharmacological effects and therapeutic potential for various diseases. However, its effects on UC are not fully understood, and the precise mechanisms remain to be deciphered. This study aimed to assess the therapeutic efficacy of scutellarin and elucidate its underlying mechanisms in treating UC. MethodsThis study utilized dextran sulfate sodium (DSS)-induced mice to evaluate the therapeutic potential of scutellarin against UC and to elucidate the mechanisms involving the gut microbiota. An antibiotics cocktail (ABX) and fecal microbiota transplantation (FMT) were also used to determine the mechanistic role of the gut microbiota. An integrative approach combining fecal metabolomics and network pharmacology analysis was used to explore the gut microbiota-directed molecular mechanism. ResultsThe results showed that scutellarin provided various therapeutic benefits in UC management, including alleviating weight loss, slowing disease progression, and reducing inflammatory damage in colon structures. The improved gut microbiota after scutellarin administration contributed to these effects. Fecal metabolome revealed that scutellarin selectively mitigated DSS-induced dysregulation of gut microbiota-derived metabolites, including glycolic acid, γ-aminobutyric acid, glutamate, tryptophan, xanthine, and β-hydroxypyruvate. Network pharmacology analysis, along with in vivo experimental verification, implicated the cAMP/PKA/NF-κB pathway in the action of these metabolites in treating UC, which may be the mechanism responsible for scutellarin's curative effects on UC. ConclusionThis study demonstrates the potential of scutellarin in alleviating UC by activating the cAMP/PKA/NF-κB pathway through gut microbiota-derived metabolites, highlighting scutellarin as a promising therapeutic agent for UC.

Fermented Soymilk with Probiotic Lactobacilli and Bifidobacterium Strains Ameliorates Dextran-Sulfate-Sodium-Induced Colitis in Rats.

Background: Current treatments for inflammatory bowel disease (IBD) are relatively futile and the extended use of drugs may reduce effectiveness. Several probiotic strains have shown promise in relieving/treating IBD symptoms. Objectives: The current study investigated the impact of fermented soymilk with a mixture of probiotic starter cultures containing Lactobacillus rhamnosus, L. casei, L. plantarum, L. acidophilus, Bifidobacterium longum, and B. animalis subsp. lactis in rats with dextran sulfate sodium (DSS)-induced colitis compared to control. Methods: Rats were randomly assigned to five groups (5 rats/group; n = 25): G1: negative normal control; G2: positive control (DSS); G3: DSS with sulfasalazine (DSS-Z); G4: DSS with soymilk (DSS-SM), and G5: DSS with fermented soymilk (DSS-FSM). Parameters monitored included the following: the disease activity index (DAI), macroscopic and histological assessments of colitis, and a fecal microbial analysis performed to assess the severity of inflammation and ulceration. Results: The DSS-FSM rats group exhibited lower DAI scores (p < 0.05) than other treated groups during the induction period. A macroscopical examination revealed no ulceration or swelling in the intestinal mucosa of rats in the DSS-FSM-treated group, resembling the findings in the negative control group. In the positive control (DSS group), the colon tissue showed increased inflammation (p < 0.05), whereas those in the DSS-SM- and DSS-FSM-treated rats groups did not show significant macroscopic scores of colitis. The positive DSS control and DSS-Z groups had crypt erosion and ulceration areas, severe crypt damage, and epithelial surface erosion, which were absent in the negative control and DSS-FSM groups. The counts of Lactobacillus spp. and Bifidobacterium spp. remained stable in both G1 and G5 over 4 weeks. The consumption of fermented soymilk with a mixture of probiotics could minimize the severity of DSS-induced colitis in rats. Conclusion, it was found that fermented soymilk containing Lactobacilli and Bifidobacterium might be an effective vehicle for reducing the severity of DSS-induced colitis in rats.

Didymin Ameliorates Dextran Sulfate Sodium (DSS)-Induced Ulcerative Colitis by Regulating Gut Microbiota and Amino Acid Metabolism in Mice.

Background: Didymin is a dietary flavonoid derived from citrus fruits and has been shown to have extensive biological functions, especially anti-inflammatory effects, but its mechanism is unclear. The purpose of this study was to investigate the potential mechanism of didymin that alleviates ulcerative colitis. Methods and Results: Our results indicated that didymin could alleviate the symptoms of ulcerative colitis, as it inhibited the expressions of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Didymin also promoted the expressions of claudin-1 and zona occludens-1(ZO-1), which are closely related with restoring colon barrier function. Didymin also increased the abundance of Firmicutes and Verrucomicobiota, while decreasing the abundance of Bacteroidota and Proteobacteria. Meanwhile, didymin significantly altered the levels of metabolites related to arginine synthesis and metabolism, and lysine degradation in the colitis mice. Utilizing network pharmacology and molecular docking, our results showed that the metabolites L-ornithine and saccharin could interact with signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-B (NF-κB). In this in vitro study, L-ornithine could reduce the expressions of transcription factors STAT3 and NF-κB, and it also inhibited the expressions of IL-6 and IL-1β in the lipopolysaccharides (LPS) induced in RAW264.7 cells, while saccharin had the opposite effect. Conclusions: Taken together, didymin can regulate gut microbiota and alter metabolite products, which can modulate STAT3 and NF-κB pathways and inhibit the expressions of inflammatory factors and inflammatory response in the DSS-induced colitis mice.

Buddlejasaponin IVb Alleviates DSS-Induced Ulcerative Colitis through the Nrf2/GPX4 Pathway and Gut Microbiota Modulation.

Buddlejasaponin IVb (BJP-IVb), a triterpenoid saponin derived from Pleurotus ostreatus, is abundant in bioactive constituents. However, its potential therapeutic benefits and underlying mechanism of action against ulcerative colitis (UC) remain elusive. Studies performed using a mouse model of colitis caused by dextran sulfate sodium showed that BJP-IVb helped reduce symptoms of UC, such as weight loss, a higher disease activity index, shorter colon length, and colon damage. It also repaired the intestinal barrier function and suppressed inflammation. BJP-IVb activated the Nrf2/HO-1 antioxidant pathway, inhibited ferroptosis, and affected protein expression and oxidative indicators. The combined use of BJP-IVb and Nrf2 inhibitor ML385 negated the effects of BJP-IVb. In Nrf2-KO mice, the protective effects of BJP-IVb were reversed. BJP-IVb inhibited ferroptosis via the Nrf2/GPX4 axis and alleviated gut microbiota dysbiosis. In conclusion, our research validates the therapeutic and protective efficacy of BJP-IVb on ulcerative colits. Additionally, it offers new perspectives on preventing colitis by focusing on the metabolism of gut microbiota using natural substances.

Dietary titanium dioxide nanoparticles impair intestinal epithelial regeneration by perturbating the function of intestinal stem cells

Intestinal health is closely linked to intestinal stem cells (ISCs), which are highly sensitive to the harmful substances in the lumen. However, there is limited knowledge regarding the effects of food additives on ISCs. This study aims to investigate the impact of dietary titanium dioxide nanoparticles (TiO2 NPs) compared with titanium dioxide microparticles (TiO2 MPs) on intestinal health associated with ISCs in response to dextran sodium sulfate (DSS)-induced enteritis in mice, as well as the related mechanism. We found that exposure to 1% (w/w) TiO2 NPs aggravated DSS-induced enteritis in mice, while this effect could not be observed under exposure to TiO2 MPs. Additionally, 1% (w/w) TiO2 NPs exposure under DSS-induced enteritis worsened the ISC-mediated regeneration of intestinal epithelium by decreasing the epithelial cell proliferation and epithelial turnover rate while increasing epithelial cell death. Meanwhile, using a 3D intestinal organoid model, we discovered that 20 μg/mL TiO2 NPs impaired ISC function and disrupted ISC fate specification both ex vivo and in vitro. Furthermore, TiO2 NPs hindered the nuclear translocation of β-catenin, reducing the overall output of Wnt signaling. Together, TiO2 NPs deteriorated the intestinal epithelial regeneration of mice with DSS-induced enteritis by perturbating ISC function and fate specification through a mechanism involving Wnt signaling. These findings highlight the adverse effect of dietary TiO2 NPs on ISCs and shed light on the particle size optimization of TiO2 food additive.

A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation.

Tolerance to the analgesic effects of opioids and resultant dose escalation is associated with worsening of side effects and greater addiction risk. Here, we compare the development of tolerance to the conventional opioid fentanyl with a novel pH-sensitive μ-opioid receptor (MOR) agonist, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP) that is active only in acidic inflammatory microenvironments. An opioid tolerance model was developed in male C57BL/6 mice, with and without dextran sulphate sodium colitis, using increasing doses of either fentanyl or NFEPP over 5 days. Visceral nociception was assessed in vivo by measuring visceromotor responses (VMRs) to noxious colorectal distensions and in vitro measuring colonic afferent nerve activity of mesenteric nerves and performing patch-clamp recordings from isolated dorsal root ganglia neurons. Somatic thermal nociception was tested using a tail immersion assay. Cardiorespiratory effects were analysed by pulse oximeter experiments. VMRs and tail immersion tests demonstrated tolerance to fentanyl, but not to NFEPP in colitis mice. Cross-tolerance also occurred to fentanyl, but not to NFEPP. The MOR agonist DAMGO inhibited colonic afferent nerve activity in colitis mice exposed to chronic NFEPP, but not those from fentanyl-treated mice. Similarly, in patch-clamp recordings from isolated dorsal root ganglia neurons, DAMGO inhibited neurons from NFEPP-, but not fentanyl-treated mice. NFEPP did not exhibit tolerance in an inflammatory pain model, unlike fentanyl. Consequently, dose escalation to maintain analgesia during an evolving inflammation could be avoided, mitigating the potential risk of side effects.

Protective Effects of Astaxanthin against Oxidative Stress: Attenuation of TNF-α-Induced Oxidative Damage in SW480 Cells and Azoxymethane/Dextran Sulfate Sodium-Induced Colitis-Associated Cancer in C57BL/6 Mice.

In this study, we investigated the protective effects of astaxanthin (AST) against oxidative stress induced by the combination of azoxymethane (AOM) and dextran sulfate sodium (DSS) in colitis-associated cancer (CAC) and TNF-α-induced human colorectal cancer cells (SW480), as well as the underlying mechanism. In vitro experiments revealed that astaxanthin reduced reactive oxygen species (ROS) generation and inhibited the expression of Phosphorylated JNK (P-JNK), Phosphorylated ERK (P-ERK), Phosphorylated p65 (P-p65), and the NF-κB downstream protein cyclooxygenase-2 (COX-2). In vivo experiments showed that astaxanthin ameliorated AOM/DSS-induced weight loss, shortened the colon length, and caused histomorphological changes. In addition, astaxanthin suppressed cellular inflammation by modulating the MAPK and NF-κB pathways and inhibiting the expression of the proinflammatory cytokines IL-6, IL-1β, and TNF-α. In conclusion, astaxanthin attenuates cellular inflammation and CAC through its antioxidant effects.

Cordycepin mitigates dextran sulfate sodium-induced colitis through improving gut microbiota composition and modulating Th1/Th2 and Th17/Treg balance

BackgroundImbalances in Th1/Th2 and Th17/Treg immune axes, coupled with disruptions in the gut microbiota (GM), play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). Cordycepin, a natural anti-inflammatory compound, holds promise in mitigating IBD by rebalancing these immune axes in conjunction with modulating the GM. The aim of this experiment is to investigate the potential of cordycepin in mitigating enteritis and elucidate the underlying mechanisms associated with its ameliorative effects on enteritis. MethodsOn the day of inducing experimental colitis with Dextran Sulfate Sodium (DSS), mice in the DSS + Cordycepin and Cordycepin groups received 50 mg/kg/day Cordycepin via intra-gastric administration (i.g.) for seven consecutive days, respectively. Mice in the DSS and control groups were treated with equal volumes of saline. On day 8, all mice were euthanized under pentobarbital sodium anesthesia. ResultsIn a DSS-induced colitis mouse model, Cordycepin treatment led to a significant reduction in the disease activity index (DAI), splenic weight, and colonic pathological injury while simultaneously improving body weight and colonic length. Furthermore, it positively impacted GM composition, resulting in decreased Th1 and Th17 cells, alongside an increase in Th2 and Treg cells. The contents of the mouse colon were extracted for microbial community analysis. Mouse blood was prepared into a single-cell suspension, and flow cytometry was used to assess the expressio of Treg, Th17, Th1, and Th2 immune cells. ConclusionsThese results underscored the effective intervention of cordycepin in ameliorating DSS-induced colitis by harmonizing the interplay between GM and immune homeostasis.

Trp53 Deletion Promotes Exacerbated Colitis, Facilitates Lgr5+ Cancer Stem Cell Expansion, and Fuels Tumorigenesis in AOM/DSS-Induced Colorectal Cancer

Colorectal cancer CRC remains one of the leading causes of cancer-related deaths worldwide, with chronic intestinal inflammation identified as a major risk factor. Notably, the tumor suppressor TP53 undergoes mutation at higher rates and earlier stages during human inflammation-driven colon tumorigenesis than in sporadic cases. We investigated whether deleting Trp53 affects inflammation-induced tumor growth and the expression of Lgr5+ cancer stem cells in mice. We examined azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis in wild-type Trp53 (+/+), heterozygous (+/−), and knockout (−/−) mice. Trp53−/− mice showed increased sensitivity to DSS colitis and earlier accelerated tumorigenesis with 100% incidence. All groups could develop invasive tumors, but knockouts displayed the most aggressive features. Unlike wild-type CRC, knockouts selectively showed increased populations of Lgr5+ colon cancer stem-like cells. Trp53 loss also boosted laminin, possibly facilitating the disruption of the tumor border. This study highlights how Trp53 deletion promotes the perfect storm of inflammation and stemness, driving colon cancer progression. Trp53 deletion dramatically shortened AOM/DSS latency and improved tumor induction efficiency, offering an excellent inflammation-driven CRC model.

Cimicifuga heracleifolia kom. Attenuates ulcerative colitis through the PI3K/AKT/NF-κB signaling pathway

Ethnopharmacological relevanceCimicifuga heracleifolia Kom. (C. heracleifolia) has demonstrated efficacy in treating gastrointestinal disorders, including splenasthenic diarrhea. Ulcerative colitis (UC), a chronic inflammatory bowel disease, shares similarities with splenasthenic diarrhea. However, the pharmacological effects of C. heracleifolia on UC and the underlying mechanisms remain unexplored. Aim of the studyThe present study investigates the therapeutic potential and mechanisms of C. heracleifolia in UC. MethodsInitially, network pharmacology analysis, encompassing ingredient screening, target prediction, protein-protein interaction (PPI) network analysis, and enrichment analysis, was employed to predict the mechanisms of C. heracleifolia. The findings were further validated using transcriptomics and functional assays in a dextran sulfate sodium (DSS)-induced UC model. Additionally, bioactive compounds were identified through surface plasmon resonance (SPR) analysis, molecular docking, and cell-based assays. ResultsA total of 52 ingredients of C. heracleifolia were screened, and 32 key targets were identified within a PPI network comprising 285 potential therapeutic targets. Enrichment analysis indicated that the anti-UC effects of C. heracleifolia are mediated through immune response modulation and the inhibition of inflammatory signaling pathways. In vivo experiments showed that C. heracleifolia mitigated histological damage in the colon, reduced the expression of phosphorylated Akt1, nuclear factor-kappa B (NF-κB) p65, and inhibitor of Kappa B kinase α/β (IKKα/β), suppressed the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and enhanced the expression of tight junction proteins. Moreover, cimigenoside, caffeic acid, and methyl caffeate were identified as the bioactive constituents responsible for the UC treatment effects of C. heracleifolia. ConclusionsIn summary, this study is the first to demonstrate that C. heracleifolia exerts therapeutic effects on UC by enhancing the intestinal mucosal barrier and inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/NF-κB signaling pathway. These findings offer valuable insights into the clinical application of C. heracleifolia for UC management.

Toll-like receptor 7 protects against intestinal inflammation and restricts the development of colonic tissue-resident memory CD8+ T cells.

The maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn's disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8+ T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses. However, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7-/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B+ tissue-resident memory CD8+ T (TRM) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid (Atg16l1ΔLyz2 ) or dendritic cells (Atg16l1ΔCd11c ) leads to a similar increase of LP TRM. Furthermore, Tlr7-/- and Atg16l1ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP TRM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7. In conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants.

Enhanced Effect of β-Lactoglobulin Immunization in Mice with Mild Intestinal Deterioration Caused by Low-Dose Dextran Sulphate Sodium: A New Experimental Approach to Allergy Studies.

Cow's milk allergy is one of the most common food allergies in children, and its pathomechanism is still under investigation. Recently, an increasing number of studies have linked food allergy to intestinal barrier dysfunction. The present study aimed to investigate changes in the intestinal microenvironment during the development of β-lactoglobulin (β-lg) allergy under conditions of early intestinal dysfunction. BALB/c mice received intraperitoneal β-lg with Freund's adjuvant, followed by oral β-lg while receiving dextran sulphate sodium salt (DSS) in their drinking water (0.2% w/v). The immunized group without DSS and the groups receiving saline, oral β-lg, or DSS served as controls. The study showed that the immunization effect was greater in mice with mild intestinal barrier dysfunction. Although DSS did not affect the mice's humoral response to β-lg, in combination with β-lg, it significantly altered their cellular response, affecting the induction and distribution of T cells in the inductive and peripheral tissues and the activation of immune mediators. Administration of β-lg to sensitized mice receiving DSS increased disease activity index (DAI) scores and pro-inflammatory cytokine activity, altered the distribution of claudins and zonulin 1 (ZO-1) in the colonic tissue, and negatively affected the balance and activity of the gut microbiota. The research model used appears attractive for studying food allergen sensitization, particularly in relation to the initial events leading to mucosal inflammation and the development of food hypersensitivity.

Insights of Expression Profile of Chemokine Family in Inflammatory Bowel Diseases and Carcinogenesis

Chemokines are integral components of the immune system and deeply involved in the pathogenesis and progression of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although a considerable amount of transcriptome data has been accumulated on these diseases, most of them are limited to a specific stage of the disease. The purpose of this study is to visually demonstrate the dynamic changes in chemokines across various stages of bowel diseases by integrating relevant datasets. Integrating the existing datasets for IBD and CRC, we compare the expression changes of chemokines across different pathological stages. This study collected 11 clinical databases from various medical centers around the world. Patients: Data of patient tissue types were classified into IBD, colorectal adenoma, primary carcinoma, metastasis, and healthy control according to the publisher’s annotation. The expression changes in chemokines in various pathological stages are statistically analyzed. The chemokines were clustered by different expression patterns. The chemokine family was clustered into four distinct expression patterns, which correspond to varying expression changes in different stages of colitis and tumor development. Certain chemokines and receptors associated with inflammation and tumorigenesis have been identified. Furthermore, it was confirmed that the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model and the azoxymethane (AOM)/ dextran sulfate sodium (DSS)-induced colon cancer model shows stronger correlations with the clinical data in terms of chemokine expression levels. This study paints a panoramic picture of the expression profiles of chemokine families at multiple stages from IBD to advanced colon cancer, facilitating a comprehensive understanding of the regulation patterns of chemokines and guiding the direction of drug development. This study provides researchers with a clear atlas of chemokine expression in the pathological processes of inflammatory bowel disease and colon cancer.

Zinc pyrithione ameliorates colitis in mice by interacting on intestinal epithelial TRPA1 and TRPV4 channels

AimsAlthough zinc pyrithione (ZPT) has been studied as topical antimicrobial and cosmetic consumer products, little is known about its pharmacological actions in gastrointestinal (GI) health and inflammation. Our aims were to investigate the effects of ZPT on transient receptor potential (TRP) channels and Ca2+ signaling in intestinal epithelial cells (IECs) and its therapeutic potential for colitis. Main methodsDigital Ca2+ imaging and patch-clamp electrophysiology were performed on human colonic epithelial cells (HCoEpiC) and rat small intestinal epithelial cells (IEC-6). The transcription levels of proinflammatory cytokines such as IL-1β were detected by RTq-PCR. Dextran sulfate sodium (DSS) was used to induce colitis in mice. Key findingsZPT dose-dependently induced Ca2+ signaling and membrane currents in IECs, which were attenuated by selective blockers of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 4 (TRPV4) channels, respectively. Interestingly, Ca2+ entry via TRPA1 channels inhibited the activity of TRPV4 channels in HCoEpiC, but not vice versa. ZPT significantly promoted migration of IECs by activating TRPA1 and TRPV4 channels. ZPT reversed lipopolysaccharides (LPS)-induced changes in mRNA expression of TRPA1 and TRPV4. Moreover, ZPT decreased mRNA levels of pro-inflammatory factors promoted by LPS in HCoEpiC, which were restored by selective TRPA1 blocker. In whole animal studies in vivo, ZPT significantly ameliorated DSS-induced body weight loss, colon shortening and increases in stool score, serum calprotectin and lactic acid (LD) in mouse model of colitis. SignificanceZPT exerts anti-colitic action likely by anti-inflammation and pro-mucosal healing through TRP channels in IECs. The present study not only expands pharmacology spectrum of ZPT in GI tract, but also repurposes it to a potential drug for colitis therapy.