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Regulation of neuroimmune interactions varies across avian species. Little is presently known about the interplay between periphery and central nervous system (CNS) in parrots, birds sensitive to neuroinflammation. Here we investigated the systemic and CNS responses to dextran sulphate sodium (DSS)- and lipopolysaccharide (LPS)-induced subclinical acute peripheral inflammation in budgerigar (Melopsittacus undulatus). Three experimental treatment groups differing in DSS and LPS stimulation were compared to controls. Individuals treated with DSS showed significant histological intestinal damage. Through quantitative proteomics we described changes in plasma (PL) and cerebrospinal fluid (CSF) composition. In total, we identified 180 proteins in PL and 978 proteins in CSF, with moderate co-structure between the proteomes. Between treatments we detected differences in immune, coagulation and metabolic pathways. Proteomic variation was associated with the levels of pro-inflammatory cytokine mRNA expression in intestine and brain. Our findings shed light on systemic impacts of peripheral low-grade inflammation in birds.

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Objective:To discuss the improvement effect of curcumin combined with fecal bacteria transplantation on the mice with dextran sulfate sodium(DSS)-induced ulcerative colitis(UC),and to clarify the related mechanism.Methods:Fifty mice were randomly divided into control,model,curcumin,fecal bacteria transplantation,and combination groups.Except for the mice in control group(given distilled water),the mice in the other groups were given distilled water containing 2%DSS to establish the UC models.The mice in curcumin group were gavaged with 0.4 mL of 60 mg·kg-1 curcumin solution once per day for 10 d;the mice in fecal bacteria transplantation group underwent enema with 0.2 mL of fecal bacteria suspension once per day for 10 d;the mice in combination group received the enema of 0.2 mL fecal bacteria suspension and gavaged with 0.4 mL of 60 mg·kg-1 curcumin solution.At the end of the experiment,the disease activity index(DAI)and colon macroscopic damage index(CDMI)of the mice in various groups were calculated;the morphology of colon tissue of the mice in various groups was detected by HE staining;the levels of interleukin(IL)-1β,tumor necrosis factor-α(TNF-α),IL-4,and IL-10 in colon tissue of the mice in various groups were detected by enzyme-linked immunosorbent assay(ELISA)method;the expression levels of occludin and zonula occludens-1(ZO-1)mRNA and proteins in colon tissue of the mice in various groups were detected by real-time fluorescence quantitative(RT-qPCR)and Western blotting methods.Results:The intestinal mucosal epithelial structure of the mice in control group was intact and continuous with regular glandular arrangement and without inflammatory cell infiltration or ulceration;the intestinal mucosal epithelial structure of the mice in model group exhibited loss of colonic mucosal epithelium,disordered glandular arrangement,reduced goblet cells,congestion and edema in mucosal and submucosal layers,and extensive infiltration of inflammatory cells with widespread small ulcers;the intestinal mucosal epithelial structure of the mice in curcumin,fecal bacteria transplantation,and combination groups exhibited relatively intact colonic mucosal epithelial structures with reduced inflammatory cell infiltration and ameliorated mucosal and submucosal congestion and edema.Compared with control group,the DAI and CDMI of the mice in model group were increased(P<0.05),the levels of IL-1β and TNF-α were increased(P<0.05),the levels of IL-4 and IL-10 were decreased(P<0.05),and the expression levels of occludin and ZO-1 mRNA and proteins were decreased(P<0.05);compared with model group,the DAI and CDMI of the mice in curcumin,fecal bacteria transplantation,and combination groups were decreased(P<0.05),the levels of IL-1β and TNF-α were decreased(P<0.05),the levels of IL-4 and IL-10 were increased(P<0.05),and the expression levels of occludin and ZO-1 mRNA and proteins were increased(P<0.05).Compared with curcumin group and fecal bacteria transplantation group,the DAI and CDMI of the mice in combination group were decreased(P<0.05),the levels of IL-1β and TNF-α were decreased(P<0.05),the levels of IL-4 and IL-10 were increased(P<0.05),and the expression levels of occludin and ZO-1 mRNA and proteins were increased(P<0.05).Conclusion:Curcumin combined with fecal bacteria transplantation can ameliorate the pathological damage in colonic tissue of the UC mice,inhibit the secretion of inflammatory factors,and promote the repaiment of intestin mucosa.

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OBJECTIVE: Sonchus arvensis L. is traditional Chinese food and medicine. We investigated protective effects of flavones from Sonchus arvensis L. (SAF) on colitis induced by dextran sulfate sodium (DSS) in mice by regulating gut microbiota (GM). METHOD: C57BL/6 mice were divided randomly: control group (CL); DSS group (ML); positive control + DSS group (AN); SAF + DSS (FE) group. The protective effects of SAF on ulcerative colitis (UC) were estimated by food intake, water intake, bodyweight loss, diarrhea, blood in stools, colon length, histology, disease activity index (DAI) score, and blood parameters. The sequencing of 16S rRNA gene was detected to investigate effect of SAF on GM. RESULTS: SAF attenuate bodyweight loss significantly. The DAI score was lower in FE group than that in ML group. Colon length was improved significantly in ML group. Pathologic changes could be ameliorated after SAF was administered to UC mice. SAF improved blood parameters of model mice. 16S rRNA sequencing revealed that it was very important to ameliorate colitis with bacteria of the phylum Verrucomicrobiota, class Verrucomicrobiae, order Verrucomicrobiales, family Akkermansiaceae, and genus Akkermansia. CONCLUSION: The SAF protective effect against colitis induced by DSS in mice may have a connection with GM diversity.

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Our research aimed to explore how resolving periodontal inflammation impacts cytokine expression in the colons of aged Wistar rats. Research studies involving animals have been conducted to investigate the two-way relationship between periodontitis and inflammatory bowel disease (IBD), where chronic inflammation in either the mouth or intestines can negatively affect the other. We allocated seventeen male Wistar rats aged between 8 and 11 months to one of four groups: (1) ligature-induced periodontitis (LIP) without the resolution of periodontal inflammation (RPI) (LIP; n = 4), (2) LIP + RPI (n = 4), (3) LIP + dextran-sulphate-sodium-induced colitis (DIC) without RPI (n = 4), and LIP + DIC + RPI (n = 5). We performed histopathological and immunological analyses on periodontal and intestinal tissues and analysed cytokine expressions using a Rat Cytokine 23-Plex Immunoassay. Our findings showed that animals with and without DIC who underwent RPI showed significantly lower levels of IL-2, IL-4, IL-5, IL-10, IL-13, IL-17, IL-18, and TNF-α in the intestine compared to those without treatment. The RPI effectively reduced the number of inflammatory cells in the lamina propria and restored the epithelial barrier in the intestine in animals with DIC. The resolution of periodontal inflammation significantly reduced the levels of pro-inflammatory cytokines and chemokines in the intestines of aged rats with and without DSS-induced colitis.

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Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.

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Inflammatory bowel disease (IBD) is a chronic ailment afflicting millions of people worldwide, with the majority of recognized cases within industrialized countries. The impacts of IBD at the individual level are long-lasting with few effective treatments available, resulting in a large burden on the health care system. A number of existing animal models are utilized to evaluate novel treatment strategies. Two commonly used models are (1) acute colitis mediated by dextran sulphate sodium (DSS) treatment of wild-type mice and (2) chronic colitis mediated by the transfer of proinflammatory T cells into immunodeficient mice. Despite the wide use of these particular systems to evaluate IBD therapeutics, the typical readouts of clinical disease progression vary depending on the model used, which may be reflective of mechanistic differences of disease induction. The most reliable indicator of disease in both models remains intestinal damage which is typically evaluated upon experimental endpoint. Herein, we evaluated the expression profile of a panel of cytokines and chemokines in both DSS and T cell transfer models in an effort to identify a number of inflammatory markers in the blood that could serve as reliable indicators of the relative disease state. Out of the panel of 25 markers tested, 6 showed statistically significant shifts with the DSS model, compared to 11 in the T cell transfer model with IL-6, IL-13, IL-22, TNF-α and IFN-γ being common markers of disease in both models. Our data highlights biological differences between animal models of IBD and helps to guide future studies when selecting efficacy readouts during the evaluation of experimental IBD therapeutics.

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BACKGROUND: Wedelolactone, main active constituent of Wedelia calendulace and Eclipta alba plants which has been traditionally used to treat various chronic inflammatory conditions. However, its mechanism of action of anti-inflammatory effect on ulcerative colitis is yet to be established. OBJECTIVE: In the present study, the effect of the wedelolactone on the myeloperoxidase activities and in the production of proinflammatory cytokines involved in the pathogenesis of chronic inflammation was assessed. MATERIALS AND METHODS: Wistar rats were randomly divided into four groups containing six animals per group. Group I (Vehicle control): tap water and vehicle; Group II (DSS control): tap water containing 5% (w/v) of DSS over 7 days, and vehicle; Group III (treatment group): Wedelolactone 50 mg/kg/day, and tap water containing 5% DSS over 7 days, Group IV (treatment group): Wedelolactone 100 mg/kg/day and tap water containing 5% DSS over 7 days over the experiment. RESULTS: Study revealed that wedelolactone treatment dramatically decrease the release of IL-1a, IL-1b, IL-2, TNF, INFγ, STAT3 and CCL-5 in colons treated with DSS. In summary, these results suggest that the inhibition of IL-6/STAT3 signaling is a potential mechanism by which wedelolactone is used in the treatment of ulcerative colitis. CONCLUSION: Oral administration of Wedelolactone (100 mg/kg) significantly attenuated pathological colonic damage and inhibited inflammatory infiltration, myeloperoxidase activities. In summary, Wedelolactone showed anti-inflammatory effect by down regulation of the IL-6/STAT3 inflammatory signaling pathway. These findings provide new insights into the pharmacological actions of wedelolactone as a potential therapeutic agent for colitis.

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OBJECTIVE: This study investigated the impact of colitis induced by dextran sulphate sodium (DSS)-induced colitis (DIC) on histopathological and immunological outcomes in the periodontal tissues of Wistar rats. BACKGROUND: Inflammatory bowel diseases (IBD) and periodontitis have been reported to present a bidirectional relationship. However, the inflammatory pathway that connects both diseases needs further investigation. MATERIAL AND METHODS: Twenty-five male Wistar rats were allocated in four groups: unilateral ligature-induced periodontitis for 14 days: LIP (n = 7); dextran sulphate sodium-induced colitis only: DIC (n = 6); DIC + LIP (n = 6) and controls (n = 6). Digital images were obtained from the histological sections. In order to assess the attachment loss (AL), the linear distance between the cementoenamel junction (CEJ) and the alveolar bone crest was measured on the mesial root using histological photomicrography's ImageJ software. Immunological analyses of gingival tissues and plasma were performed by Bio-Plex Th1/Th2 Assay. RESULTS: The DIC group showed inflammatory cells extending to the periodontal connective tissues, which contained significantly elevated expressions of IL-1α, IL-1ß, IL-2, IL-6, IL-12, IL-13, GM-CSF, IFN-γ and TNF-α compared to controls. There was no significant difference in bone loss between controls and DIC. There were no significant histopathological differences between DIC + LIP and LIP. However, DIC + LIP presented a significantly lower IL-2 and IL-5 than the LIP group. There was no bone loss difference between LIP+DIC and LIP groups. DIC + LIP group presented significantly higher levels of GM-CSF in plasma. CONCLUSION: DSS-induced colitis was associated with an overexpression of Th1/Th2- related cytokines in the gingival tissue.

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Inflammatory bowel diseases (IBD) stem from alterations in the intestinal immune system and microbial dysbiosis, but the precise interactions between bacteria and IBD remain obscure. The commensal microbiota have a profound impact on human health and diseases. Here, we developed a selective culture medium for lactate-utilizing bacteria (LUB) that function as candidate probiotics to ameliorate IBD using a mouse model. Firstly, LUB, including Megasphaera, were enriched from human faeces using a selective medium with lactate. LUB efficiently attenuated the pathology of colitis induced by dextran sulphate sodium (DSS). Next, LUB administration counteracted the dysbiosis associated with the intestinal inflammatory process, and elevated the proportion of Escherichia-Shigella in intestines. Moreover, E. coli isolated from healthy faeces downstream recapitulated lactate-utilizing bacterial community to ameliorate the severity of DSS-induced acute colitis. In conclusion, our finding revealed that LUB were sufficient to exert inflammatory protection against colitis in mice, highlighting a novel therapeutic strategy to use LUB as potentially curable probiotics for therapeutic manipulation for IBD.

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Different lines of evidences from clinical, epidemiological and biochemical studies have established that optimal nutrition including probiotic and fruit phenolics can mitigate the risk and morbidity associated with some chronic diseases. The basis for this observation is the potential synergies that may exist between probiotic strains and different bioactive components of food matrices. This study was conceptualized to compare the efficiency of a probiotic strain in two different fruit matrices. Two fruits, viz., sea buckthorn (Hippophae rhamnoides) (SBT) and apples (Malus pumila) (APJ) were chosen and the anti-inflammatory effects of L. rhamnosus GG (ATCC 53103) (LR) fortified in SBT and APJ were analysed against dextran sulphate sodium (DSS) induced colitis in zebrafish (Danio rerio). The results showed that administration of probiotic (LR) fortified, malt supplemented SBT beverage (SBT + M + LR) had better restorative potential on the intestinal barrier function and mucosal damage, in comparison to LR fortified, malt supplemented APJ beverage (APJ + M + LR). SBT + M + LR demonstrated adequate anti-oxidant potential by enhancing the CAT, SOD, GPx and GSH activities, impaired due to DSS administration. The increase in the expressions of toll like receptor (TLR)-2, TLR-4 and TLR-5 induced by DSS were significantly inhibited by SBT + M + LR administration. Gene expression of pro-inflammatory markers, (NF-κB, TNF-α, IL-1ß, IL-6, IL-8, CCL20, MPO and MMP9) were attenuated by SBT + M + LR treatment in intestinal tissues of DSS-treated zebrafishes. Notably, SBT + M + LR increased the expression of anti-inflammatory cytokine, IL-10. The study provides evidence that specific interactions between fruit matrix and probiotic strain can provide adjunct therapeutic strategy to manage intestinal inflammation.

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Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)-kynurenine (KYN)-kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)-indoleamine 2,3-dioxygenase 1 (IDO1)-aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic. This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.

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BACKGROUND: Ulcerative colitis (UC) is an intestinal disease which was characterized by intestinal inflammation, mucosal injury and fibrosis. In this paper, the effect of Huanglian Jiedu Decoction (HJD), a well-known traditional Chinese medicine with significant anti-inflammatory effect, on dextran sulphate sodium (DSS)-induced UC in mice and inhibition of JAK2/STAT3 pathway were investigated. METHODS: BALB/c mice were randomly divided into 6 groups: HJD group (high, medium and low dose), USAN group, UC group, and control group. UC in mice were induced through free access to 3% DSS solution. After being treated with HJD for 8 days, all animals were sacrifice. Pathological examination of colonic specimen was performed by H&E staining. Cytokines (TNF-α, IL-6, and IL-1ß) in colon were assayed by ELISA and immunofluorescence, MPO in colon and ATT in serum were detected by ELISA. Moreover, mice in HJD group and UC group were treated with AG490 to inhibit the expression of JAK2 protein, then the expression of JAK2 and STAT3 protein in colon was determined by western blotting and immunofluorescence staining. Furthermore, KI67 in colon was examined by immunohistochemistry, and apoptosis was detected by TUNEL staining, and collagen deposition was assayed by Masson staining after JAK2/STAT3 pathway in UC mice was inhibited by HJD. RESULTS: After mice being treated with HJD, the symptoms (weight loss and haematochezia) of UC were alleviated, and the contents of inflammatory cytokines (TNF-α, IL-6 and IL-1ß) and MPO in colon were significantly decreased. The expression of JAK2 and STAT3 protein was reduced after administration with HJD. After JAK2/STAT3 pathway being inhibited with HJD, the cell apoptosis, collagen deposition and immunoreactivity of macrophage in colon were significantly reduced, but the expression of Ki67 was markedly enhanced in both UC group and HJD group compare with control group. CONCLUSIONS: HJD treatment can alleviate intestinal mucosal damage and has the protective effect on UC by downregulating JAK2 and STAT3 expression to reduce inflammation via JAK2/STAT3 pathway.

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Encapsulation techniques and materials, explored for addressing compromised probiotic gut survival, report significant production losses resulting in <10% entrapment. Presently, we report three-time enhanced entrapment (30 ± 1.2%) of Lactobacillus acidophilus (LAB) in calcium-alginate beads, by modifying process parameters and employing polyethylene glycol (PEG). Water-loving, viscolysing and osmotic-building effects of PEG create numerous, fine voids in the alginate gel allowing efficient diffusion of crosslinking calcium ions, resulting in less leaky beads. Eudragit S100 overcoat improved LAB survival by 690 times in simulated GIT stresses.In DMH-DSS induced colitis and precancerous lesions in rats, while free LAB failed to show any protection, pharmabiotic beads significantly (p < .05) reduced lipid peroxidation, increased antioxidant levels; decreased serum inflammatory burden; downregulated COX-2, iNOS, and c-Myc expression; elevated levels of the selected gut bacteria and SCFAs especially butyrate, all of which add up to antioxidant, anti-inflammatory, balanced gut biota, and ultimately anticancer effects.

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This study was carried out to investigate the potential therapeutic effect of galangin, a promising active principle of honeybee propolis, in dextran sulphate sodium (DSS)-induced colitis in mice. We explored the possible underlying mechanisms for galangin action and the therapeutic benefit of adding galangin to the standard therapy sulphasalazine. A galangin dose of 40 mg/kg was selected based on a preliminary dose-selection study for investigation in a 4-week cyclical model of DSS-induced colitis. Mice received 3% DSS in their drinking water during the first and third weeks and were administered the treatments (40 mg/kg galangin, 100 mg/kg sulphasalazine and a combination of 20 mg/kg galangin and 50 mg/kg sulphasalazine) daily starting from the second week. Galangin significantly ameliorated DSS-induced histopathological alterations and tissue injury, down-regulated Toll-like receptor 4 expression, suppressed NF-κB p65 activation, lowered inflammatory cytokine levels and demonstrated antioxidant effects. The combination of galangin and sulphasalazine at half doses yielded comparable results to either drug alone at full dose. This study highlights galangin as a promising therapy for colitis management.

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Objective: To investigate the effect of oligosaccharide grape seed proanthocyanins (GSPE) on dextran sulphate sodium salt (DSS)-induced ulcerative colitis (UC) in mice and its mechanisms. Methods: SPF-class C57 mice were randomly divided into normal group, model group, positive group (sulfasalazine group), and GSPE groups (125, 250, 500 mg/kg). The normal group was given pure water, and the other groups were free to drink 3% DSS aqueous solution for 7 d to induce the model of UC in mice. The changes of body weight, hematochezia and stool type were recorded every day. After seven days of treatment, blood, colons and spleens were collected, and the length of the colon and the weight of the spleen were recorded. HE staining was used to evaluate the pathological changes of colonic mucosa in mice. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor TNF-α in serum and colon tissues and the levels of NO, MDA, and SOD were detected by ELISA. The changes of HO-1, NF-κB, and Nrf2 in colonic epithelial cells were analyzed by immunohistochemistry. Results: Compared with the model group, the body weight of mice in GSPE groups (250, 500 mg/kg) decreased relatively slowly, and the symptoms of diarrhea and hematochezia were improved significantly. The content of IL-1β, IL-6, TNF-α, NO, and MDA in serum and colon tissues was much lower in the administration groups than those in the model group, while the content of SOD was significantly higher (P < 0.01). The pathological tissue analysis showed that the pathological damage of colonic mucosa in the high dose group of GSPE was obviously decreased. Immunohistochemical analysis showed that GSPE groups significantly decreased the expression of NF-κB and increased the expression of Nrf2 and HO-1 (P < 0.01). Conclusion: GSPE could effectively improve the symptoms of UC induced by DSS, and regulate the expression of oxidative stress-related proteins Nrf2, HO-1 and inflammatory pathway protein NF-κB, and then affect the changes of oxidative stress indicators SOD, MDA and inflammatory factors. Therefore, GSPE plays an important role in the treatment and prevention of UC.

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BACKGROUND: Crocin has anti-inflammatory and anti-oxidative stress effects. The therapeutic effects of crocin on ulcerative colitis and related mechanisms are still unclear. OBJECTIVE: To explore the protective effect of crocin in ulcerative colitis rats and its related mechanism. METHODS: Thirty Sprague-Dawley rats were randomly divided into five groups: normal group, model group, low-dose crocin group, high-dose crocin group, and positive control group. Experimental rat model of ulcerative colitis was induced by dextran sodium sulfate. Starting on the first day of modeling, rats were routinely fed in the normal group, were given sulfasalazine by gavage in the positive drug group, and were gavaged with 0.05 and 0.1 g/kg crocin in the low-and high-dose crocin groups, respectively. RESULTS AND CONCLUSION: One week after intervention, the crocin-treated rats had significantly decreased scores on colon tissue injury and Crohn’s disease activity index(P < 0.05). Compared with the model group, crocin groups had a decrease in the content of malondialdehyde and activity of myeloperoxidase(P < 0.05), and an increase in the activity of superoxide dismutase in the colon tissue(P < 0.05). Shown by immunohistochemical staining, compared with the model group, treatment with crocin significantly reduced immune responses of tumor necrosis factor α and interleukin 23 proteins after 1 week of intervention(P < 0.05). Compared with the model group, treatment with crocin downregulated the expression levels of total protein Bax, Caspase-3, Toll-like receptor 4 and MyD88(P < 0.05), and upregulated the expression of Bcl-2 in the intestinal tissue of rats(P < 0.05). These results indicate that crocin has a certain therapeutic effect in ulcerative colitis rats and its mechanism may be related to down-regulation of the Toll-like receptor 4/MyD88 signaling pathway and inhibition of oxidative stress, inflammation and apoptosis in the colon.

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Acute and chronic colitis affect a huge proportion of the population world-wide. The etiology of colitis cases can be manifold, and diet can significantly affect onset and outcome of colitis. While many forms of acute colitis are easily treatable, chronic forms of colitis such as ulcerative colitis and Crohn's disease (summarized as inflammatory bowel diseases) are multifactorial with poorly understood pathogenesis. Inflammatory bowel diseases are characterized by exacerbated immune responses causing epithelial dysfunction and bacterial translocation. There is no cure and therapies aim at reducing inflammation and restoring intestinal barrier function. Unfortunately, most drugs can have severe side effects. Changes in diet and inclusion of nutritional supplements have been extensively studied in cell culture and animal models, and some supplements have shown promising results in clinical studies. Most of these nutritional supplements including vitamins, fatty acids and phytochemicals reduce oxidative stress and inflammation and have shown beneficial effects during experimental colitis in rodents induced by dextran sulphate sodium or 2,4,6-trinitrobenzene sulfonic acid, which remain the gold standard in pre-clinical colitis research. Here, we summarize the mechanisms through which such nutritional supplements contribute to epithelial barrier stabilization.

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BACKGROUND: Ulcerative Colitis (UC) is an Inflammatory Bowel Disease (IBD) characterized by uncontrolled immune response, diarrhoea, weight loss and bloody stools, where sustained remission is not currently achievable. Dextran Sulphate Sodium (DSS)-induced colitis is an animal model that closely mimics human UC. Ultrasound (US) has been shown to prevent experimental acute kidney injury through vagus nerve (VN) stimulation and activation of the cholinergic anti-inflammatory pathway (CAIP). Since IBD patients may present dysfunctional VN activity, our aim was to determine the effects of therapeutic ultrasound (TUS) in DSS-induced colitis. METHODS: Acute colitis was induced by 2% DSS in drinking water for 7 days and TUS was administered to the abdominal area for 7 min/day from days 4-10. Clinical symptoms were analysed, and biological samples were collected for proteomics, macroscopic and microscopic analysis, flow cytometry and immunohistochemistry. FINDINGS: TUS attenuated colitis by reducing clinical scores, colon shortening and histological damage, inducing proteomic tolerogenic response in the gut during the injury phase and early recovery of experimental colitis. TUS did not improve clinical and pathological outcomes in splenectomised mice, while α7nAChR (α7 nicotinic acetylcholine receptor - indicator of CAIP involvement) knockout animals presented with disease worsening. Increased levels of colonic F4/80+α7nAChR+ macrophages in wild type mice suggest CAIP activation. INTERPRETATION: These results indicate TUS improved DSS-induced colitis through stimulation of the splenic nerve along with possible contribution by VN with CAIP activation. FUND: Intramural Research Programs of the Clinical Centre, the National Institute of Biomedical Imaging and Bioengineering at the NIH and CAPES/Brazil.

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The effects of daucosterol have been identified in cancer therapy and neuronal diseases. However, the regulatory function of daucosterol in DSS-induced colitis has not yet been investigated. In this study, we evaluated the immunological and therapeutic effects of daucosterol in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Unlike vehicle mice, mice pre- or post-treated with daucosterol showed inhibition of body weight loss and the decrease in the disease activity index (DAI). In addition, daucosterol treatment rescued the DSS-induced decrease in colon length and disruption of the epithelial lining. Furthermore, it reduced DSS-induced production of reactive oxygen species (ROS), infiltration of macrophages, and expression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1ß. Mice with colitis showed a decreased population of Foxp3+ cells, which was upregulated by daucosterol treatment. Furthermore, daucosterol increased natural killer (NK) cell activity and inhibited excessive IgA levels in mice with DSS-induced colitis. Collectively, our findings demonstrated that daucosterol significantly alleviated DSS-induced colitis, indicating the possibility of daucosterol as a therapeutic option for colitis.

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As important epigenetic regulators, microRNA regulate protein expression by triggering the degradation of target mRNA and/or by inhibiting their translation. Dysregulation of microRNA expression has been reported in several cancers, including colorectal cancer. In this study, microRNA-array differential analysis revealed strongly enhanced expression of miR-24-1-5p in the colon tissue of azoxymethane/dextran sulphate sodium-induced mice that were fed with black raspberry anthocyanins for 9 weeks. Overexpression of miR-24-1-5p in human colorectal cancer cells significantly repressed ß-catenin expression, and simultaneously decreased cell proliferation, migration and survival. Furthermore, miR-24-1-5p could target ß-catenin and trigger a negative regulatory loop for ß-catenin and its downstream target genes. ß-Catenin signalling is vital to the formation and progression of human colorectal cancer. The current findings therefore identified miR-24-1-5p as a potent regulator of ß-catenin, and this may provide a novel chemopreventive and therapeutic strategy for ß-catenin signalling-driven colorectal cancer.

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