Decrease In Disease Activity Index Research Articles

Tiliroside Ameliorates Ulcerative Colitis by Restoring the M1/M2 Macrophage Balance via the HIF-1α/glycolysis Pathway.

Macrophages polarized to different phenotypes critically contribute to colitis development by coordinating inflammatory and anti-inflammatory processes. Herein, targeting the balance between the pro-inflammatory M1 and the anti-inflammatory M2 macrophage phenotypes can be a novel therapeutic approach for colitis. In the present study, we firstly demonstrated that tiliroside possessed the ability to alleviate the clinical symptoms of colitis as evidenced by decreased disease activity index (DAI) scores, longer colon length, reduced myeloperoxidase (MPO) activity, and improvement of colonic pathological damage in vivo. Furthermore, we showed that tiliroside modulated the balance between M1 and M2 macrophages toward a more anti-inflammatory status in colonic lamina propria but has little effect on the T cell population and epithelial barrier function in colitis mice. The macrophage depletion study further showed the protective effect of tiliroside was macrophage dependent in vivo. Mechanistically, our study demonstrated that tiliroside regulated cellular metabolism by inhibiting aerobic glycolysis in LPS and IFNγ stimulated macrophages. At the molecular level, tiliroside facilitated the proteasomal degradation of HIF-1α and downregulated mRNA expressions of HIF-1α dependent glycolytic enzymes in macrophages. Collectively, our data highlight the aberrant M1/M2 macrophage polarization in the initiation and development of ulcerative colitis and put forth the stage for considering tiliroside as a metabolic regulator in reprogramming macrophage polarization, which may serve as a promising therapeutic approach for treatment of inflammation-associated and metabolic disorders.

Strictosamide alleviates the inflammation in an acute ulcerative colitis (UC) model.

The ulcerative colitis (UC) is a typical inflammatory bowel disease (IBD) causing great damages, while strictosamide (STR) is a natural alkaloid that possesses strong anti-inflammatory property in infection and inflammation-related diseases. Our study is aimed at evaluating the anti-inflammatory activity of STR in the course of UC. Briefly, male Balb/c mice were treated with 3.5% dextran sulfate sodium (DSS) for 6 consecutive days to establish an acute model of UC, and the administration of gradient concentrations of STR was subsequently performed. Accordingly, colonic pathological alterations including the reduced ratio of colon weight/length, decreased disease activity index (DAI), and attenuated H&E damage were found in UC mice after STR treatment. Based on the analyses of real-time PCR and western blot, downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) was also determined in the colonic tissue of UC mice after the treatment of STR. ELISA and immunohistochemical staining further suggest the relief of inflammation in UC mice with decreased expressions of MPO and iNOS after STR treatment. In addition, STR was also validated to significantly inhibit NF-κB signaling in UC mice by western blot and Electrophoretic Mobility Shift Assay (EMSA). Meanwhile, restricted inflammation was also determined in STR-treated IEC6 and HT-29 cells. The utilization of PDTC, an inhibitor of NF-κB, further demonstrated that STR ameliorated the inflammation by inhibiting the NF-κB signaling in vitro. In summary, our study suggests that STR could be a potential candidate for IBD therapy.

Clophosome alleviate dextran sulphate sodium-induced colitis by regulating gut immune responses and maintaining intestinal integrity in mice.

Inflammatory bowel disease (IBD) is a chronic progressive disorder characterized by complicated gastrointestinal inflammation. Research on therapeutic agents is still urgent due to the lack of satisfactory treatments. Gut macrophages are considered to be predominant in excessive inflammatory responses. Thus, we aimed to investigate whether depletion of macrophages would have a beneficial effect on IBD and could be a potential therapeutic strategy. In this study, we established a 12-day Dextran sodium sulphate (DSS)-induced colitis mouse model and determined the effect of the macrophage depletion agent Clophosome (neutral clodronate liposomes; CNC). The results showed that CNC significantly alleviated the symptoms of colitis, as demonstrated by greater weight gain, decreased disease activity index (DAI) scores, and lower histopathological damage scores, as well was reduced levels of the proinflammatory cytokines interleukin (IL)-6 and tumour necrosis factor (TNF)-α. To investigate T cell subsets, cells were isolated from the lamina propria and cultured to analyse the expression of IL-17A, interferon (IFN)-γ and Foxp3 in CD4+ cells by flow cytometry. The data showed that during the process of colitis, the frequencies of CD4+ IL-17A+ T cells were significantly increased. Notably, CNC treatment markedly reduced the population of CD4+ IL-17A+ T cells, especially CD4+ IL-17A+ IFN-γ+ T cells. Furthermore, intestinal barrier integrity, as assessed by immunostaining of mucin and tight junction proteins, was severely disrupted in colitis. CNC improved the intestinal barrier by enhancing the expression of muc-2 and occludin. In summary, our findings demonstrated that CNC successfully ameliorated DSS-induced colitis and that its effect may be associated with inhibiting inflammatory responses and maintaining intestinal integrity.

TOXICOLOGICAL FINDINGS OF A RECOMBINANT CHOLERA TOXIN B SUBUNIT VARIANT WITH THERAPEUTIC POTENTIAL IN ULCERATIVE COLITIS

Abstract Background The cholera toxin B subunit (CTB) is the nontoxic and homopentameric component of the holotoxin. Upon binding to GM1 ganglioside on the surface of epithelial cells, CTB mediates entry and retrograde transport through the endomembrane system and disengages the catalytic A subunit in the endoplasmic reticulum (ER). EPICERTIN (EPT) is a recombinant variant of CTB with a non-native C-terminal extension harboring an ER-retention motif, KDEL. We have found that increased ER-retention time resulting from this modification allowed EPT to induce an unfolded protein response and TGF-β signaling in colon epithelial cells, triggering wound healing activity in preclinical colitis models. The unique epithelial repair activity of EPT hints at its therapeutic potential in ulcerative colitis. Objective We aim to develop data supporting a first-in-human clinical trial with an EPT enema indicated for ulcerative colitis. Here, we evaluated the efficacy and toxicity of intrarectal (IR) administration of EPT in preclinical rodent models. Results IR administration of EPT at 0.1 and 1 µM to female C57/BL6 mice (0.6 and 6.1 μg/animal) with acute dextran sodium sulfate (DSS)-induced colitis resulted in decreased disease activity index scores and increased body weight recovery, supporting a target therapeutic dose of ≤1 µM for clinical administration. A dose-escalation study was performed following a single IR exposure at 1, 2 and 5 µM (61.4, 122.8 and 307 μg/animal) in male and female Sprague Dawley rats. No drug-related adverse effects were evident in clinical observations, including clinical pathology and gross necropsy, even at the highest dose tested. A pharmacokinetics study was performed in male and female mice dosed with a 1 or 10 µM (6.1 and 61.4 μg/animal) IV bolus of EPT. Plasma samples were collected periodically for up to 24 h postdose. EPT concentrations were highest at first collection and decreased steadily until unquantifiable by 4 h. The elimination phase half-life was 0.26 to 0.3 h. When healthy and DSS-induced colitic mice (n = 72) were dosed with 1 or 10 µM EPT IR, marginal amounts of EPT were found in only 4 plasma samples scattered across groups and time points, suggesting that systemic exposure after IR administration is negligible. Conclusion These data support further development of EPT as a potential therapeutic for ulcerative colitis.

Cohousing-mediated microbiota transfer from milk bioactive components-dosed mice ameliorate colitis by remodeling colonic mucus barrier and lamina propria macrophages

ABSTRACT Human milk oligosaccharides (HMOs) and milk fat globule membrane (MFGM) are highly abundant in breast milk, and have been shown to exhibit potent immunomodulatory effects. Yet, their role in the gut microbiota modulation in relation to colitis remains understudied. Since the mixtures of fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) perfectly mimic the properties and functions of HMOs, the combination of MFGM, FOS, and GOS (CMFG) has therefore been developed and used in this study. Here, CMFG were pre-fed to mice for three weeks to investigate its preventive effect on dextran sodium sulfate (DSS) induced colitis. Moreover, CMFG-treated and vehicle-treated mice were cohoused to further elucidate the preventive role of the gut microbiota transfer in colitis. At the end of the study, 16S rDNA gene amplicon sequencing, short-chain fatty acids (SCFAs) profiling, transcriptome sequencing, histological analysis, immunofluorescence staining and flow cytometry analysis were conducted. Our results showed that CMFG pre-supplementation alleviated DSS-induced colitis as evidenced by decreased disease activity index (DAI) score, reduced body weight loss, increased colon length and mucin secretion, and ameliorated intestinal damage. Moreover, CMFG reduced macrophages in the colon, resulting in decreased levels of IL-1β, IL-6, IL-8, TNF-α, and MPO in the colon and circulation. Furthermore, CMFG altered the gut microbiota composition and promoted SCFAs production in DSS-induced colitis. Markedly, the cohousing study revealed that transfer of gut microbiota from CMFG-treated mice largely improved the DSS-induced colitis as evidenced by reduced intestinal damage and decreased macrophages infiltration in the colon. Moreover, transfer of the gut microbiota from CMFG-treated mice protected against DSS-induced gut microbiota dysbiosis and promotes SCFAs production, which showed to be associated with colitis amelioration. Collectively, these findings demonstrate the beneficial role of CMFG in the gastrointestinal diseases, and further provide evidence for the rational design of effective prophylactic functional diets in both animals and humans.

Effects of Vitamin D3 on Inflammatory Bowel Disease in Rats via the Toll-Like Receptor 4/ Myeloid Differentiation Primary Response 88/ Nuclear Factor Kappa Light Chain Enhancer of Activated B Cells Signaling Pathway

To assess the ameliorating effects of vitamin D3 on inflammatory bowel disease in rats via the Toll-like receptor 4/myeloid differential factor 88/nuclear factor kappa B signaling pathway. Thirty two rats were randomly assigned into Control group, model group (Vehicle group), low-concentration vitamin D3 group (vitamin D3 low group) and high-concentration vitamin D3 group (vitamin D3 high group). The model of inflammatory bowel disease was constructed using 3 % dextran sodium sulfate and given different concentrations of vitamin D3. Disease activity index score was calculated, colon tissues were pathologically scored by hematoxylin-eosin staining, and the mRNA expression levels of Toll-like receptor 4/myeloid differential factor 88/nuclear factor kappa B were measured by quantitative reverse transcriptionpolymerase chain reaction. The expression levels of serum tumor necrosis factor-α, pro-inflammatory factors interleukin 1β and interleukin 6, as well as anti-inflammatory factor interleukin 10 were detected through enzyme-linked immunosorbent assay. The disease activity index score, mRNA expression levels of Toll-like receptor 4/myeloid differential factor 88/nuclear factor kappa B and expression levels of tumor necrosis factor-α, interleukin 1β and interleukin 6 were significantly higher in Vehicle group than those in Control group, while the expression level of interleukin-10 was lower in Vehicle group (p<0.05). After intervention with vitamin D3, vitamin D3 low group and vitamin D3 high group had significantly decreased disease activity index score, messenger RNA expression levels of Toll-like receptor 4/myeloid differential factor 88/nuclear factor kappa B and expression levels of tumor necrosis factor-α, interleukin 1β and interleukin 6, increased interleukin-10 expression level, and relieved damage of colon tissues compared with Vehicle group (p<0.05). Vitamin D3 ameliorates intestinal injury and colonic inflammation in inflammatory bowel disease rats by suppressing the Toll-like receptor 4/myeloid differential factor 88/ nuclear factor kappa B signaling pathway and decreasing the expression of downstream pro-inflammatory factors.

New discovery of anti-ulcerative colitis active ingredients of Nostoc commune: p-Hydroxy benzaldehyde

Nostoc commune, a natural cyanobacterium, has long been appreciated as a healthy food and was identified for the treatment of ulcerative colitis (UC). In the present study, p-hydroxy benzaldehyde (HD), a purified compound isolated from the alcohol extract of Nostoc commune (AENC), alleviated dextran sodium sulfate (DSS)-induced colitis, as evidenced by improved weight loss, decreased disease activity index (DAI) scores, reduced colon shortening, reduced myeloperoxidase (MPO) activity and attenuated pathological injuries of colonic tissues through downregulating the protein and mRNA expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Moreover, HD has demonstrated in vitro efficacy against UC. Notably, HD significantly upregulated the mRNA expression of E-cadherin in DSS-induced colitis mice and HT-29 cells stimulated with lipopolysaccharide (LPS). Overall, we offer a fresh perspective on the main anti-UC ingredients in Nostoc commune. HD is a new active ingredient of Nostoc commune that alleviates DSS-induced colitis and exerts an anti-colitis effect by ameliorating intestinal mucosal injury by downregulating the expression of proinflammatory cytokines.

Immunotropic effect of rectal suppositories with vitamin D3 in dynamics of experimental ulcer colitis

Purpose of the study—to develop a new dosage form—rectal suppositories with vitamin D3 and at the preclinical stage to analyze its clinical and immunological efficacy compared to 5-aminosalicylic acid (5-ASA) in the dynamics of experimental ulcerative colitis (UC) in rats.Materials and methods. UC was simulated by cutaneous and then rectal application of a 3% solution of oxazolone. Original rectal suppositories with 1500ME of vitamin D3 were administered per rectum every 12 hours, in the comparison group with the same interval, rectal suppositories with 50 mg of 5-ASA. To assess the clinical status, the Disease activity index (DAI) scale was used, the serum concentration of IgG, IgM, IL-6, IL-8 was determined by the enzyme immunoassay using rat-specific test systems on days 2 and 6 of the experiment.The results of the study. In experimental UC, DAI rises, and the concentration of IgG, IgM, IL-8 and IL-6 in serum increases on the 2nd and 6th day of the experiment. DAI increases as serum concentrations of IgG, IgM, IL-8 and IL-6 increase. The use of vitamin D3 in UC leads to a decrease in DAI and serum concentrations of IgG, IgM, IL-8, IL-6 mainly on the 6th day of observation. The use of rectal suppositories with 5-ASA in UC leads to a decrease in DAI and the concentration of IgM, IgG, IL-6, IL-8 on the 2nd and 6th day of observation.Conclusion. The efficacy of rectal suppositories containing 1500 IU of vitamin D3 in experimental UC was found to be comparable with the use of rectal suppositories with 5-ASA based on the assessment of the clinical status and serum concentration of IgM, IgG, IL-6, IL-8.

Sodium Butyrate Alleviates Mouse Colitis by Regulating Gut Microbiota Dysbiosis.

Simple SummaryInflammatory bowel disease (IBD) is extremely harmful to animal health and can affect animal growth and production. Dextran sulfate sodium (DSS) can cause IBD in animals, resulting in diarrhea and bloody stools. The present study aimed to determine whether oral sodium butyrate can relieve DSS-induced colitis in mice. By using histological evaluation (H&E) staining technology and 16S rRNA sequence analysis, we found that the severity of colitis in mice receiving oral sodium butyrate was reduced, and the composition of gut microbiota was changed. These results indicate that sodium butyrate can relieve DSS-induced colitis in mice by restoring the balance of gut microbiota dysbiosis.Inflammatory bowel disease (IBD) develops as a result of complicated interactions between genetic susceptibility, excessive innate immunity, and environmental factors, which are mainly related to the gut microbiota. The present study aimed to elucidate the protective effects and underlying mechanisms of a short-chain fatty acid salt, sodium butyrate, on colonic inflammation induced by dextran sulfate sodium (DSS) in mice. Pretreatment with sodium butyrate attenuated colitis, as demonstrated by the decreased disease activity index (DAI), colon length shortening, spleen tumidness, and histopathology scores, while maintaining intestinal barrier integrity, as observed by H&E staining and electron microscopy. 16S rRNA sequence analysis revealed that sodium butyrate caused a remarkable alteration of the gut microbiota. Bacteroides, Lachnospiraceae, the Lachnospiraceae NK4A136 group, and Ruminiclostridium 6 presented dramatic differences after sodium butyrate supplementation. This work verifies that sodium butyrate can improve mouse colitis via microbe–host interactions by regulating the microbial community. Taken together, the findings demonstrate that sodium butyrate shows great potential as a probiotic agent for ameliorating colitis.

Anti-Inflammatory Activity and Mechanism of Hydrostatin-SN1 From Hydrophis cyanocinctus in Interleukin-10 Knockout Mice.

Biopeptides derived from marine species have garnered significant research interest owing to their anti-inflammatory, antibacterial, and anticancer activities. In our previous study, Hydrostatin-SN1, a bioactive peptide extracted from the Hydrophis cyanocinctus venom gland T7 phage display library, demonstrated anti-inflammatory activity in a dextran sulfate sodium-induced murine colitis model. In this study, we investigated the anti-inflammatory activity and the underlying mechanism of Hydrostatin-SN1 in lipopolysaccharide (LPS)-induced bone marrow-derived macrophage (BMDM) cells and interleukin (IL)-10 knockout mice. The results showed that Hydrostatin-SN1 inhibited phosphorylation of JNK, ERK1/2, and p38 and decreased the mRNA expression of tumor necrosis factor-α (TNF-α), IL-6, and IL-1β in LPS-stimulated BMDM cells in a dose-dependent manner. In LPS-induced acute shock model, a significant higher survival rate of Hydrostatin-SN1-treated mice was observed. Furthermore, Hydrostatin-SN1 reduced body weight loss, decreased disease activity index, reduced spleen index, prevented histological injury, and inhibited the expression of IL-β and phosphorylation of JNK, ERK1/2, and p38 in the colon tissue of IL-10 knockout mice. Additionally, the positive expression rate of TNF-α in mice colon was decreased. Overall, our results suggest that Hydrostatin-SN1 has significant anti-inflammatory effects, both in vitro and in vivo.

Fecal Microbiota Transplantation (FMT) Alleviates Experimental Colitis in Mice by Gut Microbiota Regulation.

Inflammatory bowel disease (IBD) is an increasing global burden and a predisposing factor to colorectal cancer. Although a number of treatment options are available, the side effects could be considerable. Studies on fecal microbiota transplantation (FMT) as an IBD intervention protocol require further validation as the underlying mechanisms for its attenuating effects remain unclear. This study aims to demonstrate the ameliorative role of FMT in an ulcerative colitis (UC) model induced by dextran sulfate sodium (DSS) and elucidate its relative mechanisms in a mouse model. It was shown that FMT intervention decreased disease activity index (DAI) levels and increased the body weight, colon weight and colon length of experimental animals. It also alleviated histopathological changes, reduced key cytokine expression and oxidative status in the colon. A down-regulated expression level of genes associated with NF-κB signaling pathway was also observed. The results of 16S rRNA gene sequencing showed that FMT intervention restored the gut microbiota to the pattern of the control group by increasing the relative abundance of Firmicutes and decreasing the abundances of Bacteroidetes and Proteobacteria. The relative abundances of the genera Lactobacillus, Butyricicoccus, Lachnoclostridium, Olsenella and Odoribacter were upregulated but Helicobacter, Bacteroides and Clostridium were reduced after FMT administration. Furthermore, FMT administration elevated the concentrations of SCFAs in the colon. In conclusion, FMT intervention could be suitable for UC control, but further validations via clinical trials are recommended.

Endogenous antisense regulates CD39 in Crohn’s disease upon interaction with nucleolin and heterogeneous-nuclear-ribonucleoprotein-A1

Abstract The ectoenzyme CD39 hydrolyzes ATP to generate immunosuppressive adenosine. We have shown that CD39 levels and activity are reduced in Treg and Th17-cells from Crohn’s patients. This impairment is linked to heightened levels of endogenous antisense (AS) present at the 3′ end of the human CD39 gene and regulating CD39 at mRNA and protein level. Here we note that CD39-specific AS is predominantly located in the nucleus of peripheral blood-derived Treg and Th17-cells of healthy subjects (HS) and Crohn’s disease patients. RNA pulldown assay followed by mass spectrometry shows that AS regulates CD39 upon interaction with nucleolin (NUCL) and heterogenous-nuclear-ribonucleoprotein-A1 (HNRNPA1). Silencing of NUCL and/or HNRNPA1 results in higher CD39 levels in both Treg and Th17-cells. Blockade of antisense in vitro using FANA oligonucleotides decreases AS while boosting CD39 in HS and Crohn’s Treg and Th17-cells. AS silencing in vivo ameliorates experimental colitis induced by trinitrobenzene-sulfonic-acid in NOD/scid/gamma mice reconstituted with antisense+ human CD4-cells and concomitantly administered FANA oligonucleotides. Compared to untreated controls, FANA-treated mice show decreased disease activity index, higher colon length, lower histology score and, phenotypically, increased proportions of circulating CD39+CD4+-cells and decreased frequencies of peripheral blood and splenic CD4+IL-17+-cells. In conclusion, CD39-specific AS dampens CD39 levels in Crohn’s Treg and Th17-cells by interacting with NUCL and HNRNPA1. Inhibition of AS controls disease activity in experimental colitis suggesting that AS blockade might serve as a novel therapeutic tool to restore CD39 and curb inflammation in Crohn’s disease.

A219 PROTECTIVE EFFECTS OF AKKERMANSIA MUCINIPHILA ON INTESTINAL BARRIER FUNCTION AND INFLAMMATION

Abstract Background Akkermansia muciniphila, an anaerobic gram-negative bacteria, accounts for ~3% of human gut microbiota. Despite its mucolytic nature, A. muciniphila has been shown to stimulate mucin production, enhance anti-inflammatory regulatory T cell proliferation and improve gut barrier integrity. Interestingly, an inverse relationship has been established between A. muciniphila and several disease states including inflammatory bowel disease (IBD) suggesting it may have protective and anti-inflammatory effects. However, the precise role and mechanism of A. muciniphila in the pathogenesis of colitis remains unknown. Thus, we hypothesize that A. muciniphila may induce protective effects on intestinal inflammation by influencing host immune response and epithelial barrier integrity. Aims (1) To investigate the protective role of A. muciniphila in intestinal inflammation in a chemically induced model of IBD and (2) to investigate the protective role of A. muciniphila in intestinal inflammation and host defense in a model of enteric parasitic infection. Methods Colitis was induced in germ-free C57BL/6 mice with 2.5% dextran sulphate sodium (DSS) after treatment with either C57BL/6 wild-type (WT) cecal contents or WT cecal contents supplemented with A. muciniphila. Colitis severity was assessed by disease activity index (DAI), macroscopic and histological scores, myeloperoxidase (MPO) assay and cytokine expression. In addition, colitis was induced by Trichuris muris, an intestinal nematode, following treatment with A. muciniphila. Post-infection, the severity of intestinal inflammation was assessed by worm burden, goblet cell staining, cytokines analysis, MPO activity and Muc2 expression. Microbial composition was assessed by 16s rRNA gene sequencing. Results In preliminary studies, mice treated with A. muciniphila and administered DSS for 5 days yielded a significant decrease in DAI, macroscopic scoring, and MPO values compared with controls. IL-10 was also elevated in mice receiving A. muciniphila. Groups receiving A. muciniphila in the T. muris model trended toward decreased worm burden, IL-4, IL-13, as well as increased levels of IL-10, goblet cell expression, and Muc2 and Muc5ac expression. A significant decrease in MPO activity was also observed in the group receiving the A. muciniphila-supplemented gavage. Microbial analysis indicated that 3 weeks post-gavage Akkermansia levels were significantly elevated in groups receiving the A. muciniphila-supplemented WT cecal contents versus WT alone. This significance was maintained post-T. muris infection. Conclusions These findings suggest that A. muciniphila may have a protective role in the context of intestinal inflammation. This research has the potential to fuel the development of novel treatments by utilizing this protective role in IBD. Funding Agencies CIHR

Galangin Protects against Symptoms of Dextran Sodium Sulfate-induced Acute Colitis by Activating Autophagy and Modulating the Gut Microbiota.

Galangin is a natural flavonoid that has been reported to provide substantial health benefits. Nevertheless, little is known about the potential effects of galangin against inflammatory bowel diseases. Here, an in vivo study was performed to investigate the preventive effects of galangin against dextran sulphate sodium (DSS)-induced acute murine colitis, which mimics the symptoms of human ulcerative colitis (UC). Pre-treatment with galangin (15 mg/kg, p.o.) resulted in a significant decreased in the macroscopic signs of DSS-induced colitic symptoms, including a decreased disease activity index, prevention of the colon length shortening, and alleviation of the pathological changes occurring in the colon. Colonic pro-inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6, as well as myeloperoxidase activities were decreased following galangin pre-treatment when compared with the DSS control group. Moreover, galangin pre-treatment significantly increased the expressions of autophagy-related proteins and promoted the formation of autophagosome in the colon. Galangin pre-treatment increased the diversity of the gut microbiota, and this was accompanied by increased levels of short-chain fatty acids. These observed changes could involve the modulating effects conferred by galangin in relation to some specific bacteria populations, including the recovery of Lactobacillus spp., and increased Butyricimonas spp. Overall, these results support the use of galangin in the prevention of UC.

Sturgeon hydrolysates alleviate DSS-induced colon colitis in mice by modulating NF-κB, MAPK, and microbiota composition.

Sturgeon muscle byproduct collected after caviar production is usually not fully utilized, and sometimes may be discarded, thus causing a lot of waste. Yet dietary protein hydrolysates, which may be derived from sturgeon muscle, have been reported to have versatile beneficial biological activities. Studying the biological activities of sturgeon muscle-derived hydrolysates holds much promise for adding value to sturgeon. The current study aimed to study the therapeutic anti-inflammatory effects of sturgeon muscle-derived hydrolysates and the underlying mechanisms. The administration of sturgeon hydrolysates (SH) significantly decreased the severity of DSS-induced damage, evidenced by increased body weight, colon length, and decreased disease activity index (DAI) and histological scores. SH also inhibited myeloperoxidase (MPO) activity and reduced the serum levels of IL-6, IL-1β, and TNF-α. Western blotting results revealed that SH suppressed DSS-induced activation of the NF-κB and MAPK pathways in the colon. Furthermore, SH partially restored the alteration of the gut microbiota in colitic mice. SH increased the Bacteroidetes/Firmicutes ratio and the relative abundance of Ruminococcaceae, Porphyromonadaceae, and Bacteroidetes S24-7, while decreased the abundance of potentially harmful bacteria Erysipelotrichaceae and Enterococcaceae. These results suggest that SH inhibited DSS-induced colitis by regulating the NF-κB and MAPK pathways and modulating microbiota composition.

Protective Effect of D-Carvone against Dextran Sulfate Sodium Induced Ulcerative Colitis in Balb/c Mice and LPS Induced RAW Cells via the Inhibition of COX-2 and TNF-α.

Ulcerative colitis (UC) is an intractable ailment, in which may chronic inflammations/ulcerations may develop in the mucosal lining of the colon with multiple recurrences. Various drugs such as steroids, immunosuppressants, and antibiotics are extensively used to treat UC. The patients suffer from adverse effects of these advanced drugs. So, they need a harmless therapeutic agent from natural sources. The therapeutic D-carvone has an anti-inflammatory action against the investigational colon cancer models. Therefore, we analyzed the effect of D-carvone on dextran sulfate sodium (DSS) provoked colitis model in mice as follows: Group I: noncolitis healthy control mice; Group II: ulcerative colitis mice models; Group III: D-carvone (40 mg/kg) + ulcerative colitis models; Group IV: sulfasalazine (50 mg/kg) + ulcerative colitis models. On the 8th day, the experimental study was terminated and serum samples and colon tissues were processed for further analysis. The effect of D-carvone at different concentration was studied on the LPS challenged RAW 264.7 cell lines. The D-carvone (40 mg/kg) treatment maintained the colon length and decreased disease activity index (DAI) score in UC animals. The increased antioxidant enzymes status and decreased oxidative stress and pro-inflammatory markers were noted in the D-carvone (40 mg/ kg) + UC mice. Histopathological study of colon tissue of D-carvone (40 mg/kg) treated UC mice displayed less mucosal damage and improved crypt integrity and goblet cells compared with DSS only provoked mice. The im-munohistochemical expression of iNOS and COX-2 was drastically diminished in the D-carvone treated UC mice. D-carvone (40 mg/kg) treatment appreciably diminished the LPS provoked NO production and pro-inflammatory modulators in the RAW 264.7 macrophage cell lines. These findings proved that D-carvone has a potential therapeutic effect to prevent LPS induced inflammation in in vitro cells and chemically induced ulcerative colitis in vivo models.

Sacral nerve stimulation prompts vagally-mediated amelioration of rodent colitis.

Neuromodulation based on the vagal anti‐inflammatory reflex has emerged as an exciting therapeutic approach for chronic inflammatory diseases. However, it is unclear whether direct stimulation of the vagus or of pelvic nerves coming from sacral roots, providing the bulk of colonic parasympathetic innervation, is the best approach. We hypothesized that sacral nerve stimulation (SNS) would be an effective treatment for colitis. Age and sex‐matched Sprague‐Dawley rats were administered 5% dextran sulphate sodium (DSS) in drinking water ad libitum for 7 days. A group of rats was sacrificed after DSS treatment, and the remaining rats were randomized to either sham‐SNS or SNS groups, which were performed for 1 hr daily for 10 days. Stimulations were delivered via chronically implanted electrodes using an 8‐channel universal pulse generator. Sacral nerve stimulation promoted recovery of colitis demonstrated by decreased disease activity index, myeloperoxidase activity, tissue TNF‐alpha, and histological scores as well as an increased colonic M2 macrophage population. Heart rate variability analysis demonstrated a decrease in low frequency and increase in high frequency with SNS, corresponding to increased vagal tone. Additionally, plasma pancreatic peptide was increased and norepinephrine was decreased after SNS in colitis while colon tissue acetylcholine was increased with SNS. This is the first study to the best of our knowledge that demonstrates the benefit of SNS with autonomic mediation. SNS alters the expression of inflammatory cytokines and macrophages as well as modulates neurotransmitters involved in systemic inflammation.

Ferruginol alleviates inflammation in dextran sulfate sodium-induced colitis in mice through inhibiting COX-2, MMP-9 and NF-κB signaling

Objective: To assess the anti-inflammatory efficacy of ferruginol on dextran sulfate sodium (DSS) stimulated ulcerative colitis mice. Methods: Ulcerative colitis was induced in C57BL/6J mice by administering 2% of DSS through drinking water for 7 d. The mice in the treatment group were treated with DAA+50 mg/kg/day ferruginol orally. In the positive control group, sulfasalazine (50 mg/kg/day) was used alongside with DSS. After induction, the bodyweight, character of stool and feces occult blood were recorded daily, the disease activity index was calculated, and the colon length, colon weight, and spleen weight were recorded. The myeloperoxidase activity was assayed by spectrophotometry. Interleukin (IL)-6, IL-1β, and tumor necrosis factor-a were determined by ELISA method, and nuclear factor-κB, cyclooxygenase-2, matrix metalloproteinases-9, and inducible nitric oxide synthase by Western blotting assays. Results: Ferruginol significantly increased the bodyweight, colon weight, colon length, and decreased disease activity index and spleen weight. It exhibited anti-inflammatory activity against DSS induced ulcerative colitis in mice by reducing the activities of myeloperoxidase, tumor necrosis factor-α, nuclear factor-κβ, IL-1β, cyclooxygenase-2, matrix metalloproteinases-9, IL-6, and inducible nitric oxide synthase. Conclusions: Ferruginol could be used to treat ulcerative colitis by attenuating the inflammation in colon cells and maintaining colonic mucosal barrier integrity.

Inhibiting microRNA-7 Expression Exhibited a Protective Effect on Intestinal Mucosal Injury in TNBS-Induced Inflammatory Bowel Disease Animal Model.

This study aimed to explore the expression and correlation of microRNA-7 (miR-7) and trefoil factor 3 (TFF3) genes and proteins in inflammatory bowel disease (IBD) mouse models and to elucidate the effect of miR-7 inhibition in the intestinal mucosa in IBD models. A TNBS-induced IBD mouse model was established. Changes in intestinal inflammation were observed by HE staining, and the expression levels of miR-7 and TFF3 were detected by RT-PCR. After miRNA-antagomir injection, the degree of colonic tissue damage and the expression levels of miR-7 and TFF3 in intestinal tissues were compared. TNBS-induced IBD mice showed significant weight loss, significantly decreased disease activity index (DAI), and a significantly increased pathological damage score. miR-7 was highly expressed in the colon tissue of IBD mice, and TFF3 was downregulated. Inhibition of the expression of miR-7 improved the stool characteristics and fecal occult blood (OB) of IBD mice, significantly increased the expression of TFF3 protein, and decreased the pathological damage scores. In the IBD mouse model, miR-7 posttranscriptionally regulates TFF3. The inhibition of miR-7 expression improves some clinical manifestations of IBD mice, reduces the pathological damage of the intestinal mucosa, and shows a protective effect in IBD.

Spontaneous colitis in IL-10-deficient mice was ameliorated via inhibiting glutaminase1.

Immunity imbalance and barrier damage in the intestinal mucosa are the main pathogenic factors of Crohn's disease (CD). Bis‐2‐(5‐phenylacetamido‐1,2,4‐thiadiazol‐2‐yl) ethyl sulfide (BPTES) is a glutaminase 1 (Gls1) inhibitor with the dual functions of increasing glutamine levels and immune regulation. In this study, we focused on the role of BPTES in CD‐like enteritis and the possible mechanisms. We found that Gls1 expression was significantly increased in CD intestinal tissue compared with control tissue. Bis‐2‐(5‐phenylacetamido‐1,2,4‐thiadiazol‐2‐yl) ethyl sulfide treatment significantly ameliorated chronic colitis in the IL‐10−/−, as manifested by decreased disease activity index, body weight change, histological inflammatory degree and inflammatory cytokine expression. Bis‐2‐(5‐phenylacetamido‐1,2,4‐thiadiazol‐2‐yl) ethyl sulfide treatment exerted protective effects on CD that were associated with the maintenance of intestinal barrier integrity and the Th/Treg balance. Bis‐2‐(5‐phenylacetamido‐1,2,4‐thiadiazol‐2‐yl) ethyl sulfide treatment may act in part through TCR‐mediated mammalian target of rapamycin complex 1 (mTORC1) signalling activation. In conclusion, inhibition of Gls1 expression attenuated chronic colitis by maintaining intestinal barrier integrity and the Th/Treg balance, thereby ameliorating CD‐like colitis.