Tanshinone IIA Protects against Dextran Sulfate Sodium- (DSS-) Induced Colitis in Mice by Modulation of Neutrophil Infiltration and Activation

Neutrophils play a critical role in the initiation and maintenance of intestinal inflammation. However, conventional neutrophil-targeted therapies can impair normal host defense. Tanshinone IIA has been recently revealed to act directly on neutrophils. Hence, we aimed at investigating whether Tanshinone IIA can protect against experimental colitis through modulation of neutrophils. We induced colitis in C57BL/6 mice by giving 3% dextran sulfate sodium (DSS) orally, and meanwhile, we treated mice daily with Tanshinone IIA intraperitoneally. The severity of colitis was evaluated by calculating disease activity index (DAI) and histological parameters. Neutrophil infiltration and activation in the colons of mice were measured. Moreover, whether Tanshinone IIA has direct effects on neutrophil migration and activation was determined in vitro. Our data showed that Tanshinone IIA significantly ameliorated the severity of DSS-induced colitis in mice, evidenced by the reduced DAI and improved colonic inflammation. In addition, Tanshinone IIA decreased neutrophil infiltration of intestinal mucosa and activation and reduced colonic inflammatory cytokines in DSS-treated mice. Furthermore, Tanshinone IIA was demonstrated to significantly suppress neutrophil migration and activation. These results provide compelling evidence that Tanshinone IIA has a therapeutic potential for alleviating inflammatory colitis in mice, which is possibly mediated by the immunomodulation of neutrophils.

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Desmethylbellidifolin Attenuates Dextran Sulfate Sodium-Induced Colitis: Impact on Intestinal Barrier, Intestinal Inflammation and Gut Microbiota

Planta Medica ◽

10.1055/a-1506-3476 ◽

2021 ◽

Author(s):

Jiaqi Wu ◽

Yuzheng Wu ◽

Yue Chen ◽

Mengyang Liu ◽

Haiyang Yu ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gut Microbiota ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Intestinal Inflammation ◽

Activity Index ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Function Evaluation ◽

Biological Drugs

AbstractUlcerative colitis has been recognized as a chronic inflammatory disease predominantly disturbing the colon and rectum. Clinically, the aminosalicylates, steroids, immunosuppressants, and biological drugs are generally used for the treatment of ulcerative colitis at different stages of disease progression. However, the therapeutic efficacy of these drugs does not satisfy the patients due to the frequent drug resistance. Herein, we reported the anti-ulcerative colitis activity of desmethylbellidifolin, a xanthone isolated from Gentianella acuta, in dextran sulfate sodium-induced colitis in mice. C57BL/6 mice were treated with 2% dextran sulfate sodium in drinking water to induce acute colitis. Desmethylbellidifolin or balsalazide sodium was orally administrated once a day. Biological samples were collected for immunohistological analysis, intestinal barrier function evaluation, cytokine measurement, and gut microbiota analysis. The results revealed that desmethylbellidifolin alleviated colon shortening and body weight loss in dextran sulfate sodium-induced mice. The disease activity index was also lowered by desmethylbellidifolin after 9 days of treatment. Furthermore, desmethylbellidifolin remarkably ameliorated colonic inflammation through suppressing the expression of interleukin-6 and tumor necrosis factor-α. The intestinal epithelial barrier was strengthened by desmethylbellidifolin through increasing levels of occludin, ZO-1, and claudins. In addition, desmethylbellidifolin modulated the gut dysbiosis induced by dextran sulfate sodium. These findings suggested that desmethylbellidifolin effectively improved experimental ulcerative colitis, at least partly, through maintaining intestinal barrier integrity, inhibiting proinflammatory cytokines, and modulating dysregulated gut microbiota.

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Lactobacillus reuteri Ameliorates Intestinal Inflammation and Modulates Gut Microbiota and Metabolic Disorders in Dextran Sulfate Sodium-Induced Colitis in Mice

Nutrients ◽

10.3390/nu12082298 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2298

Author(s):

Gang Wang ◽

Shuo Huang ◽

Shuang Cai ◽

Haitao Yu ◽

Yuming Wang ◽

...

Keyword(s):

Gut Microbiota ◽

Metabolic Disorders ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Lactobacillus Reuteri ◽

Intestinal Inflammation ◽

Intestinal Bacteria ◽

Ht 29

Lactobacillus reuteri, a commensal intestinal bacteria, has various health benefits including the regulation of immunity and intestinal microbiota. We examined whether L. reuteri I5007 could protect mice against colitis in ameliorating inflammation, modulating microbiota, and metabolic composition. In vitro, HT-29 cells were cultured with L. reuteri I5007 or lipopolysaccharide treatment under three different conditions, i.e., pre-, co- (simultaneous), and posttreatment. Pretreatment with L. reuteri I5007 effectively relieves inflammation in HT-29 cells challenged with lipopolysaccharide. In vivo, mice were given L. reuteri I5007 by gavage throughout the study, starting one week prior to dextran sulfate sodium (DSS) treatment for one week followed by two days without DSS. L. reuteri I5007 improved DSS-induced colitis, which was confirmed by reduced weight loss, colon length shortening, and histopathological damage, restored the mucus layer, as well as reduced pro-inflammatory cytokines levels. Analysis of 16S rDNA sequences and metabolome demonstrates that L. reuteri I5007 significantly alters colonic microbiota and metabolic structural and functional composition. Overall, the results demonstrate that L. reuteri I5007 pretreatment could effectively alleviate intestinal inflammation by regulating immune responses and altering the composition of gut microbiota structure and function, as well as improving metabolic disorders in mice with colitis.

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Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis

Science Translational Medicine ◽

10.1126/scitranslmed.aax2945 ◽

2019 ◽

Vol 11 (515) ◽

pp. eaax2945 ◽

Cited By ~ 29

Author(s):

Yi-Ling Chen ◽

Danuta Gutowska-Owsiak ◽

Clare S. Hardman ◽

Melanie Westmoreland ◽

Teena MacKenzie ◽

...

Keyword(s):

Atopic Dermatitis ◽

Therapeutic Potential ◽

Neutrophil Migration ◽

Neutrophil Infiltration ◽

Severity Index ◽

Fundamental Biology ◽

Targeted Inhibition

Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti–IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8–induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD.

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Inhibition of the activation of γδT17 cells through PPARγ–PTEN/Akt/GSK3β/NFAT pathway contributes to the anti-colitis effect of madecassic acid

Cell Death and Disease ◽

10.1038/s41419-020-02969-x ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Xinming Yun ◽

Yulai Fang ◽

Changjun Lv ◽

Simiao Qiao ◽

Yu Tao ◽

...

Keyword(s):

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Critical Role ◽

Centella Asiatica ◽

Cell Number ◽

Antibody Microarray ◽

Alternative Source ◽

Akt Phosphorylation ◽

Microarray Profiling

Abstract Type-17 immune response, mediated mainly by IL-17, plays a critical role in ulcerative colitis. Previously, we showed that madecassic acid (MA), the main active ingredient of Centella asiatica herbs for anti-colitis effect, ameliorated dextran sulfate sodium (DSS)-induced mouse colitis through reducing the level of IL-17. Here, we explore the effect of MA on the activation of γδT17 cells, an alternative source of IL-17 in colitis. In DSS-induced colitis mice, oral administration of MA decreased the number of γδT17 cells and attenuated the inflammation in the colon, and the anti-colitis effect of MA was significantly counteracted by redundant γδT17 cells, suggesting that the decrease in γδT17 cells is important for the anti-colitis effect of MA. In vitro, MA could inhibit the activation but not the proliferation of γδT17 cells at concentrations without evident cytotoxicity. Antibody microarray profiling showed that the inhibition of MA on the activation of γδT17 cells involved PPARγ–PTEN/Akt/GSK3β/NFAT signals. In γδT17 cells, MA could reduce the nuclear localization of NFATc1 through inhibiting Akt phosphorylation to promote GSK3β activation. Moreover, it was confirmed that MA inhibited the Akt/GSK3β/NFATc1 pathway and the activation of γδT17 cells through activating PPARγ to increase PTEN expression and phosphorylation. The correlation between activation of PPARγ, decrease in γδT17 cell number, and amelioration of colitis by MA was validated in mice with DSS-induced colitis. In summary, these findings reveal that MA inhibits the activation of γδT17 cells through PPARγ–PTEN/Akt/GSK3β/NFAT pathway, which contributes to the amelioration of colitis.

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Suppression of Th17 Cell Response in the Alleviation of Dextran Sulfate Sodium-Induced Colitis by Ganoderma lucidum Polysaccharides

Journal of Immunology Research ◽

10.1155/2018/2906494 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Bing Wei ◽

Ran Zhang ◽

Jingbo Zhai ◽

Junfeng Zhu ◽

Fangli Yang ◽

...

Keyword(s):

Weight Loss ◽

Body Weight ◽

Ganoderma Lucidum ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Therapeutic Potential ◽

Activity Index ◽

Survival Rates ◽

Body Weight Loss ◽

Disease Activity Index

Background. Ganoderma lucidum polysaccharides (GLP) has anti-inflammatory and immunomodulatory effects. Dysregulated immune responses are involved in the pathogenesis of dextran sulfate sodium (DSS)-induced colitis. The aim of this study was to assess the therapeutic potential of GLP to alleviate DSS-induced colitis. Methods. The mice were administered with GLP by intragastric gavage daily for two weeks prior to the DSS treatment. Mice were orally administered with 2.5% DSS dissolved in drinking water with GLP or water treatment for 6 days. The mice were killed on day 7 after induction of colitis. Survival rates, body weight loss, colon lengths, histological changes, and disease activity index scores (DAI) were evaluated. Results. GLP significantly improved survival rates, colon length shortening, body weight loss, histopathological score, and DAI scores in mice with DSS-induced colitis. GLP markedly suppressed the secretions of TNF-α, IL-1β, IL-6, IL-17A, and IL-4 and significantly affected populations of Th17 cells, B cells, NK cells, and NKT cells in the lamina propria lymphocytes. Conclusions. GLP prevented inflammation, maintained intestinal homeostasis, and regulated the intestinal immunological barrier functions in mice with DSS-induced colitis.

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APicrorhiza kurroaDerivative, Picroliv, Attenuates the Development of Dextran-Sulfate-Sodium-Induced Colitis in Mice

Mediators of Inflammation ◽

10.1155/2012/751629 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

De-Kui Zhang ◽

Jian-Jie Yu ◽

Yu-Min Li ◽

Li-Na Wei ◽

Yi Yu ◽

...

Keyword(s):

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Activity Index ◽

Quantitative Polymerase Chain Reaction ◽

Critical Role ◽

Disease Activity Index ◽

Enzyme Linked Immunosorbent Assay ◽

Histological Score ◽

Polymerase Chain ◽

Histology Score

Background. Free radicals and proinflammatory cytokines have been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). Picroliv, aPicrorhiza kurroaderivative, has been demonstrated to have antioxidant and anti-inflammatory effect. The purpose of the study was to investigate the effects of picroliv on experimental model of UC in mice.Materials and Methods. Picroliv was administrated orally by gavage to mice with colitis induced by dextran sulfate sodium (DSS). Disease activity index (DAI), colon length, and histology score were observed. Myeloperoxidase (MPO) activity, and SOD, MDA concentrations were measured by enzyme-linked immunosorbent assay (ELISA) while the expression of cytokine mRNAs was studied by real-time-quantitative polymerase chain reaction and also ELISA. The expression of NF-κB p65 was observed by immunohistochemistry staining and western blotting.Results. A significant improvement was observed in DAI and histological score in mice treated with picroliv, and incerased MPO activity, MDA concentrations, and the expression of IL-1β, TNF-α, and NF-κB p65 in mice with DSS-induced colitis were significantly reduced while decreased SOD level increased following administration of picroliv.Conclusion. The administration of picroliv leads to an amelioration of DSS-induced colitis, suggesting administration of picroliv may provide a therapeutic approach for UC.

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Atractylodin Attenuates Dextran Sulfate Sodium-Induced Colitis by Alleviating Gut Microbiota Dysbiosis and Inhibiting Inflammatory Response Through the MAPK Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.665376 ◽

2021 ◽

Vol 12 ◽

Author(s):

Linghang Qu ◽

Xiong Lin ◽

Chunlian Liu ◽

Chang Ke ◽

Zhongshi Zhou ◽

...

Keyword(s):

Ulcerative Colitis ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Intestinal Inflammation ◽

Mapk Pathway ◽

Activity Index ◽

Intestinal Barrier ◽

Disease Activity Index ◽

Inflammatory Factors ◽

Therapeutic Effects

In this study, we investigated the therapeutic effects and mechanism of atractylodin (ATL) on dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. We found that atractylodin could significantly reverse the effects of DSS-induced ulcerative colitis, such as weight loss, disease activity index score; shorten the colon length, and reverse the pathological changes in the colon of mice. Atractylodin could inhibit the activation of colonic macrophages by inhibiting the MAPK pathway and alleviate intestinal inflammation in the mouse model of ulcerative colitis. Moreover, it could protect the intestinal barrier by inhibiting the decrease of the tight junction proteins, ZO-1, occludin, and MUC2. Additionally, atractylodin could decrease the abundance of harmful bacteria and increase that of beneficial bacteria in the intestinal tract of mice, effectively improving the intestinal microecology. In an LPS-induced macrophage model, atractylodin could inhibit the MAPK pathway and expression of the inflammatory factors of macrophages. Atractylodin could also inhibit the production of lactate, which is the end product of glycolysis; inhibit the activity of GAPDH, which is an important rate-limiting enzyme in glycolysis; inhibit the malonylation of GAPDH, and, thus, inhibit the translation of TNF-α. Therefore, ours is the first study to highlight the potential of atractylodin in the treatment of ulcerative colitis and reveal its possible mechanism.

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Neferine, a Bisbenzylisoquinoline Alkaloid, Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500660 ◽

2018 ◽

Vol 46 (06) ◽

pp. 1263-1279 ◽

Cited By ~ 7

Author(s):

Xiaxia Wu ◽

Yanling Guo ◽

Xiangjing Min ◽

Lixia Pei ◽

Xiuping Chen

Keyword(s):

Ulcerative Colitis ◽

Protein Expression ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Activity Index ◽

Biological Activities ◽

Necrosis Factor Alpha ◽

Cox 2 ◽

Anti Inflammatory

Both the incidence and prevalence of ulcerative colitis (UC) are increasing throughout the world. Neferine, a natural alkaloid, demonstrated a variety of biological activities. In this study, the anti-inflammatory effect of neferine was investigated. Raw264.7 cells were stimulated with lipopolysaccharide (LPS) or LPS plus Z-VAD-fmk (Z-VAD). The inhibitory effect of neferine on secretion of nitrite, cytokines tumor necrosis factor alpha (TNF-[Formula: see text]) and interleukin 6 (IL-6), expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was determined. The protective effect of neferine was investigated in dextran sulfate sodium (DSS)-induced UC mouse model. Neferine significantly inhibited LPS and LPS plus Z-VAD induced secretion of nitrite, cytokines, and expression of iNOS and COX-2. Oral administration of neferine (10[Formula: see text]mg/kg and 25[Formula: see text]mg/kg) significantly reduced DSS-induced mouse weight loss, decreased disease activity index (DAI) scores, improved colon pathological changes, and decreased plasma cytokines. In addition, neferine significantly inhibited the protein expression of iNOS, COX-2, receptor-interacting protein 1 (RIP1), RIP3, mixed lineage kinase domain-like protein (MLKL), and increased the protein expression of caspase-8 in colon tissues. These data suggest that neferine was a potent anti-inflammatory agent against LPS and DSS induced inflammation both in vitro and in vivo.

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Vitamin D Receptor–Dependent Signaling Protects Mice From Dextran Sulfate Sodium-Induced Colitis

Endocrinology ◽

10.1210/en.2016-1913 ◽

2017 ◽

Vol 158 (6) ◽

pp. 1951-1963 ◽

Cited By ~ 17

Author(s):

Fa Wang ◽

Robert L. Johnson ◽

Marsha L. DeSmet ◽

Paul W. Snyder ◽

Keke C. Fairfax ◽

...

Keyword(s):

Vitamin D ◽

Epithelial Cells ◽

Vitamin D Receptor ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Immune Cell ◽

Activity Index ◽

Epithelial Damage ◽

M1 Macrophage

Abstract Low vitamin D status potentiates experimental colitis, but the vitamin D–responsive cell in colitis has not been defined. We hypothesized that vitamin D has distinct roles in colonic epithelial cells and in nonepithelial cells during colitis. We tested this hypothesis by using mice with vitamin D receptor (VDR) deletion from colon epithelial cells (CEC-VDRKO) or nonintestinal epithelial cells (NEC-VDRKO). Eight-week-old mice were treated with 1.35% dextran sulfate sodium (DSS) for 5 days and then euthanized 2 or 10 days after removal of DSS. DSS induced body weight loss and increased disease activity index and spleen size. This response was increased in NEC-VDRKO mice but not CEC-VDRKO mice. DSS-induced colon epithelial damage and immune cell infiltration scores were increased in both mouse models. Although the epithelium healed between 2 and 10 days after DSS administration in control and CEC-VDRKO mice, epithelial damage remained high in NEC-VDRKO mice 10 days after removal of DSS, indicating delayed epithelial healing. Gene expression levels for the proinflammatory, M1 macrophage (Mɸ) cytokines tumor necrosis factor-α, nitric oxide synthase 2, and interleukin-1β were significantly elevated in the colon of NEC-VDRKO mice at day 10. In vitro experiments in murine peritoneal Mɸs demonstrated that 1,25 dihydroxyvitamin D directly inhibited M1 polarization, facilitated M2 polarization, and regulated Mɸ phenotype switching toward the M2 and away from the M1 phenotype. Our data revealed unique protective roles for vitamin D signaling during colitis in the colon epithelium as well as nonepithelial cells in the colon microenvironment (i.e., modulation of Mɸ biology).

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