scholarly journals Dihydroartemisinin Protects against Dextran Sulfate Sodium-Induced Colitis in Mice through Inhibiting the PI3K/AKT and NF-κB Signaling Pathways

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ning Li ◽  
Wenjing Sun ◽  
Xin Zhou ◽  
Hao Gong ◽  
Yuqing Chen ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Signaling Pathways ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Body Weight Loss ◽  
Intestinal Epithelial ◽  
Histological Damage ◽  
Inflammatory Bowel

Ulcerative colitis is a common inflammatory bowel disease, and the activation of thePI3K/AKT and NF-κB signaling pathways plays a pivotal role in its pathogenesis. Dihydroartemisinin (DHA) is a widely used antimalarial drug and has shown anticancer effect partially through inhibiting the activation of PI3K/AKT and NF-κB. This study aimed to investigate the effect of dihydroartemisinin on ulcerative colitis and its mechanism. Adult male C57 mice were subjected to 3.0% dextran sulfate sodium (DSS) for seven days; simultaneously, dihydroartemisinin or control saline was administered by oral gavage once a day. In vitro, the intestinal epithelial cell-6 was treated with LPS for 24 hours with or without dihydroartemisinin combined with PI3K/Akt activator 740 Y-P or NF-κB activator phorbol myristate acetate. Western blotting was used to test the activation of PI3K/AKT and NF-κB. Dihydroartemisinin significantly ameliorated body weight loss, shortened colon length, and increased DAI in DSS-induced colitis. Meanwhile, histological damage was improved and was accompanied by decreased expression and secretion of proinflammatory cytokines. Moreover, DSS-induced elevation of phosphorylation of PI3K, AKT, IKKα, IκBα, and NF-κB (p65) was remarkably blunted by dihydroartemisinin both in vivo and in vitro, indicating an inhibitive property on the PI3K/AKT and NF-κB signaling pathways. Furthermore, administration of 740 Y-P or PMA significantly blocked protective activity of dihydroartemisinin against colitis in vitro. In conclusion, dihydroartemisinin can attenuate DSS-induced colitis, and its anticolitis effect might be mediated via the PI3K/AKT and NF-κB signaling pathways. DHA might serve as a promising drug for patients with ulcerative colitis.

A pan-RAF inhibitor LY3009120 inhibits necroptosis by preventing phosphorylation of RIPK1 and alleviates dextran sulfate sodium-induced colitis

2019 ◽  
Vol 133 (8) ◽  
pp. 919-932 ◽  
Author(s):  
Chong Zhang ◽  
Yiqin Luo ◽  
Qiaoling He ◽  
Shuai Liu ◽  
Andong He ◽  
...  
Keyword(s):  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Body Weight Loss ◽  
Developed Countries ◽  
Intestinal Barrier Function ◽  
Therapeutic Drug ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

Abstract A dramatic increase in the incidence of inflammatory bowel disease (IBD) has been observed in the past two decades, mainly in developed countries and also in developing regions. Necroptosis has been found to play an important role in the pathogenesis of IBD, suggesting its inhibitors are promising in clinic. However, clinical drugs targeting necroptosis are seriously lacking. Through screening a clinical compound library that contains 611 inhibitors, a pan-RAF inhibitor LY3009120 was found to be promising as a necroptosis inhibitor. LY3009120 inhibited necroptosis in vitro, and its inhibition against necroptosis was independent of its well-known activity to inhibit RAF. Surprisingly, LY3009120 prevented phosphorylation of receptor interacting serine/threonine kinase 1 (RIPK1) and subsequently phosphorylation of receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL) which happened during necroptosis. In vivo, LY3009120 significantly alleviated dextran sulfate sodium (DSS)-induced colitis as indicated by prevention of body weight loss, colon shortening, and decreased mortality. Furthermore, LY3009120 inhibited necroptosis of intestinal epithelial cells (IECs) and prevented intestinal barrier function loss. Consistently, LY3009120 decreased DSS-induced colonic inflammation, as indicated by decreased infiltration of macrophages and neutrophils, and decreased colonic TNF-α, IL-6, and IL-1β level in DSS treated mice. These results indicate that an anti-cancer pan-RAF inhibitor LY3009120 is a necroptosis inhibitor and may serve as a potential therapeutic drug for colitis.

CD39/CD73/A2a Adenosine Metabolic Pathway: Targets for Moxibustion in Treating DSS-Induced Ulcerative Colitis

2021 ◽  
Vol 49 (03) ◽  
pp. 661-676
Author(s):  
Yuanbing Zhu ◽  
Zhiqi Zhuang ◽  
Qiaofeng Wu ◽  
Sirui Lin ◽  
Na Zhao ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Animal Experiments ◽  
Treg Cells ◽  
Colonic Tissue ◽  
Colonic Epithelial Cells ◽  
A2a Receptor ◽  
Draining Lymph Nodes

Ulcerative Colitis (UC) is a chronic inflammation disease, and the incidence of UC is increasing recently. Both clinical trials and animal experiments show that moxibustion is a complementary and alternative treatment for UC. Previous studies showed that moxibustion can improve UC by regulating the balance of Tregs and Th17 (Sun et al., 2017). Treg cells is one subset of CD4[Formula: see text] T cells that exert the immunosuppressive function. CD39 and CD73, expressed on the surface of Tregs, hydrolyze ATP to AMP and are further involved in the immunosuppressive function of Tregs. In this study, we investigated the effect of moxibustion on CD39[Formula: see text] Tregs and CD73[Formula: see text] Tregs in dextran sulfate sodium (DSS) induced UC mice. The A2a receptor (A2aR), one of the targets of adenosine, was also detected. The results showed that moxibustion could increase the expression of CD39, CD73, and A2aR in colonic tissue and improve the proportion of CD39[Formula: see text] Tregs and CD73[Formula: see text] Tregs in peripheral blood, inguinal draining lymph nodes and spleen in the UC model. Additionally, A2aR agonists enhanced the cell viability of colonic epithelial cells and inhibit the production of cytokines IL-6 and TNF-[Formula: see text] in vitro, which may further influence the pathway of ATP purine signal metabolism and alleviates the gut inflammation of UC mice. Taken together, this study provides supplemental evidence to reveal the immune related mechanism of moxibustion in the treatment of UC.

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

Nutrients ◽  
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.

scholarly journals Development of a human primary gut-on-a-chip to model inflammatory processes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Claudia Beaurivage ◽  
Auste Kanapeckaite ◽  
Cindy Loomans ◽  
Kai S. Erdmann ◽  
Jan Stallen ◽  
...  
Keyword(s):  
Human Colon ◽  
In Vitro Models ◽  
Intestinal Epithelial ◽  
Activated Macrophages ◽  
Polarized Secretion ◽  
Inflammatory Processes ◽  
Inflammatory Bowel ◽  
Key Aspects

AbstractInflammatory bowel disease (IBD) is a complex multi-factorial disease for which physiologically relevant in vitro models are lacking. Existing models are often a compromise between biological relevance and scalability. Here, we integrated intestinal epithelial cells (IEC) derived from human intestinal organoids with monocyte-derived macrophages, in a gut-on-a-chip platform to model the human intestine and key aspects of IBD. The microfluidic culture of IEC lead to an increased polarization and differentiation state that closely resembled the expression profile of human colon in vivo. Activation of the model resulted in the polarized secretion of CXCL10, IL-8 and CCL-20 by IEC and could efficiently be prevented by TPCA-1 exposure. Importantly, upregulated gene expression by the inflammatory trigger correlated with dysregulated pathways in IBD patients. Finally, integration of activated macrophages offers a first-step towards a multi-factorial amenable IBD platform that could be scaled up to assess compound efficacy at early stages of drug development or in personalized medicine.

scholarly journals Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53

2020 ◽  
Vol 295 (13) ◽  
pp. 4237-4251 ◽  
Author(s):  
Jie Zhang ◽  
Min Xu ◽  
Weihua Zhou ◽  
Dejian Li ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Epithelial Cell ◽  
Bowel Disease ◽  
Intestinal Epithelial Cell ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
P53 Expression ◽  
Inflammatory Bowel

Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1−/− mice, DJ-1−/−p53−/− mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1−/− mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

scholarly journals Portulaca Extract Attenuates Development of Dextran Sulfate Sodium Induced Colitis in Mice through Activation of PPARγ

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Rui Kong ◽  
Hui Luo ◽  
Nan Wang ◽  
Jingjing Li ◽  
Shizan Xu ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Peroxisome Proliferator ◽  
Potential Candidate ◽  
Inflammatory Bowel ◽  
Peroxisome Proliferator Activated Receptors ◽  
Induced Apoptosis ◽  
Inflammatory Effect

Portulaca oleracea L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-γ (PPAR-γ), Portulaca regulation of PPAR-γ in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and four groups were established as normal control, DSS alone, DSS plus mesalamine, and DSS plus Portulaca. Severity of UC was evaluated by body weight, stool blood form, and length of colorectum. Inflammation was examined by determination of inflammatory cytokines (TNF-a, IL-6, and IL-1a). Portulaca extract was able to attenuate development of UC in DSS model similar to the treatment of mesalazine. Moreover, Portulaca extract inhibited proinflammatory cytokines release and reduced the level of DSS-induced NF-κB phosphorylation. Furthermore, Portulaca extract restored PPAR-γ level, which was reduced by DSS. In addition, Portulaca extract protected DSS induced apoptosis in mice. In conclusion, Portulaca extract can alleviate colitis in mice through regulation of inflammatory reaction, apoptosis, and PPAR-γ level; therefore, Portulaca extract can be a potential candidate for the treatment of IBD.

scholarly journals Cinacalcet Targets the Neurokinin-1 Receptor and Inhibits PKCδ/ERK/P65 Signaling to Alleviate Dextran Sulfate Sodium-Induced Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuehong Chen ◽  
Huan Liu ◽  
Qiuping Zhang ◽  
Yubin Luo ◽  
Liang Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Structural Integrity ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Therapeutic Effects ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1

Objective: Inflammatory bowel disease is an immune-mediated chronic inflammatory disease of the gastrointestinal tract for which curative drugs are currently not available. This study was performed to assess the therapeutic effects of cinacalcet on dextran sulfate sodium (DSS)-induced colitis.Methods: Primary macrophages obtained from bone marrow and the macrophage cell line RAW264.7 were used to examine the inhibitory effect of cinacalcet on cytokine production, the PKCδ/ERK/P65 signaling pathway, and NF-κB P65 translocation. Colitis was induced using DSS to assess the treatment effect of cinacalcet. Bioinformatics approaches were adopted to predict potential targets of cinacalcet, and a drug affinity responsive target stability (DARTs) assay was performed to confirm binding between cinacalcet and potential target.Results:In vivo analysis showed that cinacalcet reduced the disease activity score, prevented shortening of the colon, diminished inflammatory cell infiltration, and protected the structural integrity of the intestinal wall. Cinacalcet also reduced production of the inflammatory cytokines TNFα, IL-1β, and IL-6 in the colon and sera of mice with DSS-induced colitis. In vitro studies revealed that cinacalcet suppressed the translocation of P65 and inhibited production of the inflammatory cytokines IL-1β and IL-6. Mechanistic studies revealed that the target of cinacalcet was neurokinin-1 receptor (NK1R) and their binding was confirmed by a DARTs assay. Furthermore, the inhibition of NK-κB P65 activation was found to occur via the suppression of PKCδ/ERK/P65 signaling mediated by cinacalcet.Conclusion: Cinacalcet inhibits the activation of NF-κB and reduces the production of inflammatory cytokines by suppressing the PKCδ/ERK/P65 signaling pathway via targeting NK1R, suggesting that it can be used to treat inflammatory diseases, particularly colitis.

Baitouweng Decoction Alleviates Dextran Sulfate Sodium–Induced Ulcerative Colitis Through Nrf2/HO-1 Pathway Activation and HMGB1 Downregulation

2021 ◽  
Author(s):  
Weina Zhu ◽  
Chunhua Ma ◽  
Fuqiong Zhou ◽  
Jie Ruan ◽  
Yajie Zhang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Signaling Pathways ◽  
Adhesion Molecule ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Intercellular Adhesion Molecule ◽  
Control Group ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Aminosalicylic Acid

Abstract BackgroundThe phrase “baitouweng (BTW) decoction” was first recorded in the ancient Chinese medical text Shang Han Za Bing Lun. BTW decoction has been widely used by practitioners of (traditional) Chinese medicine.[VN1] It has been used to treat ulcerative colitis (UC) for hundreds of years. In this study, we investigated the antioxidative properties of BTW and the intestinal immunity of mice with dextran sulfate sodium (DSS)–induced UC and further investigated the mechanism by which BTW alleviates UC.MethodsUC was induced in mice by using DSS. The mice were randomly divided into the following five groups: control, DSS, BTW (5, 10, and 20 g/kg[VN2] ), berberine (BBR), and 5-aminosalicylic acid (5-ASA). Except for the control group, 3% DSS was administered in drinking water to all groups for 7 days, and and the other groups were intragastrically administered with BTW（5, 10, and 20 g/kg）、BBR and 5-ASA independently.[VN3] After gavaging for 12 days, the mice were killed. Subsequently, body weight loss, colon length, colon histopathology, inflammatory cytokine expression, and intestinal protein expression were measured.ResultsBTW effectively reduced the symptoms and histopathological scores of UC mice. Additionally, it downregulated the inflammatory factors interleukin (IL)-6 and IL-1β, the immunoglobulins vascular cell adhesion molecule 1 and intercellular adhesion molecule 1, and metalloprotease matrix metallopeptidase 9. Moreover, it downregulated high mobility group box 1 protein. Furthermore, it inhibited the nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway.ConclusionBTW considerably alleviated the inflammatory symptoms of mice with acute colitis, and the latent mechanism of BTW may be related to various signaling pathways, including the modulation of antioxidant signaling pathways such as the Nrf2/HO-1 pathway.

scholarly journals Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice

2011 ◽  
Vol 300 (6) ◽  
pp. G1115-G1123 ◽  
Author(s):  
Seema Saksena ◽  
Sonia Goyal ◽  
Geetu Raheja ◽  
Varsha Singh ◽  
Maria Akhtar ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Epithelial Cells ◽  
Bowel Disease ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Intestinal Epithelial Cells ◽  
Myeloperoxidase Activity ◽  
Intestinal Epithelial ◽  
P Glycoprotein ◽  
Inflammatory Bowel

P-glycoprotein (P-gp) mediates efflux of xenobiotics and bacterial toxins from the intestinal mucosa into the lumen. Dysregulation of P-gp has been implicated in inflammatory bowel disease. Certain probiotics have been shown to be effective in treating inflammatory bowel disease. However, direct effects of probiotics on P-gp are not known. Current studies examined the effects of Lactobacilli on P-gp function and expression in intestinal epithelial cells. Caco-2 monolayers and a mouse model of dextran sulfate sodium-induced colitis were utilized. P-gp activity was measured as verapamil-sensitive [3H]digoxin transepithelial flux. Multidrug resistant 1 (MDR1)/P-gp expression was measured by real-time quantitative PCR and immunoblotting. Culture supernatant (CS; 1:10 or 1:50, 24 h) of Lactobacillus acidophilus or Lactobacillus rhamnosus treatment of differentiated Caco-2 monolayers (21 days postplating) increased (∼3-fold) MDR1/P-gp mRNA and protein levels. L. acidophilus or L. rhamnosus CS stimulated P-gp activity (∼2-fold, P < 0.05) via phosphoinositide 3-kinase and ERK1/2 MAPK pathways. In mice, L. acidophilus or L. rhamnosus treatment (3 × 109 colony-forming units) increased mdr1a/P-gp mRNA and protein expression in the ileum and colon (2- to 3-fold). In the dextran sulfate sodium (DSS)-induced colitis model (3% DSS in drinking water for 7 days), the degree of colitis as judged by histological damage and myeloperoxidase activity was reduced by L. acidophilus. L. acidophilus treatment to DSS-treated mice blocked the reduced expression of mdr1a/P-gp mRNA and protein in the distal colon. These findings suggest that Lactobacilli or their soluble factors stimulate P-gp expression and function under normal and inflammatory conditions. These data provide insights into a novel mechanism involving P-gp upregulation in beneficial effects of probiotics in intestinal inflammatory disorders.

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