scholarly journals Microbial therapeutics for acute colitis based on genetically modified Lactococcus lactis hypersecreting IL-1Ra in mice

2020 ◽  
Vol 52 (9) ◽  
pp. 1627-1636
Author(s):  
Fu Namai ◽  
Suguru Shigemori ◽  
Tasuku Ogita ◽  
Takashi Sato ◽  
Takeshi Shimosato
Keyword(s):  
Protein Delivery ◽  
Activity Index ◽  
Genetically Modified ◽  
Interleukin 1 ◽  
Disease Activity Index ◽  
Mesenteric Lymph Nodes ◽  
Acute Colitis ◽  
Body Weight Reduction ◽  
Global Pandemic ◽  
Activity Index Score

Abstract The increased incidence of inflammatory bowel disease (IBD) in Western and rapidly Westernizing developing countries poses a global pandemic threat. The development of affordable drugs for treating IBD worldwide is thus a priority. Genetically modified lactic acid bacteria (gmLAB) as microbial therapeutics are inexpensive protein producers suitable for use as carriers of protein to the intestinal mucosa. Here, we successfully constructed gmLAB hypersecreting interleukin 1 receptor antagonist (IL-1Ra). Oral administration of these gmLAB suppressed body weight reduction and exacerbation of the disease activity index score in mice with acute colitis and decreased the number of CD4+ IL-17A+ cells in the mesenteric lymph nodes. These data suggest that the gmLAB deliver IL-1Ra to the colon, where it inhibits IL-1 signaling. We thus developed a novel IBD therapeutic that blocks IL-1 signaling using a gmLAB protein delivery system. This system could be an inexpensive oral microbial therapeutic.

scholarly journals The Importance of Hypoxia-Inducible Factors (HIF-1 and HIF-2) for the Pathophysiology of Inflammatory Bowel Disease

2020 ◽  
Vol 21 (22) ◽  
pp. 8551
Author(s):  
Evelyn L. Kerber ◽  
Claudia Padberg ◽  
Nora Koll ◽  
Vera Schuetzhold ◽  
Joachim Fandrey ◽  
...  
Keyword(s):  
Activity Index ◽  
Disease Activity Index ◽  
Conditional Knockout ◽  
Hypoxia Inducible Factors ◽  
Low Oxygen ◽  
Mesenteric Lymph Nodes ◽  
Acute Colitis ◽  
Myeloid Lineage ◽  
Dss Colitis ◽  
In Cells

(1) Background: Hypoxia is a common feature of inflammation when hypoxia inducible factors (HIFs) adapt cells to conditions of low oxygen tension and inflammation. We studied the role of HIF-1 and HIF-2 in cells of the myeloid lineage in a mouse model of acute colitis. (2) Methods: Mice with and without a conditional knockout for either Hif-1a or Hif-2a or Hif-1a and Hif-2a in cells of the myeloid lineage were treated with 2.5% dextran sodium sulfate (DSS) for 6 days to induce an acute colitis. We analyzed the course of inflammation with respect to macroscopic (disease activity index) and microscopic (histology score and immunohistochemical staining of immune cells) parameters and quantified the mRNA expression of cytokines and chemokines in the colon and the mesenteric lymph nodes. (3) Results: A conditional knockout of myeloid Hif-1a ameliorated whereas the knockout of Hif-2a aggravated murine DSS colitis by increased recruitment of neutrophils to deeper layers of the colon. This led to higher expression of Il6, Ifng, Cd11c, Cd4, and Cd8 in the colon but also induced anti-inflammatory mediators such as Foxp3 and Il10. A conditional knockout of Hif-1a and Hif-2a did not show any differences compared to wildtype mice. (4) Conclusions: Myeloid HIF-1α and HIF-2α play opposing roles in acute DSS colitis. Thus, not only a cell type specific, but also the isoform specific modulation of HIFs needs to be addressed in attempts to modify HIF for therapeutic purposes.

scholarly journals Beneficial Effect of Shikonin on Experimental Colitis Induced by Dextran Sulfate Sodium in Balb/C Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Isabel Andújar ◽  
José Luis Ríos ◽  
Rosa María Giner ◽  
José Miguel Cerdá ◽  
María del Carmen Recio
Keyword(s):  
Disease Activity ◽  
Activity Index ◽  
Disease Activity Index ◽  
Experimental Colitis ◽  
Myeloperoxidase Activity ◽  
Dependent Manner ◽  
Inflammatory Bowel ◽  
Activity Index Score ◽  
Bloody Stools ◽  
Dose Dependent

The naphthoquinone shikonin, a major component of the root ofLithospermum erythrorhizon, now is studied as an anti-inflammatory agent in the treatment of ulcerative colitis (UC). Acute UC was induced in Balb/C mice by oral administration of 5% dextran sodium sulfate (DSS). The disease activity index was evaluated, and a histologic study was carried out. Orally administered shikonin reduces induced UC in a dose-dependent manner, preventing the shortening of the colorectum and decreasing weight loss by 5% while improving the appearance of feces and preventing bloody stools. The disease activity index score was much lower in shikonin-treated mice than in the colitic group, as well as the myeloperoxidase activity. The expression of cyclooxygenase-2 was reduced by 75%, activation of NF-κB was reduced by 44%, and that of pSTAT-3 by 47%, as well as TNF-α, IL-1β, and IL-6 production. Similar results were obtained in primary macrophages culture. This is the first report of shikonin’s ability to attenuate acute UC induced by DSS. Shikonin acts by blocking the activation of two major targets: NF-κB and STAT-3, and thus constitutes a promising potential therapeutic agent for the management of the inflammatory bowel disease.

scholarly journals Indigo Naturalis Suppresses Colonic Oxidative Stress and Th1/Th17 Responses of DSS-Induced Colitis in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Hai-tao Xiao ◽  
Jiao Peng ◽  
Bo Wen ◽  
Dong-dong Hu ◽  
Xiao-peng Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chinese Medicine ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Activity Index ◽  
Disease Activity Index ◽  
Protective Effects ◽  
Mesenteric Lymph Nodes ◽  
Indigo Naturalis

Indigo naturalis (also known as Qing-dai, or QD), a traditional Chinese medicine, has been widely used as an anticolitis regimen in the clinical practice of Chinese medicine. However, the precise mechanisms behind its efficacy remain unknown. We investigated the protective effects and associated molecular mechanisms of QD in DSS-induced colitis in mice. We found that QD administration attenuated DSS-induced colon shortening, tissue damage, and the disease activity index during the onset of colitis. Moreover, QD administration significantly suppressed colonic MPO activity and increased the activities of colonic T-SOD, CAT, and GSH-Px, as well the expression of p-AMPK and Nrf-2 in colon tissues of colitic mice. In addition, QD was capable of reducing the colonic Th1 and Th17 cell cytokines, the frequencies of Th1 and Th17 cells, and the phosphorylation of p-STAT1 and p-STAT3 in the mesenteric lymph nodes of colitic mice. An in vitro assay showed that QD significantly suppressed the differentiation of Th1 and Th17 cells. These findings suggest that QD has the potential to alleviate experimental colitis by suppressing colonic oxidative stress and restraining colonic Th1/Th17 responses, which are associated with activating AMPK/Nrf-2 signals and inhibiting STAT1/STAT3 signals, respectively. These findings also support QD as an effective regimen in the treatment of IBD.

scholarly journals Use Of The Prebiotic Inulin In The Prevention Of Adverse Signs Of Acute Colitis

2015 ◽  
Vol 65 (3) ◽  
pp. 339-347
Author(s):  
Hijová Emília ◽  
Śoltésová Alena ◽  
Salaj Rastislav ◽  
Kuzma Jozef ◽  
Strojný Ladislav ◽  
...  
Keyword(s):  
Activity Index ◽  
Disease Activity Index ◽  
Coliform Bacteria ◽  
Control Group ◽  
Sprague Dawley ◽  
Acute Colitis ◽  
Colon Tissue ◽  
Diet Intervention ◽  
Average Value ◽  
Glucuronidase Activity

Abstract The aim of this study was to investigate the influence of prebiotic inulin diet intervention on the activity of β-glucuronidase and counts of coliforms and lactobacilli in fresh caecal digesta, cytokine levels (IL-6, IL-8) and transcription nuclear factor kappa beta (NFkB) activities in the colon tissue and blood samples of rats with dextran sulphate sodium (DSS) induced acute colitis. Male Sprague-Dawley rats (8 per group) were randomly divided into three groups: Control, Acute colitis and Prebiotic. Colitis was induced using 5% DSS in drinking water for 7d. DSS application significantly increased the activity of β-glucuronidase (p<0.001), increased counts of coliform bacteria and decreased lactobacilli count (p<0.05) in comparison to the control group. Serum and tissue levels of IL-6 and IL-8 as well as tissue NFkB activities showed an increased expression in the acute colitis group. These results correspond to the average value of the disease activity index score (DAI) and revealed the maximum DAI score (6.5) in the acute colitis group. A decrease in the DAI score (4.13) was observed after application of the prebiotic inulin. Inulin diet intervention positively modified the number of microorganims and decreased β-glucuronidase activity. Colon tissue activities of NFkB were significantly suppressed (p<0.001). The synthesis of proinflammatory cytokines IL-6 (p<0.01) in the serum and in the colon tissue, as well as tissue IL-8 (p<0.05) in the prebiotic group were downregulated. These findings indicate that the dietary intake of inulin suppressed the expression of the observed markers, which play an important role in the inflammatory process, which predisposes to the use of inulin in the prevention or treatment of acute colitis in human and veterinary medicine.

scholarly journals Screening of an anti-inflammatory peptide from Hydrophis cyanocinctus and analysis of its activities and mechanism in DSS-induced acute colitis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Zengjie Zheng ◽  
Hailong Jiang ◽  
Yan Huang ◽  
Jie Wang ◽  
Lei Qiu ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Activity Index ◽  
Tumor Necrosis Factor Receptor ◽  
Disease Activity Index ◽  
Acute Colitis ◽  
Surface Plasmon Resonance Analysis ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Snake has been used for centuries as a traditional Chinese medicine, especially for therapeutic treatment for inflammatory diseases; however, its mechanisms of action and active constituents remain controversial. In our study, a tumor necrosis factor receptor 1 (TNFR1) selective binding peptide, Hydrostatin-SN1 (H-SN1), which was screened from a Hydrophis cyanocinctus venom gland T7 phage display library, was shown to exhibit significant anti-inflammatory activity in vitro and in vivo. As a TNFR1 antagonist, it reduced cytotoxicity mediated by TNF-α in L929 fibroblasts and effectively inhibited the combination between TNF-α with TNFR1 in surface plasmon resonance analysis. H-SN1 was also shown to suppress TNFR1–associated signaling pathways as it minimized TNF-α-induced NF-кB and MAPK activation in HEK293 embryonic kidney and HT29 adenocarcinoma cell lines. We next determined the effect of H-SN1 in vivo using a murine model of acute colitis induced by dextran sodium sulfate, demonstrating that H-SN1 lowered the clinical parameters of acute colitis including the disease activity index and histologic scores. H-SN1 also inhibited TNF/TNFR1 downstream targets at both mRNA and protein levels. These results indicate that H-SN1 might represent a suitable candidate for use in the treatment of TNF-α-associated inflammatory diseases such as inflammatory bowel diseases.

scholarly journals Reduced sB7-H3 Expression in the Peripheral Blood of Systemic Lupus Erythematosus Patients

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Jing Sun ◽  
Huijun Lai ◽  
Dong Shen ◽  
Pingping Wu ◽  
Jie Yang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Regulatory Networks ◽  
Activity Index ◽  
Disease Activity Index ◽  
Systemic Lupus ◽  
Aberrant Expression ◽  
Activity Index Score

Both membrane-bound and soluble forms of costimulatory molecules play important roles in immune-regulatory networks. B7-H3, a member of the B7 family, has been found with aberrant expression in tumors and infectious disease. However, the significance of sB7-H3 expression in systemic lupus erythematosus (SLE) has not been investigated. Using the peripheral blood of 78 SLE patients, we established a comprehensive database containing clinical data and relevant laboratory tests. We found that sB7-H3 expression in SLE patients was significantly lower compared with the healthy individuals. In addition, sB7-H3 levels in the patients were positively correlated with the disease activity as indicated by SLE disease activity index score, rashes, fever, and inflammatory cytokines. Moreover, sB7-H3 was associated with the counts of red blood cells and hemoglobin. Our findings suggest that sB7-H3 might counteract the aberrant immune response and potentially serve as a monitoring indicator of disease progression and therapeutic target in SLE treatment.

scholarly journals Suppression of Dextran Sulfate Sodium-Induced Colitis in Mice by Radon Inhalation

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Yuichi Nishiyama ◽  
Takahiro Kataoka ◽  
Keiko Yamato ◽  
Takehito Taguchi ◽  
Kiyonori Yamaoka
Keyword(s):  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Activity Index ◽  
Disease Activity Index ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Necrosis Factor Alpha ◽  
Activated Neutrophils ◽  
Radon Inhalation ◽  
Activity Index Score

The enhanced release of reactive oxygen species from activated neutrophils plays important role in the pathogenesis of inflammatory bowel disease. We previously reported that radon inhalation activates antioxidative functions in various organs of mice. In this study, we examined the protective effects of radon inhalation on dextran sulfate sodium- (DSS) induced colitis in mice which were subjected to DSS for 7 days. Mice were continuously treated with air only (sham) or radon at a concentration of 2000 Bq/m3from a day before DSS administration to the end of colitis induction. In the results, radon inhalation suppressed the elevation of the disease activity index score and histological damage score induced by DSS. Based on the changes in tumor necrosis factor-alpha in plasma and myeloperoxidase activity in the colon, it was shown that radon inhalation suppressed DSS-induced colonic inflammation. Moreover, radon inhalation suppressed lipid peroxidation of the colon induced by DSS. The antioxidant level (superoxide dismutase and total glutathione) in the colon after DSS administration was significantly higher in mice treated with radon than with the sham. These results suggested that radon inhalation suppressed DSS-induced colitis through the enhancement of antioxidative functions in the colon.

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