scholarly journals Engineered Lactobacillus paracasei Producing Palmitoylethanolamide (PEA) Prevents Colitis in Mice

2021 ◽  
Vol 22 (6) ◽  
pp. 2945
Author(s):  
Giuseppe Esposito ◽  
Marcella Pesce ◽  
Luisa Seguella ◽  
Jie Lu ◽  
Chiara Corpetti ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Neutrophil Infiltration ◽  
Lactobacillus Paracasei ◽  
Stress Markers ◽  
Intestinal Delivery ◽  
Significant Amelioration ◽  
Inflammatory Bowel

Palmitoylethanolamide (PEA) is an N-acylethanolamide produced on-demand by the enzyme N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD). Being a key member of the larger family of bioactive autacoid local injury antagonist amides (ALIAmides), PEA significantly improves the clinical and histopathological stigmata in models of ulcerative colitis (UC). Despite its safety profile, high PEA doses are required in vivo to exert its therapeutic activity; therefore, PEA has been tested only in animals or human biopsy samples, to date. To overcome these limitations, we developed an NAPE-PLD-expressing Lactobacillus paracasei F19 (pNAPE-LP), able to produce PEA under the boost of ultra-low palmitate supply, and investigated its therapeutic potential in a murine model of UC. The coadministration of pNAPE-LP and palmitate led to a time-dependent release of PEA, resulting in a significant amelioration of the clinical and histological damage score, with a significantly reduced neutrophil infiltration, lower expression and release of pro-inflammatory cytokines and oxidative stress markers, and a markedly improved epithelial barrier integrity. We concluded that pNAPE-LP with ultra-low palmitate supply stands as a new method to increase the in situ intestinal delivery of PEA and as a new therapeutic able of controlling intestinal inflammation in inflammatory bowel disease.

scholarly journals Lactobacillus paracaseiReduces Intestinal Inflammation in Adoptive Transfer Mouse Model of Experimental Colitis

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Manuel Oliveira ◽  
Nabil Bosco ◽  
Genevieve Perruisseau ◽  
Jeanne Nicolas ◽  
Iris Segura-Roggero ◽  
...  
Keyword(s):  
Mouse Model ◽  
Adoptive Transfer ◽  
Immune Modulation ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Neutrophil Infiltration ◽  
Lactobacillus Paracasei ◽  
Therapeutic Benefits

Studies showed that specific probiotics provide therapeutic benefits in inflammatory bowel disease.In vitroevidence suggested thatLactobacillus paracaseialso called ST11 (CNCM I-2116) is a potent strain with immune modulation properties. However, little is known about its capacity to alleviate inflammatory symptomsin vivoIn this context, the main objective of this study was to investigate the role of ST11 on intestinal inflammation using the adoptive transfer mouse model of experimental colitis. Rag2-/-recipient mice were fed with ST11 (109CFU/day)a month prior toinduce colitis by adoptive transfer of naive T cells. One month later, in clear contrast to nonfed mice, weight loss was significantly reduced by 50% in ST11-fed mice. Further analysis of colon specimens revealed a significant reduction neutrophil infiltration and mucosal expression of IL1β, IL-6, and IL12 proinflammatory cytokines, whereas no consistent differences in expression of antibacterial peptides or tight junction proteins were observed between PBS and ST11-fed mice. All together, our results demonstrate that oral administration of ST11 was safe and had a significant preventive effect on colitis. We conclude that probiotics such asLactobacillus paracaseiharbor worthwhilein vivoimmunomodulatory properties to prevent intestinal inflammation by nutritional approaches.

scholarly journals The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rayko Evstatiev ◽  
Adam Cervenka ◽  
Tina Austerlitz ◽  
Gunther Deim ◽  
Maximilian Baumgartner ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Models ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Food Additives ◽  
Colorectal Carcinogenesis ◽  
Testing Procedures ◽  
Inflammatory Models ◽  
Inflammatory Bowel

AbstractInflammatory bowel disease is a group of conditions with rising incidence caused by genetic and environmental factors including diet. The chelator ethylenediaminetetraacetate (EDTA) is widely used by the food and pharmaceutical industry among numerous other applications, leading to a considerable environmental exposure. Numerous safety studies in healthy animals have revealed no relevant toxicity by EDTA. Here we show that, in the presence of intestinal inflammation, EDTA is surprisingly capable of massively exacerbating inflammation and even inducing colorectal carcinogenesis at doses that are presumed to be safe. This toxicity is evident in two biologically different mouse models of inflammatory bowel disease, the AOM/DSS and the IL10−/− model. The mechanism of this effect may be attributed to disruption of intercellular contacts as demonstrated by in vivo confocal endomicroscopy, electron microscopy and cell culture studies. Our findings add EDTA to the list of food additives that might be detrimental in the presence of intestinal inflammation, but the toxicity of which may have been missed by regulatory safety testing procedures that utilize only healthy models. We conclude that the current use of EDTA especially in food and pharmaceuticals should be reconsidered. Moreover, we suggest that intestinal inflammatory models should be implemented in the testing of food additives to account for the exposure of this primary organ to environmental and dietary stress.

scholarly journals Macrophage-derived EDA-A2 inhibits intestinal stem cells by targeting miR-494/EDA2R/β-catenin signaling in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lele Song ◽  
Renxu Chang ◽  
Xia Sun ◽  
Liying Lu ◽  
Han Gao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cross Talk ◽  
Intestinal Inflammation ◽  
Intestinal Stem Cells ◽  
Intestinal Stem Cell ◽  
Epithelial Barrier ◽  
Self Renewal ◽  
Epithelial Repair ◽  
Inflammatory Bowel

AbstractThe mucosa microenvironment is critical for intestinal stem cell self-renewal and reconstruction of the epithelial barrier in inflammatory bowel disease (IBD), where the mechanisms underlying cross-talk between intestinal crypts and the microenvironment remain unclear. Here, we firstly identified miR-494-3p as an important protector in colitis. miR-494-3p levels were decreased and negatively correlated with the severity in human IBD samples, as well as in colitis mice. In colitis crypts, a notable cytokine–cytokine receptor, miR-494-3p-targeted EDA2R and the ligand EDA-A2, suppressed colonic stemness and epithelial repair by inhibiting β-catenin/c-Myc. In differentiated IECs, miR-494-3p inhibits macrophage recruitment, M1 activation and EDA-A2 secretion by targeting IKKβ/NF-κB in colitis. A miR-494-3p agomir system notably ameliorated the severity of colonic colitis in vivo. Collectively, our findings uncover a miR-494-3p-mediated cross-talk mechanism by which macrophage-induced intestinal stem cell impairment aggravates intestinal inflammation.

Physiological Basis for Novel Drug Therapies Used to Treat the Inflammatory Bowel Diseases I. Immunology and therapeutic potential of antiadhesion molecule therapy in inflammatory bowel disease

2005 ◽  
Vol 288 (2) ◽  
pp. G169-G174 ◽  
Author(s):  
Gert Van Assche ◽  
Paul Rutgeerts
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Adhesion Molecules ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Physiological Basis ◽  
Inflammatory Bowel

Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but α4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-α4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized α4β7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.

scholarly journals MAG-EPA reduces severity of DSS-induced colitis in rats

2016 ◽  
Vol 310 (10) ◽  
pp. G808-G821 ◽  
Author(s):  
Caroline Morin ◽  
Pierre U. Blier ◽  
Samuel Fortin
Keyword(s):  
Therapeutic Potential ◽  
Combined Treatment ◽  
Neutrophil Infiltration ◽  
Antagonistic Effect ◽  
Omega 3 ◽  
Strong Activity ◽  
Tnf Α ◽  
Biochemical Analyses ◽  
Relaxing Effect

Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the intestinal mucosa of the large bowel. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines involved in UC pathogenesis. The aim of this study was to determine the preventive and therapeutic potential of eicosapentaenoic acid monoglyceride (MAG-EPA) in an in vivo rats model of UC induced by dextran sulfate sodium (DSS). DSS rats were untreated or treated per os with MAG-EPA. Morphological, histological, and biochemical analyses were performed following MAG-EPA administrations. Morphological and histological analyses revealed that MAG-EPA pretreatment (12 days pre-DSS) and treatment (6 days post-DSS) exhibited strong activity in reducing severity of disease in DSS rats. Following MAG-EPA administrations, tissue levels of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 were markedly lower compared with rats treated only with DSS. MAG-EPA per os administration decrease neutrophil infiltration in colon tissues, as depicted by myelohyperoxidase activity. Results also revealed a reduced activation of NF-κB pathways correlated with a decreased expression of COX-2 in colon homogenates derived from MAG-EPA-pretreated and treated rats. Tension measurements performed on colon tissues revealed that contractile responses to methacholine and relaxing effect induced by sodium nitroprusside were largely increased following MAG-EPA treatment. The combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in DSS rats.

HMGB1 has sparked a lot of attention as a model DAMP molecule involved in inflammation, inflammatory diseases, and cancer.

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Sterile Inflammation ◽  
Clinical Testing ◽  
Specific Function ◽  
Redox States ◽  
Fundamental Knowledge

HMGB1, the second most prevalent protein inside the nucleus after histone, has sparked a lot of attention as a model DAMP molecule involved in inflammation, inflammatory diseases, and cancer. Building on the fundamental knowledge of HMGB1 as a cytokine/chemoattractant, several in vivo and in vitro studies have indicated therapeutic potential for targeting HMGB1 and lowering tissue damage once inflammation has gone awry. A few hurdles must be cleared before HMGB1 treatment may progress further into clinical trials. The exact mechanism by which HMGB1 travels from the nucleus to the cytoplasm and then to the ECM is unclear. Different HMGB1 redox states can generate in situ modulations, making it difficult to determine the specific function of HMGB1 isoforms. Furthermore, the investigation of HMGB1 and its antagonists in disease situations is complicated by various HMGB1 receptors with various degrees of cell selectivity for a certain HMGB1 isoform or HMGB1 cofactor complex. HMGB1 targeting has been found to be beneficial in the treatment of inflammation and inflammatory diseases, notably in sepsis, sterile inflammation, autoimmune diseases, and cancer, despite the difficulties. Continued HMGB1 research might help fill in the gaps in knowledge and push HMGB1 antagonists closer to the next step of clinical testing.

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

2019 ◽  
Vol 11 (515) ◽  
pp. eaax2945 ◽  
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.

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 Studies on the Interleukin-10 Gene in Animal Models of Colitis

2001 ◽  
Vol 15 (8) ◽  
pp. 557-558
Author(s):  
Hugh J Freeman
Keyword(s):  
Inflammatory Bowel Disease ◽  
Animal Models ◽  
Bowel Disease ◽  
Inflammatory Process ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Inflammatory Bowel ◽  
Deficient Mice

Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. Interleukin-10 (IL-10) has both immunomodulatory and anti-inflammatory properties. IL-10-deficient mice develop intestinal inflammation with increased tissue levels of other cytokines, including tumour necrosis factor-alpha. In patients with inflammatory bowel disease, impaired IL-10 production by lamina propria T cells occurs and human recombinant IL-10 improves clinical parameters in inflammatory bowel disease (eg, Crohn's disease). There seem to be conflicting results in differing animal models, and the timing of administration of IL-10 relative to onset of colitis may be critical, possibly due to rapid clearance of IL-10. Interestingly, in IL-10 gene-deficient mice raised in germ-free conditions, the intestinal inflammatory changes normally observed in conventional nongerm-free conditions are not detected, suggesting a role for luminal bacteria in the pathogenesis of the inflammatory process.

scholarly journals PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium

2013 ◽  
Vol 305 (11) ◽  
pp. L805-L818 ◽  
Author(s):  
John Noel ◽  
Hui Wang ◽  
Nankang Hong ◽  
Jian-Qin Tao ◽  
Kevin Yu ◽  
...  
Keyword(s):  
Neutrophil Infiltration ◽  
Ros Production ◽  
Pulmonary Endothelium ◽  
Angiogenic Potential ◽  
Caveolin 1 ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1

We showed that stop of flow triggers a mechanosignaling cascade that leads to the generation of reactive oxygen species (ROS); however, a mechanosensor coupled to the cytoskeleton that could potentially transduce flow stimulus has not been identified. We showed a role for KATP channel, caveolae (caveolin-1), and NADPH oxidase 2 (NOX2) in ROS production with stop of flow. Based on reports of a mechanosensory complex that includes platelet endothelial cell adhesion molecule-1 (PECAM-1) and initiates signaling with mechanical force, we hypothesized that PECAM-1 could serve as a mechanosensor in sensing disruption of flow. Using lungs in situ, we observed that ROS production with stop of flow was significantly reduced in PECAM-1−/− lungs compared with lungs from wild-type (WT) mice. Lack of PECAM-1 did not affect NOX2 activation machinery or the caveolin-1 expression or caveolae number in the pulmonary endothelium. Stop of flow in vitro triggered an increase in angiogenic potential of WT pulmonary microvascular endothelial cells (PMVEC) but not of PECAM-1−/− PMVEC. Obstruction of flow in lungs in vivo showed that the neutrophil infiltration as observed in WT mice was significantly lowered in PECAM-1−/− mice. With stop of flow, WT lungs showed higher expression of the angiogenic marker VEGF compared with untreated (sham) and PECAM-1−/− lungs. Thus PECAM-1 (and caveolae) are parts of the mechanosensing machinery that generates superoxide with loss of shear; the resultant ROS potentially drives neutrophil influx and acts as an angiogenic signal.

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