scholarly journals Shining a Light on Intestinal Traffic

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Carola T. Murphy ◽  
Kenneth Nally ◽  
Fergus Shanahan ◽  
Silvia Melgar
Keyword(s):  
Leukocyte Migration ◽  
Clinical Aspects ◽  
Leukocyte Trafficking ◽  
Ligand Interactions ◽  
Inflammatory Bowel ◽  
Integrin Ligand ◽  
Major Target

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is associated with enhanced leukocyte infiltration to the gut, which is directly linked to the clinical aspects of these disorders. Thus, leukocyte trafficking is a major target for IBD therapy. Past and emerging techniques to study leukocyte trafficking bothin vitroandin vivohave expanded our knowledge of the leukocyte migration process and the role of inhibitors. Various strategies have been employed to target chemokine- and integrin-ligand interactions within the multistep adhesion cascade and the S1P/S1PR1 axis in leukocyte migration. Though there is an abundance of preclinical data demonstrating efficacy of leukocyte trafficking inhibitors, many have yet to be confirmed in clinical studies. Vigilance for toxicity and further research is required into this complex and emerging area of IBD therapy.

scholarly journals Roles of Lipid Peroxidation-Derived Electrophiles in Pathogenesis of Colonic Inflammation and Colon Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Lei Lei ◽  
Jianan Zhang ◽  
Eric A. Decker ◽  
Guodong Zhang
Keyword(s):  
Colorectal Cancer ◽  
Lipid Peroxidation ◽  
Critical Role ◽  
Redox Stress ◽  
Colonic Inflammation ◽  
Colon Tumorigenesis ◽  
Inflammatory Bowel

Redox stress is a common feature of gut disorders such as colonic inflammation (inflammatory bowel disease or IBD) and colorectal cancer (CRC). This leads to increased colonic formation of lipid-derived electrophiles (LDEs) such as 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), trans, trans-2,4-decadienal (tt-DDE), and epoxyketooctadecenoic acid (EKODE). Recent research by us and others support that treatment with LDEs increases the severity of colitis and exacerbates the development of colon tumorigenesis in vitro and in vivo, supporting a critical role of these compounds in the pathogenesis of IBD and CRC. In this review, we will discuss the effects and mechanisms of LDEs on development of IBD and CRC and lifestyle factors, which could potentially affect tissue levels of LDEs to regulate IBD and CRC development.

The therapeutic use of the zonulin inhibitor AT-1001 (Larazotide) for a variety of acute and chronic inflammatory diseases

2021 ◽  
Vol 28 ◽  
Author(s):  
Jacopo Troisi ◽  
Giorgia Venutolo ◽  
Concetta Terracciano ◽  
Matteo Delli Carri ◽  
Simone Di Micco ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Inflammatory Diseases ◽  
Endothelial Permeability ◽  
Careful Examination ◽  
Subsequent Increase ◽  
Inflammatory Bowel

Background: The involvement of intercellular tight junctions and, in particular, the modulation of their competency by the zonulin pathway with a subsequent increase in epithelial and endothelial permeability, has been described in several chronic and acute inflammatory diseases. In this scenario, Larazotide, a zonulin antagonist, could be employed as a viable therapeutic strategy. Objective: The present review aims to describe recent research and current observations about zonulin involvement in several diseases and the use of its inhibitor Larazotide for their treatment. Methods: A systematic search was conducted on PubMed and Google Scholar, resulting in 209 publications obtained with the following search query: “Larazotide,” “Larazotide acetate,” “AT-1001,” “FZI/0” and “INN-202.” After careful examination, some publications were removed from consideration because they were either not in English or were not directly related to Larazotide. Results: The obtained publications were subdivided according to Larazotide’s mechanism of action and different diseases: celiac disease, type 1 diabetes, other autoimmune diseases, inflammatory bowel disease, Kawasaki disease, respiratory (infective and/or non-infective) diseases, and other. Conclusions: A substantial role of zonulin in many chronic and acute inflammatory diseases has been demonstrated in both in vivo and in vitro, indicating the possible efficacy of a Larazotide treatment. Moreover, new possible molecular targets for this molecule have also been demonstrated.

scholarly journals Insights on the Effects of Resveratrol and Some of Its Derivatives in Cancer and Autoimmunity: A Molecule with a Dual Activity

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 91 ◽  
Author(s):  
Elena Gianchecchi ◽  
Alessandra Fierabracci
Keyword(s):  
Lupus Erythematosus ◽  
Biological Activities ◽  
Systemic Autoimmune Diseases ◽  
Organ Specific ◽  
Inflammatory Bowel ◽  
Autoimmune Hepatitis Type 1

In recent years, the interest in natural compounds exerting immunoregulatory effects has enormously increased. Among these, the polyphenol resveratrol, found in a variety of foods and beverages, including red grapes and red wine, has been demonstrated to exert both in vitro and in vivo biological activities. More specifically, it has antiaging, cardioprotective, antioxidant, immunomodulatory, anti-inflammatory and chemopreventive activities. Due to its anti-proliferative, pro-apoptotic and immunoregulatory effects, resveratrol has gained substantial attention for the treatment of cancer or autoimmunity, which represent frequently diagnosed diseases with important consequences for the health of the patients affected. The aim of the present review is to focus on the role of resveratrol in the modulation of cancer as well as of several organ-specific or systemic autoimmune diseases, including autoimmune hepatitis, type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

scholarly journals hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiu Cai ◽  
Zhi-yu Zhang ◽  
Jin-tao Yuan ◽  
Dickson Kofi Wiredu Ocansey ◽  
Qiang Tu ◽  
...  
Keyword(s):  
Peritoneal Macrophages ◽  
Human Umbilical Cord ◽  
Inflammatory Reactions ◽  
Pyrin Domain ◽  
Inflammatory Bowel ◽  
Nlrp3 Inflammasomes ◽  
Mouse Peritoneal Macrophages

Abstract Background Human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity. In this event, macrophage pyroptosis, a process of cell death following the activation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes, is believed to partially account for inflammatory reactions. However, the role of macrophage pyroptosis in the process of hucMSC-derived exosomes alleviating colitis remains unknown. This study aimed at exploring the therapeutic effect and mechanism of hucMSC-derived exosomes on colitis repair. Methods In vivo, we used BALB/c mice to establish a dextran sulfate sodium (DSS)-induced colitis model and administrated hucMSC-derived exosomes intravenously to estimate its curative effect. Human myeloid leukemia mononuclear (THP-1) cells and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) and Nigericin to activate NLRP3 inflammasomes, which simulated an inflammation environment in vitro. A microRNA mimic was used to verify the role of miR-378a-5p/NLRP3 axis in the colitis repair. Results hucMSC-derived exosomes inhibited the activation of NLRP3 inflammasomes in the mouse colon. The secretion of interleukin (IL)-18, IL-1β, and Caspase-1 cleavage was suppressed, resulting in reduced cell pyroptosis. The same outcome was observed in the in vitro cell experiments, where the co-culture of THP-1 cells and MPMs with hucMSC-derived exosomes caused decreased expression of NLRP3 inflammasomes and increased cell survival. Furthermore, miR-378a-5p was highly expressed in hucMSC-derived exosomes and played a vital function in colitis repair. Conclusion hucMSC-derived exosomes carrying miR-378a-5p inhibited NLRP3 inflammasomes and abrogated cell pyroptosis to protect against DSS-induced colitis.

scholarly journals Gastrointestinal Dopamine in Inflammatory Bowel Diseases: A Systematic Review

2021 ◽  
Vol 22 (23) ◽  
pp. 12932
Author(s):  
Magdalena Kurnik-Łucka ◽  
Paweł Pasieka ◽  
Patrycja Łączak ◽  
Marcin Wojnarski ◽  
Michał Jurczyk
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic System ◽  
Meta Analysis ◽  
Cross Sectional ◽  
Duodenal Ulcers ◽  
Inflammatory Bowel

Background: an increased prevalence of gastro-duodenal ulceration was described almost sixty years ago as prodromal to idiopathic Parkinson’s disease, while duodenal ulcers have been rarely diagnosed in patients with schizophrenia. The cytoprotective role of dopamine in animal models of gastrointestinal ulcerations has also been described. Interestingly, Parkinson’s disease (PD) might share common pathophysiological links with inflammatory bowel disease (IBD) as epidemiological and genetic links already suggest. Thus, the aim of our study was to review the existing literature on the role of the gastrointestinal dopaminergic system in IBD pathogenesis and progression. Methods: a systematic search was conducted according to the PRISMA methodology. Results: twenty-four studies satisfied the predetermined criteria and were included in our qualitative analysis. Due to different observations (cross-sectional studies) as well as experimental setups and applied methodologies (in vivo and in vitro studies) a meta-analysis could not be performed. No ongoing clinical trials with dopaminergic compounds in IBD patients were found. Conclusions: the impairment of the dopaminergic system seems to be a significant, yet underestimated, feature of IBD, and more in-depth observational studies are needed to further support the existing preclinical data.

Abstract 1130: Role Of PI3Kγ For Integrin-dependent Adhesive And Migratory Functions Of Progenitor Cells In Vitro And In Vivo

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Emmanouil Chavakis ◽  
Guillaume Carmona ◽  
Triantafyllos Chavakis ◽  
Andreas M Zeiher ◽  
Stefanie Dimmeler
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Catalytic Subunit ◽  
Β1 Integrin ◽  
Cell Homing ◽  
Integrin Ligand

Endothelial progenitor cells (EPC) are recruited to ischemic regions to improve neovascularization. β1- and β2-integrins play a crucial role for progenitor cell homing to ischemic tissues. Chemokines and their respective G-protein coupled receptors (GPCRs) are involved in the EPC homing to ischemic tissues. The phosphatidylinositol-3-kinase catalytic subunit gamma (PI3Kγ) is the PI3K isoform, which selectively transduces signals from GPCRs. Here, we investigated the role of PI3Kγ for integrin-dependent homing functions of progenitor cells. As assessed by western blot, EPC express the catalytic subunit PI3Kγ. We then studied the role of PI3Kγ for EPC migration. AS-605240 (100 nM), a selective PI3Kγ-inhibitor (Camps M, Nat. Med., 2005), significantly reduced the SDF1- and the IL-8-induced migration and the SDF1-induced transendothelial migration of human EPC. Adhesion is a further essential step during EPC homing to ischemic tissues. In this regard, the PI3Kγ-inhibitor significantly reduced the SDF1-induced adhesion of EPC on HUVEC monolayers by 69 ± 8 % and on ICAM-1, a β2-integrin ligand. However, the PI3Kγ-inhibitor did not affect the SDF1-induced adhesion of EPC on fibronectin, a β1-integrin ligand, suggesting that PI3Kγ in EPC is involved in the regulation of β2-, but not of β 1-integrin-dependent adhesion. In line with these results, inhibition PI3Kγ blocked the SDF1-induced increase of β2-, but not of β1-integrin-affinity in EPC. Beside EPC, the SDF1-induced migration and adhesion on ICAM-1 of murine bone marrow (BM)-derived Lin − progenitor cells from PI3Kγ-deficient mice (PI3Kγ − / − ) were reduced in comparison to wild type (WT) cells. In addition, PI3Kγ-deficiency led to a significant reduction of homing of murine BM-Lin − progenitor cells to ischemic muscles after intravenous infusion in the model of hind limb ischemia in comparison to WT cells (48 ± 8 % inhibition). In conclusion, these data demonstrate that PI3Kγ plays an essential role for the integrin-dependent homing of progenitor cells in vitro and in vivo. The understanding of the molecular mechanisms of progenitor cell homing is essential for the development of new therapeutic strategies in order to improve the efficacy of cell-based therapies in patients with ischemic disorders.

Multiple integrin-ligand interactions synergize in shear-resistant platelet adhesion at sites of arterial injury in vivo

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4021-4027 ◽  
Author(s):  
Sabine Grüner ◽  
Miroslava Prostredna ◽  
Valerie Schulte ◽  
Thomas Krieg ◽  
Beate Eckes ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Platelet Adhesion ◽  
Arterial Injury ◽  
Β1 Integrins ◽  
Ligand Interactions ◽  
Integrin Ligand ◽  
Aggregation Of Platelets ◽  
Αiibβ3 Integrin

Abstract Damage to the integrity of the vessel wall results in exposure of the subendothelial extracellular matrix (ECM), which triggers integrin-dependent adhesion and aggregation of platelets. The role of platelet β1 integrins in these processes remains mostly undefined. Here, we demonstrate by intravital fluorescence microscopy that platelet adhesion and thrombus growth on the exposed ECM of the injured carotid artery is not significantly altered in α2-null mice and even in mice with a Cre/loxP-mediated loss of all β1 integrins on their platelets. In contrast, inhibition of αIIbβ3 integrin on platelets in wild-type mice blocked aggregate formation and reduced platelet adhesion by 60.0%. Strikingly, αIIbβ3 inhibition had a comparable effect in α2-null mice, demonstrating that other receptors mediate shear-resistant adhesion in the absence of functional α2β1 and αIIbβ3. These were identified to be α5β1 and/or α6β1 as αIIbβ3 inhibition abrogated platelet adhesion in β1-null mice. We conclude that shear-resistant platelet adhesion on the injured vessel wall in vivo is a highly integrated process involving multiple integrin-ligand interactions, none of which by itself is essential. (Blood. 2003;102:4021-4027)

scholarly journals Influence of the microenvironment on the modulation of the host response by the typhoid toxin

2020 ◽  
Author(s):  
Océane C.B. Martin ◽  
Deborah Butter ◽  
Eleni Paparouna ◽  
Sofia D.P. Theodorou ◽  
Maria M. Haykal ◽  
...  
Keyword(s):  
Dna Damage ◽  
Intestinal Inflammation ◽  
Inflammatory Conditions ◽  
Damage Response ◽  
Health And Disease ◽  
Inflammatory Bowel ◽  
Typhoid Toxin

SummaryBacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram negative bacteria, enriched in the microbiota of Inflammatory Bowel Disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We have addressed the role of the typhoid toxin in the modulation of the host-microbial interaction in health and disease.Infection with a genotoxigenic Salmonella protected mice from intestinal inflammation. The toxin-induced DNA damage caused senescence in vivo, which was uncoupled from the inflammatory response, and associated with the maintenance of an anti-inflammatory environment. This effect was lost when infection occurred in mice suffering from inflammatory conditions that mimic Ulcerative Colitis, a form of IBD.These data highlight a complex context-dependent crosstalk between bacterial genotoxins-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Anti-obesity role of Aster glehni extract: in vivo and in vitro effects

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
HM Lee ◽  
TG Ahn ◽  
CW Kim ◽  
HJ An
Keyword(s):  
In Vitro Effects
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