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Devchand PR, Dicay M, Wallace JL. Molecular Thumbprints: Biological Signatures That Measure Loss of Identity. Biomolecules 2024; 14:1271. [PMID: 39456204 PMCID: PMC11506567 DOI: 10.3390/biom14101271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/24/2024] [Accepted: 08/26/2024] [Indexed: 10/28/2024] Open
Abstract
Each life is challenged to adapt to an ever-changing environment with integrity-simply put, to maintain identity. We hypothesize that this mission statement of adaptive homeostasis is particularly poignant in an adaptive response, like inflammation. A maladaptive response of unresolved inflammation can seed chronic disease over a lifetime. We propose the concept of a molecular thumbprint: a biological signature of loss of identity as a measure of incomplete return to homeostasis after an inflammatory response. Over time, personal molecular thumbprints can measure dynamic and precise trajectories to chronic inflammatory diseases and further loss of self to cancer. Why is this important? Because the phenotypes and molecular signatures of established complex inflammatory diseases are a far cry from the root of the complex problem, let alone the initial seed. Understanding the science behind key germinating seeds of disease helps to identify molecular factors of susceptibility, resilience, and early dietary or drug intervention. We pilot this hypothesis in a rat colitis model that is well-established for understanding molecular mechanisms of colonic health, disease, and transition of colitis to cancer.
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Affiliation(s)
- Pallavi R. Devchand
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 4N1, Canada; (M.D.); (J.L.W.)
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Eldjarn GH, Ferkingstad E, Lund SH, Helgason H, Magnusson OT, Gunnarsdottir K, Olafsdottir TA, Halldorsson BV, Olason PI, Zink F, Gudjonsson SA, Sveinbjornsson G, Magnusson MI, Helgason A, Oddsson A, Halldorsson GH, Magnusson MK, Saevarsdottir S, Eiriksdottir T, Masson G, Stefansson H, Jonsdottir I, Holm H, Rafnar T, Melsted P, Saemundsdottir J, Norddahl GL, Thorleifsson G, Ulfarsson MO, Gudbjartsson DF, Thorsteinsdottir U, Sulem P, Stefansson K. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature 2023; 622:348-358. [PMID: 37794188 PMCID: PMC10567571 DOI: 10.1038/s41586-023-06563-x] [Citation(s) in RCA: 147] [Impact Index Per Article: 73.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 08/22/2023] [Indexed: 10/06/2023]
Abstract
High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge the gap between the genome and diseases. Here we performed association studies of Olink Explore 3072 data generated by the UK Biobank Pharma Proteomics Project1 on plasma samples from more than 50,000 UK Biobank participants with phenotypic and genotypic data, stratifying on British or Irish, African and South Asian ancestries. We compared the results with those of a SomaScan v4 study on plasma from 36,000 Icelandic people2, for 1,514 of whom Olink data were also available. We found modest correlation between the two platforms. Although cis protein quantitative trait loci were detected for a similar absolute number of assays on the two platforms (2,101 on Olink versus 2,120 on SomaScan), the proportion of assays with such supporting evidence for assay performance was higher on the Olink platform (72% versus 43%). A considerable number of proteins had genomic associations that differed between the platforms. We provide examples where differences between platforms may influence conclusions drawn from the integration of protein levels with the study of diseases. We demonstrate how leveraging the diverse ancestries of participants in the UK Biobank helps to detect novel associations and refine genomic location. Our results show the value of the information provided by the two most commonly used high-throughput proteomics platforms and demonstrate the differences between them that at times provides useful complementarity.
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Affiliation(s)
| | | | - Sigrun H Lund
- deCODE Genetics/Amgen, Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | - Hannes Helgason
- deCODE Genetics/Amgen, Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | | | | | | | - Bjarni V Halldorsson
- deCODE Genetics/Amgen, Reykjavik, Iceland
- School of Technology, Reykjavik University, Reykjavik, Iceland
| | | | | | | | | | | | - Agnar Helgason
- deCODE Genetics/Amgen, Reykjavik, Iceland
- Department of Anthropology, University of Iceland, Reykjavik, Iceland
| | | | | | - Magnus K Magnusson
- deCODE Genetics/Amgen, Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Saedis Saevarsdottir
- deCODE Genetics/Amgen, Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | | | | | | | - Ingileif Jonsdottir
- deCODE Genetics/Amgen, Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Hilma Holm
- deCODE Genetics/Amgen, Reykjavik, Iceland
| | | | - Pall Melsted
- deCODE Genetics/Amgen, Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | | | | | | | - Magnus O Ulfarsson
- deCODE Genetics/Amgen, Reykjavik, Iceland
- Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland
| | - Daniel F Gudbjartsson
- deCODE Genetics/Amgen, Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | - Unnur Thorsteinsdottir
- deCODE Genetics/Amgen, Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | | | - Kari Stefansson
- deCODE Genetics/Amgen, Reykjavik, Iceland.
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
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Deng B, Liao F, Liu Y, He P, Wei S, Liu C, Dong W. Comprehensive analysis of endoplasmic reticulum stress-associated genes signature of ulcerative colitis. Front Immunol 2023; 14:1158648. [PMID: 37287987 PMCID: PMC10243217 DOI: 10.3389/fimmu.2023.1158648] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/04/2023] [Indexed: 06/09/2023] Open
Abstract
Background Endoplasmic reticulum stress (ERS) is a critical factor in the development of ulcerative colitis (UC); however, the underlying molecular mechanisms remain unclear. This study aims to identify pivotal molecular mechanisms related to ERS in UC pathogenesis and provide novel therapeutic targets for UC. Methods Colon tissue gene expression profiles and clinical information of UC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database, and the ERS-related gene set was downloaded from GeneCards for analysis. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal modules and genes associated with UC. A consensus clustering algorithm was used to classify UC patients. The CIBERSORT algorithm was employed to evaluate the immune cell infiltration. Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. The external sets were used to validate and identify the relationship of ERS-related genes with biologics. Small molecule compounds were predicted using the Connectivity Map (CMap) database. Molecular docking was performed to simulate the binding conformation of small molecule compounds and key targets. Results The study identified 915 differentially expressed genes (DEGs) and 11 ERS-related genes (ERSRGs) from the colonic mucosa of UC patients and healthy controls, and these genes had good diagnostic value and were highly correlated. Five potential small-molecule drugs sharing tubulin inhibitors were identified, including albendazole, fenbendazole, flubendazole, griseofulvin, and noscapine, among which noscapine exhibited the highest correlation with a high binding affinity to the targets. Active UC and 10 ERSRGs were associated with a large number of immune cells, and ERS was also associated with colon mucosal invasion of active UC. Significant differences in gene expression patterns and immune cell infiltration abundance were observed among ERS-related subtypes. Conclusion The results suggest that ERS plays a vital role in UC pathogenesis, and noscapine may be a promising therapeutic agent for UC by affecting ERS.
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Affiliation(s)
- Beiying Deng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fei Liao
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yinghui Liu
- Department of Geriatric, Renmin Hospital of Wuhan University, Wuhan, China
| | - Pengzhan He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shuchun Wei
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chuan Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
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Wang W, Song X, Ding S, Chen C, Ma H. Identifying the Mechanisms and Molecular Targets of Guchang Zhixie Pills on Ulcerative Colitis: Coupling Network Pharmacology with GEO Database and Experiment Verification. Comb Chem High Throughput Screen 2023; 26:2039-2056. [PMID: 36597607 DOI: 10.2174/1386207326666230103160151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 10/20/2022] [Accepted: 10/27/2022] [Indexed: 01/05/2023]
Abstract
OBJECTIVE This research investigates the mechanisms and molecular targets of the Guchang Zhixie pill (GCZXP) against ulcerative colitis (UC) in silico and in vivo. METHODS The compounds and related targets of GCZXP were collected from the traditional Chinese medicine systems pharmacology database. UC targets were from Gene Expression Omnibus and GeneCards databases. Hub genes were acquired through Cytoscape. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment were performed in the David database. R packages were used to investigate the relationship between immune cells and hub genes and the diagnostic model. AutoDock was used to verify the molecular docking of the core compounds and hub genes, as well as nuclear factor-kappa B (NF-κB) p65 and IκBα. The hub genes and NF-κB pathway were verified via experiment. RESULTS In GCZXP, a total of 51 active compounds were discovered. Enrichment analysis was used to study inflammation, chemokine activity, NF-κB signalling pathway, etc. Thirteen key therapeutic targets were involved, of which included three hub genes PTGS2, IL-1β and CXCL8. Immune infiltration revealed that all of the 3 hub genes were positively correlated with M1 macrophages, neutrophils, and activated memory CD4 cells, and negatively correlated with plasma cells. In the training and validation sets, the area under the curve (AUC) of the diagnostic model developed by hub genes reached 0.929 and 0.905, respectively, indicating a good forecasting potential. The rat experiment proved that GCZXP significantly reduced the expressions of IL-1β, CXCL8, COX-2, and NF-κB p65 while increasing IκBα and Bcl-2, alleviated colonic inflammatory injury and promoted ulcer healing. CONCLUSION GCZXP reduced the release of cytokines and regulated Bcl-2 in the treatment of UC by inhibiting the NF-κB signalling pathway.
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Affiliation(s)
- Weihao Wang
- School of Chemical and Biological Engineering, Yichun University, Yichun 336000, Jiangxi, China
| | - Xujiao Song
- School of Chemical and Biological Engineering, Yichun University, Yichun 336000, Jiangxi, China
| | - Shanshan Ding
- School of Chemical and Biological Engineering, Yichun University, Yichun 336000, Jiangxi, China
| | - Chunlin Chen
- School of Chemical and Biological Engineering, Yichun University, Yichun 336000, Jiangxi, China
| | - Hao Ma
- Aesthetic Medical School, Yichun University, Yichun 336000, Jiangxi, China
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Boeno CN, Paloschi MV, Lopes JA, Souza Silva MD, Evangelista JR, Dos Reis VP, da S Setúbal S, Soares AM, Zuliani JP. Dynamics of action of a Lys-49 and an Asp-49 PLA 2s on inflammasome NLRP3 activation in murine macrophages. Int Immunopharmacol 2022; 112:109194. [PMID: 36041255 DOI: 10.1016/j.intimp.2022.109194] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/08/2022] [Accepted: 08/22/2022] [Indexed: 11/30/2022]
Abstract
Phospholipases A2 (PLA2s) are proteins found in snake venoms with hemolytic, anticoagulant, myotoxic, edematogenic, bactericidal and inflammatory actions. In Bothrops jararacussu snake venom were isolated a Lys49-PLA2 (BthTX-I) and an Asp49-PLA2 (BthTX-II) with myotoxic and inflammatory actions. Both PLA2s can activate the NLRP3 inflammasome, an intracytoplasmic platform that recognizes molecules released when tissue is damaged liberating IL-1β that contributes to the inflammatory response observed in envenoming. The dynamic of action of BthTX-I and BthTX-II in both thioglycollate (TG)-elicited macrophages and C2C12 myoblasts and the involvement of EP1 and EP2 receptors, and PGE2 in NLRP3 inflammasome activation were evaluated. Both toxins induced PGE2 liberation and inflammasome components (NLRP3, Caspase-1, ASC, IL-1β, and IL18), IL-6, P2X7, COX-1, COX-2, EP2 and EP4 gene expression in TG-elicited macrophages but not in C2C12 myoblasts. EP2 (PF04418948) and EP4 (GW627368X) inhibitors abolished this effect. Both PLA2s also induced NLRP3 inflammasome protein expression that was abolished with the inhibitors used. Immunofluorescence and IL-1β assays confirmed the NLRP3 activation in TG-elicited macrophages with the participation of both EP2 and EP4 receptors confirming their involvement in this effect. All in all, BthTX-I and BthTX-II activate macrophages and induce the NLRP3 inflammasome complex activation with the participation of the PGE2 via COX pathway and EP2 and EP4, both PGE2 receptors, contributing to the local inflammatory effects observed in envenoming.
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Affiliation(s)
- Charles N Boeno
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Mauro V Paloschi
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Jéssica A Lopes
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Milena D Souza Silva
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Jaína R Evangelista
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Valdison P Dos Reis
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Sulamita da S Setúbal
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Andreimar M Soares
- Centro de Estudos de Biomoléculas Aplicadas à Saúde (CEBio), Fundação Oswaldo Cruz, FIOCRUZ Rondônia e Departamento de Medicina, Universidade Federal de Rondônia, UNIR, Porto Velho, RO, Brazil
| | - Juliana P Zuliani
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil; Centro de Estudos de Biomoléculas Aplicadas à Saúde (CEBio), Fundação Oswaldo Cruz, FIOCRUZ Rondônia e Departamento de Medicina, Universidade Federal de Rondônia, UNIR, Porto Velho, RO, Brazil.
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Guo S, Huang Z, Zhu J, Yue T, Wang X, Pan Y, Bu D, Liu Y, Wang P, Chen S. CBS-H 2S axis preserves the intestinal barrier function by inhibiting COX-2 through sulfhydrating human antigen R in colitis. J Adv Res 2022; 44:201-212. [PMID: 36725190 PMCID: PMC9936422 DOI: 10.1016/j.jare.2022.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 07/15/2021] [Accepted: 03/14/2022] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Lipopolysaccharide (LPS) causes lesions of the epithelial barrier, which allows translocation of pathogens from the intestinal lumen to the host's circulation. Hydrogen sulfide (H2S) regulates multiple physiological and pathological processes in colonic epithelial tissue, and CBS-H2S axis involved in multiple gastrointestinal disorder. However, the mechanism underlying the effect of the CBS-H2S axis on the intestinal and systemic inflammation in colitis remains to be illustrated. OBJECTIVES To investigate the effect of CBS-H2S axis on the intestinal and systematic inflammation related injuries in LPS induced colitis and the underlying mechanisms. METHODS Wild type and CBS-/+ mice were used to evaluate the effect of endogenous and exogenous H2S on LPS-induced colitis in vivo. Cytokine quantitative antibody array, western blot and real-time PCR were applied to detect the key cytokines in the mechanism of action. Biotin switch of S-sulfhydration, CRISPR/Cas9 mediated knockout, immunofluorescence and ActD chase assay were used in the in vitro experiment to further clarify the molecular mechanisms. RESULTS H2S significantly alleviated the symptoms of LPS-induced colitis in vivo and attenuated the increase of COX-2 expression. The sulfhydrated HuR increased when CBS express normally or GYY4137 was administered. While after knocking kown CBS, the expression of COX-2 in mice colon increased significantly, and the sulfhydration level of HuR decreased. The results in vitro illustrated that HuR can increase the stability of COX-2 mRNA, and the decrease of COX-2 were due to increased sulfhydration of HuR rather than the reduction of total HuR levels. CONCLUSION These results indicated that CBS-H2S axis played an important role in protecting intestinal barrier function in colitis. CBS-H2S axis increases the sulfhydration level of HuR, by which reduces the binding of HuR with COX-2 mRNA and inhibited the expression of COX-2.
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Affiliation(s)
- Shihao Guo
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People’s Republic of China,Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Zhihao Huang
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People’s Republic of China
| | - Jing Zhu
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People’s Republic of China
| | - Taohua Yue
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People’s Republic of China
| | - Xin Wang
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People’s Republic of China
| | - Yisheng Pan
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People’s Republic of China
| | - Dingfang Bu
- Central Laboratory, Peking University First Hospital, Peking University, 8, Beijing 100034, People’s Republic of China
| | - Yucun Liu
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People’s Republic of China
| | - Pengyuan Wang
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People's Republic of China.
| | - Shanwen Chen
- Division of General Surgery, Peking University First Hospital, Peking University, 8, Beijing 100034, People's Republic of China.
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Specific Secondary Bile Acids Control Chicken Necrotic Enteritis. Pathogens 2021; 10:pathogens10081041. [PMID: 34451506 PMCID: PMC8427939 DOI: 10.3390/pathogens10081041] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/13/2021] [Accepted: 08/13/2021] [Indexed: 12/19/2022] Open
Abstract
Necrotic enteritis (NE), mainly induced by the pathogens of Clostridium perfringens and coccidia, causes huge economic losses with limited intervention options in the poultry industry. This study investigated the role of specific bile acids on NE development. Day-old broiler chicks were assigned to six groups: noninfected, NE, and NE with four bile diets of 0.32% chicken bile, 0.15% commercial ox bile, 0.15% lithocholic acid (LCA), or 0.15% deoxycholic acid (DCA). The birds were infected with Eimeria maxima at day 18 and C. perfringens at day 23 and 24. The infected birds developed clinical NE signs. The NE birds suffered severe ileitis with villus blunting, crypt hyperplasia, epithelial line disintegration, and massive immune cell infiltration, while DCA and LCA prevented the ileitis histopathology. NE induced severe body weight gain (BWG) loss, while only DCA prevented NE-induced BWG loss. Notably, DCA reduced the NE-induced inflammatory response and the colonization and invasion of C. perfringens compared to NE birds. Consistently, NE reduced the total bile acids in the ileal digesta, while dietary DCA and commercial bile restored it. Together, this study showed that DCA and LCA reduced NE histopathology, suggesting that secondary bile acids, but not total bile acid levels, play an essential role in controlling the enteritis.
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Oliveira RGD, Damazo AS, Antonielli LF, Miyajima F, Pavan E, Duckworth CA, Lima JCDS, Arunachalam K, Martins DTDO. Dilodendron bipinnatum Radlk. extract alleviates ulcerative colitis induced by TNBS in rats by reducing inflammatory cell infiltration, TNF-α and IL-1β concentrations, IL-17 and COX-2 expressions, supporting mucus production and promotes an antioxidant effect. JOURNAL OF ETHNOPHARMACOLOGY 2021; 269:113735. [PMID: 33359865 DOI: 10.1016/j.jep.2020.113735] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/16/2020] [Accepted: 12/19/2020] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Dilodendron bipinnatum (Sapindaceae) stem bark decoction and macerate were used to treat uterine inflammation, pain in general, dermatitis and bone fractures. These homemade preparations also have diuretic, stimulant, expectorants and sedative effects and are effective in treating worm infections in the Brazilian Pantanal population. Our previous research confirmed the anti-inflammatory activity of the hydroethanolic extract of inner stem bark of D. bipinnatum (HEDb). AIM This work aimed to investigate the efficacy of HEDb in ameliorating experimental colitis in rats and to elucidate the possible mechanisms involved in the anti-ulcerative colitis properties of HEDb in rats and Caco-2 cell line. MATERIALS AND METHODS The effects on cell viability, IL-8 and TNF-α in human colon adenocarcinoma (Caco-2) were determined by flow cytometer and ELISA. Wistar rats (n = 6-7) were orally gavaged with, vehicle (0.9% saline), HEDb at doses of 20, 100 or 500 mg/kg, or mesalazine at a dose of 500 mg/kg, at 48, 24 and 1 h prior to the administration of trinitrobenzene sulfonic acid via rectal administration to induce colitis. The anti-inflammatory effects of HEDb were assessed macroscopically, by myeloperoxidase (MPO) activity and for glutathione (GSH) concentration in the colon. Additionally, colonic histopathological analyses of UC severity were conducted by different staining methods (H&E, PAS and toluidine blue). Pro-inflammatory cytokines TNF-α and IL-1β were quantified in colonic tissue by ELISA and colonic expressions of COX-2 and IL-17 were analyzed by western blotting. RESULTS HEDb was shown to be non-cytotoxic with mean viability of 80% in Caco-2 cells. HEDb pre-treatments of 1, 5 or 20 μg/mL significantly reduced TNF-α production in Caco-2 cells by 21.8% (p < 0.05), 60.5 and 82.1% (p < 0.001) respectively following LPS treatment compared to LPS alone. However, no change in IL-8 production was observed. HEDb pre-treatment of rats subjected to TNBS significantly (p < 0.001) reduced colonic lesion score. Higher doses (100 and 500 mg/kg) caused a sharp downregulation of haemorrhagic damage, leukocyte infiltration, edema and restoration of mucus production. Moreover, mast cell degranulation was inhibited. Colonic MPO activity was reduced following all doses of HEDb, reaching 51.1% ± 1.51 (p < 0.05) with the highest dose. GSH concentration was restored by 58% and 70% following 100 and 500 mg/kg of HEDb, respectively. The oral treatment of HEDb at doses 20, 100 and 500 mg/kg decreased the concentrations of TNF-α and IL-1β at all doses in comparison to vehicle treated control. In addition, HEDb inhibited the COX-2 and IL-17 expressions with maximal effect at 500 mg/kg (60.3% and 65% respectively; p < 0.001). In all trials, the effect of HEDb at all doses being 20, 100 and 500 mg/kg was statistically comparable to mesalazine (500 mg/kg). CONCLUSIONS HEDb reduces colonic damage in the TNBS colitis model and relieves oxidative and inflammatory events, at least in part, by increasing mucus production, reducing leukocyte migration and reducing TNF-α (in vivo and in vitro), IL-1β, IL-17 and COX-2 expression. Therefore, HEDb requires further investigation as a candidate for treating IBD.
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Affiliation(s)
- Ruberlei Godinho de Oliveira
- Área de Farmacologia, Departamento de Ciências Básicas Em Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso (UFMT), Cuiabá, MT, Brazil; Faculdade de Farmácia, Universidade de Cuiabá (UNIC), Cuiabá, MT, Brazil; Programa de Pós-Graduação Em Ciências Aplicadas à Atenção Hospitalar, Hospital Universitário Júlio Muller (HUJM), Cuiabá, MT, Brazil.
| | - Amílcar Sabino Damazo
- Área de Histologia, Departamento de Ciências Básicas Em Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso (UFMT), MT, Cuiabá, MT, Brazil.
| | | | - Fábio Miyajima
- Oswaldo Cruz Foundation (Fiocruz), Brench Ceará, Eusébio, Brazil.
| | - Eduarda Pavan
- Área de Farmacologia, Departamento de Ciências Básicas Em Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso (UFMT), Cuiabá, MT, Brazil.
| | - Carrie A Duckworth
- Department of Molecular Physiology & Cell Signalling, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
| | - Joaquim Corsino da Silva Lima
- Área de Farmacologia, Departamento de Ciências Básicas Em Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso (UFMT), Cuiabá, MT, Brazil.
| | - Karuppusamy Arunachalam
- Área de Farmacologia, Departamento de Ciências Básicas Em Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso (UFMT), Cuiabá, MT, Brazil; Key Laboratory of Economic Plants and Biotechnology and the Yunnan Key Laboratory for Wild Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China.
| | - Domingos Tabajara de Oliveira Martins
- Área de Farmacologia, Departamento de Ciências Básicas Em Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso (UFMT), Cuiabá, MT, Brazil.
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Fordjour L, Cai C, Bronshtein V, Bronshtein M, Aranda JV, Beharry KD. Growth factors in the fetus and pre-adolescent offspring of hyperglycemic rats. Diab Vasc Dis Res 2021; 18:14791641211011025. [PMID: 33913361 PMCID: PMC8482349 DOI: 10.1177/14791641211011025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Maternal hyperglycemia influences childhood metabolic syndrome, including obesity and hyperglycemia. We tested the hypothesis that the maternal hyperglycemia influences growth factors in the fetal and pre-adolescent offspring. METHODS Hyperglycemia was induced in pregnant rats on embryonic day (E)16 using streptozocin followed by implantation with insulin or placebo pellets at embryonic day 18 (E18). Fetuses at E20 and pre-adolescent pups at postnatal day 14 (P14) were studied: (1) normal untreated controls (CTL) at E20; (2) hyperglycemic placebo-treated (HPT) at E20; (3) hyperglycemic insulin-treated (HIT) at E20; (4) CTL at P14; and (5) HIT at P14. Fetal and pre-adolescent growth factors were determined. RESULTS Biomarkers of hypoxia were elevated in the HPT group at E20. This group did not survive to term. Maternal insulin improved fetal survival despite lower fetal body weight at E20, however, at normal birth (postnatal day 0 (P0)) and at P14, body weights and blood glucose were higher than CTL. These high levels correlated with aberrant growth factors. Maternal hyperglycemia influenced glucose-6-phosphate dehydrogenase, glucagon, insulin, interleukin-10, and leptin genes. CONCLUSIONS The impact of maternal hyperglycemia on pre-adolescent glucose and body weight was not a consequence of maternal overnutrition. This suggests an independent link which may affect offspring metabolic health in later life.
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Affiliation(s)
- Lawrence Fordjour
- Division of Neonatal-Perinatal
Medicine, Department of Pediatrics, State University of New York, Downstate Medical
Center, Brooklyn, NY, USA
| | - Charles Cai
- Division of Neonatal-Perinatal
Medicine, Department of Pediatrics, State University of New York, Downstate Medical
Center, Brooklyn, NY, USA
| | - Vadim Bronshtein
- Division of Neonatal-Perinatal
Medicine, Department of Pediatrics, State University of New York, Downstate Medical
Center, Brooklyn, NY, USA
| | - Mayan Bronshtein
- Division of Neonatal-Perinatal
Medicine, Department of Pediatrics, State University of New York, Downstate Medical
Center, Brooklyn, NY, USA
| | - Jacob V Aranda
- Division of Neonatal-Perinatal
Medicine, Department of Pediatrics, State University of New York, Downstate Medical
Center, Brooklyn, NY, USA
- Department of Ophthalmology, State
University of New York, Downstate Medical Center, Brooklyn, NY, USA
- State University of New York Eye
Institute, New York, NY, USA
| | - Kay D Beharry
- Division of Neonatal-Perinatal
Medicine, Department of Pediatrics, State University of New York, Downstate Medical
Center, Brooklyn, NY, USA
- Department of Ophthalmology, State
University of New York, Downstate Medical Center, Brooklyn, NY, USA
- State University of New York Eye
Institute, New York, NY, USA
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10
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Huang N, Wang M, Peng J, Wei H. Role of arachidonic acid-derived eicosanoids in intestinal innate immunity. Crit Rev Food Sci Nutr 2020; 61:2399-2410. [PMID: 32662287 DOI: 10.1080/10408398.2020.1777932] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Arachidonic acid (ARA), an n-6 essential fatty acid, plays an important role in human and animal growth and development. The ARA presents in the membrane phospholipids can be released by phospholipase A2. These free arachidonic acid molecules are then used to produce eicosanoids through three different pathways. Previous studies have demonstrated that eicosanoids have a wide range of physiological functions. Although they are generally considered to be pro-inflammatory molecules, recent advances have elucidated they have an effect on innate immunity via regulating the development, and differentiation of innate immune cells and the function of the intestinal epithelial barrier. Here, we review eicosanoids generation in intestine and their role in intestinal innate immunity, focusing on intestinal epithelial barrier, innate immune cell in lamina propria (LP) and their crosstalk.
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Affiliation(s)
- Ningning Huang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, PR China
| | - Miaomiao Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, PR China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, PR China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, PR China
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11
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Zhang TQ, Kuroda H, Nagano K, Terada S, Gao JQ, Harada K, Hirata K, Tsujino H, Higashisaka K, Matsumoto H, Tsutsumi Y. Development and evaluation of a simultaneous and efficient quantification strategy for final prostanoid metabolites in urine. Prostaglandins Leukot Essent Fatty Acids 2020; 157:102032. [PMID: 31734013 DOI: 10.1016/j.plefa.2019.102032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 09/19/2019] [Accepted: 11/05/2019] [Indexed: 11/16/2022]
Abstract
Prostanoids (PNs) play critical roles in various physiological and pathological processes. Therefore, it is important to understand the alternation of PN expression profiles. However, a simultaneous and efficient quantification system for final PN metabolites in urine has not yet been established. Here, we developed and evaluated a novel method to quantify all final PN metabolites. By purification using a reverse phase solid phase extraction (SPE) column, the matrix effects against the final PGD2, PGE2, and PGF2α metabolites were low, and their accuracies were nearly 100%. The matrix effects against the final PGI2 and TXA2 metabolites were high using reverse phase SPE column purification alone. By applying a tandem SPE method that combined reverse phase and ion exchange SPE columns, the matrix effects decreased so that the accuracy was nearly 100%. To validate the reliability of the method, each final metabolite was quantified from mouse urine to which the PNs (PGD2, PGE2, and PGI2) were intravenously administered. As a result, the amounts of PN metabolites were correlated with those of the PNs administered to the blood in a dose-dependent manner. To validate the method using human samples, the urinary metabolites of Crohn's disease (CD, a PN-related disease) patients and healthy individuals were quantified. All five metabolites were successfully quantified. Only final PGE2 metabolite levels were significantly higher in CD patients than those in healthy individuals, so that the urinary metabolite profiles of CD patients is determined. In conclusion, we developed a novel method to quantify all final PN metabolites simultaneously and efficiently and demonstrated the practicality of the method using human CD patient samples.
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Affiliation(s)
- Tian-Qi Zhang
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hirotaka Kuroda
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan; Life Science Business Department, Analytical and Measuring Instruments Division, Shimadzu Corporation, Kyoto, 604-8511, Japan
| | - Kazuya Nagano
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan; Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Soshi Terada
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Jian-Qing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China
| | - Kazuo Harada
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan; Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazumasa Hirata
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hirofumi Tsujino
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuma Higashisaka
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan; Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroshi Matsumoto
- Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yasuo Tsutsumi
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan; Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Global Center for Medical Engineering and Informatics, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
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12
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Oral administration of green tea polyphenols (TP) improves ileal injury and intestinal flora disorder in mice with Salmonella typhimurium infection via resisting inflammation, enhancing antioxidant action and preserving tight junction. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103654] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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Microbial metabolite deoxycholic acid controls Clostridium perfringens-induced chicken necrotic enteritis through attenuating inflammatory cyclooxygenase signaling. Sci Rep 2019; 9:14541. [PMID: 31601882 PMCID: PMC6787040 DOI: 10.1038/s41598-019-51104-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 09/24/2019] [Indexed: 12/18/2022] Open
Abstract
Necrotic enteritis (NE) caused by Clostridium perfringens infection has reemerged as a prevalent poultry disease worldwide due to reduced usage of prophylactic antibiotics under consumer preferences and regulatory pressures. The lack of alternative antimicrobial strategies to control this disease is mainly due to limited insight into the relationship between NE pathogenesis, microbiome, and host responses. Here we showed that the microbial metabolic byproduct of secondary bile acid deoxycholic acid (DCA), at as low as 50 µM, inhibited 82.8% of C. perfringens growth in Tryptic Soy Broth (P < 0.05). Sequential Eimeria maxima and C. perfringens challenges significantly induced NE, severe intestinal inflammation, and body weight (BW) loss in broiler chickens. These negative effects were diminished (P < 0.05) by 1.5 g/kg DCA diet. At the cellular level, DCA alleviated NE-associated ileal epithelial death and significantly reduced lamina propria cell apoptosis. Interestingly, DCA reduced C. perfringens invasion into ileum (P < 0.05) without altering the bacterial ileal luminal colonization. Molecular analysis showed that DCA significantly reduced inflammatory mediators of Infγ, Litaf, Il1β, and Mmp9 mRNA accumulation in ileal tissue. Mechanism studies revealed that C. perfringens induced (P < 0.05) elevated expression of inflammatory mediators of Infγ, Litaf, and Ptgs2 (Cyclooxygenases-2 (COX-2) gene) in chicken splenocytes. Inhibiting the COX signaling by aspirin significantly attenuated INFγ-induced inflammatory response in the splenocytes. Consistent with the in vitro assay, chickens fed 0.12 g/kg aspirin diet protected the birds against NE-induced BW loss, ileal inflammation, and intestinal cell apoptosis. In conclusion, microbial metabolic product DCA prevents NE-induced BW loss and ileal inflammation through attenuating inflammatory response. These novel findings of microbiome protecting birds against NE provide new options on developing next generation antimicrobial alternatives against NE.
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14
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Wallace JL. Eicosanoids in the gastrointestinal tract. Br J Pharmacol 2019; 176:1000-1008. [PMID: 29485681 PMCID: PMC6451073 DOI: 10.1111/bph.14178] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 02/06/2018] [Accepted: 02/09/2018] [Indexed: 01/06/2023] Open
Abstract
Eicosanoids play important roles in modulating inflammation throughout the body. The gastrointestinal (GI) tract, in part because of its intimate relationship with the gut microbiota, is in a constant state of low-grade inflammation. Eicosanoids like PGs, lipoxins and leukotrienes play essential roles in maintenance of mucosal integrity. On the other hand, in some circumstances, these mediators can become major drivers of inflammatory processes when the lining of the GI tract is breached. Drugs such as nonsteroidal anti-inflammatories, by altering the production of various eicosanoids, can dramatically impact the ability of the GI tract to respond appropriately to injury. Disorders such as inflammatory bowel disease appear to be driven in part by altered production of eicosanoids. Several classes of drugs have been developed that target eicosanoids. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
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Affiliation(s)
- John L Wallace
- Department of Physiology and PharmacologyUniversity of CalgaryCalgaryABT2N 4N1Canada
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15
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Jafarbeglou M, Abdouss M. Fabricating Hybrid Microsphere Substrate Based PLGA-CNT with In Situ Drug Release: Characterization and In Vitro Evaluation. ChemistrySelect 2019. [DOI: 10.1002/slct.201803326] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Maryam Jafarbeglou
- Department of Nanotechnology; Amirkabir University of Technology; Hafez Ave. Tehran Iran
| | - Majid Abdouss
- Department of Chemistry; Amirkabir University of Technology; Hafez Ave. Tehran Iran
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16
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Dou D, Chen L, Di H, Song Z, Li S, Bu X, Dai Q, Wang S, Li JX, Zhu X, Jing H. Vasopressin augments TNBS-induced colitis through enteric neuronal V 1a receptor-mediated COX-2-dependent prostaglandin release from mast cells in mice. Neurogastroenterol Motil 2019; 31:e13493. [PMID: 30334342 DOI: 10.1111/nmo.13493] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/04/2018] [Accepted: 09/20/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a functional disorder with chronic and relapsing clinical features. Vasopressin (VP) is a hormone responsible for water and stress homeostasis and also regulates gastrointestinal inflammation and motility. We explored whether VP was related to IBD pathogenesis and its possible pathway. METHODS Colitis was induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice. The disease activity and colonic damage were evaluated through a scoring system. Locations of the V1a receptor were revealed by immunochemistry method in colon. Ussing chamber technique was performed for the electrophysiological characterization by using rat ileum. The (Arg8 )-Vasopressin (AVP)-evoked short-circuit current (Isc) was recorded in the presence of conivaptan (V1a and V2 receptor antagonist), tolvaptan (V1b receptor antagonist), tetrodotoxin (TTX), atropine, cyclooxygenase (COX) inhibitors (indomethacin, nonspecific COX antagonist; SC560, COX-1 antagonist; NS560, COX-2 antagonist), and a stabilizer of mast cell (cromolyn sodium), respectively. KEY RESULTS TNBS resulted in the obvious loss of body weight and tissue damages in mice. AVP significantly aggravated the TNBS-induced colitis, which was attenuated by conivaptan but not tolvaptan. V1a receptors were found immunopositive in neurons among the enteric nervous system. AVP evoked a pulsatile response in Isc. Its amplitude, frequency, and cycle duration were around 8-15 µA/cm2 , 10-11 mHz, and 1.5 minutes, respectively. Notably, the AVP-evoked change in Isc was abolished by TTX, atropine, conivaptan, indomethacin, NS560, and cromolyn sodium, respectively. CONCLUSIONS AND INFERENCES VP-V1a receptor played the proinflammatory role in TNBS-induced colitis by promoting COX-2-dependent prostaglandin release from mucosal mast cells, which was mediated by the cholinergic pathway.
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Affiliation(s)
- Dandan Dou
- Department of Physiology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Lixin Chen
- School of Medicine, Shandong University, Jinan, China
| | - Hong Di
- School of Medicine, Shandong University, Jinan, China
| | - Zhuoran Song
- School of Medicine, Shandong University, Jinan, China
| | - Shirui Li
- School of Medicine, Shandong University, Jinan, China
| | - Xinjie Bu
- School of Medicine, Shandong University, Jinan, China
| | - Qing Dai
- School of Medicine, Shandong University, Jinan, China
| | - Shuai Wang
- School of Medicine, Shandong University, Jinan, China
| | - Jing Xin Li
- Department of Physiology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Xiaolong Zhu
- Department of Cardiac Surgery Cardiac, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Haiyan Jing
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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17
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Xu J, Cao L, Suo Y, Xu X, Sun H, Xu S, Zhu X, Yu H, Cao W. Chitosan-microcapsulated insulin alleviates mesenteric microcirculation dysfunction via modulating COX-2 and VCAM-1 expression in rats with diabetes mellitus. Int J Nanomedicine 2018; 13:6829-6837. [PMID: 30498345 PMCID: PMC6207390 DOI: 10.2147/ijn.s174030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background The study of the experiment was to display the therapeutic function of insulin-loaded chitosan (insulin/chitosan) on mesenteric microcirculation via down-regulating cyclooxygenase-2 (COX-2) and vascular cell adhesion molecule (VCAM-1) expressions in rats with diabetes mellitus (DM) as compared to free insulin. Methods Diabetic rats were administrated with 24 U/kg insulin or 120 U/kg insulin/chitosan compounds. The blood and mesenteriums were collected, blood glucose levels, arteriole velocity, arteriole diameter, venular diameter, and hemodiapedesis were measured, and COX-2, VCAM-1 expressions were measured in mesenteriums tissues. Results Both insulin and insulin/chitosan administration decreased blood glucose and improved the state of mesenteric microcirculation through down-regulating COX-2 and VCAM-1 expressions as compared to DM groups, while insulin/chitosan remarkably augmented this functions. Conclusion Chitosan-microcapsulated insulin alleviates mesenteric microcirculation dysfunction via modulating COX-2 and VCAM-1 expressions in rats with DM.
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Affiliation(s)
- Jun Xu
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
| | - Lijun Cao
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
| | - Yuan Suo
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
| | - Xiaoqin Xu
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
| | - Hui Sun
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
| | - Songao Xu
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
| | - Xiangyun Zhu
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
| | - Huijie Yu
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
| | - Weizhong Cao
- Department of Emergency Medicine, The First Hospital of Jiaxing, Jiaxing 314001, Zhejiang Province, China,
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Li Y, Shi J, Qi S, Zhang J, Peng D, Chen Z, Wang G, Wang Z, Wang L. IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE 2. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:196. [PMID: 30119635 PMCID: PMC6098640 DOI: 10.1186/s13046-018-0839-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 07/09/2018] [Indexed: 01/08/2023]
Abstract
Background Interleukin-33 (IL-33) participates in various types of diseases including cancers. Previous studies of this cytokine in cancers mainly focused on its regulation on immune responses by which IL-33 modulated cancer progression. The IL-33 triggered signals in cancer cells remain unclear. Methods We analyzed IL-33 gene expression in human colorectal cancer (CRC) tissues and carried out gene enrichment analysis with TCGA Data Portal. We studied CRC proliferation in vivo by inoculating MC38 tumors in IL-33 transgenic mice. We investigated the cell proliferation in vitro with primary CRC cells isolated from fresh human CRC tissues, human CRC cell line HT-29 and mouse CRC cell line MC38. To evaluate the proliferation modulating effects of recombinant IL-33 incubation and other administrated factors, we measured tumor growth, colony formation, cell viability, and the expression of Ki67 and proliferating cell nuclear antigen (PCNA). We used several inhibitors, prostaglandin E2 (PGE2) neutralizing antibody, ST2 blocking antibody and specific shRNA expressing plasmid to study the pathway mediating IL-33-induced CRC proliferation. The IL-33 receptor ST2 in human CRC tissues was detected by immunohistochemistry staining and western blotting. The ST2-positive or negative subsets of primary CRC cells were acquired by flow cytometry sorting. Results We found that IL-33 expression was correlated with the gene signature of cell proliferation in 394 human CRC samples. The MC38 tumors grew more rapidly and the tumor Ki67 and PCNA were expressed at higher levels in IL-33 transgenic mice than in wild-type mice. IL-33 promoted cell growth, colony formation and expression of Ki67 and PCNA in primary CRC cells as well as CRC cell lines. IL-33 activated cycloxygenase-2 (COX2) expression and increased PGE2 production, whereas the COX2 selective inhibitor and PGE2 neutralizing antibody abolished the proliferation promoting effect of IL-33. ST2 blockade, ST2-negative sorting, NF-κB specific inhibitor and NF-κB specific shRNA (shP65) abrogated the COX2 induction caused by IL-33. Conclusion IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2. IL-33 functions via its receptor ST2 and upregulates COX2 expression through NF-κB signaling. Understanding the IL-33 signal transduction in CRC cells provides potential therapeutic targets for clinical treatment. Electronic supplementary material The online version of this article (10.1186/s13046-018-0839-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yongkui Li
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jie Shi
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shanshan Qi
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jian Zhang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dong Peng
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhenzhen Chen
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zheng Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Lin Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Solano-Aguilar G, Shea-Donohue T, Madden KB, Quinoñes A, Beshah E, Lakshman S, Xie Y, Dawson H, Urban JF. Bifidobacterium animalis subspecies lactis modulates the local immune response and glucose uptake in the small intestine of juvenile pigs infected with the parasitic nematode Ascaris suum. Gut Microbes 2018; 9:422-436. [PMID: 30024817 PMCID: PMC6219643 DOI: 10.1080/19490976.2018.1460014] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
An evaluation of a localized intestinal allergic type-2 response concomitant with consumption of probiotic bacteria is not well documented. This study investigated the effect of feeding probiotic Bifidobacterium animalis subspecies lactis (Bb12) or a placebo in weaned pigs that were also inoculated with Ascaris suum (A. suum) eggs to induce a strong Th2-dependent allergic type 2 immune response. Sections of jejunal mucosa were mounted in Ussing chambers to determine changes in permeability and glucose absorption, intestine and liver samples were collected for analysis of type-2 related gene expression, jejunum examined histologically, and sera and intestinal fluid were assayed for parasite antigen specific antibody. The prototypical parasite-induced secretory response to histamine and reduced absorption of glucose in the jejunum were attenuated by feeding Bb12 without a change in mucosal resistance. Parasite antigen-specific IgA response in the serum and IgG1 and IgG2 response in the ileal fluid were significantly increased in A. suum-infected pigs treated with Bb12 compared to infected pigs given the placebo. Ascaris suum-induced eosinophilia in the small intestinal mucosa was inhibited by Bb12 treatment without affecting the normal expulsion of A. suum 4th stage larvae (L4) or the morphometry of the intestine. Expression of genes associated with Th1/Th2 cells, Treg cells, mast cells, and physiological function in the intestine were modulated in A. suum infected-pigs treated with Bb12. These results suggested that Bb12 can alter local immune responses and improve intestinal function during a nematode infection by reducing components of a strong allergenic type-2 response in the pig without compromising normal parasite expulsion.
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Affiliation(s)
- Gloria Solano-Aguilar
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD,CONTACT Gloria Solano-Aguilar 10300 Baltimore Avenue, BARC-East. Bldg 307C, Room 225, Beltsville, MD 20705, USA
| | - Terez Shea-Donohue
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
| | - Kathleen B. Madden
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD
| | | | - Ethiopia Beshah
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD
| | - Sukla Lakshman
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD
| | - Yue Xie
- Department of Parasitology, Sichuan Agricultural University, College of Veterinary Medicine, Sichuan, China
| | - Harry Dawson
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD
| | - Joseph F. Urban
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD
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Roig J, Saiz ML, Galiano A, Trelis M, Cantalapiedra F, Monteagudo C, Giner E, Giner RM, Recio MC, Bernal D, Sánchez-Madrid F, Marcilla A. Extracellular Vesicles From the Helminth Fasciola hepatica Prevent DSS-Induced Acute Ulcerative Colitis in a T-Lymphocyte Independent Mode. Front Microbiol 2018; 9:1036. [PMID: 29875750 PMCID: PMC5974114 DOI: 10.3389/fmicb.2018.01036] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/01/2018] [Indexed: 12/26/2022] Open
Abstract
The complexity of the pathogenesis of inflammatory bowel disease (ulcerative colitis and Crohn's disease) has led to the quest of empirically drug therapies, combining immunosuppressant agents, biological therapy and modulators of the microbiota. Helminth parasites have been proposed as an alternative treatment of these diseases based on the hygiene hypothesis, but ethical and medical problems arise. Recent reports have proved the utility of parasite materials, mainly excretory/secretory products as therapeutic agents. The identification of extracellular vesicles on those secreted products opens a new field of investigation, since they exert potent immunomodulating effects. To assess the effect of extracellular vesicles produced by helminth parasites to treat ulcerative colitis, we have analyzed whether extracellular vesicles produced by the parasitic helminth Fasciola hepatica can prevent colitis induced by chemical agents in a mouse model. Adult parasites were cultured in vitro and secreted extracellular vesicles were purified and used for immunizing both wild type C57BL/6 and RAG1-/- mice. Control and immunized mice groups were treated with dextran sulfate sodium 7 days after last immunization to promote experimental colitis. The severity of colitis was assessed by disease activity index and histopathological scores. Mucosal cytokine expression was evaluated by ELISA. The activation of NF-kB, COX-2, and MAPK were evaluated by immunoblotting. Administration of extracellular vesicles from F. hepatica ameliorates the pathological symptoms reducing the amount of pro-inflammatory cytokines and interfering with both MAPK and NF-kB pathways. Interestingly, the observed effects do not seem to be mediated by T-cells. Our results indicate that extracellular vesicles from parasitic helminths can modulate immune responses in dextran sulfate sodium (DSS)-induced colitis, exerting a protective effect that should be mediated by other cells distinct from B- and T-lymphocytes.
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Affiliation(s)
- Javier Roig
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain.,Facultad de Ciencias de la Salud, Universidad Europea de Valencia, Burjassot, Spain
| | - Maria L Saiz
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Alicia Galiano
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain
| | - Maria Trelis
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain.,Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe, Universitat de València, Burjassot, Spain
| | - Fernando Cantalapiedra
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain.,Veterinari de Salut Pública, Centre de Salut Pública de Manises, Burjassot, Spain
| | | | - Elisa Giner
- Departament de Farmacologia, Universitat de València, Burjassot, Spain
| | - Rosa M Giner
- Departament de Farmacologia, Universitat de València, Burjassot, Spain
| | - M C Recio
- Departament de Farmacologia, Universitat de València, Burjassot, Spain
| | - Dolores Bernal
- Departament de Bioquímica i Biologia Molecular, Universitat de València, Burjassot, Spain
| | - Francisco Sánchez-Madrid
- Facultad de Ciencias de la Salud, Universidad Europea de Valencia, Burjassot, Spain.,Immunology Service, Hospital de La Princesa, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.,Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
| | - Antonio Marcilla
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain.,Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe, Universitat de València, Burjassot, Spain
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21
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Marín M, Gimeno C, Giner RM, Ríos JL, Máñez S, Recio MAC. Influence of Dimerization of Apocynin on Its Effects in Experimental Colitis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:4083-4091. [PMID: 28485605 DOI: 10.1021/acs.jafc.7b00872] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Apocynin has been widely used as an inhibitor of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) system and shows promise as an anti-inflammatory drug. Diapocynin, the dimeric product generated by the oxidation of apocynin in the presence of myeloperoxidase (MPO), is supposed to be its active form. In this study, diapocynin has been chemically synthesized and its activity on several inflammatory mediators in LPS-stimulated RAW 264.7 macrophages and its anti-inflammatory effect on ulcerative colitis induced by dextran sodium sulfate (DSS) in mice analyzed. We found that diapocynin showed higher inhibitory activity than apocynin. The dimer reduced ROS production, TNF-α, IL-6, and IL-1β levels and inhibited iNOS and COX-2 expression as well as decreased NO and PGE2 production induced in LPS-stimulated RAW 264.7 cells. The anti-inflammatory molecular mechanism of diapocynin was associated with the suppression of NF-κB activation. However, these results were not paralleled by in vivo studies. Oral administration of apocynin and diapocynin (100 mg/kg) three times a week exhibited similar protections against experimental inflammatory bowel disease induced by DSS; therefore, apocynin should not be considered a prodrug. However, it should be taken into account that the dimer is more potent because its dose (0.3 mmol/kg) is half that of apocynin.
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Affiliation(s)
- Marta Marín
- Departament de Farmacologia, Facultat de Farmàcia, University of Valencia , Avenida Vicent Andrés Estellés s/n, 46100 Burjassot-Valencia, Spain
| | - Clotilde Gimeno
- Departament de Farmacologia, Facultat de Farmàcia, University of Valencia , Avenida Vicent Andrés Estellés s/n, 46100 Burjassot-Valencia, Spain
| | - Rosa M Giner
- Departament de Farmacologia, Facultat de Farmàcia, University of Valencia , Avenida Vicent Andrés Estellés s/n, 46100 Burjassot-Valencia, Spain
| | - José L Ríos
- Departament de Farmacologia, Facultat de Farmàcia, University of Valencia , Avenida Vicent Andrés Estellés s/n, 46100 Burjassot-Valencia, Spain
| | - Salvador Máñez
- Departament de Farmacologia, Facultat de Farmàcia, University of Valencia , Avenida Vicent Andrés Estellés s/n, 46100 Burjassot-Valencia, Spain
| | - Marı A C Recio
- Departament de Farmacologia, Facultat de Farmàcia, University of Valencia , Avenida Vicent Andrés Estellés s/n, 46100 Burjassot-Valencia, Spain
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22
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Larussa T, Oliverio M, Suraci E, Greco M, Placida R, Gervasi S, Marasco R, Imeneo M, Paolino D, Tucci L, Gulletta E, Fresta M, Procopio A, Luzza F. Oleuropein Decreases Cyclooxygenase-2 and Interleukin-17 Expression and Attenuates Inflammatory Damage in Colonic Samples from Ulcerative Colitis Patients. Nutrients 2017; 9:nu9040391. [PMID: 28420140 PMCID: PMC5409730 DOI: 10.3390/nu9040391] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/11/2017] [Accepted: 04/13/2017] [Indexed: 02/06/2023] Open
Abstract
Oleuropein (OLE) is the major phenolic secoiridoid of olive tree leaves, and its antioxidant and anti-inflammatory activities have been demonstrated in in vitro and in vivo animal models. The aim of this study was to investigate the activity of OLE in the colonic mucosa from patients with ulcerative colitis (UC). Biopsies obtained during colonoscopy from 14 patients with active UC were immediately placed in an organ culture chamber and challenged with lipopolysaccharide from Escherichia coli (EC-LPS) at 1 μg/mL in the presence or absence of 3 mM OLE. The expression of cyclooxygenase (COX)-2 and interleukin (IL)-17 was assessed in total protein extracts from treated colonic biopsies by Western blotting. Levels of IL-17 were also measured in culture supernatant by ELISA. A microscopic evaluation of the cultured biopsies was performed by conventional histology and immunohistochemistry. The expression of COX-2 and IL-17 were significantly lower in samples treated with OLE + EC-LPS compared with those treated with EC-LPS alone (0.80 ± 0.15 arbitrary units (a.u.) vs. 1.06 ± 0.19 a.u., p = 0.003, and 0.71 ± 0.08 a.u. vs. 1.26 ± 0.42 a.u., p = 0.03, respectively) as were the levels of IL-17 in culture supernatants of OLE + EC-LPS treated colonic samples (21.16 ± 8.64 pg/mL vs. 40.67 ± 9.24 pg/mL, p = 0.01). Histologically, OLE-treated colonic samples showed an amelioration of inflammatory damage with reduced infiltration of CD3, CD4, and CD20 cells, while CD68 numbers increased. The anti-inflammatory activity of OLE was demonstrated in colonic biopsies from UC patients. These new data support a potential role of OLE in the treatment of UC.
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Affiliation(s)
- Tiziana Larussa
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Manuela Oliverio
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Evelina Suraci
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Marta Greco
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Roberta Placida
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Serena Gervasi
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Raffaella Marasco
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Maria Imeneo
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Donatella Paolino
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Luigi Tucci
- Pathology Unit, Pugliese-Ciaccio Hospital, 88100 Catanzaro, Italy.
| | - Elio Gulletta
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Massimo Fresta
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Antonio Procopio
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Francesco Luzza
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
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23
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Lomax AE, Pradhananga S, Bertrand PP. Plasticity of neuroeffector transmission during bowel inflammation 1. Am J Physiol Gastrointest Liver Physiol 2017; 312:G165-G170. [PMID: 28082285 DOI: 10.1152/ajpgi.00365.2016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Revised: 01/03/2017] [Accepted: 01/03/2017] [Indexed: 01/31/2023]
Abstract
Altered gastrointestinal (GI) function contributes to the debilitating symptoms of inflammatory bowel diseases (IBD). Nerve circuits contained within the gut wall and outside of the gut play important roles in modulating motility, mucosal fluid transport, and blood flow. The structure and function of these neuronal populations change during IBD. Superimposed on this plasticity is a diminished responsiveness of effector cells - smooth muscle cells, enterocytes, and vascular endothelial cells - to neurotransmitters. The net result is a breakdown in the precisely orchestrated coordination of motility, fluid secretion, and GI blood flow required for health. In this review, we consider how inflammation-induced changes to the effector innervation of these tissues, and changes to the tissues themselves, contribute to defective GI function in models of IBD. We also explore the evidence that reversing neuronal plasticity is sufficient to normalize function during IBD.
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Affiliation(s)
- Alan E Lomax
- Gastrointestinal Disease Research Unit, Queen's University, Kingston, Ontario, Canada; and
| | - Sabindra Pradhananga
- Gastrointestinal Disease Research Unit, Queen's University, Kingston, Ontario, Canada; and
| | - Paul P Bertrand
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia
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24
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Moreno-Borque R, Matito A, Álvarez-Twose I, Morgado JM, Sánchez-Muñoz L, Orfao A, Escribano L. Response to celecoxib in a patient with indolent systemic mastocytosis presenting with intractable diarrhea. Ann Allergy Asthma Immunol 2016; 115:456-7. [PMID: 26505934 DOI: 10.1016/j.anai.2015.08.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 07/28/2015] [Accepted: 08/12/2015] [Indexed: 10/22/2022]
Affiliation(s)
- Ricardo Moreno-Borque
- Servicio de Alergología, Hospital Rey Juan Carlos, Móstoles, Madrid; Spanish Network on Mastocytosis, Toledo, Spain.
| | - Almudena Matito
- Spanish Network on Mastocytosis, Toledo, Spain; Instituto de Estudios de Mastocitosis de Castilla-La Mancha, Hospital Virgen del Valle, Toledo, Spain
| | - Ivan Álvarez-Twose
- Spanish Network on Mastocytosis, Toledo, Spain; Instituto de Estudios de Mastocitosis de Castilla-La Mancha, Hospital Virgen del Valle, Toledo, Spain
| | - Jose Mario Morgado
- Spanish Network on Mastocytosis, Toledo, Spain; Instituto de Estudios de Mastocitosis de Castilla-La Mancha, Hospital Virgen del Valle, Toledo, Spain
| | - Laura Sánchez-Muñoz
- Spanish Network on Mastocytosis, Toledo, Spain; Instituto de Estudios de Mastocitosis de Castilla-La Mancha, Hospital Virgen del Valle, Toledo, Spain
| | - Alberto Orfao
- Spanish Network on Mastocytosis, Toledo, Spain; Servicio General de Citometría, Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
| | - Luis Escribano
- Spanish Network on Mastocytosis, Toledo, Spain; Servicio General de Citometría, Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
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25
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Le Loupp AG, Bach-Ngohou K, Bourreille A, Boudin H, Rolli-Derkinderen M, Denis MG, Neunlist M, Masson D. Activation of the prostaglandin D2 metabolic pathway in Crohn's disease: involvement of the enteric nervous system. BMC Gastroenterol 2015; 15:112. [PMID: 26338799 PMCID: PMC4558965 DOI: 10.1186/s12876-015-0338-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 08/24/2015] [Indexed: 02/08/2023] Open
Abstract
Background Recent works provide evidence of the importance of the prostaglandin D2 (PGD2) metabolic pathway in inflammatory bowel diseases. We investigated the expression of PGD2 metabolic pathway actors in Crohn’s disease (CD) and the ability of the enteric nervous system (ENS) to produce PGD2 in inflammatory conditions. Methods Expression of key actors involved in the PGD2 metabolic pathway and its receptors was analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in colonic mucosal biopsies of patients from three groups: controls, quiescent and active CD patients. To determine the ability of the ENS to secrete PGD2 in proinflammatory conditions, Lipocalin-type prostaglandin D synthase (L-PGDS) expression by neurons and glial cells was analyzed by immunostaining. PGD2 levels were determined in a medium of primary culture of ENS and neuro-glial coculture model treated by lipopolysaccharide (LPS). Results In patients with active CD, inflamed colonic mucosa showed significantly higher COX2 and L-PGDS mRNA expression, and significantly higher PGD2 levels than healthy colonic mucosa. On the contrary, peroxysome proliferator-activated receptor Gamma (PPARG) expression was reduced in inflamed colonic mucosa of CD patients with active disease. Immunostaining showed that L-PGDS was expressed in the neurons of human myenteric and submucosal plexi. A rat ENS primary culture model confirmed this expression. PGD2 levels were significantly increased on primary culture of ENS treated with LPS. This production was abolished by AT-56, a specific competitive L-PGDS inhibitor. The neuro-glial coculture model revealed that each component of the ENS, ECG and neurons, could contribute to PGD2 production. Conclusions Our results highlight the activation of the PGD2 metabolic pathway in Crohn’s disease. This study supports the hypothesis that in Crohn’s disease, enteric neurons and glial cells form a functional unit reacting to inflammation by producing PGD2.
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Affiliation(s)
- Anne-Gaelle Le Loupp
- INSERM Unité 913, 1 rue Gaston Veil, Nantes, F-44035, France. .,Université Nantes, 1 quai de Tourville, BP 13522, Nantes, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Laboratoire de Biochimie, Institut de Biologie, CHU de Nantes, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Kalyane Bach-Ngohou
- INSERM Unité 913, 1 rue Gaston Veil, Nantes, F-44035, France. .,Université Nantes, 1 quai de Tourville, BP 13522, Nantes, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Laboratoire de Biochimie, Institut de Biologie, CHU de Nantes, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Arnaud Bourreille
- INSERM Unité 913, 1 rue Gaston Veil, Nantes, F-44035, France. .,Université Nantes, 1 quai de Tourville, BP 13522, Nantes, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Laboratoire de Biochimie, Institut de Biologie, CHU de Nantes, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Hélène Boudin
- INSERM Unité 913, 1 rue Gaston Veil, Nantes, F-44035, France. .,Université Nantes, 1 quai de Tourville, BP 13522, Nantes, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Malvyne Rolli-Derkinderen
- INSERM Unité 913, 1 rue Gaston Veil, Nantes, F-44035, France. .,Université Nantes, 1 quai de Tourville, BP 13522, Nantes, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Marc G Denis
- INSERM Unité 913, 1 rue Gaston Veil, Nantes, F-44035, France. .,Université Nantes, 1 quai de Tourville, BP 13522, Nantes, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Laboratoire de Biochimie, Institut de Biologie, CHU de Nantes, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Michel Neunlist
- INSERM Unité 913, 1 rue Gaston Veil, Nantes, F-44035, France. .,Université Nantes, 1 quai de Tourville, BP 13522, Nantes, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Damien Masson
- INSERM Unité 913, 1 rue Gaston Veil, Nantes, F-44035, France. .,Université Nantes, 1 quai de Tourville, BP 13522, Nantes, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Laboratoire de Biochimie, Institut de Biologie, CHU de Nantes, 1 place Alexis Ricordeau, Nantes, F-44093, France.
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26
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Kudva AK, Shay AE, Prabhu KS. Selenium and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2015; 309:G71-7. [PMID: 26045617 PMCID: PMC4504954 DOI: 10.1152/ajpgi.00379.2014] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 05/31/2015] [Indexed: 01/31/2023]
Abstract
Dietary intake of the micronutrient selenium is essential for normal immune functions. Selenium is cotranslationally incorporated as the 21st amino acid, selenocysteine, into selenoproteins that function to modulate pathways involved in inflammation. Epidemiological studies have suggested an inverse association between selenium levels and inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis that can potentially progress to colon cancer. However, the underlying mechanisms are not well understood. Here we summarize the current literature on the pathophysiology of IBD, which is multifactorial in origin with unknown etiology. We have focused on a few selenoproteins that mediate gastrointestinal inflammation and activate the host immune response, wherein macrophages play a pivotal role. Changes in cellular oxidative state coupled with altered expression of selenoproteins in macrophages drive the switch from a proinflammatory phenotype to an anti-inflammatory phenotype to efficiently resolve inflammation in the gut and restore epithelial barrier integrity. Such a phenotypic plasticity is accompanied by changes in cytokines, chemokines, and bioactive metabolites, including eicosanoids that not only mitigate inflammation but also partake in restoring gut homeostasis through diverse pathways involving differential regulation of transcription factors such as nuclear factor-κB and peroxisome proliferator-activated receptor-γ. The role of the intestinal microbiome in modulating inflammation and aiding in selenium-dependent resolution of gut injury is highlighted to provide novel insights into the beneficial effects of selenium in IBD.
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Affiliation(s)
- Avinash K. Kudva
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - Ashley E. Shay
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - K. Sandeep Prabhu
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania
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27
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Le Loupp AG, Bach-Ngohou K, Bettan A, Denis M, Masson D. [Dual role for prostaglandin D2 in intestinal epithelial homeostasis]. Med Sci (Paris) 2015; 31:617-21. [PMID: 26152165 DOI: 10.1051/medsci/20153106014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Prostaglandin D2 (PGD2) and derivatives are lipid mediators involved in the control of the intestinal epithelial barrier homeostasis. Their involvement in the pathophysiology of chronic inflammatory bowel disease (IBD) is still debated. Several results highlight the duality of PGD2 as an anti- or pro-inflammatory mediator. This duality seems to be related to a differential expression of its receptors by intestinal epithelial cells and the surrounding immunocompetent cells. The enteric glial cells from the enteric nervous system (ENS) express the lipocalin-type-prostaglandin D synthase and secrete PGD2 and 15d-PGJ2. The protective role of the ENS in the homeostatic control of the epithelial intestinal barrier and its involvement in the pathogenesis of IBD have already been demonstrated. Thus, these lipid mediators seem to be new actors of the neuro-glio-epithelial unit and could play a crucial role maintaining gut barrier integrity.
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Affiliation(s)
- Anne-Gaelle Le Loupp
- Inserm UMR913, institut des maladies de l'appareil digestif, Université de Nantes, CHU Hôtel-Dieu, 1, place Alexis Ricordeau, 44093 Nantes, France - Laboratoire de Biochimie, institut de biologie, CHU Nantes, 9, quai Moncousu, 44093 Nantes, France
| | - Kalyane Bach-Ngohou
- Inserm UMR913, institut des maladies de l'appareil digestif, Université de Nantes, CHU Hôtel-Dieu, 1, place Alexis Ricordeau, 44093 Nantes, France - Laboratoire de Biochimie, institut de biologie, CHU Nantes, 9, quai Moncousu, 44093 Nantes, France
| | - Armel Bettan
- Inserm UMR913, institut des maladies de l'appareil digestif, Université de Nantes, CHU Hôtel-Dieu, 1, place Alexis Ricordeau, 44093 Nantes, France
| | - Marc Denis
- Inserm UMR913, institut des maladies de l'appareil digestif, Université de Nantes, CHU Hôtel-Dieu, 1, place Alexis Ricordeau, 44093 Nantes, France - Laboratoire de Biochimie, institut de biologie, CHU Nantes, 9, quai Moncousu, 44093 Nantes, France
| | - Damien Masson
- Inserm UMR913, institut des maladies de l'appareil digestif, Université de Nantes, CHU Hôtel-Dieu, 1, place Alexis Ricordeau, 44093 Nantes, France - Laboratoire de Biochimie, institut de biologie, CHU Nantes, 9, quai Moncousu, 44093 Nantes, France
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28
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Dai L, King DW, Perera DS, Lubowski DZ, Burcher E, Liu L. Inverse expression of prostaglandin E2-related enzymes highlights differences between diverticulitis and inflammatory bowel disease. Dig Dis Sci 2015; 60:1236-46. [PMID: 25666316 DOI: 10.1007/s10620-014-3478-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 11/30/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND Prostaglandin E2 (PGE2) is the dominant prostaglandin in the colon and is associated with colonic inflammation. PGE2 levels are regulated not only by cyclooxygenases (COX-1 and COX-2) but also by 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the major PGE2-degrading enzyme. Information about the involvement of 15-PGDH in colonic inflammation is sparse. AIM We thus aimed to determine the gene expression and immunoreactivity (IR) of COX-1, COX-2, and 15-PGDH in colonic mucosa from patients with diverse inflammatory disorders: ulcerative colitis (UC), Crohn's disease (CD), and acute diverticular disease (DD). METHODS RNA from human colonic mucosa was extracted and assessed for gene expression by real-time PCR. Intact colon sections were processed for immunohistochemistry with immunostaining of the mucosal areas quantified using ImageJ. RESULTS In colonic mucosa of both UC and CD, COX-2 mRNA and COX-2-IR were significantly increased, whereas 15-PGDH mRNA and 15-PGDH-IR were significantly reduced. In macroscopically undamaged acute DD mucosa, the opposite findings were seen: for both gene expression and immunoreactivity, there was a significant downregulation of COX-2 and upregulation of 15-PGDH. COX-1 mRNA and COX-1-IR remained unchanged in all diseases. CONCLUSIONS Our study for the first time demonstrated differential expression of the PGE2-related enzymes COX-2 and 15-PGDH in colonic mucosa from UC, CD, and acute DD. The reduction of 15-PGDH in IBD provides an additional mechanism for PGE2 increase in IBD. With respect to DD, alterations of PGE2-related enzymes suggest that a low PGE2 level may precede the onset of inflammation, thus providing new insight into the pathogenesis of DD.
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Affiliation(s)
- Liying Dai
- Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia
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Schulz K, Sommer O, Jargon D, Utzolino S, Clement HW, Strate T, von Dobschuetz E. Cytokine and radical inhibition in septic intestinal barrier failure. J Surg Res 2014; 193:831-40. [PMID: 25277359 DOI: 10.1016/j.jss.2014.08.056] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 08/27/2014] [Accepted: 08/28/2014] [Indexed: 11/29/2022]
Abstract
BACKGROUND Breakdown of the intestinal barrier is a driving force of sepsis and multiple organ failure. Radical scavengers or cytokine inhibitors may have a therapeutic impact on intestinal failure. Therapeutic effects on different sites of small intestine and colon have not been compared. Therefore, we investigated time-dependent intestinal permeability changes and their therapeutic inhibition in colon and small intestine with an ex vivo model. METHODS Male Sprague-Dawley rats were either pretreated for 24 h with lipopolysaccharide (LPS) intraperitoneally alone or in combination with a radical scavenger (pyruvate or Tempol) or a cytokine inhibitor (parecoxib or vasoactive intestinal peptide). The gastrointestinal permeability was measured by time-dependent fluorescein isothiocyanate inulin diffusion using washed and everted tube-like gut segments. Blood and tissue samples were taken to investigate the development of inflammatory cytokine level (interleukin 6) in the context of cytokine inhibition and reactive oxygen species level via nicotinamide adenine dinucleotide phosphate oxidase activity in radical scavenger groups. RESULTS After LPS treatment, mucosal permeability was enhanced up to 170% in small intestine and colon. In the small intestine the most significant reduction in permeability was found for pyruvate and parecoxib. Treatment with vasoactive intestinal peptide and parecoxib resulted in the most pronounced reduction of permeability in the colon. CONCLUSIONS Our data suggest that cytokine inhibitors and radical scavengers have pronounced effects in LPS-induced disrupted intestinal barrier of the colon and small intestine. Our novel model comparing different anatomic sites and different points in time after the onset of sepsis may contribute to gain new insight into mechanisms and treatment options of sepsis-related gut mucosal breakdown.
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Affiliation(s)
- Konrad Schulz
- Department of General and Visceral Surgery, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
| | - Olaf Sommer
- Department of Child and Adolescent Psychiatry and Psychotherapy, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Dirk Jargon
- Department of General and Visceral Surgery, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Stefan Utzolino
- Department of General and Visceral Surgery, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Hans-Willi Clement
- Department of Child and Adolescent Psychiatry and Psychotherapy, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Tim Strate
- Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek St. Adolf-Stift, Reinbek, Germany
| | - Ernst von Dobschuetz
- Department of General and Visceral Surgery, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek St. Adolf-Stift, Reinbek, Germany
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The universe of arachidonic acid metabolites in inflammatory bowel disease: can we tell the good from the bad? Curr Opin Gastroenterol 2014; 30:347-51. [PMID: 24837228 DOI: 10.1097/mog.0000000000000075] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW This review summarizes recent developments in the role of soluble mediators of inflammation, particularly arachidonic acid metabolites, in inflammatory bowel disease (IBD). RECENT FINDINGS The role of prostaglandin E2 in immune regulation has been better defined. Prostaglandin E2 promotes not only immune tolerance and epithelial homeostasis but also the proinflammatory Th17 pathway. Prostaglandin D2 has been established as promoting the resolution of inflammation in the gastrointestinal mucosa. The 12-lipoxygenase product hepoxilin A3 mediates the migration of neutrophils from the mucosa into the lumen. SUMMARY Recent studies of soluble mediators, especially arachidonic acid metabolites, have defined their proinflammatory and anti-inflammatory roles in IBD.
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Short SS, Wang J, Castle SL, Fernandez GE, Smiley N, Zobel M, Pontarelli EM, Papillon SC, Grishin AV, Ford HR. Low doses of celecoxib attenuate gut barrier failure during experimental peritonitis. J Transl Med 2013; 93:1265-75. [PMID: 24126890 PMCID: PMC3966546 DOI: 10.1038/labinvest.2013.119] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2013] [Revised: 09/13/2013] [Accepted: 09/14/2013] [Indexed: 02/08/2023] Open
Abstract
The intestinal barrier becomes compromised during systemic inflammation, leading to the entry of luminal bacteria into the host and gut origin sepsis. Pathogenesis and treatment of inflammatory gut barrier failure is an important problem in critical care. In this study, we examined the role of cyclooxygenase-2 (COX-2), a key enzyme in the production of inflammatory prostanoids, in gut barrier failure during experimental peritonitis in mice. I.p. injection of LPS or cecal ligation and puncture (CLP) increased the levels of COX-2 and its product prostaglandin E2 (PGE2) in the ileal mucosa, caused pathologic sloughing of the intestinal epithelium, increased passage of FITC-dextran and bacterial translocation across the barrier, and increased internalization of the tight junction (TJ)-associated proteins junction-associated molecule-A and zonula occludens-1. Luminal instillation of PGE2 in an isolated ileal loop increased transepithelial passage of FITC-dextran. Low doses (0.5-1 mg/kg), but not a higher dose (5 mg/kg) of the specific COX-2 inhibitor Celecoxib partially ameliorated the inflammatory gut barrier failure. These results demonstrate that high levels of COX-2-derived PGE2 seen in the mucosa during peritonitis contribute to gut barrier failure, presumably by compromising TJs. Low doses of specific COX-2 inhibitors may blunt this effect while preserving the homeostatic function of COX-2-derived prostanoids. Low doses of COX-2 inhibitors may find use as an adjunct barrier-protecting therapy in critically ill patients.
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Affiliation(s)
- Scott S. Short
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA,Department of Surgery, University of Southern California, Los Angeles, CA
| | - Jin Wang
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA
| | - Shannon L. Castle
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA,Department of Surgery, University of Southern California, Los Angeles, CA
| | | | - Nancy Smiley
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA
| | - Michael Zobel
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA
| | - Elizabeth M. Pontarelli
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA,Department of Surgery, University of Southern California, Los Angeles, CA
| | - Stephanie C. Papillon
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA,Department of Surgery, University of Southern California, Los Angeles, CA
| | - Anatoly V. Grishin
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA,Department of Surgery, University of Southern California, Los Angeles, CA
| | - Henri R. Ford
- Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA,Department of Surgery, University of Southern California, Los Angeles, CA
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Mucosal loss with increased expression of IL-6, IL-8, and COX-2 in a formula-feeding only neonatal rat model of necrotizing enterocolitis. J Pediatr Surg 2013; 48:2301-7. [PMID: 24210203 DOI: 10.1016/j.jpedsurg.2013.04.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 04/08/2013] [Accepted: 04/14/2013] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The aim of our study is to establish a reliable neonatal rat model by formula feeding only for evaluation of early surgical intervention on the course of experimental necrotizing enterocolitis (NEC). MATERIAL AND METHODS Newborn Sprague-Dawley rats were divided into 50 breast-fed (group 1) and 38 formula fed (Similac/Esbilac, group 2) animals. The pups were sacrificed on the 4th, 5th, and 6th day of life and the terminal intestine examined for macroscopic and histologic changes as well as cytokine expression. RESULTS The histological mucosal damage was significantly higher of group 2 compared to group 1. The area of the vital mucosa of group 2 was significantly (58.57%, p<0.001) lower compared to group 1 (75.12%). The mRNA expression of the inflammatory cytokines IL-6, IL-8 and COX-2 was significantly 2-, 5- and 10-fold increased in group 2 compared to group 1. DISCUSSION Formula fed newborn rats displayed an inflammatory enterocolitis similar to human NEC. Our study demonstrates a significant loss of mucosa in animals with NEC having increased expression levels of IL-6, IL-8 and COX-2. Mucosal loss appears to be a distinct feature of experimental NEC and has to be correlated with the human disease.
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Masoodi M, Pearl DS, Eiden M, Shute JK, Brown JF, Calder PC, Trebble TM. Altered colonic mucosal Polyunsaturated Fatty Acid (PUFA) derived lipid mediators in ulcerative colitis: new insight into relationship with disease activity and pathophysiology. PLoS One 2013; 8:e76532. [PMID: 24204637 PMCID: PMC3799829 DOI: 10.1371/journal.pone.0076532] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 08/31/2013] [Indexed: 01/08/2023] Open
Abstract
Objectives Ulcerative colitis (UC) is a relapsing inflammatory disorder of unconfirmed aetiology, variable severity and clinical course, characterised by progressive histological inflammation and with elevation of eicosanoids which have a known pathophysiological role in inflammation. Therapeutic interventions targetting eicosanoids (5-aminosalicylates (ASA)) are effective first line and adjunctive treatments in mild-moderate UC for achieving and sustaining clinical remission. However, the variable clinical response to 5-ASA and frequent deterioration in response to cyclo-oxygenase (COX) inhibitors, has prompted an in depth simultaneous evaluation of multiple lipid mediators (including eicosanoids) within the inflammatory milieu in UC. We hypothesised that severity of inflammation is associated with alteration of lipid mediators, in relapsing UC. Design Study was case-control design. Mucosal lipid mediators were determined by LC-MS/MS lipidomics analysis on mucosal biopsies taken from patients attending outpatients with relapsing UC. Univariate and multivariate statistical analyses were used to investigate the association of mucosal lipid mediators, with the disease state and severity graded histologically. Results Levels of PGE2, PGD2, TXB2, 5-HETE, 11-HETE, 12-HETE and 15-HETE are significantly elevated in inflamed mucosa and correlate with severity of inflammation, determined using validated histological scoring systems. Conclusions Our approach of capturing inflammatory mediator signature at different stages of UC by combining comprehensive lipidomics analysis and computational modelling could be used to classify and predict mild-moderate inflammation; however, predictive index is diminished in severe inflammation. This new technical approach could be developed to tailor drug treatments to patients with active UC, based on the mucosal lipid mediator profile.
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Affiliation(s)
- Mojgan Masoodi
- Nestlé Institute of Health Sciences, Lausanne, Switzerland
- Medical Research Council, Cambridge, Cambridgeshire, United Kingdom
- Department of Nutritional Sciences, University of Toronto, Ontario, Canada
- * E-mail: (MM); (DSP)
| | - Daniel S. Pearl
- Department of Gastroenterology, Portsmouth Hospital NHS Trust, Portsmouth, Hampshire, United Kingdom
- Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, Hampshire, United Kingdom
- Department of Gastroenterology, Taunton and Somerset NHS Foundation Trust, Taunton, Somerset, United Kingdom
- * E-mail: (MM); (DSP)
| | - Michael Eiden
- Medical Research Council, Cambridge, Cambridgeshire, United Kingdom
| | - Janis K. Shute
- Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, Hampshire, United Kingdom
| | - James F. Brown
- Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, Hampshire, United Kingdom
| | - Philip C. Calder
- Human Development and Health Academic Unit, University of Southampton, Southampton, United Kingdom
- NIHR Biomedical Research Centre in Nutrition, University Hospitals Southampton NHS Foundation Trust and University of Southampton, Southampton, United Kingdom
| | - Timothy M. Trebble
- Department of Gastroenterology, Portsmouth Hospital NHS Trust, Portsmouth, Hampshire, United Kingdom
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Shiina T, Gurung YB, Suzuki Y, Takewaki T, Shimizu Y. Alteration of neuromuscular transmissions in the hamster colon following the resolution of TNBS-induced colitis. J Physiol Sci 2013; 63:241-9. [PMID: 23568479 PMCID: PMC10717828 DOI: 10.1007/s12576-013-0256-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 01/28/2013] [Indexed: 11/27/2022]
Abstract
The aim of this study was to determine whether trinitrobenzene sulfonic acid-induced colitis leads to alterations in enteric neuronal transmission in hamsters. We assessed the mechanical responses induced by the application of electrical field stimulation (EFS) in isolated segments of the distal colon. The EFS-induced relaxation and contraction were blocked by a nitric oxide synthase inhibitor and by the combination of antagonists for tachykinin NK1 and NK2 receptors and muscarinic acetylcholine receptors, respectively. The mechanical responses to EFS were attenuated in the inflamed colon at 7 days and were recovered by 30 days after inflammation treatment. In addition, we found that purinergic and opioidergic excitatory neural components are expressed following the resolution of colitis. These results suggest that colonic inflammation causes indiscriminate damage to enteric neurons but that neuronal components are restored and that new excitatory neural components, compensating for the contractile responses in smooth muscle after colitis, are expressed.
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Affiliation(s)
- Takahiko Shiina
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Yanagido 1-1, Gifu, 501-1193 Japan
| | - Yam B. Gurung
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Yanagido 1-1, Gifu, 501-1193 Japan
| | - Yuji Suzuki
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Yanagido 1-1, Gifu, 501-1193 Japan
| | - Tadashi Takewaki
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Yanagido 1-1, Gifu, 501-1193 Japan
| | - Yasutake Shimizu
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Yanagido 1-1, Gifu, 501-1193 Japan
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Giner E, Recio MC, Ríos JL, Giner RM. Oleuropein protects against dextran sodium sulfate-induced chronic colitis in mice. JOURNAL OF NATURAL PRODUCTS 2013; 76:1113-1120. [PMID: 23758110 DOI: 10.1021/np400175b] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
The anti-inflammatory effect of oleuropein (1), the major phenolic secoiridoid in Olea europaea, was evaluated in an experimental model of chronic colitis in mice. Animals were exposed to four repeated cycles of dextran sodium sulfate in drinking water followed by a 7-day rest period. Animals receiving a standard diet supplemented with 0.25% of 1 (equivalent to 500 mg/kg/day) for 56 days exhibited a decrease of inflammatory symptoms, as reflected by improvement of disease activity index and histopathological changes. It was found that 1 decreased inflammatory cell recruitment and the release of inflammatory cytokines interleukin (IL)-1β and IL-6 with increased IL-10 levels in colon tissue. Colon expression of cyclooxygenase-2 and inducible nitric oxide synthase was reduced significantly by 1. The anti-inflammatory molecular mechanism of 1 was associated with the suppression of the phosphorylation of p38 mitogen-activated protein kinase and might be mediated by up-regulation of annexin A1. In addition, 1 ameliorated intestinal wound healing in IEC-18 monolayers. Therefore, oleuropein seems to be a promising active molecule in experimental ulcerative colitis.
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Affiliation(s)
- Elisa Giner
- Departament de Farmacologia, Facultat de Farmàcia, Universitat de València , Burjassot, Spain
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Yang Y, Tang LQ, Wei W. Prostanoids receptors signaling in different diseases/cancers progression. J Recept Signal Transduct Res 2013; 33:14-27. [DOI: 10.3109/10799893.2012.752003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Bento AF, Leite DFP, Marcon R, Claudino RF, Dutra RC, Cola M, Martini AC, Calixto JB. Evaluation of chemical mediators and cellular response during acute and chronic gut inflammatory response induced by dextran sodium sulfate in mice. Biochem Pharmacol 2012; 84:1459-69. [PMID: 23000912 DOI: 10.1016/j.bcp.2012.09.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 09/11/2012] [Accepted: 09/13/2012] [Indexed: 01/05/2023]
Abstract
Inflammatory bowel disease (IBD) affects millions of people worldwide but its pathophysiology remains unclear. Therefore, experimental models of colitis have contributed crucially for the understanding of IBD, and also in the investigations for effective therapies. Herein we investigated the kinetics of inflammatory mediator production and cell infiltration during acute and chronic dextran sodium sulfate (DSS)-induced colitis. The induction phases with DSS were characterized by severe disease activity with massive colonic polymorphonuclear infiltration and increased levels of tumor necrosis factor-α (TNF-α), keratinocyte-derived chemokine (CXCL1/KC), interleukin (IL)-17 and vascular adhesion molecule-1 (VCAM-1). Interestingly, in the recovery periods, we found marked increase of anti-inflammatory mediators IL-10, IL-4, transforming growth factor-β (TGF-β) and cyclooxygenase 2 (COX-2) that seems be essential for the resolution of intestinal inflammation. Furthermore, nuclear factor κB (NFκB) and regulatory T cell marker forkhead box P3 (FoxP3) were increased gradually during experimental colitis, demonstrating a discrepant profile response and evident immune disbalance in the chronic phase of intestinal mucosal inflammation. Taken together, these results provide valuable information for studies on DSS-induced colitis and especially for the identification of biomarkers that predict disease course and possible therapeutic interventions.
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Affiliation(s)
- Allisson Freire Bento
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil
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Wallace JL, Ferraz JGP, Muscara MN. Hydrogen sulfide: an endogenous mediator of resolution of inflammation and injury. Antioxid Redox Signal 2012; 17:58-67. [PMID: 22017247 PMCID: PMC3342563 DOI: 10.1089/ars.2011.4351] [Citation(s) in RCA: 168] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
SIGNIFICANCE Hydrogen sulfide is emerging as an important mediator of many aspects of inflammation, and perhaps most importantly as a factor promoting the resolution of inflammation and repair of injury. RECENT ADVANCES In the gastrointestinal tract, H(2)S has been shown to promote healing of ulcers and the resolution of mucosal inflammation. On the other hand, suppression of endogenous H(2)S synthesis impairs mucosal defense and leads to increased granulocyte infiltration. H(2)S has been exploited in the design of more effective and safe anti-inflammatory drugs. CRITICAL ISSUES Enteric bacteria can be a significant source of H(2)S, which could affect mucosal integrity; indeed, luminal H(2)S can serve as an alternative to oxygen as a metabolic substrate for mitochondrial respiration in epithelial cells. Enterocytes and colonocytes thereby represent a "metabolic barrier" to the diffusion of bacteria-derived H(2)S into the subepithelial space. A compromise of this barrier could result in modulation of mucosal function and integrity by bacterial H(2)S. FUTURE DIRECTIONS Improvements in methods for measurement of H(2)S and development of more selective inhibitors are crucial for gaining a better understanding of the pathophysiological importance of this mediator. Results from animal studies suggest that H(2)S-releasing agents are promising therapeutic agents for many indications, but these compounds need to be assessed in a clinical setting.
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Affiliation(s)
- John L Wallace
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
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Keely S, Kelly CJ, Weissmueller T, Burgess A, Wagner BD, Robertson CE, Harris JK, Colgan SP. Activated fluid transport regulates bacterial-epithelial interactions and significantly shifts the murine colonic microbiome. Gut Microbes 2012; 3:250-60. [PMID: 22614705 PMCID: PMC3427217 DOI: 10.4161/gmic.20529] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Within the intestinal mucosa, epithelial cells serve multiple functions to partition the lumen from the lamina propria. As part of their natural function, intestinal epithelial cells actively transport electrolytes with passive water movement as a mechanism for mucosal hydration. Here, we hypothesized that electrogenic Cl(-) secretion, and associated mucosal hydration, influences bacterial-epithelial interactions and significantly influences the composition of the intestinal microbiota. An initial screen of different epithelial secretagogues identified lubiprostone as the most potent agonist for which to define these principles. In in vitro studies using cultured T84 cells, lubiprostone decreased E. coli translocation in a concentration-dependent manner (p < 0.001) and decreased S. typhimurium internalization and translocation by as much as 71 ± 6% (p < 0.01). Such decreases in bacterial translocation were abolished by inhibition of electrogenic Cl(-) secretion and water transport using the Na/K/Cl(-) antagonist bumetanide (p < 0.01). Extensions of these findings to microbiome analysis in vivo revealed that lubiprostone delivered orally to mice fundamentally shifted the intestinal microbiota, with notable changes within the Firmicutes and Bacteroidetes phyla of resident colonic bacteria. Such findings document a previously unappreciated role for epithelial Cl(-) secretion and water transport in influencing bacterial-epithelial interactions and suggest that active mucosal hydration functions as a primitive innate epithelial defense mechanism.
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Affiliation(s)
- Simon Keely
- Mucosal Inflammation Program; Department of Medicine; University of Colorado School of Medicine; Aurora, CO USA,School of Biomedical Sciences and Pharmacy; University of Newcastle; New Castle, Australia
| | - Caleb J. Kelly
- Mucosal Inflammation Program; Department of Medicine; University of Colorado School of Medicine; Aurora, CO USA
| | - Thomas Weissmueller
- Mucosal Inflammation Program; Department of Medicine; University of Colorado School of Medicine; Aurora, CO USA,Department of Anesthesiology and Perioperative Pain; Brigham and Women’s Hospital and Harvard Medical School; Boston, MA USA
| | - Adrianne Burgess
- Mucosal Inflammation Program; Department of Medicine; University of Colorado School of Medicine; Aurora, CO USA
| | - Brandie D. Wagner
- Department of Biostatistics and Informatics; Colorado School of Public Health; University of Colorado Denver; Aurora, CO USA
| | - Charles E. Robertson
- Department of Molecular; Cellular and Developmental Biology; University of Colorado; Boulder, CO USA
| | - J. Kirk Harris
- Department of Pediatrics, Pulmonary Medicine; Children’s Hospital Colorado; Aurora, CO USA
| | - Sean P. Colgan
- Mucosal Inflammation Program; Department of Medicine; University of Colorado School of Medicine; Aurora, CO USA,Correspondence to: Sean P. Colgan,
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Therapeutic effect of antisecretory factor-rich egg yolk on the late phases of 2,4,6-trinitrobenzenesulphonic acid colitis in mice. Br J Nutr 2011; 106:1522-8. [PMID: 21733301 DOI: 10.1017/s0007114511002042] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Antisecretory factor (AF) is expressed in all tissues of mammals, inhibits intestinal hypersecretion and has anti-inflammatory properties as well. Endogenous AF synthesis may be stimulated by feeding hydrothermally processed cereals. Alternatively, freeze-dried egg yolk can be used as a source of exogenous AF. Several reports have suggested that AF from freeze-dried egg yolk may be useful in inflammatory bowel disease. We assessed the effect of freeze-dried, AF-rich egg yolk intake on 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis. Balb/c mice were randomised to receive (1) AF in sterile drinking-water (4 g/l, n 38) and (2) sterile drinking-water alone (vehicle, n 38) from TNBS or saline administration onwards. Different subsets of mice were killed at weeks 1-3 after TNBS or saline administration. Macroscopic and microscopic damage was assessed in colonic specimens. Eicosanoid and cytokine production was evaluated in supernatants of 24 h-incubated colonic explants. Myeloperoxidase activity was measured in frozen colonic samples, while apoptosis was assessed in paraffined samples by the in situ oligoligation method. AF-treated mice showed a milder colonic damage compared with the vehicle group, which became statistically significant at week 3. This was accompanied by decreased IL-2, IL-1 and leukotriene B4 production at weeks 2 and 3, as well as increased interferon-γ at week 1, in AF-treated mice compared with vehicle-treated mice. AF-treated mice had significantly increased counts of apoptotic cells in the lamina propria at weeks 1 and 2 post-TNBS. In conclusion, the administration of AF-rich egg yolk has a therapeutic effect in the late phases of TNBS colitis in Balb/c mice.
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Systematic review of animal models of post-infectious/post-inflammatory irritable bowel syndrome. J Gastroenterol 2011; 46:164-74. [PMID: 20848144 DOI: 10.1007/s00535-010-0321-6] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2010] [Accepted: 08/19/2010] [Indexed: 02/07/2023]
Abstract
AIMS Post-infectious irritable bowel syndrome (PI-IBS) is a subset of IBS which occurs after an episode of acute gastrointestinal infections. The mechanisms of PI-IBS are not fully understood. Currently, numerous animal models have been used in the study of PI-IBS. This article reviews the strengths and weaknesses of these models. METHODS All relevant articles were identified by searching in Ovid SP from 1962, the year the term PI-IBS was coined, up to December 31, 2009. The types of model were categorized as either post-infectious or post-inflammatory, and the characteristics of each kind of model were listed. RESULTS Based on our literature search, 268 articles were identified. Of those articles, 50 were included in this review. The existing PI-IBS models include infection with bacteria (e.g., Campylobacter jejuni, Salmonella enterica, and Campylobacter rodentium), and infection with parasites (e.g., Trichinella spiralis, Nippostrongylus brasiliensis, and Cryptosporidium parvum). The post-inflammatory IBS models are commonly induced with chemical agents, such as acetic acid, deoxycholic acid, dextran sulfate sodium, mustard oil, zymosan, and trinitrobenzene sulfonic acid (TNBS). TNBS is the most commonly used agent for post-inflammatory IBS models, but the experimental protocol varies. These models have one or more aspects similar to IBS patients. CONCLUSIONS Different methods have been used for the development of post-infectious or post-inflammatory IBS models. Each model has its weaknesses and strengths. More studies are needed to establish post-infection IBS models using more common pathogens. A standard protocol in developing TNBS-induced post-inflammatory IBS model is needed.
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López-Posadas R, Ballester I, Mascaraque C, Suárez MD, Zarzuelo A, Martínez-Augustin O, Sánchez de Medina F. Flavonoids exert distinct modulatory actions on cyclooxygenase 2 and NF-kappaB in an intestinal epithelial cell line (IEC18). Br J Pharmacol 2010; 160:1714-26. [PMID: 20649574 DOI: 10.1111/j.1476-5381.2010.00827.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Cyclooxygenase 2 (COX-2) is involved in inflammatory bowel disease, but the effect of flavonoids at the intestinal epithelial level is unknown. We aimed to characterize the effect and structure-activity relationship of nine selected flavonoids on COX-2 expression in intestinal epithelial cell (IEC)18 cells. We also investigated the signal transduction pathway(s) responsible for the effects observed. EXPERIMENTAL APPROACH Intestinal epithelial cell 18, a non-tumour cell line with intestinal epithelial phenotype, was used. COX-2 was measured by Western blot and the involvement of the NF-kappaB pathway assessed by Western blot, pharmacological inhibition, luciferase reporter assays and nuclear translocation experiments. KEY RESULTS The effect of flavonoids on COX-2 expression depended on the experimental conditions tested [non-stimulated and lipopolysaccharide (LPS)-stimulated]. Flavonoids caused an increase in COX-2 expression and NF-kappaB-dependent gene transcription under basal conditions. Conversely, under LPS stimulation flavonoids increased, decreased or did not affect COX-2 levels depending on the specific type. Variable effects were observed on extracellular signal regulated kinase/p38/c-Jun N-terminal kinase phosphorylation and p50/65 nuclear translocation. CONCLUSION AND IMPLICATIONS The effect of flavonoids on COX-2 expression depended on the balance of the interference with IkappaB-alpha phosphorylation and other signalling targets, and therefore depends on the experimental conditions and on the type of flavonoids. This is expected to result in different effects in inflammatory conditions. In general, flavonoids may limit epithelial COX-2 expression in inflammatory conditions while favouring it when inflammation is not present.
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Affiliation(s)
- R López-Posadas
- Department of Pharmacology, School of Pharmacy, University of Granada, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Granada, Spain
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Hassan A, Ibrahim A, Mbodji K, Coëffier M, Ziegler F, Bounoure F, Chardigny JM, Skiba M, Savoye G, Déchelotte P, Marion-Letellier R. An α-linolenic acid-rich formula reduces oxidative stress and inflammation by regulating NF-κB in rats with TNBS-induced colitis. J Nutr 2010; 140:1714-21. [PMID: 20724486 DOI: 10.3945/jn.109.119768] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
We have previously shown that α-linolenic acid (ALA), a (n-3) PUFA exerts in vitro antiinflammatory effects in the intestine. In this study, we aimed to evaluate its effect on inflammatory and oxidative stress in a colitis model. Colitis was induced in 2 groups at d 0 by intrarectal injection of 2-4-6-trinitrobenzen sulfonic acid (TNBS), whereas the control group received the vehicle. Rats we fed 450 mg . kg(-1) . d(-1) of ALA (TNBS+ALA) while the other colitic group (TNBS) and the control group were fed an isocaloric corn oil formula for 14 d (from d -7 to d 7). RBC fatty acid composition was assessed. Oxidative stress was studied by measuring urinary 8-isoprostanes (8-IP) and colon glutathione (GSH) concentration and inducible nitric oxide synthase (iNOS) expression. Colitis was assessed histologically, by production of proinflammatory mediators, including cytokines, leukotrienes B(4) (LTB(4)), and cyclooxygenase-2 (COX-2) and by nuclear factor-κB (NF-κB) activation. The ALA-rich diet significantly increased the RBC levels of ALA, eicosapentaenoic acid, and docosapentaenoic acid (n-3) compared with the TNBS group (P < 0.01 for all). The beneficial effect of ALA supplementation on oxidative stress was reflected by lower urinary 8-IP levels (P < 0.05), a normalized colon GSH concentration (P < 0.01), and reduced colon iNOS expression (P < 0.05) compared with the TNBS group. ALA also protected against colon inflammation as assessed by lower tumor necrosis factor-α secretion and mRNA level (P < 0.05), reduced NF-κB activation (P = 0.01), and lower colon lipid mediator concentrations such as LTB(4) and COX-2 (P < 0.05) compared with the TNBS group. These findings show that an ALA-rich formula is beneficial to TNBS-induced colitic rats via inhibition of oxidative and inflammatory stress.
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Affiliation(s)
- Aktham Hassan
- Appareil Digestif Environnement Nutrition, Medicine University, I.F.R. 23, Institute of biomedical research, 22, 76183 Rouen cedex, France
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Abstract
BACKGROUND The ability to control uptake across the mucosa and protect from damage of harmful substances from the lumen is defined as intestinal barrier function. A disturbed barrier dysfunction has been described in many human diseases and animal models, for example, inflammatory bowel disease, irritable bowel syndrome, and intestinal hypersensitivity. In most diseases and models, alterations are seen both of the paracellular pathway, via the tight junctions, and of the transcellular routes, via different types of endocytosis. Recent studies of pathogenic mechanisms have demonstrated the important role of neuroimmune interaction with the epithelial cells in the regulation of barrier function. Neural impulses from extrinsic vagal and/or sympathetic efferent fibers or intrinsic enteric nerves influence mucosal barrier function via direct effects on epithelial cells or via interaction with immune cells. For example, by nerve-mediated activation by corticotropin-releasing hormone or cholinergic pathways, mucosal mast cells release a range of mediators with effects on transcellular, and/or paracellular permeability (for example, tryptase, TNF-alpha, nerve growth factor, and interleukins). PURPOSE In this review, we discuss current physiological and pathophysiological aspects of the intestinal barrier and, in particular, its regulation by neuroimmune factors.
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Affiliation(s)
- A V Keita
- Department of Clinical and Experimental Medicine, Division of Surgery and Clinical Oncology, Faculty of Health Science, University Hospital, Linköping, Sweden
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A pro-resolution mediator, prostaglandin D(2), is specifically up-regulated in individuals in long-term remission from ulcerative colitis. Proc Natl Acad Sci U S A 2010; 107:12023-7. [PMID: 20547854 DOI: 10.1073/pnas.1004982107] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Patients with ulcerative colitis (UC) experience unpredictable bouts of active inflammation and ulceration. Relatively little attention has been paid to the role of antiinflammatory mediators in the pathogenesis of UC, although rodent studies suggest an important role of prostaglandin (PG) D(2) in the resolution of tissue injury and inflammation. The present study was performed to determine if colonic PGD(2) synthesis was altered in patients in remission from UC and if expression of the key enzymes and receptors related to PGD(2) was altered. During routine colon-cancer screening, colonic biopsies were obtained from healthy individuals, some of whom had been in remission from UC, without treatment, for >4 y. UC patients with active disease or in medically induced remission were also biopsied. Only patients with active UC exhibited elevated expression of several proinflammatory cytokines (TNFalpha and IFNgamma) and colonic PGE(2) synthesis. In contrast, colonic PGD(2) synthesis was only elevated ( approximately 3-fold) in the healthy individuals with a prior history of UC. This group also exhibited significantly elevated expression of DP1, the key receptor mediating the antiinflammatory actions of PGD(2). Expression of the synthetic enzymes cyclooxygenase-1, cyclooxygenase-2, and hematopoietic PGD synthase was not altered in the healthy individuals with a prior history of UC. These results show a marked up-regulation of synthesis of an antiinflammatory prostanoid and expression of its receptor, specifically in individuals in long-term remission from UC. This is consistent with animal studies showing the importance of PGD(2) in the induction and maintenance of remission from colitis.
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Cattaruzza F, Spreadbury I, Miranda-Morales M, Grady EF, Vanner S, Bunnett NW. Transient receptor potential ankyrin-1 has a major role in mediating visceral pain in mice. Am J Physiol Gastrointest Liver Physiol 2010; 298:G81-91. [PMID: 19875705 PMCID: PMC2806099 DOI: 10.1152/ajpgi.00221.2009] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The excitatory ion channel transient receptor potential ankyrin-1 (TRPA1) is prominently expressed by primary afferent neurons and is a mediator of inflammatory pain. Inflammatory agents can directly activate [e.g., hydroxynonenal (HNE), prostaglandin metabolites] or indirectly sensitize [e.g., agonists of protease-activated receptor (PAR(2))] TRPA1 to induce somatic pain and hyperalgesia. However, the contribution of TRPA1 to visceral pain is unknown. We investigated the role of TRPA1 in visceral hyperalgesia by measuring abdominal visceromotor responses (VMR) to colorectal distention (CRD) after intracolonic administration of TRPA1 agonists [mustard oil (MO), HNE], sensitizing agents [PAR(2) activating peptide (PAR(2)-AP)], and the inflammatory agent trinitrobenzene sulfonic acid (TNBS) in trpa1(+/+) and trpa1(-/-) mice. Sensory neurons innervating the colon, identified by retrograde tracing, coexpressed immunoreactive TRPA1, calcitonin gene-related peptide, and substance P, expressed TRPA1 mRNA and responded to MO with depolarizing currents. Intracolonic MO and HNE increased VMR to CRD and induced immunoreactive c-fos in spinal neurons in trpa1+/+ but not in trpa1(-/-) mice. Intracolonic PAR(2)-AP induced mechanical hyperalgesia in trpa1+/+ but not in trpa1(-/-) mice. TNBS-induced colitis increased in VMR to CRD and induced c-fos in spinal neurons in trpa1(+/+) but not in trpa1(-/-) mice. Thus TRPA1 is expressed by colonic primary afferent neurons. Direct activation of TRPA1 causes visceral hyperalgesia, and TRPA1 mediates PAR(2)-induced hyperalgesia. TRPA1 deletion markedly reduces colitis-induced mechanical hyperalgesia in the colon. Our results suggest that TRPA1 has a major role in visceral nociception and may be a therapeutic target for colonic inflammatory pain.
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Affiliation(s)
| | - Ian Spreadbury
- 3Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario, Canada
| | - Marcela Miranda-Morales
- 3Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario, Canada
| | | | - Stephen Vanner
- 3Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario, Canada
| | - Nigel W. Bunnett
- Departments of 1 Surgery and ,2Physiology, University of California, San Francisco, California;
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Resta-Lenert SC, Barrett KE. Modulation of intestinal barrier properties by probiotics: role in reversing colitis. Ann N Y Acad Sci 2009; 1165:175-82. [PMID: 19538304 DOI: 10.1111/j.1749-6632.2009.04042.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Probiotic bacteria, commensals selected for their presumed therapeutic properties when ingested orally, have attracted increasing attention for their possible efficacy in a range of gastrointestinal disorders, including the inflammatory bowel diseases of Crohn's disease and ulcerative colitis. Since the barrier properties of the intestinal epithelium are believed to be compromised as a consequence (or perhaps as a cause) of intestinal inflammation, we hypothesized that probiotics might ameliorate such epithelial dysfunction as part of their spectrum of beneficial effects. We have used both cell line and animal models to test this hypothesis and show that two probiotics have significant effects on epithelial barrier properties, both at baseline and when deranged by inflammatory cytokines or in the setting of inflammation in a mouse model of colitis. Moreover, the probiotics also normalize epithelial ion transport function, which could also contribute to clinical efficacy. Overall, our studies extend the spectrum of functional effects attributable to probiotics, and may provide a rationale for their use in a range of gastrointestinal disorders associated with epithelial dysfunction.
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Affiliation(s)
- Silvia C Resta-Lenert
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0003, USA
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Hons IM, Burda JE, Grider JR, Mawe GM, Sharkey KA. Alterations to enteric neural signaling underlie secretory abnormalities of the ileum in experimental colitis in the guinea pig. Am J Physiol Gastrointest Liver Physiol 2009; 296:G717-26. [PMID: 19221017 PMCID: PMC2670664 DOI: 10.1152/ajpgi.90472.2008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Inflammatory bowel diseases (IBD) can involve widespread gastrointestinal dysfunction, even in cases in which inflammation is localized to a single site. The underlying pathophysiology of dysfunction in noninflamed regions is unclear. We examined whether colitis is associated with altered electrogenic ion transport in the ileal mucosa and/or changes in the properties of ileal submucosal neurons. Colitis was induced by administration of trinitrobenzene sulfonic acid (TNBS), and the uninflamed ileum from animals was examined 3, 7, and 28 days later. Electrogenic ion transport was assessed in Ussing chambers. Intracellular microelectrode recordings were used to examine the neurophysiology of the submucosal plexus of the ileum in animals with colitis. Noncholinergic secretion was reduced by 33% in the ileum from animals 7 days after the induction of colitis. The epithelial response to vasoactive intestinal peptide (VIP) was unaltered in animals with colitis, but the response to carbachol was enhanced. Slow excitatory synaptic transmission was dramatically reduced in VIP-expressing, noncholinergic secretomotor neurons. This change was detected as early as 3 days following TNBS treatment. No changes to fast synaptic transmission or the number of VIP neurons were observed. In addition, cholinergic secretomotor neurons fired more action potentials during a given stimulus, and intrinsic primary afferent neurons had broader action potentials in animals with colitis. These findings implicate changes to enteric neural circuits as contributing factors in inflammation-induced secretory dysfunction at sites proximal to a localized inflammatory insult.
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Affiliation(s)
- Ian M. Hons
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
| | - Joshua E. Burda
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
| | - John R. Grider
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
| | - Gary M. Mawe
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
| | - Keith A. Sharkey
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
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Martínez-Augustin O, Romero-Calvo I, Suárez MD, Zarzuelo A, de Medina FS. Molecular bases of impaired water and ion movements in inflammatory bowel diseases. Inflamm Bowel Dis 2009; 15:114-27. [PMID: 18626965 DOI: 10.1002/ibd.20579] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The intestine is dedicated to the absorption of water and nutrients. Fine tuning of this process is necessary to maintain an adequate balance and inflammation disrupts the equilibrium. This review summarizes the current evidence in this field. Classical mechanisms proposed include alteration of epithelial integrity, augmented secretion, and reduced absorption. In addition, intestinal inflammation is associated with defects in epithelial barrier function. However, our understanding of the phenomenon has been complicated by the fact that ionic secretion is in fact diminished in vivo, even after inflammation has subsided. Inhibited ionic secretion can be reversed partially or totally in vitro by maneuvers such as blockade of inducible nitric oxide synthase or removal of the submucosal layer. Disturbances in ionic absorption are less well characterized but clearly involve both electroneutral and electrogenic Na(+) absorption. Altered ionic transport is associated with changes in the expression and function of the transporters, including the Na(+)/K(+) ATPase, the sodium/potassium/chloride cotransporter 1 (NKCC1), the sodium/hydrogen exchanger 3 (NHE3), and the epithelial sodium channel (ENaC), as well as to the modulation of intracellular signaling. Further investigation is needed in this area in order to provide an integrated paradigm of ionic transport in the inflamed intestine. In particular, we do not know exactly how diarrhea ensues in inflammation and, consequently, we do not have specific pharmacological tools to combat this condition effectively and without side effects. Moreover, whether transport disturbances are reversible independently of inflammatory control is unknown.
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Affiliation(s)
- Olga Martínez-Augustin
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada, Spain
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McCole DF, Barrett KE. Decoding epithelial signals: critical role for the epidermal growth factor receptor in controlling intestinal transport function. Acta Physiol (Oxf) 2009; 195:149-59. [PMID: 18983445 DOI: 10.1111/j.1748-1716.2008.01929.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The intestinal epithelium engages in bidirectional transport of fluid and electrolytes to subserve the physiological processes of nutrient digestion and absorption, as well as the elimination of wastes, without excessive losses of bodily fluids that would lead to dehydration. The overall processes of intestinal ion transport, which in turn drive the secretion or absorption of water, are accordingly carefully regulated. We and others have identified the epidermal growth factor receptor (EGFr) as a critical regulator of mammalian intestinal ion transport. In this article, we focus on our studies that have uncovered the intricate signalling mechanisms downstream of EGFr that regulate both chloride secretion and sodium absorption by colonocytes. Emphasis will be placed on the EGFr-associated regulatory pathways that dictate the precise outcome to receptor activation in response to signals that may seem, on their face, to be quite similar if not identical. The concepts to be discussed underlie the ability of the intestinal epithelium to utilize a limited set of signalling effectors to produce a variety of outcomes suitable for varying physiological and pathophysiological demands. Our findings therefore are relevant not only to basic biological principles, but also may ultimately point to new therapeutic targets in intestinal diseases where ion transport is abnormal.
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Affiliation(s)
- D F McCole
- Department of Medicine, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, USA
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