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Souza RF, Machado FA, Caetano MAF, De Paulo CB, Castelucci P. Effect of Anti-TNF Monoclonal Antibody on Enteric Neurons and Enteric Glial Cells in Experimental Colitis. Dig Dis Sci 2025; 70:1375-1394. [PMID: 39946069 DOI: 10.1007/s10620-025-08872-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 01/14/2025] [Indexed: 04/06/2025]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) affect both enteric neurons and enteric glia, with tumor necrosis factor-alpha (TNF-α) playing a role as an inflammatory mediator. AIMS Analyze the effects of the anti-TNF monoclonal antibody on the myenteric plexus in an experimental model of colitis. METHODS C57BL/6 mice received 3% dextran sodium sulfate (DSS) in drinking water for 7 days in both the DSS and DSS + ADA groups. The Sham group received water. The DSS + ADA group received ADA anti-TNF-α on day 2 of DSS intake. The ADA group was given water throughout the period and received an anti-TNF-α injection on day 2. The study evaluated the number of neurons per ganglion, and the area of the neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), pan-neuronal marker (PGP9.5), and tumor necrosis factor receptor 2 (TNFR2) immunoreactive (-ir). Double labeling of PGP9.5 with an enteric glial marker (GFAP) was also performed. RESULTS DSS successfully induced experimental colitis (EC). TNFR2 was detected in the myenteric neurons in all groups. EC affected the enteric neurons, showing a decrease in the number of TNFR2-ir, ChAT-ir, nNOS-ir, and PGP9.5-ir neurons, whereas enteric glial cells increased in both the DSS and DSS + ADA groups. The DSS + ADA group showed number of nNOS-ir, ChAT-ir, and PGP9.5-ir neurons per ganglion similar to Sham group. EC also affected the neuronal profile, resulting in smaller areas in the DSS and DSS + ADA groups. CONCLUSION Myenteric neurons are immunoreactive to the TNFR2. DSS altered the myenteric plexus, and anti-TNF monoclonal antibody treatment proved effective against EC due to preventing the pathology from developing.
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Affiliation(s)
- Roberta Figueiroa Souza
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 2415, São Paulo, 05508-000, Brasil
| | - Felipe Alexandre Machado
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 2415, São Paulo, 05508-000, Brasil
| | - Marcos Antônio Ferreira Caetano
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 2415, São Paulo, 05508-000, Brasil
| | - Caroline Bures De Paulo
- Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo, 05508-270, Brazil
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 2415, São Paulo, 05508-000, Brasil.
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Araruna MEC, Alves Júnior EB, de Lima Serafim CA, Pessoa MMB, de Souza Pessôa ML, Alves VP, Sobral MV, da Silva MS, Alves AF, de Paiva Sousa MC, Araújo AA, Batista LM. (-)-Fenchone Ameliorates TNBS-Induced Colitis in Rats via Antioxidant, Immunomodulatory, and Cytoprotective Mechanisms. Pharmaceuticals (Basel) 2024; 18:18. [PMID: 39861081 PMCID: PMC11769309 DOI: 10.3390/ph18010018] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND (-)-Fenchone is a bicyclic monoterpene present in the plant species Foeniculum vulgare Mill, Thuja occidentalis L. (tuja), and Lavandula stoechas (lavender). These plants have therapeutic value in the treatment of intestinal disorders. AIM To evaluate intestinal anti-inflammatory activity in an acute and chronic trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. METHODS Intestinal anti-inflammatory effects were assessed using the acute and chronic TNBS-induced colitis model in rats. The mechanisms were evaluated from colonic tissue fragments of the acute and chronic models. RESULTS Oral administration of the (-)-fenchone (37.5-300 mg/kg) acute phase or (150 mg/kg) (p < 0.001) chronic phase reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. At a dose of 150 mg/kg, the acute and chronic phase decreased malondialdehyde (MDA) and myeloperoxidase (MPO) (p < 0.001), restored glutathione (GSH) levels and superoxide dismutase (SOD) (p < 0.001), decreased immunomarking for factor nuclear kappa B (NF-κB) and levels of interleukin (IL)-1 and tumor necrosis factor α (TNF-α), and maintained IL-10 and TGF-β basal levels. Furthermore, increased immunostaining for zonula occludens 1 (ZO-1) was observed. CONCLUSIONS (-)-fenchone has intestinal anti-inflammatory activity related to cytoprotection of the intestinal barrier, as well as antioxidant and immunomodulatory effects.
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Affiliation(s)
- Maria Elaine Cristina Araruna
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
| | - Edvaldo Balbino Alves Júnior
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
| | - Catarina Alves de Lima Serafim
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
| | - Matheus Marley Bezerra Pessoa
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
| | - Michelle Liz de Souza Pessôa
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
| | - Vitória Pereira Alves
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
| | - Marianna Vieira Sobral
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
| | - Marcelo Sobral da Silva
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
| | - Adriano Francisco Alves
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
- Department of Physiology and Pathology, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil;
| | - Maria Carolina de Paiva Sousa
- Department of Physiology and Pathology, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil;
| | - Aurigena Antunes Araújo
- Department of Morphology, Histology and Basic Pathology, Biosciences Center, Federal University of Rio Grande do Norte (UFRN), Natal CEP 59078-970, RN, Brazil;
| | - Leônia Maria Batista
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa CEP 58051-970, PB, Brazil; (M.E.C.A.); (E.B.A.J.); (C.A.d.L.S.); (M.M.B.P.); (M.L.d.S.P.); (V.P.A.); (M.V.S.); (M.S.d.S.); (A.F.A.)
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Caetano MAF, Magalhães HIR, Duarte JRL, Conceição LB, Castelucci P. Butyrate Protects Myenteric Neurons Loss in Mice Following Experimental Ulcerative Colitis. Cells 2023; 12:1672. [PMID: 37443707 PMCID: PMC10340616 DOI: 10.3390/cells12131672] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/08/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
The enteric nervous system is affected by inflammatory bowel diseases (IBD). Gut microbiota ferments dietary fibers and produces short-chain fatty acids, such as Butyrate, which bind to G protein-coupled receptors, such as GPR41, and contribute to maintaining intestinal health. This work aimed to study the GPR41 in myenteric neurons and analyze the effect of Butyrate in mice submitted to experimental ulcerative colitis. The 2, 4, 6 trinitrobenzene sulfonic acid (TNBS) was injected intrarectally in C57BL/6 mice (Colitis). Sham group received ethanol (vehicle). One group was treated with 100 mg/kg of Sodium Butyrate (Butyrate), and the other groups received saline. Animals were euthanized 7 days after colitis induction. Analyzes demonstrated colocalization of GPR41 with neurons immunoreactive (-ir) to nNOS and ChAT-ir and absence of colocalization of the GPR41 with GFAP-ir glia. Quantitative results demonstrated losses of nNOS-ir, ChAT-ir, and GPR41-ir neurons in the Colitis group and Butyrate treatment attenuated neuronal loss. The number of GFAP-ir glia increased in the Colitis group, whereas Butyrate reduced the number of these cells. In addition, morphological alterations observed in the Colitis group were attenuated in the Butyrate group. The presence of GPR41 in myenteric neurons was identified, and the treatment with Butyrate attenuated the damage caused by experimental ulcerative colitis.
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Affiliation(s)
- Marcos A. F. Caetano
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil; (M.A.F.C.); (J.R.L.D.); (L.B.C.)
| | - Henrique I. R. Magalhães
- Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo 05508-270, Brazil;
| | - Jheniffer R. L. Duarte
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil; (M.A.F.C.); (J.R.L.D.); (L.B.C.)
| | - Laura B. Conceição
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil; (M.A.F.C.); (J.R.L.D.); (L.B.C.)
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil; (M.A.F.C.); (J.R.L.D.); (L.B.C.)
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de Oliveira ECS, Dalmau LM, de Almeida Costa CAR, de Almeida Junior LD, Ballard CR, Maróstica Junior MR, Stahl MA, Grimaldi R, Witaicenis A, Di Stasi LC. Dietary intervention with avocado (Persea americana Mill.) ameliorates intestinal inflammation induced by TNBS in rats. Inflammopharmacology 2023; 31:485-498. [PMID: 36586042 DOI: 10.1007/s10787-022-01128-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 12/15/2022] [Indexed: 01/01/2023]
Abstract
Nutritional interventions have been shown to be an interesting approach for the treatment of chronic diseases, including inflammatory bowel disease (IBD). Persea americana Mill. (avocado), is a potential food to be used for the prevention or treatment of intestinal inflammation, due to its nutritional value and pharmacological effects. In this study we evaluated if the dietary intervention with avocado fruit pulp could as an intestinal anti-inflammatory diet using a trinitrobenzenesulfonic acid (TNBS) model of intestinal inflammation in rats. For this purpose, 5, 10 or 20% of avocado fruit pulp was incorporated in the diet of rats, for 21 days before and 7 days after TNBS-induced intestinal inflammation. Dietary intervention with avocado fruit pulp (20%) decreased the extension of colonic lesions (1.38 ± 0.99 vs. 2.67 ± 0.76 cm), weight/length colon ratio (151.03 ± 31.45 vs. 197.39 ± 49.48 cm), inhibited myeloperoxidase activity (891.2 ± 243.2 vs 1603 ± 158.2 U/g), reduced tumor necrosis factor-α (53.94 ± 6.45 vs. 114.9 ± 6.21 pg/mg), interleukin-1β (583.6 ± 106.2 vs. 1259 ± 81.68 pg/mg) and interferon gamma (27.95 ± 2.97 vs. 47.79 ± 3.51 pg/mg) levels and prevented colonic glutathione depletion (2585 ± 77.2 vs 1778 ± 167.2 nmol/g). The consumption of enriched diet with 20% avocado pulp by 28 days did not promote any alterations in the biochemical or behavioral parameters evaluated. Avocado showed intestinal anti-inflammatory activity, modulating immune response, and acting as antioxidant. The dietary intervention with avocado was safe, suggesting its potential as a complementary treatment in intestinal inflammation.
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Affiliation(s)
- Ellen Cristina Souza de Oliveira
- Laboratory of Phytomedicines, Pharmacology and Biotechnology, Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, SP, CEP 18618-689, Brazil.
| | - Lesvi Moya Dalmau
- Laboratory of Phytomedicines, Pharmacology and Biotechnology, Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, SP, CEP 18618-689, Brazil
| | - Celso Acácio Rodrigues de Almeida Costa
- Laboratory of Phytomedicines, Pharmacology and Biotechnology, Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, SP, CEP 18618-689, Brazil
| | - Luiz Domingues de Almeida Junior
- Laboratory of Phytomedicines, Pharmacology and Biotechnology, Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, SP, CEP 18618-689, Brazil
| | - Cíntia Reis Ballard
- Department of Food Science and Nutrition, School of Food Engineering, University of Campinas-UNICAMP, Campinas, SP, CEP 13083-862, Brazil
| | - Mário Roberto Maróstica Junior
- Department of Food Science and Nutrition, School of Food Engineering, University of Campinas-UNICAMP, Campinas, SP, CEP 13083-862, Brazil
| | - Marcella Aparecida Stahl
- Fats and Oils Laboratory, School of Food Engineering, University of Campinas-UNICAMP, Campinas, SP, CEP 13083-861, Brazil
| | - Renato Grimaldi
- Fats and Oils Laboratory, School of Food Engineering, University of Campinas-UNICAMP, Campinas, SP, CEP 13083-861, Brazil
| | - Aline Witaicenis
- Laboratory of Phytomedicines, Pharmacology and Biotechnology, Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, SP, CEP 18618-689, Brazil
| | - Luiz Claudio Di Stasi
- Laboratory of Phytomedicines, Pharmacology and Biotechnology, Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, SP, CEP 18618-689, Brazil
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Tavares EDA, Guerra GCB, da Costa Melo NM, Dantas-Medeiros R, da Silva ECS, Andrade AWL, de Souza Araújo DF, da Silva VC, Zanatta AC, de Carvalho TG, de Araújo AA, de Araújo-Júnior RF, Zucolotto SM. Toxicity and Anti-Inflammatory Activity of Phenolic-Rich Extract from Nopalea cochenillifera (Cactaceae): A Preclinical Study on the Prevention of Inflammatory Bowel Diseases. PLANTS (BASEL, SWITZERLAND) 2023; 12:594. [PMID: 36771677 PMCID: PMC9921826 DOI: 10.3390/plants12030594] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/04/2023] [Accepted: 01/11/2023] [Indexed: 06/18/2023]
Abstract
Phenolic compounds have been scientifically recognized as beneficial to intestinal health. The cactus Nopalea cochenillifera, used as anti-inflammatory in traditional medicine, is a rich source of these bioactive compounds. The present study aimed to investigate the phytochemical profile of N. cochenillifera extract and evaluate its acute toxicity and anti-inflammatory effect on 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis in rats. The total phenolic content per gram of dry extract was 67.85 mg. Through HPLC-IES-MSn, a total of 25 compounds such as saccharides, organic acids, phenolic acids and flavonoids were characterized. The dose of 2000 mg/kg of extract by an oral route showed no signs of toxicity, mortality or significant changes in biochemical and hematological parameters. Regarding intestinal anti-inflammatory effects, animals were treated with three different doses of extract or sulfasalazine. Macroscopic analysis of the colon indicated that the extract decreased the disease activity index. Levels of IL-1β and TNF-α decreased, IL-10 increased and MDA and MPO enzyme levels decreased when compared with the control group. In addition, a down-regulation of MAPK1/ERK2 and NF-κB p65 pathway markers in colon tissue was observed. The epithelial integrity was improved according to histopathological and immunohistological analysis. Thus, the extract provided strong preclinical evidence of being effective in maintaining the remission of colitis.
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Affiliation(s)
- Emanuella de Aragão Tavares
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Gerlane Coelho Bernardo Guerra
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Graduate Program in Pharmaceutical Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
| | - Nadja Maria da Costa Melo
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Renato Dantas-Medeiros
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | | | - Anderson Wilbur Lopes Andrade
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | | | - Valéria Costa da Silva
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Ana Caroline Zanatta
- Department of Biomolecular Sciences, Faculty of Pharmaceutical Sciences of Ribeirão Preto, São Paulo University, São Paulo, Ribeirão Preto 14040-903, Brazil
| | - Thaís Gomes de Carvalho
- Program Degree in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
| | - Aurigena Antunes de Araújo
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Graduate Program in Pharmaceutical Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
- Program Degree in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
| | - Raimundo Fernandes de Araújo-Júnior
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Program Degree in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
- Cancer and Inflammation Research Laboratory, Morphology Department, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Silvana Maria Zucolotto
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Graduate Program in Pharmaceutical Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
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Li Y, Sheng L, Jena PK, Gilbert MC, Wan YJY, Mao H. Retinoic Acid Signaling Is Compromised in DSS-Induced Dysbiosis. Nutrients 2022; 14:2788. [PMID: 35889745 PMCID: PMC9315703 DOI: 10.3390/nu14142788] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 02/04/2023] Open
Abstract
Obesity and malnutrition both cause dysbiosis and dampen retinoic acid (RA) signaling pathways, which play pivotal roles in biological processes. The current study evaluates a hypothesis that colitis-associated dysbiosis also has systemic negative impacts on RA signaling. Thus, we studied the effects of inflammation, under a vitamin A-sufficient condition, on RA signaling using mouse colitis models induced by dextran sulfate sodium. That data showed that intestinal inflammation resulted in reduced RA signaling in the liver, brain, gut, and adipose tissues measured by analyzing the expression of genes encoding for the synthesis, oxidation, transport, and receptor of RA. The expression of RA-regulated gut homing molecules including α4β7 integrin, and CCR9, along with MADCAM1 were all reduced in colitis mice revealing compromised immunity due to reduced RA signaling. The data also showed that the development of colitis was accompanied by dysbiosis featured with reduced Lactobacillaceae and Verrucomicrobiaceae but an expansion of Erysipelotrichaceae and others. Colitis resulted in reduced butyrate-producing bacteria and increased methane-generating bacteria. Additionally, dysbiosis was associated with induced Il-1β, Ifn-γ, and Tnf-α mRNA but reduced Il-22, Il-17f, and Rorγt transcripts in the colon. Together, intestinal inflammation inhibits RA signaling in multiple organs. RA is essential in regulating various biological processes, it is critical to detect RA signaling reduction in tissues even when vitamin A deficiency is absent. Moreover, probiotics can potentially prevent dysbiosis and reverse compromised RA signaling, having systemic health benefits.
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Affiliation(s)
- Yongchun Li
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China;
- Department of Infectious Diseases, The Six Affiliated Hospital, South China University of Technology, Foshan 528200, China
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA; (L.S.); (P.K.J.); (M.C.G.)
| | - Lili Sheng
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA; (L.S.); (P.K.J.); (M.C.G.)
| | - Prasant Kumar Jena
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA; (L.S.); (P.K.J.); (M.C.G.)
| | - Miranda Claire Gilbert
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA; (L.S.); (P.K.J.); (M.C.G.)
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA; (L.S.); (P.K.J.); (M.C.G.)
| | - Hua Mao
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China;
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Evangelinellis MM, Souza RF, Mendes CE, Castelucci P. Effects of a P2X7 receptor antagonist on myenteric neurons in the distal colon of an experimental rat model of ulcerative colitis. Histochem Cell Biol 2022; 157:65-81. [PMID: 34626216 DOI: 10.1007/s00418-021-02039-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2021] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel diseases (IBDs) are chronic diseases of the gastrointestinal tract that include ulcerative colitis and Crohn's disease and affect enteric neurons. Research has shown that Brilliant Blue G (BBG), a P2X7 receptor antagonist, restores enteric neurons following ischemia and reperfusion. This study aimed to evaluate the effect of BBG on myenteric neurons of the distal colon in an experimental rat model of ulcerative colitis. Colitis was induced by injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the large intestine. BBG was administered 1 h after colitis induction and for five consecutive days thereafter. Distal colons were collected 24 h or 7 days after TNBS injection. The animals were divided into 24-h and 7-day sham (vehicle injection rather than colitis induction), 24-h colitis, 24-h BBG, 7-day colitis and 7-day BBG groups. The disease activity index (DAI), neuronal density and profile of neuronal nitric oxide synthase (nNOS)-, choline acetyltransferase (ChAT)- and P2X7 receptor-immunoreactive enteric neurons were analyzed, and histological analysis was performed. The results showed recovery of the DAI and histological tissue integrity in the BBG groups compared to those in the colitis groups. In addition, the numbers of neurons positive for nNOS, ChAT and the P2X7 receptor per area were decreased in the colitis groups, and these measures were recovered in the BBG groups. Neuronal size was increased in the colitis groups and restored in the BBG groups. In conclusion, BBG is effective in improving experimental ulcerative colitis, and the P2X7 receptor may be a therapeutic target.
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Affiliation(s)
- Mariá Munhoz Evangelinellis
- Department of Surgery, Faculty of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr Orlando Marques de Paiva, 87, São Paulo, CEP 05508-270, Brazil
| | - Roberta Figueiroa Souza
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Dr. Lineu Prestes, 2415, São Paulo, CEP 05508-900, Brazil
| | - Cristina Eusébio Mendes
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Dr. Lineu Prestes, 2415, São Paulo, CEP 05508-900, Brazil
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Dr. Lineu Prestes, 2415, São Paulo, CEP 05508-900, Brazil.
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Amaldoss MJN, Najar IA, Kumar J, Sharma A. Therapeutic efficacy of rifaximin loaded tamarind gum polysaccharide nanoparticles in TNBS induced IBD model Wistar rats. Rep Pract Oncol Radiother 2021; 26:712-729. [PMID: 34760306 DOI: 10.5603/rpor.a2021.0100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/12/2021] [Indexed: 12/25/2022] Open
Abstract
Background Rifaximin is a non-systemic antibiotic used in the treatment of inflammatory bowel disease (IBD). Antibiotics are demonstrating a significant role in the treatment of IBD by altering the dysbiotic colonic microbiota and decreases the immunogenic and inflammatory response in the patient population. Mucoadhesive colon targeted nanoparticles provide the site-specific delivery and extended stay in the colon. Since the bacteria occupy the lumen, spread over the surface of epithelial cells, and adhere to the mucosa, delivering the rifaximin as a nanoparticles with the mucoadhesive polymer enhances the therapeutic efficacy in IBD. The objective was to fabricate and characterize the rifaximin loaded tamarind gum nanoparticles and study the therapeutic efficacy in the TNBS-induced IBD model rats. Materials and methods The experimentation includes fabrication and characterization of drug excipient compatibility by FTIR. The fabricated nanoparticles were characterized for the hydrodynamic size and zeta potential by photon correlation spectroscopy and also analyzed by TEM. Selected best formulation was subjected to the therapeutic efficacy study in TNBS-induced IBD rats, and the macroscopic, microscopic and biochemical parameters were reported. Results The study demonstrated that the formulation TGN1 is best formulation in terms of nanoparticle characterization and hydrodynamic size which showed the hydrodynamic size of 171.4 nm and the zeta potential of -26.44 mV and other parameters such as TEM and drug release studies were also reported. Conclusions The therapeutic efficacy study revealed that TGN1 is efficiently reduced the IBD inflammatory conditions as compared to the TNBS control group and reference drug mesalamine group.
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Affiliation(s)
- Maria John Newton Amaldoss
- Australian Centre for Nanomedicine, University of New South Wales, Sydney, NSW 2052, Australia.,Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.,Swift School of Pharmacy Rajpura, Punjab, India
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Chi H, Wang D, Chen M, Lin J, Zhang S, Yu F, Zhou J, Zheng X, Zou Y. Shaoyao Decoction Inhibits Inflammation and Improves Intestinal Barrier Function in Mice With Dextran Sulfate Sodium-Induced Colitis. Front Pharmacol 2021; 12:524287. [PMID: 33959000 PMCID: PMC8093868 DOI: 10.3389/fphar.2021.524287] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
Shaoyao decoction (SYD), a classical traditional Chinese medicine formula, is effective for the treatment of inflammatory bowel disease (IBD). This study was designed to investigate the therapeutic effects of SYD on IBD and possible mechanisms. Dextran sulfate sodium (DSS, 3.5%) was used to induce colitis in C57BL/6 mice. Disease phenotypes were investigated based on disease activity index (DAI), colon length, and microscopic and macroscopic scores. Additionally, the presence of proinflammatory cytokines, immune cell infiltrates, intestinal cell proliferation, apoptosis, epithelial permeability, signal transducer and activator of transcription 3 (STAT3), and nuclear factor-κB (NF-κB) signaling, as well as the intestinal mucosal barrier function, were investigated. The administration of SYD significantly ameliorated the clinical signs, suppressed the levels of proinflammatory cytokines, and reduced immune cell infiltrates into colonic tissues of DSS-induced colitis model mice. SYD also significantly reduced the DSS-induced activation of STAT3 and NF-κB signaling. Furthermore, SYD promoted epithelial integrity by regulating epithelial cell apoptosis and epithelial permeability. Finally, we demonstrated that SYD protected the intestinal barrier function by significantly regulating the mucus layer genes Muc1, Muc2, Muc4, and Tff3, as well as the epithelial barrier genes Z O -1 and Occludin. Our results indicate that SYD has a protective effect on DSS-induced colitis, which is attributable to its anti-inflammatory activity and intestinal barrier function-enhancing effects. These results provide valuable insights into the pharmacological actions of SYD for the treatment of IBD.
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Affiliation(s)
- Honggang Chi
- Department of Traditional Chinese Medicine, The Second Clinical Medical College, Guangdong Medical University, Dongguan, China.,Department of Traditional Chinese Medicine, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, China
| | - Dan Wang
- Department of Pharmacology, Guangdong Medical University, Dongguan, China
| | - Mengting Chen
- Department of Pharmacology, Guangdong Medical University, Dongguan, China
| | - Jiantao Lin
- Department of Pharmacology, Guangdong Medical University, Dongguan, China
| | - Shuhua Zhang
- Department of Traditional Chinese Medicine, The Second Clinical Medical College, Guangdong Medical University, Dongguan, China
| | - Fengyan Yu
- The Second Clinical Medical College, Guangdong Medical University, Dongguan, China
| | - Jun Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuebao Zheng
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, China
| | - Ying Zou
- Department of Traditional Chinese Medicine, The Second Clinical Medical College, Guangdong Medical University, Dongguan, China.,Department of Traditional Chinese Medicine, Dongguan Liaobu Hospital, Dongguan, China
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10
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11
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Formiga RDO, Alves Júnior EB, Vasconcelos RC, Guerra GCB, Antunes de Araújo A, de Carvalho TG, Garcia VB, de Araújo Junior RF, Gadelha FAAF, Vieira GC, Sobral MV, Barbosa Filho JM, Spiller F, Batista LM. p-Cymene and Rosmarinic Acid Ameliorate TNBS-Induced Intestinal Inflammation Upkeeping ZO-1 and MUC-2: Role of Antioxidant System and Immunomodulation. Int J Mol Sci 2020; 21:E5870. [PMID: 32824269 PMCID: PMC7461622 DOI: 10.3390/ijms21165870] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/04/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
p-Cymene (p-C) and rosmarinic acid (RA) are secondary metabolites that are present in medicinal herbs and Mediterranean spices that have promising anti-inflammatory properties. This study aimed to evaluate their intestinal anti-inflammatory activity in the trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. p-C and RA (25-200 mg/kg) oral administration reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. Both compounds (200 mg/kg) decreased malondialdehyde (MDA) and myeloperoxidase (MPO), restored glutathione (GSH) levels, and enhanced fluorescence intensity of superoxide dismutase (SOD). They also decreased interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and maintained IL-10 basal levels. Furthermore, they modulated T cell populations (cluster of differentiation (CD)4+, CD8+, or CD3+CD4+CD25+) analyzed from the spleen, mesenteric lymph nodes, and colon samples, and also decreased cyclooxigenase 2 (COX-2), interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), and nuclear transcription factor kappa B subunit p65 (NFκB-p65) mRNA transcription, but only p-C interfered in the suppressor of cytokine signaling 3 (SOCS3) expression in inflamed colons. An increase in gene expression and positive cells immunostained for mucin type 2 (MUC-2) and zonula occludens 1 (ZO-1) was observed. Altogether, these results indicate intestinal anti-inflammatory activity of p-C and RA involving the cytoprotection of the intestinal barrier, maintaining the mucus layer, and preserving communicating junctions, as well as through modulation of the antioxidant and immunomodulatory systems.
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Affiliation(s)
- Rodrigo de Oliveira Formiga
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa 58051970, Brazil; (R.d.O.F); (E.B.A.J.); (F.A.A.F.G.); (G.C.V.); (M.V.S.); (J.M.B.F.)
| | - Edvaldo Balbino Alves Júnior
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa 58051970, Brazil; (R.d.O.F); (E.B.A.J.); (F.A.A.F.G.); (G.C.V.); (M.V.S.); (J.M.B.F.)
| | - Roseane Carvalho Vasconcelos
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59064-741, Brazil; (R.C.V); (G.C.B.G.); (A.A.d.A.)
| | - Gerlane Coelho Bernardo Guerra
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59064-741, Brazil; (R.C.V); (G.C.B.G.); (A.A.d.A.)
| | - Aurigena Antunes de Araújo
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59064-741, Brazil; (R.C.V); (G.C.B.G.); (A.A.d.A.)
| | - Thaís Gomes de Carvalho
- Department of Morphology, Histology and Basic Pathology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59064-741, Brazil; (T.G.d.C.); (V.B.G.); (R.F.d.A.J.)
| | - Vinícius Barreto Garcia
- Department of Morphology, Histology and Basic Pathology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59064-741, Brazil; (T.G.d.C.); (V.B.G.); (R.F.d.A.J.)
| | - Raimundo Fernandes de Araújo Junior
- Department of Morphology, Histology and Basic Pathology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59064-741, Brazil; (T.G.d.C.); (V.B.G.); (R.F.d.A.J.)
| | - Francisco Allysson Assis Ferreira Gadelha
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa 58051970, Brazil; (R.d.O.F); (E.B.A.J.); (F.A.A.F.G.); (G.C.V.); (M.V.S.); (J.M.B.F.)
| | - Giciane Carvalho Vieira
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa 58051970, Brazil; (R.d.O.F); (E.B.A.J.); (F.A.A.F.G.); (G.C.V.); (M.V.S.); (J.M.B.F.)
| | - Marianna Vieira Sobral
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa 58051970, Brazil; (R.d.O.F); (E.B.A.J.); (F.A.A.F.G.); (G.C.V.); (M.V.S.); (J.M.B.F.)
| | - José Maria Barbosa Filho
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa 58051970, Brazil; (R.d.O.F); (E.B.A.J.); (F.A.A.F.G.); (G.C.V.); (M.V.S.); (J.M.B.F.)
| | - Fernando Spiller
- Department of Pharmacology, Federal University of Santa Catarina (UFSC), Florianópolis 88037-000, Brazil;
| | - Leônia Maria Batista
- Postgraduate Program in Natural and Synthetic Bioactive Products, Health Sciences Center, Federal University of Paraíba (UFPB), João Pessoa 58051970, Brazil; (R.d.O.F); (E.B.A.J.); (F.A.A.F.G.); (G.C.V.); (M.V.S.); (J.M.B.F.)
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12
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Andrade AWL, Guerra GCB, de Souza Araújo DF, de Araújo Júnior RF, de Araújo AA, de Carvalho TG, Fernandes JM, Diez-Echave P, Hidalgo-García L, Rodriguez-Cabezas ME, Gálvez J, Zucolotto SM. Anti-Inflammatory and Chemopreventive Effects of Bryophyllum pinnatum (Lamarck) Leaf Extract in Experimental Colitis Models in Rodents. Front Pharmacol 2020; 11:998. [PMID: 32848723 PMCID: PMC7403504 DOI: 10.3389/fphar.2020.00998] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/19/2020] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel diseases, mainly ulcerative colitis and Crohn's disease are characterized by chronic inflammation in the intestine. Currently several therapeutic strategies available to treat inflammatory bowel diseases. Though, most treatments can be associated with serious adverse effects what justifies the search for new treatments. In this sense, we highlight the interest in herbal products rich in bioactive compounds which immunomodulatory and antioxidant properties as is the case of Bryophyllum pinnatum (Crassulaceae). This plant is used in traditional medicine in Brazil for treating inflammatory diseases. We hypothesized that hydroethanolic B. pinnatum leaf extract has intestinal anti-inflammatory effects on two experimental colitis models: 2.4-dinitrobenzene sulfonic acid (DNBS) in rats, and dextran sulfate sodium (DSS) in mice. Ultra-fast liquid chromatography method used for the quantification of the main compounds indicated good linearity, specificity, selectivity, precision, robustness and accuracy. The major flavonoids (mg/g of the extract) quantified were: quercetin 3-O-α-L-arabinopyranosyl-(1→2)-α-L-rhamnopyranoside (35.56 ± 0.086 mg/g), kaempferol 3-O-α-L-arabinopyranosyl-(1→2)-α-L-rhamnopyranoside (4.66 ± 0.076 mg/g) and quercetin-3-O-rhamnopyranoside (4.56 ± 0.026 mg/g). The results obtained in the DNBS and DSS models indicate that extract has both chemopreventive and anti-inflammatory effects, observing a significant reduction in the disease activity index score, and less macroscopic and microscopic damage. The extract promoted downregulation of Toll-like receptor and kappa B p65 nuclear factor gene expression, leading to a reduction in pro-inflammatory and oxidative mediators, chemokines, and cell adhesion molecules. This immunomodulatory property was proposed that one of the possible action mechanisms of extract. An improvement in intestinal damage was also associated with a reduction in oxidative stress and infiltration of leukocytes, as evidenced by the reduction in malonaldialdehyde and myeloperoxidase activity and increase in total glutathione in the colonic tissue. Moreover, the extract improved the cytoarchitecture of the colonic tissue and the integrity of the intestinal epithelial barrier by restoring the expression of the proteins associated with mucosa protection. In view of the beneficial effects showed by the B. pinnatum leaf extract in preclinical rodent models of colitis there is the potential to conduct some future clinical studies to ensure safe and effective development of a phytotherapeutic treatment for human inflammatory bowel diseases.
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Affiliation(s)
- Anderson Wilbur Lopes Andrade
- Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil.,Health Science Center, Postgraduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal, Brazil
| | | | | | - Raimundo Fernandes de Araújo Júnior
- Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil.,Postgraduate Program in Functional and Structural Biology, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil
| | | | - Thaís Gomes de Carvalho
- Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil
| | - Júlia Morais Fernandes
- Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Patrícia Diez-Echave
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), University of Granada, Granada, Spain.,CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Laura Hidalgo-García
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), University of Granada, Granada, Spain.,CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Maria Elena Rodriguez-Cabezas
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), University of Granada, Granada, Spain.,CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Julio Gálvez
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), University of Granada, Granada, Spain.,CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Silvana Maria Zucolotto
- Health Science Center, Postgraduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal, Brazil
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13
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Souza RF, Evangelinellis MM, Mendes CE, Righetti M, Lourenço MCS, Castelucci P. P2X7 receptor antagonist recovers ileum myenteric neurons after experimental ulcerative colitis. World J Gastrointest Pathophysiol 2020; 11:84-103. [PMID: 32587788 PMCID: PMC7303980 DOI: 10.4291/wjgp.v11.i4.84] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 04/04/2020] [Accepted: 04/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The P2X7 receptor is expressed by enteric neurons and enteric glial cells. Studies have demonstrated that administration of a P2X7 receptor antagonist, brilliant blue G (BBG), prevents neuronal loss. AIM To report the effects of BBG in ileum enteric neurons immunoreactive (ir) following experimental ulcerative colitis in Rattus norvegicus albinus. METHODS 2,4,6-trinitrobenzene sulfonic acid (TNBS group, n = 5) was injected into the distal colon. BBG (50 mg/kg, BBG group, n = 5) or vehicle (sham group, n = 5) was given subcutaneously 1 h after TNBS. The animals were euthanized after 24 h, and the ileum was removed. Immunohistochemistry was performed on the myenteric plexus to evaluate immunoreactivity for P2X7 receptor, neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), HuC/D and glial fibrillary acidic protein. RESULTS The numbers of nNOS-, ChAT-, HuC/D-ir neurons and glial fibrillary acidic protein-ir glial cells were decreased in the TNBS group and recovered in the BBG group. The neuronal profile area (μm2) demonstrated that nNOS-ir neurons decreased in the TNBS group and recovered in the BBG group. There were no differences in the profile areas of ChAT- and HuC/D-ir neurons. CONCLUSION Our data conclude that ileum myenteric neurons and glial cells were affected by ulcerative colitis and that treatment with BBG had a neuroprotective effect. Thus, these results demonstrate that the P2X7 receptor may be an important target in therapeutic strategies.
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Affiliation(s)
| | - Mariá Munhoz Evangelinellis
- Department of Surgery, Faculty of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo 05508-900, Brazil
| | | | - Marta Righetti
- Department of Anatomy, University of São Paulo, São Paulo 05508-900, Brazil
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Ni Y, Liu M, Yu H, Chen Y, Liu Y, Chen S, Ruan J, Da A, Zhang Y, Wang T. Desmethylbellidifolin From Gentianella acuta Ameliorate TNBS-Induced Ulcerative Colitis Through Antispasmodic Effect and Anti-Inflammation. Front Pharmacol 2019; 10:1104. [PMID: 31616306 PMCID: PMC6764246 DOI: 10.3389/fphar.2019.01104] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 08/28/2019] [Indexed: 12/24/2022] Open
Abstract
Desmethylbellidifolin (DMB) is a natural xanthone extracted from Gentianella acuta, which is used as the antidiarrhea drug in traditional Mongolian medicines. It remains unknown whether DMB can ameliorate ulcerative colitis (UC). In this study, trinitrobenzenesulfonic acid (TNBS)-induced colitis rats were treated with G. acuta extract (GAE) or DMB for 10 days. Body weight, food and water intake, rectal bleeding score, diarrhea score, and histopathological parameters were measured. Rat colon were collected to determine myeloperoxidase, nitric oxide levels, and inflammatory cytokines expression. In addition, the role of DMB on lipopolysaccharide stimulated RAW264.7 cell inflammatory response and intestine smooth muscle contraction was determined. The results showed that GAE and DMB treatment could significantly alleviate TNBS-induced UC. Colon morphological alteration, nitric oxide level, and inflammatory cytokines level, such as nitric oxide synthase, interleukin-6, tumor necrosis factor-α, and cyclooxygenase-2, were decreased. In addition, DMB attenuated lipopolysaccharide-induced nitric oxide release and proinflammatory cytokine expression in RAW264.7 cells. In isolated mice intestinal tissue, DMB also reduced the intestine smooth muscle spontaneous contraction and inhibited KCl, acetylcholine, BaCl2, or histamine-induced intestine smooth muscle active tension, while the active frequency was unaffected. Our results demonstrated that GAE and its active constituent DMB could inhibit TNBS-induced UC, reducing inflammatory response and alleviate colon muscle spasm, suggesting that DMB may be a good candidate for subsequent development as a multitargeting drug for UC treatment.
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Affiliation(s)
- Yajuan Ni
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mengyang Liu
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Haiyang Yu
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yue Chen
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yanxia Liu
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
| | - Suyile Chen
- Alxa League Mongolian Medical Hospital, Bayanhaote, China
| | - Jingya Ruan
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
| | | | - Yi Zhang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tao Wang
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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15
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Feehan KT, Gilroy DW. Is Resolution the End of Inflammation? Trends Mol Med 2019; 25:198-214. [DOI: 10.1016/j.molmed.2019.01.006] [Citation(s) in RCA: 148] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 01/11/2019] [Accepted: 01/14/2019] [Indexed: 12/12/2022]
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da Silva VC, de Araújo AA, de Souza Araújo DF, Souza Lima MCJ, Vasconcelos RC, de Araújo Júnior RF, Langasnner SMZ, de Freitas Fernandes Pedrosa M, de Medeiros CACX, Guerra GCB. Intestinal Anti-Inflammatory Activity of the Aqueous Extract from Ipomoea asarifolia in DNBS-Induced Colitis in Rats. Int J Mol Sci 2018; 19:ijms19124016. [PMID: 30545135 PMCID: PMC6321343 DOI: 10.3390/ijms19124016] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/12/2018] [Accepted: 11/27/2018] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease is triggered by an uncontrolled immune response associated with genetic, environmental, and intestinal microbiota imbalance. Ipomoea asarifolia (IA), popularly known as “salsa” or “brave salsa”, belongs to the Convolvulaceae family. The aim of this approach was to study the preventive effect of IA aqueous extract in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in rats. Rats pretreated with IA extract or sulfasalazine (SSZ) received intracolonic instillation of DNBS in 50% ethanol (v/v). IA extract presented a protective effect against intestinal inflammation, with improvement in the disease activity index and macroscopic damage. IA or SSZ significantly reduced myeloperoxidase activity, and also down-regulation of the gene expression of JNK1, NF-κβ-p65, STAT3, and decreased levels of TNFα, IL-1β, and increased IL-10, associated with a significant improvement of oxidative stress, in addition to a reduction in MDA and an increase of glutathione in colonic tissue. The protective effect of the extract was also confirmed in histological evaluation, showing preservation of the colonic cytoarchitecture. Immunohistochemical analysis revealed down-regulation of NF-κβ-p65, iNOS, IL-17, and up-regulation of SOCs-1 and MUC-2. IA extract presents antioxidant and anti-inflammatory intestinal properties, and proved to be a potential application for preventing damage induced by DNBS.
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Affiliation(s)
- Valéria Costa da Silva
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59072-970, Brazil.
| | - Aurigena Antunes de Araújo
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59072-970, Brazil.
| | | | - Maíra Conceição Jerônimo Souza Lima
- Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte, Natal 59012-570, Brazil.
| | - Roseane Carvalho Vasconcelos
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59072-970, Brazil.
| | - Raimundo Fernandes de Araújo Júnior
- Department of Morphology, Histology and Basic Pathology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59072-970, Brazil.
| | - Silvana Maria Zucolotto Langasnner
- Research Group on Bioactive Natural Products, Department of Pharmacy, Federal University of Rio Grande do Norte, Natal 59012-570, Brazil.
| | - Matheus de Freitas Fernandes Pedrosa
- Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte, Natal 59012-570, Brazil.
| | | | - Gerlane Coelho Bernardo Guerra
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59072-970, Brazil.
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Rodrigues R, Guerra G, Soares J, Santos K, Rolim F, Assis P, Araújo D, de Araújo Júnior RF, Garcia VB, de Araújo AA, Queiroga R. Lactobacillus rhamnosus EM1107 in goat milk matrix modulates intestinal inflammation involving NF-κB p65 and SOCs-1 in an acid-induced colitis model. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.09.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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18
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Dou YX, Zhou JT, Wang TT, Huang YF, Chen VP, Xie YL, Lin ZX, Gao JS, Su ZR, Zeng HF. Self-nanoemulsifying drug delivery system of bruceine D: a new approach for anti-ulcerative colitis. Int J Nanomedicine 2018; 13:5887-5907. [PMID: 30319255 PMCID: PMC6167998 DOI: 10.2147/ijn.s174146] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Bruceine D (BD) is a major bioactive component isolated from the traditional Chinese medicinal plant Brucea javanica which has been widely utilized to treat dysentery (also known as ulcerative colitis [UC]). Methods To improve the water solubility and absolute bioavailability of BD, we developed a self-nanoemulsifying drug delivery system (SNEDDS) composing of MCT (oil), Solutol HS-15 (surfactant), propylene glycol (co-surfactant) and BD. The physicochemical properties and pharmacokinetics of BD-SNEDDS were characterized, and its anti-UC activity and potential mechanism were evaluated in TNBS-induced UC rat model. Results The prepared nanoemulsion has multiple beneficial aspects including small mean droplet size, low polydispersity index (PDI), high zeta potential (ZP) and excellent stability. Transmission electron microscopy showed that nanoemulsion droplets contained uniform shape and size of globules. Pharmacokinetic studies demonstrated that BD-SNEDDS exhibited enhanced pharmacokinetic parameters as compared with BD-suspension. Moreover, BD-SNEDDS significantly restored the colon length and body weight, reduced disease activity index (DAI) and colon pathology, decreased histological scores, diminished oxidative stress, and suppressed TLR4, MyD88, TRAF6, NF-κB p65 protein expressions in TNBS-induced UC rat model. Conclusion These results demonstrated that BD-SNEDDS exhibited highly improved oral bioavailability and advanced anti-UC efficacy. In conclusion, our current results provided a foundation for further research of BD-SNEDDS as a potential complementary therapeutic agent for UC treatment.
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Affiliation(s)
- Yao-Xing Dou
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.,Department of Pharmacy, The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China,
| | - Jiang-Tao Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.,Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Tong-Tong Wang
- Department of Pharmacy, The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China,
| | - Yan-Feng Huang
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Vicky Ping Chen
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - You-Liang Xie
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Zhi-Xiu Lin
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Jian-Sheng Gao
- Guangzhou Baiyunshan Mingxing Pharmaceutical Co. Ltd., Guangzhou, People's Republic of China
| | - Zi-Ren Su
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Hui-Fang Zeng
- Department of Pharmacy, The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China,
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Romero-Calvo I, Ocón B, Gámez-Belmonte R, Hernández-Chirlaque C, de Jonge HR, Bijvelds MJ, Martínez-Augustin O, Sánchez de Medina F. Adenylyl cyclase 6 is involved in the hyposecretory status of experimental colitis. Pflugers Arch 2018; 470:1705-1717. [PMID: 30094477 DOI: 10.1007/s00424-018-2187-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/12/2018] [Accepted: 07/24/2018] [Indexed: 12/12/2022]
Abstract
One of the cardinal symptoms of intestinal inflammation is diarrhea. Acute intestinal inflammation is associated with inhibition of ion absorption and increased secretion, along with fluid leakage due to epithelial injury and changes in permeability. However, in the chronic situation, a downregulation of both absorptive and secretory transport has been reported. We investigated how experimental colitis reduces cAMP levels in intestinal epithelial cells through modulation of adenylyl cyclases (AC). Primary colonic epithelial cells obtained from rats with trinitrobenzenesulfonic acid colitis and non-colitic controls were analyzed for AC expression by RT-qPCR and Western blot, following a preliminary microarray analysis. AC6 and AC5 were found to be expressed in colonocytes, and downregulated by inflammation, with the former exhibiting considerably higher mRNA levels in both cases. To test the hypothesis that inflammatory cytokines may account for this effect, Caco 2 cells were treated with IL-1β, TNF-α, or IFN-γ. All three cytokines inhibited forskolin evoked short-circuit currents in Ussing chambers and lowered intracellular cAMP, but failed to alter AC6 mRNA levels. AC5/AC6 expression was however inhibited in mouse jejunal organoids treated with IFN-γ and TNF-α, but not IL-1β. Gene knockdown of AC6 resulted in a significant decrease of ion secretion in T84 cells. We conclude that the disturbances in ion secretion observed in rat TNBS colitis are associated with low intracellular levels of cAMP in the epithelium, which may be explained in part by the downregulation of AC5/AC6 expression by proinflammatory cytokines.
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Affiliation(s)
- Isabel Romero-Calvo
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, Campus de Cartuja s/n, 18071, Granada, Spain
| | - Borja Ocón
- Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Reyes Gámez-Belmonte
- Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Cristina Hernández-Chirlaque
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, Campus de Cartuja s/n, 18071, Granada, Spain
| | - Hugo R de Jonge
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Marcel J Bijvelds
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Olga Martínez-Augustin
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, Campus de Cartuja s/n, 18071, Granada, Spain.
| | - Fermín Sánchez de Medina
- Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
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20
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Hofma BR, Wardill HR, Mavrangelos C, Campaniello MA, Dimasi D, Bowen JM, Smid SD, Bonder CS, Beckett EA, Hughes PA. Colonic migrating motor complexes are inhibited in acute tri-nitro benzene sulphonic acid colitis. PLoS One 2018; 13:e0199394. [PMID: 29933379 PMCID: PMC6014673 DOI: 10.1371/journal.pone.0199394] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 06/06/2018] [Indexed: 01/04/2023] Open
Abstract
Background Inflammatory Bowel Disease (IBD) is characterized by overt inflammation of the intestine and is typically accompanied by symptoms of bloody diarrhea, abdominal pain and cramping. The Colonic Migrating Motor Complex (CMMC) directs the movement of colonic luminal contents over long distances. The tri-nitrobenzene sulphonic acid (TNBS) model of colitis causes inflammatory damage to enteric nerves, however it remains to be determined whether these changes translate to functional outcomes in CMMC activity. We aimed to visualize innate immune cell infiltration into the colon using two-photon laser scanning intra-vital microscopy, and to determine whether CMMC activity is altered in the tri-nitro benzene sulphonic (TNBS) model of colitis. Methods Epithelial barrier permeability was compared between TNBS treated and healthy control mice in-vitro and in-vivo. Innate immune activation was determined by ELISA, flow cytometry and by 2-photon intravital microscopy. The effects of TNBS treatment and IL-1β on CMMC function were determined using a specialized organ bath. Results TNBS colitis increased epithelial barrier permeability in-vitro and in-vivo. Colonic IL-1β concentrations, colonic and systemic CD11b+ cell infiltration, and the number of migrating CD11b+ cells on colonic blood vessels were all increased in TNBS treated mice relative to controls. CMMC frequency and amplitude were inhibited in the distal and mid colon of TNBS treated mice. CMMC activity was not altered by superfusion with IL-1β. Conclusions TNBS colitis damages the epithelial barrier and increases innate immune cell activation in the colon and systemically. Innate cell migration into the colon is readily identifiable by two-photon intra-vital microscopy. CMMC are inhibited by inflammation, but this is not due to direct effects of IL-1β.
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Affiliation(s)
- Ben R. Hofma
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Centre for Nutrition and GI Diseases, Adelaide Medical School, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Hannah R. Wardill
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Centre for Nutrition and GI Diseases, Adelaide Medical School, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Chris Mavrangelos
- Centre for Nutrition and GI Diseases, Adelaide Medical School, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Melissa A. Campaniello
- Centre for Nutrition and GI Diseases, Adelaide Medical School, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, Australia
| | - David Dimasi
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Joanne M. Bowen
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Scott D. Smid
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Claudine S. Bonder
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | | | - Patrick A. Hughes
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Centre for Nutrition and GI Diseases, Adelaide Medical School, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, Australia
- * E-mail:
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Chen Z, Ni W, Yang C, Zhang T, Lu S, Zhao R, Mao X, Yu J. Therapeutic Effect of Amomum villosum on Inflammatory Bowel Disease in Rats. Front Pharmacol 2018; 9:639. [PMID: 29973876 PMCID: PMC6019447 DOI: 10.3389/fphar.2018.00639] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/29/2018] [Indexed: 12/12/2022] Open
Abstract
Introduction:Amomum villosum Lour., a herbaceous plant in the ginger family, has been proven to be effective in treating gastrointestinal diseases. It has been listed in the Chinese Pharmacopeia as a legal source of Amomi Fructus. In our previous study, we demonstrated that treatment with extracts of A. villosum prevented the development and progression of intestinal mucositis. In the current study, we aimed to verify and explain the potential beneficial effects of A. villosum on inflammatory bowel disease (IBD). Methods: The effect of water extracts (WEAV) and volatile oil of A. villosum (VOAV) were evaluated on the immunological role of T lymphocytes and intestinal microecology in IBD rats induced with 2,4,6-trinitrobenzenesulfonic acid (TNBS). Body weight, food intake, colon length/weight, and disease activity index (DAI) as well as tissue damage scores were evaluated. The inflammatory response to IBD was assessed by measuring the expression of myeloperoxidase, interleukin (IL)-17 (IL-17), interferon-γ (IFN-γ), IL-10, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β). The percentage of regulatory CD4+ T cells in rat spleen was measured by flow cytometry and effects on the microbial community were evaluated by 16S rDNA gene sequencing. Results: All TNBS-induced rats showed typical clinical manifestations of IBD. IBD rats in the WEAV and VOAV treatment groups were effective in relieving body weight and appetite loss. Middle and high dosage of VOAV and WEAV significantly reduced the DAI, and tissue damage scores, whereas colon weight/length ratio was increase. All rats in the WEAV and VOAV groups showed significantly decreased IFN-γ levels and increased levels of IL-10 and TGF-β. Moreover, we observed that the percentage of regulatory CD4+ T cells was significantly enhanced during treatment with WEAV. In addition, administration of WEAV and VOAV effectively inhibited the release of enterogenic endotoxin, increased short-chain fatty acid-producing bacteria belonging to Firmicutes and Bacteroidetes, and decreased the abundance of Proteobacteria. Conclusion: Treatment with WEAV and VOAV significantly attenuated intestinal inflammation in IBD rats, which was possibly associated with its regulation on inflammatory cytokine and CD4+CD25+FOXP3+ T cells. Moreover, WEAV and VOAV may help maintaining the balance of intestinal microecology.
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Affiliation(s)
- Zhu Chen
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Wanye Ni
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Caixia Yang
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Ting Zhang
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Shanhong Lu
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Ronghua Zhao
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Xiaojian Mao
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Jie Yu
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, Kunming, China
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22
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Anti-Inflammatory Effects of an Extract of Polygonum hydropiper Stalks on 2,4,6-Trinitrobenzenesulphonic Acid-Induced Intestinal Inflammation in Rats by Inhibiting the NF- κB Pathway. Mediators Inflamm 2018; 2018:6029135. [PMID: 29853790 PMCID: PMC5964420 DOI: 10.1155/2018/6029135] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 02/06/2018] [Accepted: 03/11/2018] [Indexed: 12/17/2022] Open
Abstract
The stalks of Polygonum hydropiper L. (PHL) have been traditionally used in clinical practice for thousands of years in China to treat various inflammatory diseases. However, little research has been conducted to investigate the anti-inflammatory effects of PHL on TNBS-induced intestinal inflammation in rats. The aim of the present study was to investigate the anti-inflammatory effects and to explain the underlying mechanism of PHL on TNBS-induced intestinal inflammation in rats. PHL (125, 250, and 500 mg/kg) was given for 7 consecutive days to rats with intestinal inflammation induced by TNBS. Oral administration of an aqueous extract of a high dose of PHL (H-PHL) significantly improved TNBS-induced symptoms such as the macroscopic score and histological examination. H-PHL treatment significantly ameliorated the activity of MPO and improved the GSH content. In addition, there was a downregulation of the TNBS-induced increase in the activity of iNOS and levels of Cox-2, TNF-α, and IL-1β while the protein expression of NF-κB was significantly unregulated after administration of H-PHL. The present findings suggested that H-PHL has a protective effect on experimental intestinal inflammation in rats and its anti-inflammatory effects are closely related to inhibition of NF-κB signal pathways.
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23
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Celiberto LS, Bedani R, Dejani NN, Ivo de Medeiros A, Sampaio Zuanon JA, Spolidorio LC, Tallarico Adorno MA, Amâncio Varesche MB, Carrilho Galvão F, Valentini SR, Font de Valdez G, Rossi EA, Cavallini DCU. Effect of a probiotic beverage consumption (Enterococcus faecium CRL 183 and Bifidobacterium longum ATCC 15707) in rats with chemically induced colitis. PLoS One 2017; 12:e0175935. [PMID: 28437455 PMCID: PMC5402984 DOI: 10.1371/journal.pone.0175935] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 04/03/2017] [Indexed: 12/11/2022] Open
Abstract
Background Some probiotic strains have the potential to assist in relieving the symptoms of inflammatory bowel disease. The impact of daily ingestion of a soy-based product fermented by Enterococcus faecium CRL 183 and Lactobacillus helveticus 416 with the addition of Bifidobacterium longum ATCC 15707 on chemically induced colitis has been investigated thereof within a period of 30 days. Methods Colitis was induced by dextran sulfate sodium. The animals were randomly assigned into five groups: Group C: negative control; Group CL: positive control; Group CLF: DSS with the fermented product; Group CLP: DSS with the non-fermented product (placebo); Group CLS: DSS with sulfasalazine. The following parameters were monitored: disease activity index, fecal microbial analyses, gastrointestinal survival of probiotic microorganisms and short-chain fatty acids concentration in the feces. At the end of the protocol the animals’ colons were removed so as to conduct a macroscopical and histopathological analysis, cytokines and nitrite quantification. Results Animals belonging to the CLF group showed fewer symptoms of colitis during the induction period and a lower degree of inflammation and ulceration in their colon compared to the CL, CLS and CLP groups (p<0.05). The colon of the animals in groups CL and CLS presented severe crypt damage, which was absent in CLF and CLP groups. A significant increase in the population of Lactobacillus spp. and Bifidobacterium spp. at the end of the protocol was verified only in the CLF animals (p<0.05). This group also showed an increase in short-chain fatty acids (propionate and acetate). Furthermore, the intestinal survival of E. faecium CRL 183 and B. longum ATCC 15707 in the CLF group has been confirmed by biochemical and molecular analyzes. Conclusions The obtained results suggest that a regular intake of the probiotic product, and placebo to a lesser extent, can reduce the severity of DSS-induced colitis on rats.
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Affiliation(s)
- Larissa Sbaglia Celiberto
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
| | - Raquel Bedani
- Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Naiara Naiana Dejani
- Universidade de São Paulo (USP), Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto. Departamento de Bioquimica e Imunologia, SP, Brasil
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - Alexandra Ivo de Medeiros
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - José Antonio Sampaio Zuanon
- Universidade Estadual Paulista (UNESP), Faculdade de Odontologia, Araraquara. Departametno de Fisiologia e Patologia, SP, Brasil
| | - Luis Carlos Spolidorio
- Universidade Estadual Paulista (UNESP), Faculdade de Odontologia, Araraquara. Departametno de Fisiologia e Patologia, SP, Brasil
| | - Maria Angela Tallarico Adorno
- Universidade de São Paulo (USP), Faculdade de Engenharia, São Carlos. Departamento de Hidraúlica e Saneamento, SP, Brasil
| | | | - Fábio Carrilho Galvão
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - Sandro Roberto Valentini
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | | | - Elizeu Antonio Rossi
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
| | - Daniela Cardoso Umbelino Cavallini
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
- * E-mail:
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24
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Pereira SR, Pereira R, Figueiredo I, Freitas V, Dinis TCP, Almeida LM. Comparison of anti-inflammatory activities of an anthocyanin-rich fraction from Portuguese blueberries (Vaccinium corymbosum L.) and 5-aminosalicylic acid in a TNBS-induced colitis rat model. PLoS One 2017; 12:e0174116. [PMID: 28329021 PMCID: PMC5362129 DOI: 10.1371/journal.pone.0174116] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 02/25/2017] [Indexed: 12/11/2022] Open
Abstract
Despite the actual therapeutic approaches for inflammatory bowel disease (IBD), efficient and secure alternative options remain a research focus. In this context, anthocyanins seem promising natural anti-inflammatory agents, but their action mechanisms and efficacy as compared with established drugs still require more clarification. The main aim of this study was to compare the anti-inflammatory action of a chemically characterized anthocyanin-rich fraction (ARF), obtained from Portuguese blueberries (Vaccinium corymbosum L.), with that of 5-aminosalicylic acid (5-ASA), a first-line drug in IBD, in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model. Such fraction showed a high content and great molecular diversity of anthocyanins, with malvidin-3-galactoside and petunidin-3-arabinoside in the highest concentrations. After daily administration by intragastric infusion for 8 days, ARF, at a molar anthocyanin concentration about 30 times lower than 5-ASA, showed a higher effectiveness in counteracting the intestinal inflammation, as assessed by i) body weight variation and colon damage score, ii) reduction in leukocyte infiltration, iii) increase in antioxidant defenses and iv) by downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in colon tissue homogenates. The strong inhibition of COX-2 expression seems to be a crucial anti-inflammatory mechanism common to both ARF and 5-ASA, but the additional higher abilities of anthocyanins to downregulate iNOS and to decrease leukocytes infiltration and to increase antioxidant defenses in colon may account for the much higher anti-inflammatory action of anthocyanins. These data may contribute to the development of a promising natural approach in IBD management.
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Affiliation(s)
- Sónia R. Pereira
- CNC-Center for Neuroscience and Cell Biology, Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Rita Pereira
- CNC-Center for Neuroscience and Cell Biology, Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | | | - Victor Freitas
- Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Teresa C. P. Dinis
- CNC-Center for Neuroscience and Cell Biology, Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Leonor M. Almeida
- CNC-Center for Neuroscience and Cell Biology, Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
- * E-mail:
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Zou Y, Lin J, Li W, Wu Z, He Z, Huang G, Wang J, Ye C, Cheng X, Ding C, Zheng X, Chi H. Huangqin-tang ameliorates dextran sodium sulphate-induced colitis by regulating intestinal epithelial cell homeostasis, inflammation and immune response. Sci Rep 2016; 6:39299. [PMID: 27982094 PMCID: PMC5159883 DOI: 10.1038/srep39299] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 11/21/2016] [Indexed: 12/30/2022] Open
Abstract
Huangqin-tang (HQT) is a traditional Chinese medicine (TCM) formula widely used for the treatment of inflammatory bowel disease in China. However, the molecular mechanisms by which HQT protects the colon are unclear. We studied the protective effects of HQT and the underlying mechanisms in an experimental mouse model and in vitro. In vivo, dextran sodium sulphate (DSS)-induced acute and chronic colitis were significantly ameliorated by HQT as gauged by phenotypic, histopathologic and inflammatory manifestations of the disease. Mechanistically, DSS-induced nuclear factor-κB (NF-κB) signalling was inhibited by HQT. Moreover, HQT-treated mice demonstrated significant changes in cell apoptosis, expression of apoptosis-associated genes such as caspase-3, bax, bcl-2, and intestinal permeability. HQT also increased occluding and zonula occludens-1 (ZO-1), inhibited cell proliferation (Ki67), and increased regulatory T cells numbers, protein expression of Foxp3 and IL-10 in the colonic tissue. In vitro, HQT down-regulated production of pro-inflammatory cytokines and supressed the NF-κB signalling pathway in lipopolysaccharides-induced RAW 264.7 macrophages. Our study suggests that HQT plays a critical role in regulating intestinal epithelial cell homeostasis, inflammation and immune response in colitis and offers novel therapeutic options in the management of inflammatory bowel disease.
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Affiliation(s)
- Ying Zou
- Department of Traditional Chinese Medicine, Scientific Research Platform, The Second Clinical Medical College, Guangdong Medical University, Dongguan 523808, China.,Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Jiantao Lin
- Traditional Chinese Medicine and New Drug Research Institute, Guangdong Medical University, Dongguan 523808, China
| | - Wenyang Li
- Department of Traditional Chinese Medicine, Scientific Research Platform, The Second Clinical Medical College, Guangdong Medical University, Dongguan 523808, China
| | - Zhuguo Wu
- The Second Clinical Medical College, Guangdong Medical University, Dongguan 523808, China
| | - Zhiwei He
- Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Guoliang Huang
- Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Jian Wang
- Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Caiguo Ye
- Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Xiaoyan Cheng
- Department of Traditional Chinese Medicine, Scientific Research Platform, The Second Clinical Medical College, Guangdong Medical University, Dongguan 523808, China
| | - Congcong Ding
- Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Xuebao Zheng
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Honggang Chi
- Department of Traditional Chinese Medicine, Scientific Research Platform, The Second Clinical Medical College, Guangdong Medical University, Dongguan 523808, China
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Huangqin-Tang Ameliorates TNBS-Induced Colitis by Regulating Effector and Regulatory CD4(+) T Cells. BIOMED RESEARCH INTERNATIONAL 2015; 2015:102021. [PMID: 26347453 PMCID: PMC4539427 DOI: 10.1155/2015/102021] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 12/11/2014] [Indexed: 02/08/2023]
Abstract
Huangqin-Tang decoction (HQT) is a classic traditional Chinese herbal formulation that is widely used to ameliorate the symptoms of gastrointestinal disorders, including inflammatory bowel disease (IBD). This study was designed to investigate the therapeutic potential and immunological regulatory activity of HQT in experimental colitis in rats. Using an animal model of colitis by intrarectally administering 2,4,6-trinitrobenzenesulfonic acid (TNBS), we found that administration of HQT significantly inhibited the severity of TNBS-induced colitis in a dose-dependent manner. In addition, treatment with HQT produced better results than that with mesalazine, as shown by improvedweight loss bleeding and diarrhoea scores, colon length, and intestinal inflammation. As for potential immunological regulation of HQT action, the percentages of Th1 and Th17 cells were reduced, but those Th2 and Treg cells were enhanced in LPMCs after HQT treatment. Additionally, HQT lowered the levels of Th1/Th17-associated cytokines but increased production of Th2/Treg-associated cytokines in the colon and MLNs. Furthermore, we observed a remarkable suppression of the Th1/Th17-associated transcription factors T-bet and ROR-γt. However, expression levels of the Th2/Treg-associated transcription factors GATA-3 and Foxp3 were enhanced during treatment with HQT. Our results suggest that HQT has the therapeutic potential to ameliorate TNBS-induced colitis symptoms. This protective effect is possibly mediated by its effects on CD4(+) T cells subsets.
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Seito LN, Sforcin JM, Bastos JK, Di Stasi LC. Zeyheria montana Mart. (Bignoniaceae) as source of antioxidant and immunomodulatory compounds with beneficial effects on intestinal inflammation. ACTA ACUST UNITED AC 2014; 67:597-604. [PMID: 25556766 DOI: 10.1111/jphp.12354] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 10/26/2014] [Indexed: 01/29/2023]
Abstract
OBJECTIVES Zeyheria montana is a medicinal plant used in Brazilian folk medicine for treating skin affections, ulcers, inflammation and diarrhoea, and as an antisyphilitic and antiblenorrhagic agent, but little is known about its mechanisms of action. Herein, a bio-guided assay was carried out to further evaluate its antioxidant and immunomodulatory effects, and the possible benefits on experimental intestinal inflammation. METHODS Extracts, partitions, fractions and isolated compounds were tested for inhibition of lipid peroxidation. Isolated compounds were tested in vitro for its antioxidant and immunomodulatory action prior to in-vivo evaluation in trinitrobenzenesulfonic acid-induced rat colitis. KEY FINDINGS Two major compounds were identified in the leaf dichloromethane extract: 3'-hydroxy-5,7,4'-trimethoxyflavone and 6-hydroxy-5,7-dimethoxyflavone, which exhibited an antioxidant activity. The compounds protected the colonic glutathione levels in more than 90% despite the absence of protection against the gross macroscopic colonic damage. In addition, the compounds inhibited IL-1ß secretion by macrophages in 91.5% and 72.7% respectively, whereas both reduced IL-6 secretion in about 44.5%. CONCLUSIONS The major active compounds from Z. montana leaves exerted antioxidant and immunomodulatory effects, endorsing the use of Z. montana in folk medicine as an anti-inflammatory agent. However, further investigation is still needed regarding medicinal plants and the identification of candidate compounds for the treatment of the inflammatory bowel diseases.
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Affiliation(s)
- Leonardo Noboru Seito
- Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTech), Department of Pharmacology, Biosciences Institute, UNESP - Univ Estadual Paulista, Botucatu, SP, Brazil
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Preventive effects of Escherichia coli strain Nissle 1917 with different courses and different doses on intestinal inflammation in murine model of colitis. Inflamm Res 2014; 63:873-83. [PMID: 25118782 DOI: 10.1007/s00011-014-0761-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 07/23/2014] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To analyze the in vivo effect of Escherichia coli Nissle 1917 (EcN) with different courses and different doses to Sprague-Dawley rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis. METHODS The probiotic was orally administered with different courses of treatment (with or without pre-administration) and different doses (10(7)-10(9) CFU/day) to Sprague-Dawley rats with TNBS-induced colitis. Therapeutic effects, levels of cytokine in serum, mRNA and protein expression were analyzed. RESULTS Oral EcN administration after TNBS-induced improved colitis dose dependently. In parallel, a reduction of disease activity index and colonic MPO activity together with a decreased level of TNF-α and a trend of increased IL-10 expression was detected. Pre-administration of 10(7)CFU/day EcN to TNBS-treated rats resulted in a significant protection against inflammatory response and colons isolated from these rats exhibited a more pronounced expression of ZO-1 than the other groups. In the group of pre-administration of 10(9)CFU/day, the condition was not improved but deteriorated. CONCLUSIONS This study convincingly demonstrates that pre-administration of probiotic EcN with low dose is able to protect colitis of rats and mediate up-regulation of ZO-1 expression, but long-term of high-dose EcN may do harm to colitis.
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Intestinal anti-inflammatory activity of the Serpylli herba extract in experimental models of rodent colitis. J Crohns Colitis 2014; 8:775-88. [PMID: 24411672 DOI: 10.1016/j.crohns.2013.12.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 12/02/2013] [Accepted: 12/17/2013] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Nowadays, there is an increasing interest for alternative options in the treatment of inflammatory bowel diseases (IBDs) that combine efficacy and an adequate safety profile. METHODS The intestinal anti-inflammatory effects of Serpylli herba, the officinal drug in the European Pharmacopeia composed by the aerial parts of wild thyme (Thymus serpyllum), were evaluated in the trinitrobenzenesulfonic acid (TNBS)-induced rat colitis and dextran sodium sulfate (DSS)-induced mouse colitis, which are well characterized experimental models with some resemblance to human IBD. RESULTS S. herba extract exerted an intestinal anti-inflammatory effect in both experimental models of colitis, as evidenced both histologically, since it facilitated the tissue recovery of the damaged colon, and biochemically as showed by the improvement of the different inflammatory markers evaluated, including myeloperoxidase activity, glutathione content, and leukotriene B4 levels as well as the expression of the inducible proteins iNOS and COX-2. This beneficial effect was associated with the reduction in the expression of different cytokines, like TNFα, IL-1β, IFNγ, IL-6 and IL-17, the chemokine MCP-1, and the adhesion molecule ICAM-1, thus ameliorating the altered immune response associated with the colonic inflammation. CONCLUSION S. herba extract displays an anti-inflammatory effect on different models of rodent colitis that could be attributed to its immunomodulatory properties.
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Li J, Chen C, Cao XN, Wang GH, Hu JB, Wang J. Efficacy of topical versus oral 5-aminosalicylate for treatment of 2,4,6-trinitrobenzene sulfonic acid-induced ulcerative colitis in rats. ACTA ACUST UNITED AC 2014; 34:59-65. [PMID: 24496680 DOI: 10.1007/s11596-014-1232-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Revised: 10/28/2013] [Indexed: 02/07/2023]
Abstract
5-aminosalicylic acid (5-ASA) is drug of choice for the treatment of ulcerative colitis (UC). In this study, the efficacy of topical versus oral 5-ASA for the treatment of UC was examined as well as the action mechanism of this medication. A flexible tube was inserted into the rat cecum to establish a topical administration model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced UC. A total of 60 rats were divided into sham operation group (receiving an enema of 0.9% saline solution instead of the TNBS solution via the tube), model group, topical 5-ASA group, oral Etiasa group (a release agent of mesalazine used as positive control) and oral 5-ASA group (n=12 each). Different treatments were administered 1 day after UC induction. The normal saline (2 mL) was instilled twice a day through the tube in the sham operation group and model group. 5-ASA was given via the tube in the topical 5-ASA group (7.5 g/L, twice per day, 100 mg/kg), and rats in the oral Etiasa group and oral 5-ASA group intragastrically received Etiasa (7.5 g/L, twice per day, 100 mg/kg) and 5-ASA (7.5 g/L, twice per day, 100 mg/kg), respectively. The body weight was recorded every day. After 7 days of treatment, blood samples were drawn from the heart to harvest the sera. Colonic tissues were separated and prepared for pathological and related molecular biological examinations. The concentrations of 5-ASA were detected at different time points in the colonic tissues, feces and sera in different groups by using the high pressure liquid chromatography (HPLC). The results showed that the symptoms of acute UC, including bloody diarrhea and weight loss, were significantly improved in topical 5-ASA-treated rats. The colonic mucosal damage, both macroscopical and histological, was significantly relieved and the myeloperoxidase activity was markedly decreased in rats topically treated with 5-ASA compared with those treated with oral 5-ASA or Etiasa. The mRNA and protein expression of IL-1β, IL-6, and TNF-α was down-regulated in the colonic tissue of rats topically treated with 5-ASA, significantly lower than those from rats treated with oral 5-ASA or Etiasa. The concentrations of 5-ASA in the colonic tissue were significantly higher in the topical 5-ASA group than in the oral 5-ASA and oral Etiasa groups. It was concluded that the topical administration of 5-ASA can effectively increase the concentration of 5-ASA in the colonic tissue, decrease the expression of proinflammatory cytokines, alleviate the colonic pathological damage and improve the symptoms of TNBS-induced acute UC in rats.
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Affiliation(s)
- Jin Li
- Department of Oncology Surgery, Xuzhou Central Hospital (Affiliated Hospital of Medical College of Southeast University), Xuzhou, 221009, China
| | - Cheng Chen
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xiao-Nian Cao
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Gui-Hua Wang
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jun-Bo Hu
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Jing Wang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Leung L, Kang J, Rayyan E, Bhakta A, Barrett B, Larsen D, Jelinek R, Willey J, Cochran S, Broderick TL, Al-Nakkash L. Decreased basal chloride secretion and altered cystic fibrosis transmembrane conductance regulatory protein, Villin, GLUT5 protein expression in jejunum from leptin-deficient mice. Diabetes Metab Syndr Obes 2014; 7:321-30. [PMID: 25092993 PMCID: PMC4112754 DOI: 10.2147/dmso.s63714] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Patients with diabetes and obesity are at increased risk of developing disturbances in intestinal function. In this study, we characterized jejunal function in the clinically relevant leptin-deficient ob/ob mouse, a model of diabetes and obesity. We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from 12-week-old ob/ob and lean C57BL/6J (female and male) mice. The basal Isc was significantly decreased (~30%) in the ob/ob mice (66.5±5.7 μA/cm(2) [n=20]) (P< 0.05) compared with their lean counterparts (95.1±9.1 μA/cm(2) [n=19]). Inhibition with clotrimazole (100 μM, applied bilaterally) was significantly reduced in the ob/ob mice (-7.92%±3.67% [n=15]) (P<0.05) compared with the lean mice (10.44%±7.92% [n=15]), indicating a decreased contribution of Ca(2+)-activated K(+) (KCa) channels in the ob/ob mice. Inhibition with ouabain (100 μM, applied serosally) was significantly reduced in the ob/ob mice (1.40%±3.61%, n=13) (P< 0.05) versus the lean mice (18.93%±3.76% [n=18]), suggesting a potential defect in the Na(+)/K(+)-adenosine triphosphate (ATP)ase pump with leptin-deficiency. Expression of cystic fibrosis transmembrane conductance regulatory protein (CFTR) (normalized to glyceraldehyde-3-phosphate dehydrogenase [GAPDH]) was significantly decreased ~twofold (P<0.05) in the ob/ob mice compared with the leans, whilst crypt depth was unchanged. Villi length was significantly increased by ~25% (P<0.05) in the ob/ob mice compared with the leans and was associated with an increase in Villin and GLUT5 expression. GLUT2 and SGLT-1 expression were both unchanged. Our data suggests that reduced basal jejunal Isc in ob/ob mice is likely a consequence of reduced CFTR expression and decreased activity of the basolateral KCa channel and Na(+)/K(+)-ATPase. Understanding intestinal dysfunctions in ob/ob jejunum may allow for the development of novel drug targets to treat obesity and diabetes.
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Affiliation(s)
- Lana Leung
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Jonathan Kang
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Esa Rayyan
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Ashesh Bhakta
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Brennan Barrett
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - David Larsen
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Ryan Jelinek
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Justin Willey
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Scott Cochran
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Tom L Broderick
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Layla Al-Nakkash
- Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
- Correspondence: Layla Al-Nakkash, Department of Physiology, Midwestern University, 19555 N 59th Avenue, Glendale, AZ, 85308, USA, Tel +1 623 572 3719, Fax +1 623 572 3673, Email
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Orsi PR, Seito LN, Di Stasi LC. Hymenaea stigonocarpa Mart. ex Hayne: A tropical medicinal plant with intestinal anti-inflammatory activity in TNBS model of intestinal inflammation in rats. JOURNAL OF ETHNOPHARMACOLOGY 2013; 151:380-385. [PMID: 24211392 DOI: 10.1016/j.jep.2013.10.056] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 10/17/2013] [Accepted: 10/23/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Stem bark and fruit pulp of Hymenaea stigonocarpa Mart ex. Hayne (Fabaceae) has been popularly used to treat inflammation and gastrointestinal diseases including ulcers, diarrhea and gastric pain. The aim of this study was to investigate the intestinal anti-inflammatory activity of a methanol extract derived from the stem bark and diet with fruit pulp of Hymenaea stigonocarpa in the TNBS model of intestinal inflammation in rats. MATERIAL AND METHODS The intestinal anti-inflammatory activity of stem bark extract (100, 200 and 400mg/kg) and fruit pulp (10% and 5% in diet) was measured against the intestinal inflammatory process induced by TNBS (trinitrobenzesulphonic acid) in rats. The protective effects were evaluated as follows: evaluation of intestinal damage (damage score, extension of lesion, colon weight/length ratio), incidence of diarrhea and adherence to adjacent organs, colon glutathione (GSH) and malondialdehyde (MDA) contents, myeloperoxidase (MPO) and alkaline phosphatase (AP) activities. In addition, in vitro studies on lipid peroxidation in rat brain membranes and phytochemical profile were performed with both stem bark and fruit pulp. RESULTS Treatment with 100, 200 and 400mg/kg of stem bark extract and 10% fruit pulp flour showed protective effects in the TNBS-induced colon damage, which was related to inhibition of MPO and AP activities, reduction in colon MDA content, and counteraction of GSH depletion induced by inflammatory process. A concentration-dependent inhibitory effect on the lipid peroxidation in rat brain membranes for stem bark and fruit pulp was determined, with an IC50 value of 5.25 ± 0.23 μg/mL and 27.33 ± 0.09 μg/mL, respectively. Similar phytochemical composition was observed in fruit and stem bark, including mainly flavonoids, condensed tannins and terpenes. CONCLUSIONS Stem bark extract and fruit pulp flour of Hymenaea stigonocarpa prevented TNBS-induced colonic damage in rats and this protective effect were associated to an improvement of intestinal oxidative stress. The observed anti-inflammatory and antioxidant effects may be associated to the presence of flavonoids and tannins in the stem bark and fruit pulp of Hymenaea stigonocarpa.
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Affiliation(s)
- Patrícia Rodrigues Orsi
- Department of Pharmacology, Institute of Biosciences, Univ. Estadual Paulista, UNESP, Botucatu, SP, CEP 18618-970, Brazil
| | - Leonardo Noboru Seito
- Department of Pharmacology, Institute of Biosciences, Univ. Estadual Paulista, UNESP, Botucatu, SP, CEP 18618-970, Brazil
| | - Luiz Claudio Di Stasi
- Department of Pharmacology, Institute of Biosciences, Univ. Estadual Paulista, UNESP, Botucatu, SP, CEP 18618-970, Brazil.
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Epicatechin used in the treatment of intestinal inflammatory disease: an analysis by experimental models. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:508902. [PMID: 23346204 PMCID: PMC3546492 DOI: 10.1155/2012/508902] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 12/11/2012] [Indexed: 01/12/2023]
Abstract
Background. This study was pathway of (−)-epicatechin (EC) in the prevention and treatment of intestine inflammation in acute and chronic rat models. Methods. Intestine inflammation was induced in rats using TNBS. The morphological, inflammatory, immunohistochemical, and immunoblotting characteristics of colon samples were examined. The effects of EC were evaluated in an acute model at doses of 5, 10, 25, and 50 mg/kg by gavage for 5 days. The chronic colitis model was induced 1st day, and treated for 21 days. For the colitis relapse model, the induction was repeated on 14th. Results. EC10 and EC50 effectively reduced the lesion size, as assessed macroscopically; and confirmed by microscopy for EC10. The glutathione levels were higher in EC10 group but decreased COX-2 expression and increased cell proliferation (PC) were observed, indicating an anti-inflammatory activity and a proliferation-stimulating effect. In the chronic colitis model, EC10 showed lower macroscopic and microscopic lesion scores and increase in glutathione levels. As in the acute model, a decrease in COX-2 expression and an increase in PC in EC10, the chronic model this increase maybe by the pathway EGF expression. Conclusion. These results confirm the activity of EC as an antioxidant that reduces of the lesion and that has the potential to stimulate tissue healing, indicating useful for preventing and treating intestine inflammation.
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Fruet AC, Seito LN, Rall VLM, Di Stasi LC. Dietary intervention with narrow-leaved cattail rhizome flour (Typha angustifolia L.) prevents intestinal inflammation in the trinitrobenzenesulphonic acid model of rat colitis. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 12:62. [PMID: 22559191 PMCID: PMC3505175 DOI: 10.1186/1472-6882-12-62] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 05/04/2012] [Indexed: 12/18/2022]
Abstract
Background Inflammatory bowel disease (IBD) is a chronic inflammation of the intestinal epithelium that is driven by the intestinal immune system, oxidative stress and the loss of tolerance to the luminal microbiota. The use of dietary products containing ingredients such as fibres and carbohydrates and/or antioxidant compounds have been used as a therapeutic strategy for intestinal diseases because these products are considered effective in the modulation of the immune system and colonic microbiota. We investigated the beneficial effects of cattail rhizome flour (Typha angustifolia L.) in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. In addition, we investigated the effects of cattail rhizome flour on the intestinal anti-inflammatory activity of prednisolone, which is a reference drug that is used for treatment of human IBD. Methods The present study included the preparation of flour from rhizomes of cattail (Typha angustifolia L.); an evaluation of the qualitative phytochemical profile of cattail rhizomes; an evaluation of the efficacy of cattail rhizome flour in TNBS-induced rat colitis; an evaluation of the synergistic effects of cattail rhizome flour on the intestinal anti-inflammatory activity of prednisolone; and macroscopic, clinical, biochemical, histopathological and microbiological studies to assess the healing effects of cattail rhizome flour and its synergistic effects in TNBS-induced rat colitis. The data were analysed by ANOVA, Kruskal-Wallis and χ2 tests. Results We tested several concentrations of cattail rhizome flour and found that dietary supplementation with 10% cattail rhizome flour showed the best effects at reducing the extension of the lesion, the colon weight ratio, adherences to adjacent organs and diarrhoea. These effects were related to inhibition of myeloperoxidase (MPO) and alkaline phosphatase (AP) activities and an attenuation of glutathione (GSH) depletion. The 10% cattail rhizome flour was as effective as prednisolone, and no synergistic effects were observed. Saponins, flavonoids and coumarins were detected in the rhizome flour. No changes were observed in the total number of lactic bacteria after dietary supplementation with cattail rhizome flour. Conclusions Dietary supplementation with 10% cattail rhizome flour and its combination with prednisolone prevent TNBS-induced colonic damage in rats, but no synergistic effects were observed. The prevention of TNBS-induced colon damage was associated with an improvement in intestinal oxidative stress, which likely resulted from the antioxidant properties of the active compounds detected in the cattail rhizome. This protective effect was not related to an improvement in lactic bacteria counts.
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Scarminio V, Fruet AC, Witaicenis A, Rall VL, Di Stasi LC. Dietary intervention with green dwarf banana flour (Musa sp AAA) prevents intestinal inflammation in a trinitrobenzenesulfonic acid model of rat colitis. Nutr Res 2012; 32:202-9. [DOI: 10.1016/j.nutres.2012.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Revised: 12/13/2011] [Accepted: 01/09/2012] [Indexed: 10/28/2022]
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Takagi T, Naito Y, Uchiyama K, Okuda T, Mizushima K, Suzuki T, Handa O, Ishikawa T, Yagi N, Kokura S, Ichikawa H, Yoshikawa T. Rebamipide promotes healing of colonic ulceration through enhanced epithelial restitution. World J Gastroenterol 2011; 17:3802-9. [PMID: 21987622 PMCID: PMC3181441 DOI: 10.3748/wjg.v17.i33.3802] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Revised: 01/18/2011] [Accepted: 01/25/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy of rebamipide in a rat model of colitis and restitution of intestinal epithelial cells in vitro.
METHODS: Acute colitis was induced with trinitrobenzene sulfonic acid (TNBS) in male Wistar rats. Rats received intrarectal rebamipide treatment daily starting on day 7 and were sacrificed on day 14 after TNBS administration. The distal colon was removed to evaluate the various parameters of inflammation. Moreover, wound healing assays were used to determine the enhanced restitution of rat intestinal epithelial (RIE) cells treated with rebamipide.
RESULTS: Intracolonic administration of rebamipide accelerated TNBS-induced ulcer healing. Increases in the wet weight of the colon after TNBS administration were significantly inhibited by rebamipide. The wound assay revealed that rebamipide enhanced the migration of RIE cells through phosphorylation of extracellular signal-regulated kinase (ERK) and activation of Rho kinase.
CONCLUSION: Rebamipide enema healed intestinal injury by enhancing restitution of RIE cells, via ERK activation. Rebamipide might be a novel therapeutic approach for inflammatory bowel disease.
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Cestari SH, Bastos JK, Di Stasi LC. Intestinal Anti-Inflammatory Activity of Baccharis dracunculifolia in the Trinitrobenzenesulphonic Acid Model of Rat Colitis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2011:524349. [PMID: 19592480 PMCID: PMC3136549 DOI: 10.1093/ecam/nep081] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2009] [Accepted: 05/28/2009] [Indexed: 12/27/2022]
Abstract
Baccharis dracunculifolia DC (Asteraceae) is a Brazilian medicinal plant popularly used for its antiulcer and anti-inflammatory properties. This plant is the main botanical source of Brazilian green propolis, a natural product incorporated into food and beverages to improve health. The present study aimed to investigate the chemical profile and intestinal anti-inflammatory activity of B. dracunculifolia extract on experimental ulcerative colitis induced by trinitrobenzenosulfonic acid (TNBS). Colonic damage was evaluated macroscopically and biochemically through its evaluation of glutathione content and its myeloperoxidase (MPO) and alkaline phosphatase activities. Additional in vitro experiments were performed in order to test the antioxidant activity by inhibition of induced lipid peroxidation in the rat brain membrane. Phytochemical analysis was performed by HPLC using authentic standards. The administration of plant extract (5 and 50 mg kg−1) significantly attenuated the colonic damage induced by TNBS as evidenced both macroscopically and biochemically. This beneficial effect can be associated with an improvement in the colonic oxidative status, since plant extract prevented glutathione depletion, inhibited lipid peroxidation and reduced MPO activity. Caffeic acid, p-coumaric acid, aromadendrin-4-O-methyl ether, 3-prenyl-p-coumaric acid, 3,5-diprenyl-p-coumaric acid and baccharin were detected in the plant extract.
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Affiliation(s)
- Sílvia Helena Cestari
- Laboratory of Phytomedicines, Department of Pharmacology, Instituto de Biociências, São Paulo State University-UNESP, Botucatu 18.618-000, São Paulo, Brazil
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Witaicenis A, Fruet AC, Salem L, Di Stasi LC. Dietary polydextrose prevents inflammatory bowel disease in trinitrobenzenesulfonic acid model of rat colitis. J Med Food 2011; 13:1391-6. [PMID: 21091252 DOI: 10.1089/jmf.2009.0275] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a multifactorial intestinal disorder that involves interactions among the immune system, genetic susceptibility, and environmental factors, especially the bacterial flora. Polydextrose, a polysaccharide constituted by 90% nondigestible and nonabsorbable soluble fibers, has several physiological effects consistent with those of dietary fibers, including proliferation of colon microflora. Because sulfasalazine presents serious side effects through long-term use at high doses, the aim of the present study was to evaluate the preventative effect of polydextrose on trinitrobenzenesulfonic acid-induced intestinal inflammation and its effects on the intestinal anti-inflammatory activity of sulfasalazine. Results indicated that polydextrose and its association with sulfasalazine present an anti-inflammatory effect that reduces myeloperoxidase activity, counteracts glutathione content, and promotes reductions in lesion extension and colonic weight/length ratio.
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Affiliation(s)
- Aline Witaicenis
- Laboratory of Phytomedicines, Department of Pharmacology, Institute of Biosciences, São Paulo State University-UNESP, Botucatu, São Paulo, Brazil
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Shi XZ, Winston JH, Sarna SK. Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis. Am J Physiol Gastrointest Liver Physiol 2011; 300:G41-51. [PMID: 20947704 PMCID: PMC3025515 DOI: 10.1152/ajpgi.00358.2010] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Crohn's disease and ulcerative colitis are clinically, immunologically, and morphologically distinct forms of inflammatory bowel disease (IBD). However, smooth muscle function is impaired similarly in both diseases, resulting in diarrhea. We tested the hypothesis that differential cellular, genetic, and immunological mechanisms mediate smooth muscle dysfunction in two animal models believed to represent the two diseases. We used the rat models of trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colonic inflammations, which closely mimic the clinical and morphological features of Crohn's disease and ulcerative colitis, respectively. DSS inflammation induced oxidative stress initially in mucosa/submucosa, which then propagated to the muscularis externa to impair smooth muscle function. The muscularis externa showed no increase of cytokines/chemokines. On the other hand, TNBS inflammation almost simultaneously induced oxidative stress, recruited or activated immune cells, and generated cytokines/chemokines in both mucosa/submucosa and muscularis externa. The generation of cytokines/chemokines did not correlate with the recruitment and activation of immune cells. Consequently, the impairment of smooth muscle function in DSS inflammation was primarily due to oxidative stress, whereas that in TNBS inflammation was due to both oxidative stress and proinflammatory cytokines. The impairment of smooth muscle function in DSS inflammation was due to suppression of Gα(q) protein of the excitation-contraction coupling. In TNBS inflammation, it was due to suppression of the α(1C)1b subunit of Ca(v)1.2b channels, CPI-17 and Gα(q). TNBS inflammation increased IGF-1 and TGF-β time dependently in the muscularis externa. IGF-1 induced smooth muscle hyperplasia; both IGF-1 and TGF-β induced hypertrophy. In conclusion, both TNBS and DSS induce transmural inflammation, albeit with different types of inflammatory mediators. The recruitment or activation of immune cells does not correlate directly with the intensity of generation of inflammatory mediators. The inflammatory mediators in TNBS and DSS inflammations target different genes to impair smooth muscle function.
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Affiliation(s)
- Xuan-Zheng Shi
- 1Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine and
| | - John H. Winston
- 1Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine and
| | - Sushil K. Sarna
- 1Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine and ,2Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas
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Shi XZ, Sarna SK. Homeostatic and therapeutic roles of VIP in smooth muscle function: myo-neuroimmune interactions. Am J Physiol Gastrointest Liver Physiol 2009; 297:G716-25. [PMID: 19661154 PMCID: PMC2763800 DOI: 10.1152/ajpgi.00194.2009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We tested the hypothesis that spontaneous release of vasoactive intestinal peptide (VIP) from enteric neurons maintains homeostasis in smooth muscle function in mild inflammatory insults and that infusion of exogenous VIP has therapeutic effects on colonic smooth muscle dysfunction in inflammation. In vitro experiments were performed on human colonic circular smooth muscle tissues and in vivo on rats. The incubation of human colonic circular smooth muscle strips with TNF-alpha suppressed their contractile response to ACh and the expression of the pore-forming alpha(1C) subunit of Ca(v)1.2 channels. VIP reversed both effects by blocking the translocation of NF-kappaB to the nucleus and its binding to the kappaB recognition sites on halpha(1C)1b promoter. The translocation of NF-kappaB was inhibited by blocking the degradation of IkappaBbeta. Induction of inflammation by a subthreshold dose of 17 mg/kg trinitrobenzene sulfonic acid (TNBS) in rats moderately decreased muscularis externa concentration of VIP, and it had little effect on the contractile response of circular smooth muscle strips to ACh. The blockade of VIP and pituitary adenylate cyclase-activating peptide receptors 1/2 during mild inflammatory insult significantly worsened the suppression of contractility and the inflammatory response. The induction of more severe inflammation by 68 mg/kg TNBS induced marked suppression of colonic circular muscle contractility and decrease in serum VIP. Exogenous infusion of VIP by an osmotic pump reversed these effects. We conclude that the spontaneous release of VIP from the enteric motor neurons maintains homeostasis in smooth muscle function in mild inflammation by blocking the activation of NF-kappaB. The infusion of exogenous VIP mitigates colonic inflammatory response and smooth muscle dysfunction.
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Affiliation(s)
- Xuan-Zheng Shi
- 1Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine and
| | - Sushil K. Sarna
- 1Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine and ,2Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas
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Arribas B, Rodríguez-Cabezas ME, Camuesco D, Comalada M, Bailón E, Utrilla P, Nieto A, Concha A, Zarzuelo A, Gálvez J. A probiotic strain of Escherichia coli, Nissle 1917, given orally exerts local and systemic anti-inflammatory effects in lipopolysaccharide-induced sepsis in mice. Br J Pharmacol 2009; 157:1024-33. [PMID: 19486007 PMCID: PMC2737661 DOI: 10.1111/j.1476-5381.2009.00270.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Revised: 02/12/2009] [Accepted: 02/18/2009] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Escherichia coli Nissle 1917 is a probiotic strain used in the treatment of intestinal immune diseases, including ulcerative colitis. The aim of the present study was to test if this probiotic bacterium can also show systemic immunomodulatory properties after oral administration. EXPERIMENTAL APPROACH The probiotic strain was administered to rats or mice for 2 weeks before its assay in two experimental models of altered immune response, the trinitrobenzenesulphonic acid (TNBS) model of rat colitis, localized in the colon, and the lipopolysaccharide (LPS) model of systemic septic shock in mice. Inflammatory status was evaluated both macroscopically and biochemically after 1 week in the TNBS model or after 24 h in the LPS shock model. In addition, splenocytes were obtained from mice and stimulated, ex vivo, with concanavalin A or LPS to activate T or B cells, respectively, and cytokine production (IL-2, IL-5 and IL-10) by T cells and IgG secretion by B cells measured. KEY RESULTS E. coli Nissle 1917 was anti-inflammatory in both models of altered immune response. This included a reduction in the pro-inflammatory cytokine tumour necrosis factor-alpha both in the intestine from colitic rats, and in plasma and lungs in mice treated with LPS. The systemic beneficial effect was associated with inhibited production of the T cell cytokines and by down-regulation of IgG release from splenocyte-derived B cells. CONCLUSIONS AND IMPLICATIONS The anti-inflammatory effects of E. coli Nissle 1917 given orally were not restricted to the gastrointestinal tract.
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Affiliation(s)
- B Arribas
- Centro de Investigaciones Biomédicas en Red - Enfermedades Hepáticas y Digestivas (CIBER-EHD), Department of Pharmacology, Center for Biomedical Research, University of Granada, Granada, Spain
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Relationship between mast cells and the colitis with relapse induced by trinitrobenzesulphonic acid in Wistar rats. Mediators Inflamm 2009; 2009:432493. [PMID: 19436763 PMCID: PMC2680139 DOI: 10.1155/2009/432493] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2008] [Revised: 01/15/2009] [Accepted: 03/17/2009] [Indexed: 01/29/2023] Open
Abstract
The present study aimed to clarify the role of mast cells in colitis with
relapse induced in Wistar rats by trinitrobenzenosulphonic
acid. Colitis induction increased the histamine concentration
in the colon, which peaked on day 26. The number of mast cells,
probably immature, was ten times higher on day 8. Different from
animals infected with intestinal parasites, after colitis remission,
mast cells do not migrate to the spleen, showing that mast cell
proliferation presents different characteristics depending on the
inflammation stimuli. Treatment with sulfasalazine, doxantrazole,
quercetin, or nedocromil did not increase the histamine concentration
or the mast cell number in the colon on day 26, thereby showing
absence of degranulation of these cells. In conclusion, although mast
cell proliferation is associated with colitis, these cells and their
mediators appear to play no clear role in the colitis with
relapses.
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Motagally MA, Neshat S, Lomax AE. Inhibition of sympathetic N-type voltage-gated Ca2+ current underlies the reduction in norepinephrine release during colitis. Am J Physiol Gastrointest Liver Physiol 2009; 296:G1077-84. [PMID: 19264956 DOI: 10.1152/ajpgi.00006.2009] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and impairment of norepinephrine release from sympathetic varicosities. The sympathetic innervation of the GI tract modulates motility, blood flow, and secretion, and therefore defective norepinephrine release may contribute to symptom generation in IBD. Accordingly, our aim here was to utilize the mouse model of dextran sulfate sodium (DSS; 5% wt/vol) of IBD to determine how norepinephrine release is reduced during GI inflammation. We hypothesized that the inflammation-induced reduction in norepinephrine release was due to inhibition of voltage-gated Ca(2+) current (I(Ca)) in prevertebral sympathetic neurons. We compared [(3)H]norepinephrine release in the colon and jejunum and I(Ca) amplitude in superior mesenteric ganglion (SMG) neurons from control mice and mice with DSS-induced colitis. Changes to voltage-gated Ca(2+) channels were investigated by fura 2-AM Ca(2+) imaging, perforated patch-clamp electrophysiology, and real-time PCR. Depolarization-induced norepinephrine release from the inflamed colon and uninflamed jejunum was significantly impaired in mice treated with DSS, as was depolarization-induced Ca(2+) influx in SMG neurons. Colitis reduced I(Ca) in SMG neurons by inhibiting omega-conotoxin GVIA (300 nM)-sensitive N-type Ca(2+) channels. The omega-conotoxin GVIA-sensitive component of norepinephrine release was significantly smaller in the colon during colitis. The inhibition of I(Ca) was accompanied by a decrease in mRNA encoding the Ca(2+) channel alpha subunit (CaV 2.2) and a rightward shift in the voltage dependence of activation of I(Ca). These findings suggest that DSS-induced colitis attenuates norepinephrine release in the colon and jejunum due to inhibition of N-type voltage-gated Ca(2+) channels. This may contribute to functional alterations in both inflamed and uninflamed regions of the GI tract during inflammation.
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Affiliation(s)
- Mohamed A Motagally
- Department of Physiology, Gastrointestinal Diseases Research Unit and Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
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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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Saksena S, Dwivedi A, Singla A, Gill RK, Tyagi S, Borthakur A, Alrefai WA, Ramaswamy K, Dudeja PK. Characterization of the 5'-flanking region and regulation of expression of human anion exchanger SLC26A6. J Cell Biochem 2008; 105:454-66. [PMID: 18655181 PMCID: PMC2705132 DOI: 10.1002/jcb.21842] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
SLC26A6 (putative anion transporter 1, PAT1) has been shown to play an important role in mediating the luminal Cl(-)/OH(-)(HCO(3)(-)) exchange process in the intestine. Very little is known about the molecular mechanisms involved in the transcriptional regulation of intestinal SLC26A6 gene expression in the intestine. Current studies were, therefore, designed to clone and characterize the 5'-regulatory region of the human SLC26A6 gene and determine the mechanisms involved in its regulation. A 1,120 bp (p-964/+156) SLC26A6 promoter fragment cloned upstream to the luciferase reporter gene in pGL2-basic exhibited high promoter activity when transfected in Caco2 cells. Progressive deletions of the 5'-flanking region demonstrated that -214/-44 region of the promoter harbors cis-acting elements important for maximal SLC26A6 promoter activity. Since, diarrhea associated with inflammatory bowel diseases is attributed to increased secretion of pro-inflammatory cytokines, we examined the effects of IFNgamma (30 ng/ml, 24 h) on SLC26A6 function, expression and promoter activity. IFNgamma decreased both SLC26A6 mRNA and function and repressed SLC26A6 promoter activity. Deletion analysis indicated that IFNgamma response element is located between -414/-214 region and sequence analysis of this region revealed the presence of potential Interferon Stimulated Responsive Element (ISRE), a binding site (-318/-300 bp) for interferon regulatory factor-1 transcription factor (IRF-1). Mutations in the potential ISRE site abrogated the inhibitory effects of IFNgamma. These studies provided novel evidence for the involvement of IRF-1 in the regulation of SLC26A6 gene expression by IFNgamma in the human intestine.
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Affiliation(s)
- Seema Saksena
- Department of Medicine, University of Illinois at Chicago, Jesse Brown VA Medical Center, Chicago, Illinois 60612, USA.
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Luchini AC, Rodrigues-Orsi P, Cestari SH, Seito LN, Witaicenis A, Pellizzon CH, Di Stasi LC. Intestinal anti-inflammatory activity of coumarin and 4-hydroxycoumarin in the trinitrobenzenesulphonic acid model of rat colitis. Biol Pharm Bull 2008; 31:1343-50. [PMID: 18591772 DOI: 10.1248/bpb.31.1343] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Coumarins represent an important class of phenolic compounds with multiple biological activities, including inhibition of lipidic peroxidation and neutrophil-dependent anion superoxide generation, anti-inflammatory and immunosuppressor actions. All of these proprieties are essential for that a drug may be used in the treatment of inflammatory bowel disease. The present study examined intestinal anti-inflammatory activity of coumarin and its derivative, the 4-hydroxycoumarin on experimental ulcerative colitis in rats. This was performed in two different experimental settings, i.e. when the colonic mucosa is intact or when the mucosa is in process of recovery after an initial insult. The results obtained revealed that the coumarin and 4-hydroxycoumarin, at doses of 5 and 25 mg/kg, significantly attenuated the colonic damage induced by trinitrobenzenesulphonic acid (TNBS) in both situations, as evidenced macroscopically, microscopically and biochemically. This effect was related to an improvement in the colonic oxidative status, since coumarin and 4-hydroxycoumarin prevented the glutathione depletion that occurred as a consequence of the colonic inflammation.
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Affiliation(s)
- Ana Carolina Luchini
- Laboratory of Phytomedicines, Department of Pharmacology, Instituto de Biociências, São Paulo State University (UNESP), Botucatu, SP, Brazil
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Chung HL, Yue GGL, To KF, Su YL, Huang Y, Ko WH. Effect of Scutellariae Radix extract on experimental dextran-sulfate sodium-induced colitis in rats. World J Gastroenterol 2007; 13:5605-11. [PMID: 17948935 PMCID: PMC4172740 DOI: 10.3748/wjg.v13.i42.5605] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the effect of Scutellariae Radix extract (SRE) on ulcerative colitis (UC) in rats induced by dextran-sulfate sodium (DSS).
METHODS: Colitis was induced in male Sprague-Dawley (SD) rats (170-180 g) by 4% dextran sulfate sodium (DSS, wt/v; MW 54000) in drinking water for 8 d. The treated rats received 4% DSS and SRE orally (100 mg/kg per day). Control rats received either tap water or SRE only. Macroscopic assessment which included body weight changes, fecal occult blood and stool consistency were determined daily. At the appointed time, the rats were sacrificed and the entire colons were removed. The colon length and the myeloperoxidase (MPO) activity were measured. The severity of colitis was graded by morphological and histological assessments. The ion transport activity of the colonic mucosa was assessed by electrophysiological technique.
RESULTS: Rats treated with oral administration of 4% DSS regularly developed clinical and macroscopic signs of colitis. Treatment with SRE relieved the symptoms, including the reduction in body weight, shortening and ulceration of the colon. Administration of SRE also significantly reduced the histological damage induced by DSS. Moreover, the ISC responses of the colonic mucosa to forskolin were suppressed after the induction of colitis. The stimulated ion transport activity of DSS-rats treated with SRE displayed significant improvement in the secretory responsiveness.
CONCLUSION: SRE was effective in treating acute DSS-induced ulcerative colitis, as gauged by reduced clinical disease, improved macroscopic and histological damage scores, and enhanced recovery of normal colonic secretory function.
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Peran L, Camuesco D, Comalada M, Nieto A, Concha A, Adrio JL, Olivares M, Xaus J, Zarzuelo A, Galvez J. Lactobacillus fermentum, a probiotic capable to release glutathione, prevents colonic inflammation in the TNBS model of rat colitis. Int J Colorectal Dis 2006; 21:737-46. [PMID: 16052308 DOI: 10.1007/s00384-005-0773-y] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/05/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel disease is associated with intestinal oxidative stress. In the present study we test the preventative effect of Lactobacillus fermentum, a probiotic that produces per se glutathione, in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. METHODS Colitis was induced in rats by intracolonic administration of 10 mg of TNBS dissolved in 0.25 ml of 50% ethanol. L. fermentum was administered orally (5x10(8) CFU suspended in 0.5 ml of skim milk) to a group of rats for 3 weeks, starting 2 weeks before colitis induction. Colonic damage was evaluated both histologically and biochemically, and the colonic luminal contents were used for bacterial studies as well as for short chain fatty acid (SCFA) production. RESULTS L. fermentum treatment resulted in an amelioration of the inflammatory response in colitic rats as evidenced histologically and by a significant reduction of colonic MPO activity (P<0.05). The probiotic partially counteracted the colonic glutathione depletion induced by the inflammatory process. In addition, probiotic-treated colitic rats showed significant lower colonic tumour necrosis factor (TNF)alpha levels (P<0.01) and inducible nitric oxide synthase (iNOS) expression when compared to non-treated rats. Finally, the probiotic induced growth of Lactobacilli species and production of SCFA in colonic contents in comparison with control colitic rats. CONCLUSION Administration of the probiotic L. fermentum facilitates the recovery of the inflamed tissue in the TNBS model of rat colitis, an effect associated with increased levels of glutathione as well as with amelioration of the production of some of the mediators involved in the inflammatory response of the intestine, such as TNFalpha and NO.
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Affiliation(s)
- Laura Peran
- Department of Pharmacology, School of Pharmacy, University of Granada, Campus Universitario La Cartuja s/n, 18071 Granada, Spain
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Spencer SJ, Hyland NP, Sharkey KA, Pittman QJ. Neonatal immune challenge exacerbates experimental colitis in adult rats: potential role for TNF-alpha. Am J Physiol Regul Integr Comp Physiol 2006; 292:R308-15. [PMID: 16973935 DOI: 10.1152/ajpregu.00398.2006] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Early life events and childhood infections have been associated with the development and onset of inflammatory bowel disease in adulthood. However, the consequences of neonatal infection in the development and severity of colitis are not established. We investigated the effects of a neonatal (postnatal day 14) or juvenile (postnatal day 28) immune challenge with LPS on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced damage and weight loss, as well as on food intake and body temperature in adult rats. Neonatally (n)LPS-treated rats developed more severe colitis than control animals, reflected in a greater loss of weight and a significantly increased macroscopic tissue damage score. These findings were associated with a hypothermic response after TNBS treatment in nLPS rats, but not in neonatally saline-treated rats receiving TNBS. These differences were not seen after TNBS in rats that had received LPS on postnatal day 28. Plasma corticosterone was measured as an index of adult hypothalamic-pituitary-adrenal (HPA) axis activation as was TNF-alpha, a proinflammatory cytokine associated with inflammatory bowel disease. Four days after TNBS treatment, plasma corticosterone was unaltered in all groups; however, TNF-alpha was significantly increased in adult TNBS-treated rats that had LPS as neonates compared with all other groups. In conclusion, neonatal, but not later, exposure to LPS produces long-term exacerbations in the development of colitis in adults. This change is independent of HPA axis activation 4 days after TNBS treatment but is associated with increased circulating TNF-alpha, suggestive of an exaggerated immune response in adults exposed to neonatal infection.
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Affiliation(s)
- Sarah J Spencer
- Hotchkiss Brain Institute and Institute of Infection, Immunity, and Inflammation, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
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Comalada M, Bailón E, de Haro O, Lara-Villoslada F, Xaus J, Zarzuelo A, Gálvez J. The effects of short-chain fatty acids on colon epithelial proliferation and survival depend on the cellular phenotype. J Cancer Res Clin Oncol 2006; 132:487-97. [PMID: 16788843 DOI: 10.1007/s00432-006-0092-x] [Citation(s) in RCA: 153] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2005] [Accepted: 03/01/2006] [Indexed: 12/12/2022]
Abstract
PURPOSE The short-chain fatty acids (SCFA) are produced via anaerobic bacterial fermentation of dietary fiber within the colonic lumen. Among them, butyrate is thought to protect against colon carcinogenesis. However, few studies analyze the effects of butyrate, and other SCFA, on normal epithelial cells and on epithelial regeneration during disease recovery. Since there are controversial in vitro studies, we have explored the effects of SCFA on different biological processes. METHODS We used both tumoral (HT-29) and normal (FHC) epithelial cells at different phenotypic states. In addition, we analyzed the in vivo activity of soluble dietary fiber and SCFA production in the proliferation rate and regeneration of intestinal epithelial cells. RESULTS The effect of butyrate on epithelial cells depends on the phenotypic cellular state. Thus, in nondifferentiated, high proliferative adenocarcinoma cells, butyrate significantly inhibited proliferation while increased differentiation and apoptosis, whereas other SCFA studied did not. However, in normal cells or in differentiated cultures as well as in in vivo studies, the normal proliferation and regeneration of damaged epithelium is not affected by butyrate or SCFA exposure. CONCLUSION Although butyrate could exert antiproliferative effects in tumor progression, its production is safe and without consequences for the normal epithelium growth.
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Affiliation(s)
- Mònica Comalada
- Department of Pharmacology, School of Pharmacy, University of Granada, Campus Universitario "La Cartuja" s/n, 18071, Granada, Spain.
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