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Kaden T, Alonso‐Román R, Stallhofer J, Gresnigt MS, Hube B, Mosig AS. Leveraging Organ-on-Chip Models to Investigate Host-Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease. Adv Healthc Mater 2025; 14:e2402756. [PMID: 39491534 PMCID: PMC12004439 DOI: 10.1002/adhm.202402756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/29/2024] [Indexed: 11/05/2024]
Abstract
Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.
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Affiliation(s)
- Tim Kaden
- Dynamic42 GmbH07745JenaGermany
- Institute of Biochemistry IICenter for Sepsis Control and CareJena University Hospital07747JenaGermany
| | - Raquel Alonso‐Román
- Department of Microbial Pathogenicity MechanismsLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Junior Research Group Adaptive Pathogenicity StrategiesLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
| | | | - Mark S. Gresnigt
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Junior Research Group Adaptive Pathogenicity StrategiesLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
| | - Bernhard Hube
- Department of Microbial Pathogenicity MechanismsLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Institute of MicrobiologyFaculty of Biological SciencesFriedrich Schiller University07743JenaGermany
| | - Alexander S. Mosig
- Institute of Biochemistry IICenter for Sepsis Control and CareJena University Hospital07747JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
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2
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Wang Y, Huang Z, Gui Z, Yang B, You F, Yang G, Zhang X, Chang X, Meng X. Supplementation with Akkermansia muciniphila improved intestinal barrier and immunity in zebrafish (Danio rerio). FISH & SHELLFISH IMMUNOLOGY 2024; 154:109935. [PMID: 39357628 DOI: 10.1016/j.fsi.2024.109935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 09/28/2024] [Accepted: 09/29/2024] [Indexed: 10/04/2024]
Abstract
Akkermansia muciniphila (Akk), a second-generation probiotic known for its ability to regulate intestinal function in mammals, is not yet fully understood in the context of aquaculture. This study aims to investigate the effects of different forms of Akk on intestinal barrier function and immune response in zebrafish (Danio rerio) under high-fat diet conditions. The experimental groups included a control group, a high-fat diet group, an Akk group, and a group receiving various concentrations of pasteurized Akkermansia muciniphila (P-Akk) along with a high-fat diet. Evaluation methods included histological examination with hematoxylin and eosin staining, ultrastructural analysis using transmission electron microscopy, real-time fluorescence quantitative analysis, and transcriptome sequencing technology. The results showed that both the Akk and P-Akk groups exhibited a significant increase in villi number and length compared to the high-fat group. Furthermore the expression levels of claudin, claudin-2, occludin A, occludin B, and other genes were significantly upregulated, while the expression levels of intestinal proinflammatory factors genes and proteins were significantly downregulated. Compared to the high-fat group, the Akk group showed a more complete and well-preserved nucleus, mitochondria, and tight junction structures. Additionally, the morphology of intestinal epithelial microvilli in the medium and high concentration Akk group was complete and dense. The expressions of tlr2 and nf-κb were upregulated, while the expressions of myd88 and nod2 were downregulated in the medium- and high-concentration Akk groups. Akk may improve immune dysfunction in high-fat fed zebrafish through the TLR2/NF-κB signaling pathway, which requires further study. Transcriptome analysis revealed significant upregulation of the immune-related gene pigr, significant downregulation of stat3, and significant upregulation of the intercellular adhesion molecule f11r. In conclusion, dietary Akk supplementation alleviated intestinal barrier damage and immune dysfunction in high-fat zebrafish. This study provides important insights into the potential use of Akk in fish and lays the foundation for further studies on its role in fish immunity.
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Affiliation(s)
- Yawei Wang
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China.
| | - Zhenyi Huang
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China.
| | - Zewei Gui
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China.
| | - Boya Yang
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China.
| | - Fu You
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China.
| | - Guokun Yang
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, 453007, PR China.
| | - Xindang Zhang
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, 453007, PR China.
| | - Xulu Chang
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, 453007, PR China.
| | - Xiaolin Meng
- College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, 453007, PR China.
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3
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Li Q, Zhang S, Zhou Q, Gu C, Liu Y, Zhang J, Zhang J. Tocotrienol suppresses colitis-associated cancer progression through TLR4 signaling in a mouse model of colorectal cancer. Curr Res Toxicol 2024; 7:100196. [PMID: 39411685 PMCID: PMC11474223 DOI: 10.1016/j.crtox.2024.100196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 09/20/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
This study aimed to evaluate the preventive efficacy of tocotrienol in inhibiting the nuclear factor-kappa B (NF-κB) mediated inflammation pathways in colorectal cancer. We utilized the azoxymethane (AOM) and dextran sulfate sodium salt (DSS) to induce colitis-associated colorectal cancer (CAC) mice model. In generating a CAC model, mice were intraperitoneally injected with AOM at a concentration of 10 mg/kg body weight. Seven days after the AOM injection, mice drinking water containing 3 % DSS for 1 week, followed by a 2-week period of regular water. This cycle of DSS treatment (1-week 3 % DSS+2-week water) was repeated for two additional cycles. Mice were randomly divided into five groups (n = 20/group), including Blank group, Model group, three different dosages tocotrienol groups (Low dose group [50 mg/kg], Medium dose group [75 mg/kg], and High dose group [100 mg/kg]). The protective effects of tocotrienol were assessed using histological, flow cytometry, western blot and mouse Luminex assay. Compared with the blank group, expressions of toll-like receptor 4 (TLR4), myeloid differentiation protein 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF-6), NF-κB, Interleukin (IL)-6 and tumor necrosis factor (TNF) -α were increased in model group, while IL-4 and IL-10 were decreased in model group (P<0.05). Tocotrienol prevented carcinogenesis and decreased the IL-6, TNF-α, MyD88, TLR4, TRAF-6 and NF-κB expression levels, compared with the model group (P<0.05). Compared with the model group, the expression of IL-10 was increased in medium dose group and high dose group (P<0.05). The protective effects of tocotrienol may be related to the inhibition of TLR4 /MyD88 /NF-κB mediated inflammatory signaling pathways. Therefore, the use of tocotrienol can improve the abnormal expression of cytokines in a mouse model of colorectal cancer and inhibit the occurrence and development of colorectal cancer.
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Affiliation(s)
- Qian Li
- School of Public Health, Qilu Medical University, Shandong 255300, China
| | - Shujing Zhang
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
- NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Tianjin 300011, China
| | - Qinghong Zhou
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
- NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Tianjin 300011, China
| | - Chenxi Gu
- Disease Prevention and Control Center of Binhu District, Wuxi City, Jiangsu 214100, China
| | - Yinghua Liu
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
- NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Tianjin 300011, China
| | - Jing Zhang
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
- NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Tianjin 300011, China
| | - Jingshu Zhang
- School of Public Health, Nanjing Medical University, Nanjing 211166, China
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4
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Voitalov I, Zhang L, Kilpatrick C, Withers JB, Saleh A, Akmaev VR, Ghiassian SD. The module triad: a novel network biology approach to utilize patients' multi-omics data for target discovery in ulcerative colitis. Sci Rep 2022; 12:21685. [PMID: 36522454 PMCID: PMC9755270 DOI: 10.1038/s41598-022-26276-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Tumor necrosis factor-[Formula: see text] inhibitors (TNFi) have been a standard treatment in ulcerative colitis (UC) for nearly 20 years. However, insufficient response rate to TNFi therapies along with concerns around their immunogenicity and inconvenience of drug delivery through injections calls for development of UC drugs targeting alternative proteins. Here, we propose a multi-omic network biology method for prioritization of protein targets for UC treatment. Our method identifies network modules on the Human Interactome-a network of protein-protein interactions in human cells-consisting of genes contributing to the predisposition to UC (Genotype module), genes whose expression needs to be modulated to achieve low disease activity (Response module), and proteins whose perturbation alters expression of the Response module genes to a healthy state (Treatment module). Targets are prioritized based on their topological relevance to the Genotype module and functional similarity to the Treatment module. We demonstrate utility of our method in UC and other complex diseases by efficiently recovering the protein targets associated with compounds in clinical trials and on the market . The proposed method may help to reduce cost and time of drug development by offering a computational screening tool for identification of novel and repurposing therapeutic opportunities in UC and other complex diseases.
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Affiliation(s)
- Ivan Voitalov
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
| | - Lixia Zhang
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
| | - Casey Kilpatrick
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
| | - Johanna B. Withers
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
| | - Alif Saleh
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
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5
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Cao Q, Mertens RT, Sivanathan KN, Cai X, Xiao P. Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine. J Leukoc Biol 2022; 112:313-331. [PMID: 35593111 PMCID: PMC9543232 DOI: 10.1002/jlb.3ru0322-176r] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/06/2022] Open
Abstract
The intestinal tract is a complex ecosystem where numerous cell types of epithelial, immune, neuronal, and endothelial origin coexist in an intertwined, highly organized manner. The functional equilibrium of the intestine relies heavily on the proper crosstalk and cooperation among each cell population. Furthermore, macrophages are versatile, innate immune cells that participate widely in the modulation of inflammation and tissue remodeling. Emerging evidence suggest that macrophages are central in orchestrating tissue homeostasis. Herein, we describe how macrophages interact with epithelial cells, neurons, and other types of mesenchymal cells under the context of intestinal inflammation, followed by the therapeutic implications of cellular crosstalk pertaining to the treatment of inflammatory bowel disease.
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Affiliation(s)
- Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Randall Tyler Mertens
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kisha Nandini Sivanathan
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Xuechun Cai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Xiao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.,The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
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6
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Upadhyay G, Tiwari N, Maurya H, Upadhyay J, Joshi R, Ansari MN. In vivo wound-healing and antioxidant activity of aqueous extract of Roylea elegans leaves against physically induced burn model in Wistar albino rats. 3 Biotech 2021; 11:442. [PMID: 34631343 PMCID: PMC8455744 DOI: 10.1007/s13205-021-02993-4] [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: 07/05/2021] [Accepted: 09/10/2021] [Indexed: 01/04/2023] Open
Abstract
Roylea elegans Wall. ex Benth. is a lemon-scented hoary shrub belonging to the mint family (Lamiaceae). Traditionally, a local tribe of the Himalayan region uses leaves for scabs and skin infections. The aerial parts and leaves are widely used to cure various skin ailments. The plant is well known for two furanoid diterpenes, royeleganin and royelegafuran. The aqueous extract of Roylea elegans (AERE) leaves was investigated for wound-healing effects in rats using a physically induced burn model by assessing different parameters. Animals were divided into four groups (six rats in each group). Group I animals were considered as disease control and topically given base cream. Group II was considered as standard control and treated topically with Framycetin sulphate cream (1% w/w). Group III and IV animals were treated topically with creams containing 5 or 10% of AERE, respectively. Several parameters such as wound contraction rate, epithelialization period, and enzymatic and non-enzymatic antioxidant markers along with pro- and anti-inflammatory cytokines were studied followed by histopathological studies. The animals treated with AERE cream exhibited significant declination in the wound area and increased collagen content as compared to the disease control group. The results showed that the lower dose (5%) of AERE produced a significant decrease in the epithelialization period, wound contraction rate, and collagen content. Increased levels of cytokine production may be one of the mechanisms in accelerating the wound-healing process. The study established the traditional claim as an antioxidant and wound-healing potential of Roylea elegans by promoting the accelerated wound-healing activity against the physically induced burn model.
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Affiliation(s)
- Gaurav Upadhyay
- MIT College of Pharmacy, MIT Group of Institutions, Ram Ganga Vihar, Phase- II, MDA, Moradabad, 244001 Uttar Pradesh India
| | - Nidhi Tiwari
- Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organisation, Delhi, 110054 India
| | - Harikesh Maurya
- M.G.B. Rajat College of Pharmacy and Management, Baskhari, Gohila, Ambedkar Nagar, India
| | - Jyoti Upadhyay
- School of Health Sciences, Department of Pharmaceutical Sciences Energy Acre Campus, University of Petroleum and Energy Studies, Bidholi, Dehradun, 248007 Uttarakhand India
| | - Rohit Joshi
- Division of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palmpur, 176061 India
| | - Mohd Nazam Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Alkharj, 11942 Saudi Arabia
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7
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Hodoodi F, Allah-Tavakoli M, Tajik F, Fatemi I, Moghadam Ahmadi A. The effect of head cooling and remote ischemic conditioning on patients with traumatic brain injury. iScience 2021; 24:102472. [PMID: 34169235 PMCID: PMC8207229 DOI: 10.1016/j.isci.2021.102472] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/12/2020] [Accepted: 04/22/2021] [Indexed: 11/17/2022] Open
Abstract
Cerebral impairment caused by an external force to the head is known as traumatic brain injury (TBI). The aim of this study was to determine the role of local hypothermia and remote ischemic conditioning (RIC) on oxidative stress, inflammatory response after TBI, and other involved variables. The present study is a clinical trial on 84 patients with TBI who were divided into 4 groups. The head cooling for 1.5 to 6 hr was performed in the first three days after TBI. RIC intervention was performed within the golden time after TBI in the form of four 5-min cycles with full cuff and 5 min of emptying of cuff. The group receiving the head cooling technique recovered better than the group receiving the RIC technique. Generally, combination of the two interventions of head cooling and RIC techniques is more effective on the improvement of clinical status of patients than each separate technique.
The effect of the head cooling method in controlling secondary injury in patients with TBI. The effect of the RIC method in controlling secondary injury in patients with TBI. Comparison of two interventions of head cooling and RIC. Evaluation of clinical and paraclinical parameters.
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Affiliation(s)
- Fardin Hodoodi
- Department of Physiology and Pharmacology, Schoole of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
| | - Mohammad Allah-Tavakoli
- Department of Physiology and Pharmacology, Schoole of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
- Physiology-pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Farzad Tajik
- Department of Clinical Research Sciences, Department of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
- Department of Neurology, Department of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
| | - Iman Fatemi
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran
| | - Amir Moghadam Ahmadi
- Department of Neurology, Department of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Corresponding author
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8
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Bian X, Wu W, Yang L, Lv L, Wang Q, Li Y, Ye J, Fang D, Wu J, Jiang X, Shi D, Li L. Administration of Akkermansia muciniphila Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice. Front Microbiol 2019; 10:2259. [PMID: 31632373 PMCID: PMC6779789 DOI: 10.3389/fmicb.2019.02259] [Citation(s) in RCA: 380] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/17/2019] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) develop as a result of complex interactions among genes, innate immunity and environmental factors, which are related to the gut microbiota. Multiple clinical and animal data have shown that Akkermansia muciniphila is associated with a healthy mucosa. However, its precise role in colitis is currently unknown. Our study aimed to determine its protective effects and underlying mechanisms in a dextran sulfate sodium (DSS)-induced colitis mouse model. Twenty-four C57BL/6 male mice were administered A. muciniphila MucT or phosphate-buffered saline (PBS) once daily by oral gavage for 14 days. Colitis was induced by drinking 2% DSS from days 0 to 6, followed by 2 days of drinking normal water. Mice were weighed daily and then sacrificed on day 8. We found that A. muciniphila improved DSS-induced colitis, which was evidenced by reduced weight loss, colon length shortening and histopathology scores and enhanced barrier function. Serum and tissue levels of inflammatory cytokines and chemokines (TNF-α, IL1α, IL6, IL12A, MIP-1A, G-CSF, and KC) decreased as a result of A. muciniphila administration. Analysis of 16S rDNA sequences showed that A. muciniphila induced significant gut microbiota alterations. Furthermore, correlation analysis indicated that pro-inflammatory cytokines and other injury factors were negatively associated with Verrucomicrobia, Akkermansia, Ruminococcaceae, and Rikenellaceae, which were prominently abundant in A. muciniphila-treated mice. We confirmed that A. muciniphila treatment could ameliorate mucosal inflammation either via microbe-host interactions, which protect the gut barrier function and reduce the levels of inflammatory cytokines, or by improving the microbial community. Our findings suggest that A. muciniphila may be a potential probiotic agent for ameliorating colitis.
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Affiliation(s)
- Xiaoyuan Bian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Wenrui Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Liya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Longxian Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Qing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Yating Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Jianzhong Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Daiqiong Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Jingjing Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Xianwan Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
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9
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Li Q, Shan Q, Sang X, Zhu R, Chen X, Cao G. Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:177-201. [PMID: 30612460 DOI: 10.1142/s0192415x19500095] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of autoimmune diseases, including ulcerative colitis and Crohn’s disease, characterized by nonspecific inflammation in the gut. Total glycoside of peony (TGP) has been widely used for treatment of autoimmune diseases because of its pharmacological effects. However, it is lack of depth in whether TGP regulate T helper 17 cell (Th17) / T regulatory cell (Treg) immune balance or interleukin 23 (IL-23) / IL-17 axis to achieve the goal of treating IBD. Hence, the aim of this study was to investigate the effects of TGP on experimental colitis mice and the related mechanisms. In the present study, we demonstrated that administration of TGP effectively attenuates colonic inflammation of TNBS-induced colitis mice, mainly reflected in significantly improved clinical parameters, reduced inflammatory response and myeloperoxidase (MPO) activity, even stronger systemic immune ability and effective improvement of Th17/Treg immune disorders. In addition, there was a stronger immunosuppressive ability in a positive cluster of differentiation 4 (CD4[Formula: see text]) T-lymphocytes from the TGP treated mouse colon, characterized by the inhibition of high levels of inflammatory factors and increased regulatory T cells. Importantly, high-dose TGP has similar therapeutic effects as salicylazosulfapyridine (SASP) on IBD treatment. The potential mechanisms might be, at least in part, related to the adjustment of imbalance of Th17/Treg cells and the inhibition of IL-23/IL17 inflammatory signal axis.
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Affiliation(s)
- Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou 310022, P. R. China
| | - Qiyuan Shan
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xianan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xiaocheng Chen
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, P. R. China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
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10
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Wei W, Ding M, Zhou K, Xie H, Zhang M, Zhang C. Protective effects of wedelolactone on dextran sodium sulfate induced murine colitis partly through inhibiting the NLRP3 inflammasome activation via AMPK signaling. Biomed Pharmacother 2017; 94:27-36. [DOI: 10.1016/j.biopha.2017.06.071] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 05/29/2017] [Accepted: 06/20/2017] [Indexed: 02/07/2023] Open
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Soubh AA, Abdallah DM, El-Abhar HS. Geraniol ameliorates TNBS-induced colitis: Involvement of Wnt/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways. Life Sci 2015; 136:142-50. [DOI: 10.1016/j.lfs.2015.07.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 06/13/2015] [Accepted: 07/03/2015] [Indexed: 02/07/2023]
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Joo M, Kim HS, Kwon TH, Palikhe A, Zaw TS, Jeong JH, Sohn UD. Anti-inflammatory Effects of Flavonoids on TNBS-induced Colitis of Rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014; 19:43-50. [PMID: 25605996 PMCID: PMC4297761 DOI: 10.4196/kjpp.2015.19.1.43] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 10/28/2014] [Accepted: 11/22/2014] [Indexed: 01/08/2023]
Abstract
It has been shown that the extracts including eupatilin and quercetin-3-β-D-glucuronopyranoside had mucoprotective effects on the esophagus and stomach through their antioxidant activities. This study was designed to investigate the anti-inflammatory effect of these flavonoid compounds in an animal model of inflammatory bowel disease induced by 2,4,6-trinitrobenzene sulfonic acid. Experimental colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid. Extracts including eupatilin or quercetin-3-β-D-glucuronopyranoside were orally administered to animals 48, 24, and 1 h prior to the induction of colitis and then again 24 h later. The animals were sacrificed 48 h after by 2,4,6-trinitrobenzene sulfonic acid treatment and the macroscopic appearance of the colonic lesions was scored in a blinded manner on a scale of 1 to 10. The inflammatory response to colitis induction was assessed by measuring myeloperoxidase activity, nitric oxide production, tumor necrosis factor-α expression, total glutathione levels, and malondialdehyde concentrations in the colon. The results indicated that extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside dose-dependently improved the morphology of the lesions induced by 2,4,6-trinitrobenzene sulfonic acid and reduced the ulcer index accordingly. In addition, rats receiving extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside showed significantly decreased levels of mucosal myeloperoxidase activity, nitric oxide production, tumor necrosis factor-α expression, and malondialdehyde levels, and increased total glutathione levels. Extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside ameliorated the inflammatory response and colonic injury in acute colitis by decreasing oxidative stress and neutrophil activation. Extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside may inhibit acute colitis.
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Affiliation(s)
- Minjae Joo
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea
| | - Han Sang Kim
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea
| | - Tae Hoon Kwon
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea
| | - Alisha Palikhe
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea
| | - Tin Sandar Zaw
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Korea
| | - Uy Dong Sohn
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea
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Total glucosides of peony attenuates 2,4,6-trinitrobenzene sulfonic acid/ethanol-induced colitis in rats through adjustment of TH1/TH2 cytokines polarization. Cell Biochem Biophys 2014; 68:83-95. [PMID: 23771723 DOI: 10.1007/s12013-013-9696-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The present study is to investigate effects of total glucosides of peony (TGP) on 2,4,6-trinitrobenzene sulfonic acid (TNBS)/ethanol-induced colitis in rats and to explore potential clinical use of TGP for treatment of inflammatory bowel disease. Sixty Sprague-Dawley rats were randomly grouped into normal controls, model controls, sulfasalazine (SASP) controls (100 mg/kg/day), and low, medium, and high-dose TGP groups (25, 50, and 100 mg/kg/day, respectively). 24 h following colonic instillation of TNBS, TGP, and SASP were given by gastric gavage three times a day for 7 days. Disease activity index (DAI), colon macroscopic damage index (CMDI), histopathological score (HPS), and myeloperoxidase (MPO) activity were evaluated. Levels of serum TNF-α, IL-1β, and IL-10 were measured by ELISA, and expression of TNF-α, IL-1β, and IL-10 mRNA and protein in colonic tissues was detected by RT-PCR and western blot, respectively. Compared with rats in the model controls, TGP (50 or 100 mg/kg/day)-treated rats with TNBS/ethanol-induced colitis showed significant improvements of DAI, CMDI, HPS, and MPO activity. Moreover, administration of TGP (50 or 100 mg/kg/day) decreased the up-regulated levels of serum TNF-α and IL-1β, and expression of TNF-α and IL-1β mRNA and protein in colonic tissues, and increased the serum IL-10 and colonic IL-10 mRNA and protein level. And there was no significant difference compared with administration of SASP (P > 0.05). TGP attenuates TNBS/ethanol-induced colitis in rats and its efficacy is similar to SASP, the potential mechanism might be related to the adjustment of Th1/Th2 cytokines polarization by decreasing pro-inflammatory cytokine TNF-α and IL-1β, and increasing anti-inflammatory cytokine IL-10.
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Kim KH, Park SJ, Lee YJ, Lee JE, Song CH, Choi SH, Ku SK, Kang SJ. Inhibition of UVB-induced skin damage by exopolymers from Aureobasidium pullulans SM-2001 in hairless mice. Basic Clin Pharmacol Toxicol 2014; 116:73-86. [PMID: 24964914 DOI: 10.1111/bcpt.12288] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 06/11/2014] [Indexed: 11/28/2022]
Abstract
Because antioxidants from natural sources may be an effective approach to the treatment and prevention of UV radiation-induced skin damage, the effects of purified exopolymers from Aureobasidium pullulans SM-2001 ('E-AP-SM2001') were evaluated in UVB-induced hairless mice. E-AP-SM2001 consists of 1.7% β-1,3/1,6-glucan, fibrous polysaccharides and other organic materials, such as amino acids, and mono- and di-unsaturated fatty acids (linoleic and linolenic acids) and shows anti-osteoporotic and immunomodulatory effects, through antioxidant and anti-inflammatory mechanisms. Hairless mice were treated topically with vehicle, E-AP-SM2001 stock and two and four times diluted solutions once per day for 15 weeks against UVB irradiation (three times per week at 0.18 J/cm(2) ). The following parameters were evaluated in skin samples: myeloperoxidase (MPO) activity, cytokine levels [interleukin (IL)-1β and IL-10], endogenous antioxidant content (glutathione, GSH), malondialdehyde (MDA) levels, superoxide anion production; matrix metalloproteases (MMP-1, -9 and -13), GSH reductase and Nox2 (gp91phox) mRNA levels, and immunoreactivity for nitrotyrosine (NT), 4-hydroxynonenal (HNE), caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP). Photoageing was induced by UVB irradiation through ROS-mediated inflammation, which was related to the depletion of endogenous antioxidants, activation of MMPs and keratinocyte apoptosis. Topical treatment with all three doses of E-AP-SM2001 and 5 nm myricetin attenuated the UV-induced depletion of GSH, activation of MMPs, production of IL-1β, the decrease in IL-10 and keratinocyte apoptosis. In this study, E-AP-SM2001 showed potent inhibitory effects against UVB-induced skin photoageing. Thus, E-AP-SM2001 may be useful as a functional ingredient in cosmetics, especially as a protective agent against UVB-induced skin photoageing.
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Affiliation(s)
- Kyung Hu Kim
- Department of Histology and Anatomy, College of Korean Medicine, Daegu Haany University, Gyeongsan, Korea
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Wang T, Zhou YT, Chen XN, Zhu AX, Wu BH. Remote ischemic postconditioning protects against gastric mucosal lesions in rats. World J Gastroenterol 2014; 20:9519-9527. [PMID: 25071347 PMCID: PMC4110584 DOI: 10.3748/wjg.v20.i28.9519] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 01/21/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protective effects of remote ischemic postconditioning (RIP) against limb ischemia-reperfusion (IR)-induced gastric mucosal injury.
METHODS: Gastric IR was established in male Wistar rats by placing an elastic rubber band under a pressure of 290-310 mmHg on the proximal part of both lower limbs for 3 h followed by reperfusion for 0, 1, 3, 6, 12 or 24 h. RIP was performed using three cycles of 30 s of reperfusion and 30 s of reocclusion of the femoral aortic immediately after IR and before reperfusion for up to 24 h. Rats were randomly assigned to receive IR (n = 36), IR followed by RIP (n = 36), or sham treatment (n = 36). Gastric tissue samples were collected from six animals in each group at each timepoint and processed to determine levels of malondialdehyde (MDA), superoxide dismutase (SOD), xanthine oxidase (XOD) and myeloperoxidase (MPO). Additional samples were processed for histologic analysis by hematoxylin and eosin staining. Blood samples were similarly collected to determine serum levels of lactate dehydrogenase (LDH), creatine kinase (CK), tumor necrosis factor (TNF)-α and interleukin (IL)-10.
RESULTS: The pathologic changes in gastric tissue induced by IR were observed by light microscopy. Administration of RIP dramatically reduced the gastric damage score after 6 h of reperfusion (5.85 ± 0.22 vs 7.72 ± 0.43; P < 0.01). In addition, RIP treatment decreased the serum activities of LDH (3.31 ± 0.32 vs 6.46 ± 0.03; P < 0.01), CK (1.94 ± 0.20 vs 4.54 ± 0.19; P < 0.01) and the concentration of TNF-α (53.82 ± 0.85 vs 88.50 ± 3.08; P < 0.01), and elevated the concentration of IL-10 (101.46 ± 5.08 vs 99.77 ± 4.32; P < 0.01) induced by IR at 6 h. Furthermore, RIP treatment prevented the marked elevation in MDA (3.79 ± 0.29 vs 6.39 ± 0.81) content, XOD (7.81 ± 0.75 vs 10.37 ± 2.47) and MPO (0.47 ± 0.05 vs 0.82 ± 0.03) activities, and decrease in SOD (4.95 ± 0.32 vs 3.41 ± 0.38; P < 0.01) activity in the gastric tissue as measured at 6 h.
CONCLUSION: RIP provides effective functional protection and prevents cell injury to gastric tissue induced by limb IR via anti-inflammatory and antioxidant actions.
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Efficacy of topical formulations containing Pimenta pseudocaryophyllus extract against UVB-induced oxidative stress and inflammation in hairless mice. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2013; 127:153-60. [PMID: 24041853 DOI: 10.1016/j.jphotobiol.2013.08.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 07/27/2013] [Accepted: 08/19/2013] [Indexed: 11/23/2022]
Abstract
Plants rich in antioxidant substances may be a promising strategy for preventing UV-induced oxidative and inflammatory damage of the skin. Pimenta pseudocaryophyllus is native to Brazil and presents flavonoids and other polyphenolic compounds in high concentration. Thus, the present study evaluated the possible effects of topical formulations containing P. pseudocaryophyllus ethanolic extract (PPE) at inhibiting UV-B irradiation-induced oxidative stress and inflammation. PPE was administered on the dorsal skin of hairless mice using two formulations: F1 (non-ionic emulsion with high lipid content) and F2 (anionic emulsion with low lipid content) before and after UV-B irradiation. The following parameters were evaluated in skin samples: edema, myeloperoxidase activity, cytokines levels, matrix metalloprotease-9 (MMP-9) secretion/activity, reduced glutathione (GSH), superoxide anion and lipid peroxidation levels, and mRNA expression for glutathione reductase and gp91phox. The UV-B irradiation increased all parameters, except for IL-10 levels and glutathione reductase mRNA expression, which were not altered, and GSH levels, which were reduced by exposure to UV-B light. Treatments with F1 and F2 containing PPE inhibited UV-B-induced edema formation (89% and 86%), myeloperoxidase activity (85% and 81%), IL-1β production (62% and 82%), MMP-9 activity (71% and 74%), GSH depletion (73% and 85%), superoxide anion (83% and 66%) and TBARS (100% and 100%) levels, increased glutathione reductase (2.54 and 2.55-fold) and reduced gp91phox (67% and 100%) mRNA expression, respectively. F2 containing PPE also increased IL-10 levels. Therefore, this study demonstrates the effectiveness of topical formulations containing PPE in inhibiting UV-B irradiation-induced inflammation and oxidative stress of the skin.
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Roy P, Amdekar S, Kumar A, Singh R, Sharma P, Singh V. In vivo antioxidative property, antimicrobial and wound healing activity of flower extracts of Pyrostegia venusta (Ker Gawl) Miers. JOURNAL OF ETHNOPHARMACOLOGY 2012; 140:186-192. [PMID: 22265749 DOI: 10.1016/j.jep.2012.01.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Revised: 01/04/2012] [Accepted: 01/07/2012] [Indexed: 05/31/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pyrostegia venusta (Ker Gawl) Miers. (Bignoniaceae), has been traditionally used as a remedy for treating white patches and infections on the skin (leukoderma, vitiligo). AIM OF THE STUDY To investigate wound healing and antimicrobial activity of flower extract of Pyrostegia venusta, including in vivo antioxidant activity. MATERIALS AND METHODS Methanolic extracts of Pyrostegia venusta flowers were studied for wound healing efficiency along with its effect on pro-inflammatory and anti-inflammatory cytokines was assessed using excision and incision model of wound repair in Wistar rats. Healing was assessed by the rate of wound contraction, tensile strength, breaking strength, hydroxyproline and hexosamine content. Antimicrobial activity of the flower extract against twelve microorganisms was also assessed. In vivo antioxidant activity was performed to understand the mechanism of wound healing potency. RESULTS The results indicated that Pyrostegia venusta extract has potent wound healing capacity as evident from the wound contraction and increased tensile strength. Hydroxyproline and hexosamine expression were also correlative with the healing pattern observed. Pyrostegia venusta extract exhibited moderate antimicrobial activity against the organisms: Bacillus subtilis, Staphylococcus epidermidis, Staphylococcus pyogenes, Staphylococcus aureus, Escherichia coli, Micrococcus luteus, Enterobacter aerogenes, Salmonella typhi, Pseudomonas aeruginosa, Candida albicans, Aspergillus niger and Candida tropicana. During early wound healing phase TNF-α and IL-6 level were found to be up regulated by Pyrostegia venusta treatment. CONCLUSION Increased wound contraction and tensile strength, augmented hydroxyproline and hexosamine content along with antioxidative activity and moderate antimicrobial activity support the early wound healing exhibited by Pyrostegia venusta flower extract. Induction in cytokine production may be one of the mechanisms involved in accelerating the wound healing by Pyrostegia venusta extract. Results suggest that Pyrostegia venusta may be useful in the tropical management of wound healing.
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Affiliation(s)
- Purabi Roy
- Department of Microbiology, Barkatullah University, Hoshangabad Road, Habibganj, Bhopal 462024, Madhya Pradesh, India.
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Fan YM, Zhang LF, Zhao Y, Chen LL. Significance of RhoC and IQGAP1 expression in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2011; 19:2841-2845. [DOI: 10.11569/wcjd.v19.i27.2841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the expression of RhoC and IQGAP1 proteins in hepatocellular carcinoma (HCC) and to analyze their clinicopathological significance.
METHODS: The expression of RhoC and IQGAP1 proteins was detected by immunohistochemistry in 56 HCC specimens and 15 normal liver specimens. The association of RhoC and IQGAP1 protein expression with clinicopathologicalparamters was analyzed.
RESULTS: The positive rates of RhoC and IQGAP1 expression were significantly higher in HCC than in normal liver tissue (66% vs 20%; 75% vs 13%, both P < 0.05). The expression of RhoC and IQGAP1 proteins was related to tumor differentiation and invasion in HCC (both P < 0.05). A positive correlation was noted between the expression of RhoC and that of IQGAP1 in HCC(r = 0.631, P < 0.05).
CONCLUSION: RhoC and IQGAP1 play significant roles in promoting the progression of HCC. Expression of RhoC and IQGAP1 can be used as useful parameters for clinical assessment of biological behavior and prognosis of HCC.
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Gu QP, Xie JF, Chen J, Zhang Y, Hong K, Bai AP. Treatment of murine colitis with IL-10-secreting Escherichia coli. Shijie Huaren Xiaohua Zazhi 2011; 19:2835-2840. [DOI: 10.11569/wcjd.v19.i27.2835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the therapeutic effect of interleukin-10 (IL-10)-secreting Escherichia coli (E. coli) on murine colitis.
METHODS: Sixty 6-8-wk-old female BALB/c mice were divided into six groups: normal control group, dextran sulfate sodium (DSS) group, empty plasmid-transformed E.coli (E.coli0) group, IL-10 gene-transformed E.coli (E.coli/mIL-10) group, DSS + E.coli0 group, and DSS + E.coli/mIL-10 group. The DSS, DSS + E.coli0, and DSS + E.coli/mIL-10 groups were fed 5 % DSS solution for 7 d to induce colitis, while the other groups were given normal tap water. The E.coli0 and DSS + E.coli0 groups were intragastrically given E.coli0; the E.coli/mIL-10 and DSS + E.coli/mIL-10 groups were given recombinant E.coli/mIL-10; and the DSS and normal control groups were given LB (Luria-Bertain) medium. The treatment lasted for 8 days. Disease activity index (DAI) was recorded each day. The expression of TNF-α, NF-κB p65 and myeloperoxidase (MPO) in the colon was measured at the end of the experiment.
RESULTS: Mice in the DSS + E.coli/mIL-10 group showed a lower DAI than those in the DSS and DSS + E.coli0 groups from day 4 to the end of the experiment. The levels of TNF-α and MPO in the colon and the expression of NF-κB P65 in the nuclei of inflammatory cells were lower in the DSS + E.coli/mIL-10 group (172.46 pg/g ± 22.23 pg/g, 2.35 U/g ± 0.15 U/g) than in the DSS (237.85 pg/g ± 14.86 pg/g, 4.15 U/g ± 0.29 U/g) and DSS + E.coli0 groups (239.81 pg/g ± 50.38 pg/g, 3.5 U/g ±1.23 U/g) at the end of experiment. No colonic injury was observed in mice in the normal control, E.coli/IL-10 and E.coli0 groups.
CONCLUSION: Local delivery of IL-10 gene-transformed E.coli ameliorates DSS-inducd murine colitis possibly by decreasing proinflammatory cytokine production and inhibiting NF-κB activation. Gene therapy strategies using engineered E.coli encoding immunoregulatory cytokines may provide a potential approach for treatment of inflammatory bowel disease.
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Raghavendran HRB, Srinivasan P, Rekha S. Immunomodulatory activity of fucoidan against aspirin-induced gastric mucosal damage in rats. Int Immunopharmacol 2010; 11:157-63. [PMID: 21084063 DOI: 10.1016/j.intimp.2010.11.002] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2010] [Revised: 10/10/2010] [Accepted: 11/01/2010] [Indexed: 12/17/2022]
Abstract
Gastric ulcers and related complications associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, represent a major global health problem. In the present study, we investigate the immunological activity of fucoidan against aspirin-induced gastric mucosal damage in rats. Thirty-six rats were randomly divided into the following, normal (Carboxy methyl cellulose 0.05 %), aspirin (Asp-400mg/kg) treated, fucoidan alone (Fu-0.02 g/kg, daily for 14 days) and Fu+Asp. Cytokines, total nitrite and nitrate (NOx) analysis and tissue localization of Cyclooxygenase 1, 2 and epidermal growth factor receptor (EGFR) were done using Elisa and immunohistochemistry respectively. Histopathology of gastric tissue, collagen deposition was performed using Hematoxylin and Eosin and Masson's trichrome were performed. Treatment of rats with a single dose of aspirin (400mg/kg, orally) led to significant alterations in the levels of total nitrite and nitrate (NOx), interleukins (IL-4, 6, 10, 12), tumor necrosis factor (TNF-α), and interferon gamma (IFN-γ). Notably, collagen deposition in glandular tissue and localization of cyclooxygenase 1, 2, and epidermal growth factor were considerably affected in aspirin-treated rats. These severities were prevented to a significant extent in rats pretreated with fucoidan (0.02 g/kg/day for two weeks orally). Our findings collectively indicate that the gastro-protective effect of fucoidan against aspirin-induced ulceration in rats is mediated through its immunomodulatory properties.
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Affiliation(s)
- Hanumantha Rao Balaji Raghavendran
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, 22-5 Daeheung-dong, Jung-gu, Daejeon, Republic of Korea.
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Shin K, Horigome A, Yamauchi K, Yaeshima T, Iwatsuki K. Orally administered lactoperoxidase ameliorates dextran sulfate sodium-induced colitis in mice by up-regulating colonic interleukin-10 and maintaining peripheral regulatory T cells. Int Immunopharmacol 2009; 9:1387-93. [DOI: 10.1016/j.intimp.2009.08.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Revised: 07/21/2009] [Accepted: 08/19/2009] [Indexed: 11/28/2022]
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Barada KA, Mourad FH, Sawah SI, Khoury C, Safieh-Garabedian B, Nassar CF, Tawil A, Jurjus A, Saadé NE. Up-regulation of nerve growth factor and interleukin-10 in inflamed and non-inflamed intestinal segments in rats with experimental colitis. Cytokine 2007; 37:236-245. [PMID: 17517520 DOI: 10.1016/j.cyto.2007.04.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2007] [Revised: 03/28/2007] [Accepted: 04/11/2007] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases are characterized by dysregulated immune response to the normal microflora and structural and functional changes of the enteric nervous system which occur in inflamed as well as non-inflamed areas of the bowel. This study describes the changes in the expression of nerve growth factor (NGF) and interleukin-10 (IL-10) in the colon and in various segments of the small intestine in two rat models of experimental colitis induced by iodoacetamide or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Levels of NGF and IL-10 were measured by ELISA in tissue homogenate sampled from duodenum, jejunum, ileum and colon at different time intervals. NGF and IL-10 increased significantly in homogenates of strips isolated from all small intestinal segments, 3-6h after iodoacetamide or TNBS administration and remained elevated until the colonic inflammation subsided. Similar but more pronounced increase occurred in areas of the colon adjacent to the ulcer. Histologic examinations revealed inflammatory changes in the colon; however, examination of sections from the small intestines did not reveal significant differences between controls and rats with colitis. The marked up-regulation of nerve growth factor and interleukin-10 in colitis suggests that they play a role in limiting or resolving inflammation and in preventing it from becoming uncontrolled. It also suggests that experimental colitis may be associated with latent inflammation in the small bowel.
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Affiliation(s)
- Kassem A Barada
- Department of Internal Medicine, Faculty of Arts and Sciences, American University of Beirut, Riad El Solh, Beirut, Lebanon.
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Whittle BJR, Varga C, Pósa A, Molnár A, Collin M, Thiemermann C. Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3beta. Br J Pharmacol 2006; 147:575-82. [PMID: 16314851 PMCID: PMC1616977 DOI: 10.1038/sj.bjp.0706509] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The effects of the inhibitors of glycogen synthase kinase-3beta (GSK-3beta), TDZD-8 and SB 415286, which can substantially reduce the systemic inflammation associated with endotoxic shock in vivo, have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid (TNBS) in the rat. Administration of the GSK-3beta inhibitor TDZD-8 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days) caused a dose-dependent reduction in the colonic inflammation induced by intracolonic TNBS assessed after 3 days, both as the area of macroscopic involvement and as a score using 0-10 scale. Likewise, following administration of the GSK-3beta inhibitor SB 415286 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days), the extent and degree of the TNBS-provoked colonic inflammation was reduced. Administration of either TDZD-8 or SB 415286 reduced the fall in body weight following challenge with TNBS at each dose level studied. The increase in myeloperoxidase activity, an index of neutrophil infiltration into the TNBS-induced inflamed colon, was significantly inhibited by both TDZD-8 and SB 415286 at each dose level. The increase in the levels of the proinflammatory cytokine, TNF-alpha, in the inflamed colon was also significantly inhibited by either compound at the highest doses evaluated. The elevated levels of the transcription factor NF-kappaB subunit p65, as determined by Western blot in the nuclear extracts from the TNBS-provoked inflamed colonic tissue, were dose-dependently reduced by TDZD-8 or SB 415286 treatment. These findings demonstrate that two chemically distinct selective inhibitors of the activity of GSK-3beta reduce the inflammation and tissue injury in a rat model of acute colitis. The mechanisms underlying this anti-inflammatory action may be related to downregulation of NF-kappaB activity, involved in the generation of proinflammatory mediators.
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Affiliation(s)
- Brendan J R Whittle
- Centre for Experimental Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK.
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Eamlamnam K, Patumraj S, Visedopas N, Thong-Ngam D. Effects of Aloe vera and sucralfate on gastric microcirculatory changes, cytokine levels and gastric ulcer healing in rats. World J Gastroenterol 2006; 12:2034-9. [PMID: 16610053 PMCID: PMC4087681 DOI: 10.3748/wjg.v12.i13.2034] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the effects of Aloe vera and sucralfate on gastric microcirculatory changes, cytokine levels and gastric ulcer healing.
METHODS: Male Spraque-Dawley rats (n= 48) were divided into four groups. Group1 served as control group, group 2 as gastric ulcer group without treatment, groups 3 and 4 as gastric ulcer treatment groups with sucralfate and Aloe vera. The rats from each group were divided into 2 subgroups for study of leukocyte adherence, TNF-α and IL-10 levels and gastric ulcer healing on days 1 and 8 after induction of gastric ulcer by 20 % acetic acid.
RESULTS: On day 1 after induction of gastric ulcer, the leukocyte adherence in postcapillary venule was significantly (P< 0.05) increased in the ulcer groups when compared to the control group. The level of TNF-α was elevated and the level of IL-10 was reduced. In the ulcer groups treated with sucralfate and Aloe vera, leukocyte adherence was reduced in postcapillary venule. The level of IL-10 was elevated, but the level of TNF-α had no significant difference. On day 8, the leukocyte adherence in postcapillary venule and the level of TNF-α were still increased and the level of IL-10 was reduced in the ulcer group without treatment. The ulcer treated with sucralfate and Aloe vera had lower leukocyte adherence in postcapillary venule and TNF-α level. The level of IL-10 was still elevated compared to the ulcer group without treatment. Furthermore, histopathological examination of stomach on days 1 and 8 after induction of gastric ulcer showed that gastric tissue was damaged with inflammation. In the ulcer groups treated with sucralfate and Aloe vera on days 1 and 8, gastric inflammation was reduced, epithelial cell proliferation was enhanced and gastric glands became elongated. The ulcer sizes were also reduced compared to the ulcer group without treatment.
CONCLUSION: Administration of 20 % acetic acid can induce gastric inflammation, increase leukocyte adherence in postcapillary venule and TNF-α level and reduce IL-10 level. Aloe vera treatment can reduce leukocyte adherence and TNF-α level, elevate IL-10 level and promote gastric ulcer healing.
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Affiliation(s)
- Kallaya Eamlamnam
- Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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25
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Sasaki M, Mathis JM, Jennings MH, Jordan P, Wang Y, Ando T, Joh T, Alexander JS. Reversal of experimental colitis disease activity in mice following administration of an adenoviral IL-10 vector. JOURNAL OF INFLAMMATION-LONDON 2005; 2:13. [PMID: 16259632 PMCID: PMC1291390 DOI: 10.1186/1476-9255-2-13] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2005] [Accepted: 10/31/2005] [Indexed: 02/07/2023]
Abstract
Genetic deficiency in the expression of interleukin-10 (IL-10) is associated with the onset and progression of experimental inflammatory bowel disease (IBD). The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10), an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate), a common model of colitis. Adenoviral IL-10 (Ad-IL10) transfected mice developed high levels of IL-10 (394 +/- 136 pg/ml) within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS), Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSS-treated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10) gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation.
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Affiliation(s)
- Makoto Sasaki
- Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, 71130-3932, USA
| | - J Michael Mathis
- Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, LA, 71130-3932, USA
| | - Merilyn H Jennings
- Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, 71130-3932, USA
| | - Paul Jordan
- Department of Gastroenterology, LSU Health Sciences Center, Shreveport, LA, 71130-39322, USA
| | - Yuping Wang
- Department of Obstetrics and Gynecology, LSU Health Sciences Center, Shreveport, LA, 71130-39322, USA
| | - Tomoaki Ando
- Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, 71130-3932, USA
| | - Takashi Joh
- Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - J Steven Alexander
- Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, 71130-3932, USA
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Varga C, Horvath K, Berko A, Thurmond RL, Dunford PJ, Whittle BJR. Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat. Eur J Pharmacol 2005; 522:130-8. [PMID: 16213481 DOI: 10.1016/j.ejphar.2005.08.045] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2005] [Revised: 07/01/2005] [Accepted: 08/18/2005] [Indexed: 11/23/2022]
Abstract
The histamine H(4) receptor is a G-protein coupled receptor with little homology to the pro-inflammatory histamine H(1) receptor, expressed on cells of the immune system with hematopoietic lineage such as eosinophils and mast cells. The effects of the recently described highly selective histamine H(4) receptor antagonists JNJ 10191584 and JNJ 7777120 have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid over 3 days in the rat. Treatment with JNJ 10191584 (10-100 mg/kg p.o., b.i.d.) caused a dose-dependent reduction in macroscopic damage, inhibition of the TNBS-provoked elevation of both colonic myeloperoxidase and tumour necrosis factor-alpha (TNF-alpha), and a reduction in the histologically assessed increase in mucosal and submucosal thickness and neutrophil infiltration. JNJ 7777120 (100 mg/kg p.o., b.i.d.) likewise reduced the macroscopic injury and the increases in colonic myeloperoxidase and TNF-alpha levels. These findings indicate a pro-inflammatory role for the histamine H(4) receptor in this model and suggest a novel pharmacological approach to the treatment of colitis.
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Affiliation(s)
- Csaba Varga
- Department of Comparative Physiology, Szeged University, Hungary
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27
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Di Giacinto C, Marinaro M, Sanchez M, Strober W, Boirivant M. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. THE JOURNAL OF IMMUNOLOGY 2005; 174:3237-46. [PMID: 15749854 DOI: 10.4049/jimmunol.174.6.3237] [Citation(s) in RCA: 393] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recent studies of murine models of mucosal inflammation suggest that, whereas some kinds of bacterial microflora are inducers of disease, others, known as probiotics, prevent disease. In the present study, we analyzed the regulatory cytokine and cell response to probiotic (VSL#3) administration in the context of the Th1 T cell colitis induced by trinitrobenzene sulfonic acid treatment of SJL/J mice. Daily administration of probiotics for 3 wk to mice during a remission period between a first and second course of colitis induced by trinitrobenzene sulfonic acid, resulted in a milder form of recurrent colitis than observed in mice administered PBS during this same period. This protective effect was attributable to effects on the lamina propria mononuclear cell (LPMC) population, because it could be transferred by LPMC from probiotic-treated mice to naive mice. Probiotic administration was associated with an early increase in the production of IL-10 and an increased number of regulatory CD4+ T cells bearing surface TGF-beta in the form of latency-associated protein (LAP) (LAP+ T cells). The latter were dependent on the IL-10 production because administration of anti-IL-10R mAb blocked their appearance. Finally, the LAP+ T cells were essential to the protective effect of probiotics because administration of anti-IL-10R or anti-TGF-beta at the initiation of recurrent colitis induction or depletion of LAP+ T cells from LPMC abolished the latter's capacity to transfer protection to naive recipients. These studies show that probiotic (VSL#3) administration during a remission period ameliorates the severity of recurrent colitis by inducing an immunoregulatory response involving TGF-beta-bearing regulatory cells.
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Affiliation(s)
- Claudia Di Giacinto
- Immune-Mediated Diseases Section, Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
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28
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Castagliuolo I, Beggiao E, Brun P, Barzon L, Goussard S, Manganelli R, Grillot-Courvalin C, Palù G. Engineered E. coli delivers therapeutic genes to the colonic mucosa. Gene Ther 2005; 12:1070-8. [PMID: 15815705 DOI: 10.1038/sj.gt.3302493] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Taking advantage of the proximity of bowel mucosa to luminal bacteria, we have attempted to deliver a therapeutic gene to the colonic mucosa by oral administration of an invasive and non-pathogenic Escherichia coli. E. coli diamenopimelate (dap) auxotroph, harboring plasmid pGB2Omegainv-hly, express the inv gene from Yersinia pseudotubercolosis that confers the ability to invade nonprofessional phagocytic cells and the hly gene from Listeria monocytogenes that allows expression of lystreriolysin O, a perforin cytolysin able to perfore phagosomal membranes. This bacterial vector invades and transfers functional DNA to epithelial cells in vitro. We have shown that this strain carrying a therapeutic gene (pC1OmegaTGF-beta1) can significantly reduce the severity of experimental colitis in mice. However, as a consequence of mucosal barrier disruption during colitis, vector-specific mRNA transcripts could be recovered from the colon and also from extra-colonic tissues. We therefore replaced the constitutive CMV promoter in pC1OmegaTGF-beta1 by the inflammation-inducible interleukin-8 promoter generating plasmid pC1OmegaTGF-beta1IND. Plasmid-specific TGF-beta1 mRNA transcripts were detectable in mouse CMT-93 epithelial cells incubated with E. coli BM2710/pGB2Omegainv-hly carrying pC1OmegaTGF-beta1IND following exposure to inflammatory cytokines. Furthermore, the transcripts were detectable only within inflamed tissues and the therapeutic effects were comparable to those in animals treated with E. coli BM2710/pGB2Omegainv-hly+pC1OmegaTGF-beta1. In summary, engineered enteric bacteria can efficiently deliver in vivo therapeutic genes to the intact intestinal mucosa and regulation expression of the therapeutic gene by an inflammation-inducible promoter prevents its dissemination during colitis.
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Affiliation(s)
- I Castagliuolo
- Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy
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29
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Naito Y, Takagi T, Yoshikawa T. Heme oxygenase-1: a new therapeutic target for inflammatory bowel disease. Aliment Pharmacol Ther 2004; 20 Suppl 1:177-84. [PMID: 15298625 DOI: 10.1111/j.1365-2036.2004.01992.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of biliverdin, free iron and carbon monoxide (CO). Three mammalian HO isozymes have been identified, one of which, HO-1, is a stress-responsive protein induced by various oxidative agents. HO-2 and HO-3 genes are constitutively expressed. Recent studies demonstrate that the expression of HO-1 in response to different inflammatory mediators may contribute to the resolution of inflammation and have protective effects in several organs against oxidative injury. Although the mechanism underlying the anti-inflammatory actions of HO-1 remains poorly defined, both CO and biliverdin/bilirubin have been implicated in this response. In the intestinal tract, HO-1 is shown to be transcriptionally induced in response to oxidative stress, preconditioning and acute inflammation. Recent studies suggest that the induction of HO-1 expression plays a critical protective role in intestinal damage models induced by trinitrobenzene sulphonic acid or dextran sulphate sodium, indicating that activation of HO-1 may act as an endogenous defensive mechanism to reduce inflammation and tissue injury in the intestinal tract. These in vitro and in vivo data suggest that HO-1 may be a novel therapeutic target in patients with inflammatory bowel disease.
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Affiliation(s)
- Y Naito
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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30
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Stasi MA, Ruggiero V, Ursillo A, Taurelli R, Aglianò M, Weber E, Lorenzoni P, Sorrentino V, Pacifici L, Carminati P. Ameliorating effects of the immunomodulator 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole in an experimental model of colitis in the rat. Eur J Pharmacol 2004; 494:263-72. [PMID: 15212983 DOI: 10.1016/j.ejphar.2004.05.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2004] [Accepted: 05/11/2004] [Indexed: 01/21/2023]
Abstract
The therapeutic efficacy of the immunomodulator 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (ST1959) in colonic inflammation was assessed in rats. One hour following colonic instillation of ethanolic 2,4,6-trinitrobenzene sulphonic acid (TNBS), intracolonic administration of 0.4 mg/kg ST1959 was started and continued once daily for 1 or 2 weeks. Daily administration of ST1959 for 1 week significantly reduced macroscopic and histological damage, myeloperoxidase activity, and colonic tissue levels of tumour necrosis factor-alpha and interferon-gamma. ST1959 did not affect interleukin-12 levels but significantly enhanced the production of interleukin-10 (sixfold increase). Two weeks of ST1959 treatment reduced the thickness of the colonic wall and myeloperoxidase activity to the same extent, and the histologic appearance of the mucosa was largely restored. The ameliorating effects seem to be ascribable to an impairment of both neutrophil infiltration/activation and tumour necrosis factor-alpha and interferon-gamma production, possibly consequent to the observed increase in the colonic tissue levels of the potent anti-inflammatory cytokine interleukin-10. Similar results were observed with the reference drug 5-aminosalycilic acid.
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Affiliation(s)
- Maria Antonietta Stasi
- Pharmacology Department-R&D, Sigma-tau S.p.A., Via Pontina km 30.400, 00040 Pomezia (RM), Italy.
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31
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Castagliuolo I, Brun P, Tormen D, Palò G. Lymphocytes endowed with colon-selective homing and engineered to produce TGF-beta1 prevent the development of dinitrobenzene sulphonic acid colitis. Eur J Gastroenterol Hepatol 2003; 15:1257-65. [PMID: 14624147 DOI: 10.1097/00042737-200312000-00002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Gene therapy is an attractive approach to the treatment of inflammatory diseases. However, the lack of tissue targeting of available vectors jeopardizes their clinical use. AIMS Since alpha4beta7 integrin mediates lymphocyte homing to the intestinal mucosa, we tested the possibility of in-vitro engineering alpha4beta7-bearing lymphocytes to restrict the production of a therapeutic cytokine, transforming growth factor (TGF)-beta1, to within the colonic mucosa. METHODS Lymphocytes were isolated from colonic lamina propria or spleen and transfected with either pC1 or pC1/TGF-beta1. RESULTS Transfected spleen and lamina propria cells released TGF-beta1 for up to 5 days in vitro and administration of 107 spleen cells, but not 106 lamina propria or spleen cells, to normal mice caused a significant rise in circulating TGF-beta1. Following intrarectal injection of dinitrobenzene sulphonic acid, intraperitoneal administration of lamina propria or spleen cells transfected with pC1/TGF-beta1, but not pC1, significantly reduced colitis-associated body weight loss, colonic myeloperoxidase (MPO) activity, interleukin-1beta levels, and macroscopic and microscopic inflammatory damage. Vector-specific TGF-beta1 mRNA transcripts were detectable in the colon and liver following injection of lamina propria lymphocytes, and in the spleen, liver and colon following administration of spleen lymphocytes. Incubation of pC1/TGF-beta1-transfected lamina propria lymphocytes with anti-alpha4beta7 integrin antibody blocked their protective effects and caused the disappearance of vector-specific TGF-beta1 transcripts from the colonic mucosa. CONCLUSION We conclude that lymphocytes are an efficient vehicle for transient gene therapy and that cells bearing alpha4beta7 integrins preferentially deliver therapeutic genes to the colonic mucosa.
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Affiliation(s)
- Ignazio Castagliuolo
- Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy.
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Braat H, Peppelenbosch MP, Hommes DW. Interleukin-10-based therapy for inflammatory bowel disease. Expert Opin Biol Ther 2003; 3:725-31. [PMID: 12880373 DOI: 10.1517/14712598.3.5.725] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In recent years it has become clear that chronic inflammatory bowel disease (IBD), especially Crohn's disease (CD), is caused by a loss of tolerance against the autologous bacterial flora of the intestine. Tolerance against the indigenous flora requires optimal recognition of antigens by pattern recognition receptors and the presence of important regulatory cells and cytokines. Interleukin-10 (IL-10) has a major role in the regulatory network of cytokines controlling mucosal tolerance, and it is, therefore, not surprising that this cytokine is proposed as a potent anti-inflammatory biological therapy in chronic IBD. This review will discuss the characteristics of IL-10, its immunoregulatory properties in mice and humans, and the use of IL-10 as a treatment for CD. The review will summarise the clinical studies that have taken place and discuss the lessons learned from these trials. Finally, the advantages and disadvantages of promising new strategies of IL-10 treatment, including gene therapy and the use of genetically modified bacteria, will be discussed. Both novel therapies have been shown to be successful in animal models of disease, and clinical testing is currently underway. The future goal of IL-10 treatment should be focused on mucosal delivery and remission maintenance instead of remission induction. In conclusion, it can be said that despite the disappointing results of IL-10 therapy so far, there is still enough rationale for the use of IL-10 as an anti-inflammatory biological treatment in chronic IBD.
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Affiliation(s)
- Henri Braat
- Department of Experimental Internal Medicine, Academic Medical Center, Meiberdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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33
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Sasaki M, Jordan P, Houghton J, Meng X, Itoh M, Joh T, Alexander JS. Transfection of IL-10 expression vectors into endothelial cultures attenuates alpha4beta7-dependent lymphocyte adhesion mediated by MAdCAM-1. BMC Gastroenterol 2003; 3:3. [PMID: 12625840 PMCID: PMC151603 DOI: 10.1186/1471-230x-3-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2002] [Accepted: 02/20/2003] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Enhanced expression of MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is associated with the onset and progression of inflammatory bowel disease. The clinical significance of elevated MAdCAM-1 expression is supported by studies showing that immunoneutralization of MAdCAM-1, or its ligands reduce inflammation and mucosal damage in models of colitis. Interleukin-10 (IL-10) is an endogenous anti-inflammatory and immunomodulatory cytokine that has been shown to prevent inflammation and injury in several animal studies, however clinical IL-10 treatment remains insufficient because of difficulties in the route of IL-10 administration and its biological half-life. Here, we examined the ability of introducing an IL-10 expression vector into endothelial cultures to reduce responses to a proinflammatory cytokine, TNF-alpha METHODS A human IL-10 expression vector was transfected into high endothelial venular ('HEV') cells (SVEC4-10); we then examined TNF-alpha induced lymphocyte adhesion to lymphatic endothelial cells and TNF-alpha induced expression of MAdCAM-1 and compared these responses to control monolayers. RESULTS Transfection of the IL-10 vector into endothelial cultures significantly reduced TNF-alpha induced, MAdCAM-1 dependent lymphocyte adhesion (compared to non-transfected cells). IL-10 transfected endothelial cells expressed less than half (46 +/- 6.6%) of the MAdCAM-1 induced by TNF-alpha (set as 100%) in non-transfected (control) cells. CONCLUSION Our results suggest that gene therapy of the gut microvasculature with IL-10 vectors may be useful in the clinical treatment of IBD.
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Affiliation(s)
- Makoto Sasaki
- Louisiana State University Health Sciences Center-Shreveport (LSUHSC-S) Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, LA, USA
| | - Paul Jordan
- LSUHSC-S Gastroenterology, 1501 Kings Highway, Shreveport, LA, USA
| | - Jeff Houghton
- Louisiana State University Health Sciences Center-Shreveport (LSUHSC-S) Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, LA, USA
| | - Xianmin Meng
- Thomas Jefferson University Dermatology and Cutaneous Biol., 233 South 10street, Suite 450, Philadelphia, PA, USA
| | - Makoto Itoh
- Nagoya City University Graduate School of Medical Sciences Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-ku, Nagoya, Japan
| | - Takashi Joh
- Nagoya City University Graduate School of Medical Sciences Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-ku, Nagoya, Japan
| | - J Steven Alexander
- Louisiana State University Health Sciences Center-Shreveport (LSUHSC-S) Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, LA, USA
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Villegas I, La Casa C, Orjales A, Alarcón de la Lastra C. Effects of dosmalfate, a new cytoprotective agent, on acute and chronic trinitrobenzene sulphonic acid-induced colitis in rats. Eur J Pharmacol 2003; 460:209-18. [PMID: 12559383 DOI: 10.1016/s0014-2999(02)02949-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Activated neutrophils and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) are clearly involved in the pathogenesis of bowel disease. Increased expression of epidermal growth factor-receptor (EGF receptor) has been reported for the colon mucosa surrounding areas of ulceration, suggesting a pivotal role in mucosal defence and repair. In this study, we examined the effects of dosmalfate, a new flavonoid derivative compound (diosmin heptakis) with antioxidant and cytoprotective properties, on acute and chronic experimental trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. The inflammation response was assessed by neutrophil infiltration as evaluated by histology and myeloperoxidase activity. Mucosal TNF-alpha production and histological analysis of the lesions was also carried out. In addition, we studied the expression of the EGF receptor inmunohistochemically during the healing of TNBS-induced chronic colitis. A 2-day treatment with 400 or 800 mg/kg of dosmalfate ameliorated the colon damage score and the incidence of adhesions. It also significantly (P<0.05) decreased myeloperoxidase activity and colonic mucosal production of TNF-alpha. Chronic treatment (14 days) with 800 mg/kg/day of dosmalfate also had significant protective effects on TNBS-induced colitis which were reflected by significant attenuation (P<0.05) of the damage score while the inflammatory indicators were not improved. The chronic beneficial effect of dosmalfate was apparently related to the enhancement of EGF receptor expression. These findings confirm the protective effects of dosmalfate in acute and chronic experimental colitis.
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Affiliation(s)
- Isabel Villegas
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Profesor García González Street, 41012 Seville, Spain
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Van Montfrans C, Rodriguez Pena MS, Pronk I, Ten Kate FJW, Te Velde AA, Van Deventer SJH. Prevention of colitis by interleukin 10-transduced T lymphocytes in the SCID mice transfer model. Gastroenterology 2002; 123:1865-76. [PMID: 12454844 DOI: 10.1053/gast.2002.37067] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Regulatory CD4(+) cells secreting the anti-inflammatory cytokine interleukin (IL)-10 play a key role in maintaining the immune balance in the intestinal mucosa. In this study we engineered primary CD4(+) cells to express IL-10 and investigated the efficacy of this approach in offering protection against experimental colitis. METHODS Spleen-derived CD4(+) cells were transduced by using a retroviral vector to simultaneously express IL-10 and green fluorescent protein (GFP). The therapeutic benefit of CD4(+) cells transduced with IL-10 GFP was studied in experimental colitis, induced by transfer of CD45RB(high) CD4(+) cells to severe combined immunodeficient mice, and in acute trinitrobenzene sulfonic acid (TNBS)-induced colitis. RESULTS Transferred engineered GFP fluorescent cells were detected for at least 15 weeks in peripheral blood, spleens, colon, and lymph nodes draining the intestine of recipient SCID mice. IL-10-GFP CD4(+) cells prevented CD45RB(high)-induced transfer colitis effectively, whereas no effect was observed after transfer of nontransduced CD4(+) cells. IL-10-GFP CD45RB(high) CD4(+) cells lost the capacity to induce colitis. By contrast, no therapeutic benefit was observed in TNBS-induced colitis. CONCLUSIONS Primary murine CD4(+) cells that were engineered to express IL-10 by retroviral transduction act as regulatory cells in CD45RB(high)-induced transfer colitis. This approach may induce long-term maintenance of mucosal immune homeostasis in Crohn's disease.
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Affiliation(s)
- Catherine Van Montfrans
- Department of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
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Lindsay J, Van Montfrans C, Brennan F, Van Deventer S, Drillenburg P, Hodgson H, Te Velde A, Sol Rodriguez Pena M. IL-10 gene therapy prevents TNBS-induced colitis. Gene Ther 2002; 9:1715-21. [PMID: 12457286 DOI: 10.1038/sj.gt.3301841] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2002] [Accepted: 06/25/2002] [Indexed: 12/11/2022]
Abstract
The transfer of genes encoding immunomodulatory proteins to the intestinal mucosa is a promising new approach to the treatment of Crohn's disease (CD). This study investigates the therapeutic efficacy of an adenoviral vector encoding IL-10 (AdvmuIL-10) in experimental colitis. BALB/c mice were treated with a single intravenous injection of AdvmuIL-10, empty cassette virus (Adv0) or PBS prior to the induction of trinitrobenzene sulphonic acid (TNBS) colitis. AdvmuIL-10 treatment prevented the severe loss of body weight associated with TNBS administration. In addition, AdvmuIL-10 therapy led to a significant reduction in both stool markers of inflammation (IL-1beta and TNFR-II) and acute phase response (serum amyloid protein). Finally, the histological scores of mice with TNBS colitis treated with AdvmuIL-10 were significantly lower than Adv0- or PBS-treated controls. The therapeutic efficacy of AdvmuIL-10 was associated with a decrease in the IFN-gamma and IL-6 levels detected in colonic homogenates from mice with TNBS colitis, whereas no effect was observed on cytokine release from stimulated systemic lymphocytes. Thus, AdvmuIL-10 is an effective therapy in the TNBS model of colitis. Gene therapy strategies using adenoviral vectors encoding IL-10 may prove to be a potent therapy for chronic inflammatory conditions such as CD.
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Affiliation(s)
- J Lindsay
- The Kennedy Institute of Rheumatology, Imperial College School of Medicine, London, UK
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Togawa JI, Nagase H, Tanaka K, Inamori M, Nakajima A, Ueno N, Saito T, Sekihara H. Oral administration of lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. J Gastroenterol Hepatol 2002; 17:1291-8. [PMID: 12423274 DOI: 10.1046/j.1440-1746.2002.02868.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS The natural immunomodulator, lactoferrin, is widespread among various biological fluids and is known to exert an anti-inflammatory effect. However, there has been only one study that examined the mode of action of lactoferrin in reducing intestinal damage. We investigated the therapeutic role of lactoferrin and its effect on the levels of pro-inflammatory and anti-inflammatory cytokines, by using a rat model of dextran sulfate sodium (DSS) induced-colitis. METHODS Male Sprague-Dawley rats were given distilled drinking water containing 2.5% (wt/vol) synthetic DSS ad libitum. Bovine lactoferrin was given once daily through gavage, starting 3 days before beginning the DSS administration, until death. The whole colon was removed to be examined macroscopically and histologically. Myeloperoxidase activity, and pro-inflammatory and anti-inflammatory cytokines in the colonic tissue were also measured. RESULTS Dextran sulfate sodium-induced colitis was attenuated by oral administration of lactoferrin in a dose-dependent manner, as reflected by improvement in clinical disease activity index, white blood cell count and hemoglobin concentration, macroscopic and histological scores, and myeloperoxidase activity. Reduced inflammation in response to lactoferrin was correlated with the significant induction of the anti-inflammatory cytokines, interleukin-4 and interleukin-10, and with significant reductions in the pro-inflammatory cytokines, tumor necrosis factor alpha, interleukin-1beta, and interleukin-6. CONCLUSIONS We concluded that oral administration of lactoferrin exerts a protective effect against the development of colitis in rats via modulation of the immune system and correction of cytokine imbalance. Lactoferrin has potential as a new therapeutic agent for inflammatory bowel disease.
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Affiliation(s)
- Jun-Ichi Togawa
- Third Department of Internal Medicine, Yokohama City University School of Medicine, Japan.
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Togawa JI, Nagase H, Tanaka K, Inamori M, Umezawa T, Nakajima A, Naito M, Sato S, Saito T, Sekihara H. Lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. Am J Physiol Gastrointest Liver Physiol 2002; 283:G187-95. [PMID: 12065306 DOI: 10.1152/ajpgi.00331.2001] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Natural immunomodulator lactoferrin is known to exert an anti-inflammatory effect. However, there have been no studies that examine the mode of action of lactoferrin in reducing intestinal damage. We investigated the effect of lactoferrin on a trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rats. Bovine lactoferrin was given once daily through gavage, starting 3 days before (preventive mode) or just after TNBS administration (treatment mode) until death. The distal colon was removed to be examined. Colitis was attenuated by lactoferrin via both modes in a dose-dependent manner, as reflected by improvement in macroscopic and histological scores and myeloperoxidase activity. Lactoferrin caused significant induction of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10, significant reductions in the proinflammatory cytokines tumor necrosis factor-alpha and IL-1beta, and downregulation of the nuclear factor-kappaB pathway. We concluded that lactoferrin exerts a protective effect against colitis in rats via modulation of the immune system and correction of cytokine imbalance. Lactoferrin has potential as a new therapeutic agent for inflammatory bowel disease.
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Affiliation(s)
- Jun-Ichi Togawa
- Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama 236-0004, Japan.
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Chen YK, Hsuen SS, Lin LM. Expression of inducible nitric oxide synthase in human oral premalignant epithelial lesions. Arch Oral Biol 2002; 47:387-92. [PMID: 12015219 DOI: 10.1016/s0003-9969(02)00011-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Increased expression of inducible nitric oxide synthase (iNOS) has been found at the protein level in human oral epithelial dysplasias, but, a corresponding expression at the mRNA level has not been demonstrated. The purpose here was to assess the expression of iNOS mRNA and its correlation with the expression of the enzyme protein in human buccal premalignant epithelial lesions. Activities for iNOS protein (57/80, 64%) and mRNA (53/80, 53%) were detected in the specimens examined. Cytoplasmic and/or nuclear staining for iNOS protein was detected immunohistochemically in a number of mild oral epithelial dysplasias (16/20, 80%), moderate to severe oral epithelial dysplasias (14/20, 70%), submucous fibrosis (14/20, 70%) and verrucous hyperplasia (13/20, 65%). Upon in situ reverse transcription-polymerase chain reaction (RT-PCR), the cellular location of iNOS mRNA was compatible with the immunohistochemical findings. Furthermore, iNOS mRNA was found in 15 specimens of mild oral epithelial dysplasia (15/20, 75%), 13 specimens of moderate to severe oral epithelial dysplasia (13/20, 65%), 13 specimens of submucous fibrosis (13/20, 65%) and 12 specimens of verrucous hyperplasia (12/20, 60%). No iNOS protein or mRNA was found in samples of normal buccal mucosa, or in negative controls. Further studies on the characteristics of iNOS-positive cells and more long-term clinical follow-up data are needed.
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Affiliation(s)
- Yuk-Kwan Chen
- Oral Pathology Department, School of Dentistry, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, Taiwan.
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Bobin-Dubigeon C, Collin X, Grimaud N, Robert JM, Le Baut G, Petit JY. Effects of tumour necrosis factor-alpha synthesis inhibitors on rat trinitrobenzene sulphonic acid-induced chronic colitis. Eur J Pharmacol 2001; 431:103-10. [PMID: 11716848 DOI: 10.1016/s0014-2999(01)01410-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The fact that tumour necrosis factor-alpha (TNF-alpha) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's disease, suggests that TNF-alpha synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-alpha synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-betapicolyl-tetrafluorophtalimide), on colonic inflammation in trinitrobenzene sulphonic acid-induced colitis in rats. Rats received JM 34 maleate (100 mg/kg) and XC 21 (50 mg/kg) 1 h before colitis induction and then daily for 8 days by oral gavage. The colon was removed on day 8 and processed for clinical score, myeloperoxidase activity, and soluble TNF-alpha release. Treatment with XC 21, as well as dexamethasone and sulphasalazine, reduced colonic damage and decreased (except with dexamethasone) the incidence of diarrhoea. JM 34 maleate failed to improve the clinical signs of chronic colitis. After trinitrobenzene sulphonic acid-induced colitis, myeloperoxidase activity and TNF-alpha colonic mucosal production were substantially increased compared to the control (saline instillation). Both of these inflammatory indicators were then significantly decreased (P< or =0.05) after the four chronic treatments (JM 34 maleate, XC 21, sulphasalazine, and dexamethasone). XC 21 appeared to be as efficient as sulphasalazine in improving colonic inflammation.
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Affiliation(s)
- C Bobin-Dubigeon
- Department of Pharmacology and Pharmacokinetics, College of Pharmacy, University of Nantes, 1 rue Gaston Veil, 44035, Nantes, France
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Lindsay JO, Hodgson HJ. Review article: the immunoregulatory cytokine interleukin-10--a therapy for Crohn's disease? Aliment Pharmacol Ther 2001; 15:1709-16. [PMID: 11683684 DOI: 10.1046/j.1365-2036.2001.01093.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The gastrointestinal tract serves as a barrier between the host and the vast array of foreign antigens that are contained within its lumen. The mucosal immune system must balance two opposing functions: to mount an immune response to pathogens, whilst maintaining tolerance to antigens derived from commensal bacteria and food. This balance is regulated by both cellular interactions and the release of soluble mediators called cytokines. Diseases such as ulcerative colitis and Crohn's disease are characterized by alterations in the balance of pro-inflammatory and regulatory cytokines. Interleukin-10 is a regulatory cytokine which inhibits both antigen presentation and subsequent pro-inflammatory cytokine release. In addition, there is evidence that it promotes the formation of antigen-specific regulatory T-cell clones. The pivotal role played by interleukin-10 within the mucosal immune system is demonstrated both by the chronic ileocolitis that develops in gene-targeted interleukin-10 knock-out mice, and by its therapeutic efficacy in several animal models of colitis. However, trials of daily systemic interleukin-10 administration in patients with Crohn's disease have reported only a modest clinical response. Advances in the analysis of functional polymorphisms in the interleukin-10 gene may allow therapy to be targeted to patients who will respond. Finally, therapeutic strategies utilizing gene therapy may enhance mucosal delivery and increase therapeutic response.
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Affiliation(s)
- J O Lindsay
- Department of Gastroenterology, Imperial College School of Medicine, London, UK.
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Ko JK, Sham NF, Guo X, Cho CH. Beneficial intervention of experimental colitis by passive cigarette smoking through the modulation of cytokines in rats. J Investig Med 2001; 49:21-9. [PMID: 11217144 DOI: 10.2310/6650.2001.34087] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Epidemiologic observations have indicated that cigarette smoking decreases the risk of ulcerative colitis, but the modes of action remain anonymous. The present study aimed to investigate the beneficial effects of passive cigarette smoking using an animal colitis model. We hypothesized that the underlying mechanisms may involve immunoregulation of cytokines. METHODS Experimental colitis was induced in rats by enema administration of 2,4-dinitrobenzene sulfonic acid (DNBS). Passive cigarette smoking by rats was performed for 1 hour once daily, from 3 days before DNBS enema until they were sacrificed on day 8. Other groups of DNBS-treated rats received therapeutic treatment of cyclosporin A or pentoxifylline, a tumor necrosis factor (TNF)-alpha inhibitor. Macroscopic and histologic damage were graded, and the colonic levels of different cytokines and the levels/activities of parameters related to neutrophil activation were also measured. RESULTS DNBS-induced colonic damage was improved in passive-cigarette-smoking rats. This was accompanied by attenuation of the elevated colonic myeloperoxidase and inducible nitric oxide synthase activities and leukotriene B4 level. Likewise, the augmentation in colonic levels of TNF-alpha, interleukin (IL)-1 beta, and IL-6 in colitis rats was also alleviated by passive cigarette smoking. In contrast, the deprivation of colonic IL-10 during colitis was preserved in cigarette-smoking rats. These effects were similarly accomplished by pentoxifylline and, to some degree, by cyclosporin A. CONCLUSIONS The results support the idea that the beneficial effects of passive cigarette smoking in experimental colitis involved immunoregulation of cytokines in colonic tissues.
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Affiliation(s)
- J K Ko
- Department of Pharmacology, Faculty of Medicine, University of Hong Kong, 5 Sasson Road, Hong Kong, China.
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Reddix RA, Liu X, Miller MJ, Niu X, Powell A. Constitutive nitric oxide release modulates neurally-evoked chloride secretion in guinea pig colon. Auton Neurosci 2000; 86:47-57. [PMID: 11269924 DOI: 10.1016/s1566-0702(00)00206-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The role of constitutive nitric oxide (NO) release in enteric neural pathways regulating ion transport was examined in guinea pig distal colon, in vitro and ex vivo. In in vitro studies, 43% of colonic preparations exhibited oscillations in baseline short-circuit current (Isc), which were reduced by tetrodotoxin (TTX). The NO chelator, hemoglobin (Hb), and neuronal NO synthase inhibitor, 7-nitroindazole (7-NI), significantly increased the baseline Isc in these tissues, which was reduced by TTX. In tissues without oscillations in baseline Isc, Hb reduced the Isc, while 7-NI had little effect. In all tissues, electrical field stimulation (EFS; 15 V/10 Hz) caused a biphasic increase in the Isc which was enhanced by both Hb and 7-NI. In the ex vivo studies, basal release of nitric oxide was significantly lower in colonic segments isolated from guinea pigs administered N omega-nitro-L-arginine methyl ester (L-NAME) i.p. compared to control tissues. Moreover, carbachol, caused a 10-fold increase in NO release in control tissues, but had no effect in tissues isolated from the L-NAME group. L-NAME increased tissue conductance and EFS-induced changes in Isc, which were reversed by L-arginine. However, carbachol-induced ion secretion was unaltered in the L-NAME group compared to control animals. The results suggest that, in guinea pig colon, constitutive enteric NO release tonically suppresses submucous neural activity and it is involved in the maintenance of basal epithelial chloride secretion and mucosal permeability. Hence, constitutive NO promotes a delicate balance between pro-absorptive and pro-secretory processes in guinea pig colon.
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Affiliation(s)
- R A Reddix
- Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
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Davidson NJ, Fort MM, Müller W, Leach MW, Rennick DM. Chronic colitis in IL-10-/- mice: insufficient counter regulation of a Th1 response. Int Rev Immunol 2000; 19:91-121. [PMID: 10723680 DOI: 10.3109/08830180009048392] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
IL-10-deficient (IL-10-/-) mice, generated by a gene-targeted mutation, develop abnormal immune responses as a result of uncontrolled interactions between antigen presenting cells and lymphocytes. The studies reviewed herein have focused on the enterocolitis that spontaneously develops in IL-10-/- mice. Not unexpectedly, heightened production of proinflammatory mediators accompanied pathologic changes in the gastrointestinal tract of young mutants. In a series of studies, the proinflammatory mediators responsible for initiating the pathogenic response were distinguished from those that were elicited as a consequence of persistent inflammation. We have also investigated the possibility that different mediators are involved in the inductive versus the maintenance phase of disease. The findings of these mechanistic studies as they relate to our understanding of progressive inflammatory disease and the role of IL-10 in controlling the acute and chronic stages are discussed.
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Affiliation(s)
- N J Davidson
- DNAX Research Institute of Cellular and Molecular Biology, Palo Alto, CA 94304, USA
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46
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Stallmach A, Wittig B, Giese T, Pfister K, Hoffmann JC, Bulfone-Paus S, Kunzendorf U, Meuer SC, Zeitz M. Protection of trinitrobenzene sulfonic acid-induced colitis by an interleukin 2-IgG2b fusion protein in mice. Gastroenterology 1999; 117:866-76. [PMID: 10500069 DOI: 10.1016/s0016-5085(99)70345-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND & AIMS We have shown in previous studies that an interleukin 2 (IL-2)-IgG2b fusion protein suppresses both humoral and cellular immune reactions in a murine model of DTH reaction. We now analyze the effects of IL-2-IgG2b in a model of intestinal inflammation in mice induced by the hapten reagent 2,4, 6-trinitrobenzene sulfonic acid (TNBS) that mimics immunologic characteristics of human Crohn's disease. METHODS In TNBS-induced colitis, colonic and splenic T-cell subsets were characterized by immunohistochemistry and flow cytometry. Cytokine synthesis was studied by semiquantitative reverse-transcription polymerase chain reaction and intracellular cytokine staining in CD4(+) T cells. RESULTS When mice were treated with IL-2-IgG2b, improvement in both wasting disease and histopathologic signs of colonic inflammation was observed. An increase in the number of colonic CD4(+)/CD25(+) T cells and increased synthesis of the immunosuppressive cytokine IL-10 also occurred. The protective role of IL-10 was demonstrated by the finding that neutralization of IL-10 in vivo using IL-10-specific antibodies inhibited the IL-2-IgG2b effects in TNBS-induced colitis. CONCLUSIONS These studies show for the first time that the IL-2-IgG2b fusion protein can abrogate experimental colitis by local induction of IL-10-secreting T cells.
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Affiliation(s)
- A Stallmach
- Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
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47
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Reuter BK, Wallace JL. Phosphodiesterase inhibitors prevent NSAID enteropathy independently of effects on TNF-alpha release. THE AMERICAN JOURNAL OF PHYSIOLOGY 1999; 277:G847-54. [PMID: 10516151 DOI: 10.1152/ajpgi.1999.277.4.g847] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
Abstract
Although the ability of nonsteriodal anti-inflammatory drugs (NSAIDs) to injure the small intestine has been well established in humans and animals, the mechanism involved in this type of injury has yet to be elucidated. The cytokine tumor necrosis factor-alpha (TNF-alpha) has recently been demonstrated to play a critical role in the pathogenesis of NSAID-induced gastric damage. We therefore assessed the possibility that TNF-alpha is similarly involved in the pathogenesis of NSAID-induced small intestinal injury. Administration of multiple doses (n = 4) of diclofenac, but not a single dose, resulted in profound macroscopic damage in the intestine and significantly increased levels of TNF-alpha in intestinal tissue and bile. Pretreatment of rats with a phosphodiesterase inhibitor, pentoxifylline, theophylline, or rolipram, significantly attenuated the macroscopic intestinal ulceration produced by diclofenac administration. However, inhibition of TNF-alpha release with thalidomide or immunoneutralization with a polyclonal antibody directed against TNF-alpha failed to afford any protection. These results suggest that the cytokine TNF-alpha does not play a critical role in NSAID-induced small intestinal injury. Therefore, phosphodiesterase inhibitors mediate their protective effect through a mechanism independent of TNF-alpha synthesis inhibition.
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Affiliation(s)
- B K Reuter
- Department of Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
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Ny L, Persson K, Larsson B, Chan J, Weiss LM, Wittner M, Huang H, Tanowitz HB. Localization and activity of nitric oxide synthases in the gastrointestinal tract of Trypanosoma cruzi-infected mice. J Neuroimmunol 1999; 99:27-35. [PMID: 10496174 DOI: 10.1016/s0165-5728(99)00085-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Chagas' disease, caused by the protozoan parasite, Trypanosoma cruzi, is associated with gastrointestinal abnormalities. Since nitric oxide (NO) has been shown to be a factor influencing intestinal function we evaluated the distributions and activities of the NO synthase (NOS) isoforms, in the gut of mice infected with T. cruzi. Ca2+-dependent (NOS1/NOS3) activity was decreased, whereas Ca2+-independent (NOS2) activity was increased in infected mice. NOS2-immunoreactivity was demonstrated in cells within the muscle layers and epithelium in infected mice and NOS1 immunoreactivity was seen in nerve structures. These data indicate that alterations in the NO-system may be important in the pathogenesis of the gastrointestinal manifestations in Chagas' disease.
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Affiliation(s)
- L Ny
- Department of Clinical Pharmacology, Lund University Hospital, Sweden
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49
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Wallace JL, Vergnolle N, Muscará MN, Asfaha S, Chapman K, McKnight W, Del Soldato P, Morelli A, Fiorucci S. Enhanced anti-inflammatory effects of a nitric oxide-releasing derivative of mesalamine in rats. Gastroenterology 1999; 117:557-66. [PMID: 10464131 DOI: 10.1016/s0016-5085(99)70448-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Nitric oxide (NO)-releasing derivatives of cyclooxygenase inhibitors exhibit enhanced anti-inflammatory activity and greatly reduced gastrointestinal toxicity. We evaluated whether a similar derivatization of mesalamine (5-aminosalicylic acid) would improve its anti-inflammatory activity. METHODS Effects of an NO-releasing derivative of mesalamine (NCX-456; NO-mesalamine) were compared with those of mesalamine itself and 2 other NO donors in a rat model of colitis. These drugs were compared for their ability to inhibit leukocyte adherence to the vascular endothelium in vivo, interleukin (IL)-1beta and interferon (IFN)-gamma release in vitro (splenocytes and colon), and messenger RNA expression in the inflamed colon. RESULTS NO-mesalamine was significantly more effective than mesalamine in reducing the severity of colitis (damage and granulocyte infiltration). Unlike mesalamine, NO-mesalamine significantly suppressed leukocyte adherence to the vascular endothelium in vivo. NO-mesalamine inhibited IL-1beta and IFN-gamma release and caspase 1 activity in splenocytes; such effects were not found in the inflamed colon. CONCLUSIONS These studies show that an NO-releasing derivative of mesalamine has significantly enhanced anti-inflammatory activity, including improved efficacy in a rat model of colitis. The improved efficacy of this derivative is most likely caused by its enhanced ability to suppress leukocyte infiltration and possibly to scavenge peroxynitrite.
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Affiliation(s)
- J L Wallace
- Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada.
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50
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Lamrani A, Tulliez M, Chauvelot-Moachon L, Chaussade S, Mauprivez C, Hagnéré AM, Vidon N. Effects of octreotide treatment on early TNF-alpha production and localization in experimental chronic colitis. Aliment Pharmacol Ther 1999; 13:583-94. [PMID: 10233181 DOI: 10.1046/j.1365-2036.1999.00515.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Colitis induced by trinitrobenzene sulphonic acid (TNB) is a model of Th1 disease, mainly explored from the third day of induction. It has recently been shown that octreotide and other somatostatin analogues can modify inflammatory/immune processes by acting on cytokines. AIM To examine TNFalpha production and the effect of preventive treatment with octreotide, during the early phase of TNB-colitis. METHODS Thirty milligrams TNB with 50% ethanol was instilled into the colon of male Wistar rats. Treated groups received octreotide (2x10 microg x day/rat) or dexamethasone (1x2 mg x day/kg), subcutaneously, with the first injection before TNB. Eight and 80 h later, the colon was excised and processed for histology, TNFalpha immunohistochemistry, quantification of cytokine release ex vivo and tissue-inducible NO synthase (iNOS) activity. RESULTS Maximal TNFalpha production was observed at the 8th hour, associated with intense immunostaining of the external muscle layer. Octreotide treatment decreased TNFalpha expression (staining and activity) and iNOS activity. At the 80th hour, submucosal macrophages were positive for TNFalpha and colonic production of IL1beta and interferon gamma was increased; all these effects were reduced by octreotide treatment. CONCLUSIONS TNFalpha was expressed early by resident muscle cells, before staining of infiltrated immune cells and increased production of interferon gamma. TNFalpha regulation by octreotide suggests that this drug might exert anti-inflammatory properties via smooth muscle cells.
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Affiliation(s)
- A Lamrani
- Department of Pharmacology, CNRS 1534, Paris, France; Laboratoire de recherche en pathologie digestive and Division of Gastroenterology, Paris, France
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