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1
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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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Liu J, Ren H, Zhang C, Li J, Qiu Q, Zhang N, Jiang N, Lovell JF, Zhang Y. Orally-Delivered, Cytokine-Engineered Extracellular Vesicles for Targeted Treatment of Inflammatory Bowel Disease. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2304023. [PMID: 37728188 DOI: 10.1002/smll.202304023] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 09/11/2023] [Indexed: 09/21/2023]
Abstract
The use of orally-administered therapeutic proteins for treatment of inflammatory bowel disease (IBD) has been limited due to the harsh gastrointestinal environment and low bioavailability that affects delivery to diseased sites. Here, a nested delivery system, termed Gal-IL10-EVs (C/A) that protects interleukin 10 (IL-10) from degradation in the stomach and enables targeted delivery of IL-10 to inflammatory macrophages infiltrating the colonic lamina propria, is reported. Extracellular vesicles (EVs) carrying IL-10 are designed to be secreted from genetically engineered mammalian cells by a plasmid system, and EVs are subsequently modified with galactose, endowing the targeted IL-10 delivery to inflammatory macrophages. Chitosan/alginate (C/A) hydrogel coating on Gal-IL10-EVs enables protection from harsh conditions in the gastrointestinal tract and favorable delivery to the colonic lumen, where the C/A hydrogel coating is removed at the diseased sites. Gal-IL10-EVs control the production of reactive oxygen species (ROS) and inhibit the expression of proinflammatory cytokines. In a murine model of colitis, Gal-IL10-EVs (C/A) alleviate IBD symptoms including inflammatory responses and disrupt colonic barriers. Taken together, Gal-IL10-EVs (C/A) features biocompatibility, pH-responsive drug release, and macrophage-targeting as a therapeutic platform for oral delivery of bioactive proteins for treating intestinal diseases.
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Affiliation(s)
- Jingang Liu
- School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300350, P. R. China
| | - He Ren
- School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300350, P. R. China
| | - Chen Zhang
- School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300350, P. R. China
| | - Jiexin Li
- School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300350, P. R. China
| | - Qian Qiu
- School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300350, P. R. China
| | - Nan Zhang
- School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300350, P. R. China
| | - Ning Jiang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, P. R. China
| | - Jonathan F Lovell
- Department of Biomedical Engineering, The State University of New York at Buffalo, Buffalo, NY, 14260, USA
| | - Yumiao Zhang
- School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300350, P. R. China
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3
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Khan R, Jori C, Ansari MM, Ahmad A, Nadeem A, Siddiqui N, Sultana S. α-Terpineol Mitigates Dextran Sulfate Sodium-Induced Colitis in Rats by Attenuating Inflammation and Apoptosis. ACS OMEGA 2023; 8:29794-29802. [PMID: 37599911 PMCID: PMC10433518 DOI: 10.1021/acsomega.3c04317] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 07/20/2023] [Indexed: 08/22/2023]
Abstract
Ulcerative colitis (UC) is one of the major inflammatory disorders of the gastrointestinal tract. α-Terpineol (αTL) is naturally present in several plants, and it belongs to the monoterpenes category. αTL possesses various pharmacological properties such as antioxidant, antibacterial, antifungal, anticancer, and antiulcer activities. Importantly, αTL has been reported to possess potent anti-inflammatory effects also. In this study, we hypothesize that αTL may have protective effects against dextran sodium sulfate (DSS)-induced colitis in Wistar rats. Animals were randomly allocated to 3 groups of 6 rats each. In group III, αTL was administered at a dose of 50 mg/kg b. wt. orally from days 1 to 14, while in groups II and III, 4% DSS in drinking water was given to rats ad libitum from the 7th to 14th days. After 24 h of the last dose of αTL, all animals were euthanized. αTL administration reduced the DSS-induced colonic disease activity index, tissue damage, and goblet cell disintegration. αTL suppressed the orchestration of mast cells in the inflamed colon, enhanced the immunostaining of NF-kB-p65, COX-2, iNOS, p53, caspase-9, and cleaved caspase-3, and suppressed the immunostaining of connexin-43, survivin, and Bcl-2. The activities of caspases-9 and -3 were reduced significantly by αTL pretreatment, as also confirmed by calorimetric assays. Moreover, αTL significantly attenuated the nitric oxide level and myeloperoxidase activity. Histological results further support the fact that αTL reduced DSS-induced colonic damage and reduced inflammatory cell infiltration. Overall, our findings suggest that αTL has strong protective effects against DSS-induced colitis by mitigating inflammatory and apoptotic responses.
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Affiliation(s)
- Rehan Khan
- Chemical
Biology Unit, Institute of Nano Science
and Technology, Knowledge City, Sector-81, Mohali 140306, Punjab, India
| | - Chandrashekhar Jori
- Chemical
Biology Unit, Institute of Nano Science
and Technology, Knowledge City, Sector-81, Mohali 140306, Punjab, India
| | - Md. Meraj Ansari
- Centre
for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and
Research, S.A.S Nagar,
Sector 67, Mohali 160062, Punjab, India
| | - Anas Ahmad
- Julia
McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology,
Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases
and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Ahmed Nadeem
- Department
of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nahid Siddiqui
- Amity
Institute of Biotechnology, Amity University, Noida 201303, India
| | - Sarwat Sultana
- Department
of Medical Elementology and Toxicology, Jamia Hamdard, New Delhi 110062, India
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4
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Izco M, Schleef M, Schmeer M, Carlos E, Verona G, Alvarez-Erviti L. Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord. Pharmaceutics 2023; 15:pharmaceutics15041230. [PMID: 37111717 PMCID: PMC10145068 DOI: 10.3390/pharmaceutics15041230] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
The development of effective disease-modifying therapies to halt Parkinson's disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression.
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Affiliation(s)
- Maria Izco
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
| | | | - Marco Schmeer
- PlasmidFactory GmbH & Co. KG, 33607 Bielefeld, Germany
| | - Estefania Carlos
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
| | - Guglielmo Verona
- Centre for Amyloidosis, UCL Medical School, Rowland Hill Street, London NW3 2PF, UK
| | - Lydia Alvarez-Erviti
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
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5
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Hortal M, Fabregat A, Lledo B, Ortiz JA, Moliner B, Bernabeu A, Bernabeu R. IL-6/IL-10 and IL-1β/IL-4 ratios associated with poor ovarian response in women undergoing in-vitro fertilization. Eur J Obstet Gynecol Reprod Biol 2023; 280:68-72. [PMID: 36410244 DOI: 10.1016/j.ejogrb.2022.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 11/04/2022] [Accepted: 11/11/2022] [Indexed: 11/19/2022]
Abstract
The aim of this work was to evaluate whether serum cytokines levels are associated with ovarian response in IVF. 149 patients were included in a retrospective study. Cytokines IL-2, IL-4, IL- 6, IL-8, IL-10, VEGF, IFNγ, TNFα, IL-1α, IL-1β, MCP-1 and EGF were measured by sandwich immunoassay previously to ovarian stimulation. Performing hierarchical cluster analysis, we observed that the antral follicle count, the total oocytes recovered and the MII recovered are grouped in the same cluster as the cytokines IL-2-4-6-10-1α-1β, IFNγ y TNFα. Then, we found that the ratio between IL and 6 and IL-10 was higher in low responder women (2.15 versus 1.55; p = 0.035). If we establish 0.9 as a cut-off for the IL-6/IL-10, we observed that above this value the risk of having a low response to ovarian stimulation was more than 3 times greater than below this value (22.9 % versus 6.0 %; p = 0.007). Also, the ratio IL-1β/IL-4 was higher in patients with normal or suboptimal response (0.62 versus 0.34; p = 0.034) and any patient with low response had a value greater than 0.7 (p = 0.003). As a conclusion, the IL-6/IL-10 and IL-1β/IL-4 ratios showed differences between normoresponder women and patients with low ovarian response.
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Affiliation(s)
- M Hortal
- Instituto Bernabeu Biotech, 03016 Alicante, Spain
| | - A Fabregat
- Instituto Bernabeu Biotech, 03016 Alicante, Spain
| | - B Lledo
- Instituto Bernabeu Biotech, 03016 Alicante, Spain.
| | - J A Ortiz
- Instituto Bernabeu Biotech, 03016 Alicante, Spain
| | - B Moliner
- Instituto Bernabeu of Fertility and Gynaecology, 03016 Alicante, Spain
| | - A Bernabeu
- Instituto Bernabeu of Fertility and Gynaecology, 03016 Alicante, Spain
| | - R Bernabeu
- Instituto Bernabeu of Fertility and Gynaecology, 03016 Alicante, Spain
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6
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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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7
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Feng X, Xiao Y, He J, Yang M, Guo Q, Su T, Huang Y, Yi J, Li CJ, Luo XH, Liu XW, Zhou HY. Long noncoding RNA Gm31629 protects against mucosal damage in experimental colitis via YB-1/E2F pathway. JCI Insight 2022; 7:150091. [PMID: 35143419 PMCID: PMC8986069 DOI: 10.1172/jci.insight.150091] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 02/09/2022] [Indexed: 11/17/2022] Open
Abstract
Mucosal healing is a key treatment goal for inflammatory bowel disease, and adequate epithelial regeneration is required for an intact gut epithelium. However, the underlying mechanism is unclear. Long non-coding RNAs (lncRNAs) have been reported to be involved in the development of inflammatory bowel disease. Here, we report that a lncRNA named Gm31629, decreases in intestinal epithelial cells in response to inflammatory stimulation. Gm31629 deficiency leads to exacerbated intestinal inflammation and delayed epithelial regeneration in dextran sulfate sodium (DSS) -induced colitis model. Mechanistically, Gm31629 promotes E2F pathways and cell proliferation by stabilizing Y-box protein 1 (YB-1), thus facilitating epithelial regeneration. Genetic overexpression of Gm31629 protects against DSS-induced colitis in vivo. Theaflavin 3-gallate, a natural compound mimicking Gm31629, alleviates DSS-induced epithelial inflammation and mucosal damage. These results demonstrate an essential role of lncRNA Gm31629 in linking intestinal inflammation and epithelial cell proliferation, providing a potential therapeutic approach to inflammatory bowel disease.
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Affiliation(s)
- Xu Feng
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Ye Xiao
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Jian He
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, China
| | - Mi Yang
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Qi Guo
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Tian Su
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Yan Huang
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Jun Yi
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Chang-Jun Li
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Xiang-Hang Luo
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Xiao-Wei Liu
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, China
| | - Hai-Yan Zhou
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
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Hartwig O, Shetab Boushehri MA, Shalaby KS, Loretz B, Lamprecht A, Lehr CM. Drug delivery to the inflamed intestinal mucosa - targeting technologies and human cell culture models for better therapies of IBD. Adv Drug Deliv Rev 2021; 175:113828. [PMID: 34157320 DOI: 10.1016/j.addr.2021.113828] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/19/2022]
Abstract
Current treatment strategies for inflammatory bowel disease (IBD) seek to alleviate the undesirable symptoms of the disorder. Despite the higher specificity of newer generation therapeutics, e.g. monoclonal antibodies, adverse effects still arise from their interference with non-specific systemic immune cascades. To circumvent such undesirable effects, both conventional and newer therapeutic options can benefit from various targeting strategies. Of course, both the development and the assessment of the efficiency of such targeted delivery systems necessitate the use of suitable in vivo and in vitro models representing relevant pathophysiological manifestations of the disorder. Accordingly, the current review seeks to provide a comprehensive discussion of the available preclinical models with emphasis on human in vitro models of IBD, along with their potentials and limitations. This is followed by an elaboration on the advancements in the field of biology- and nanotechnology-based targeted drug delivery systems and the potential rooms for improvement to facilitate their clinical translation.
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Affiliation(s)
- Olga Hartwig
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany
| | | | - Karim S Shalaby
- Department of Pharmaceutics, University of Bonn, D-53121 Bonn, Germany; Department of Pharmaceutics and Industrial Pharmacy, Ain Shams University, Cairo, Egypt
| | - Brigitta Loretz
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany
| | - Alf Lamprecht
- Department of Pharmaceutics, University of Bonn, D-53121 Bonn, Germany.
| | - Claus-Michael Lehr
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany.
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9
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Derosa G, Maffioli P, D’Angelo A, Cipolla G, Moro E, Crema F. Effects of experimental colitis in rats on incretin levels, inflammatory markers, and enteric neuronal function. Arch Med Sci 2021; 17:1087-1092. [PMID: 34336036 PMCID: PMC8314401 DOI: 10.5114/aoms.2019.86704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 09/02/2018] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION The aim of the study was to assess the effects of chronic inflammation on incretin levels, inflammatory markers, and enteric neuronal function measured in isolated preparations of smooth muscle of rat. MATERIAL AND METHODS We induced experimental colitis using 2,4-dinitrobenzenesulfonic acid (DNBS) in 17 Albino male Sprague-Dawley rats, while 16 rats were used as a control. They were housed in temperature-controlled rooms in a 12-h light/dark cycle at 22-24°C and 50 to 60% humidity. We evaluated in both inflamed and healthy rats: fasting plasma glucose concentration, fasting plasma insulin, myeloperoxidase, active glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), and GLP-2 levels, adiponectin, and C-reactive protein (CRP). We also evaluated colonic longitudinal smooth muscle contractile activity. RESULTS Intrarectal administration of DNBS reduced body weight gain in inflamed rats. We recorded higher levels of fasting plasma glucose, and insulin in inflamed rats. We observed higher levels of myeloperoxidase and CRP, and lower levels of ADN in inflamed rats. We recorded higher levels of GIP, GLP-1, and GLP-2 in inflamed rats compared to the healthy ones. Regarding functional response of colon intestinal smooth muscle after electrical stimulation, we recorded a lower functional response of colon intestinal smooth muscle after electrical stimulation in inflamed rats. CONCLUSIONS We can conclude that chronic inflammation leads to an increase of incretin levels and to a decrease of functional response of colon intestinal smooth muscle after electrical stimulation.
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Affiliation(s)
- Giuseppe Derosa
- Centre of Diabetes and Metabolic Diseases, Department of Internal Medicine and Therapeutics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, PAVIA, Italy
- Center for Prevention, Surveillance, Diagnosis and Treatment of Rare Diseases, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
- Center for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, University of Pavia, Pavia, Italy
- Laboratory of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Pamela Maffioli
- Centre of Diabetes and Metabolic Diseases, Department of Internal Medicine and Therapeutics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, PAVIA, Italy
- Center for Prevention, Surveillance, Diagnosis and Treatment of Rare Diseases, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Angela D’Angelo
- Centre of Diabetes and Metabolic Diseases, Department of Internal Medicine and Therapeutics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, PAVIA, Italy
- Center for Prevention, Surveillance, Diagnosis and Treatment of Rare Diseases, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
- Laboratory of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Giovanna Cipolla
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Elisabetta Moro
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Francesca Crema
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
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10
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Zhang X, Zhao H, Shi X, Jia X, Yang Y. Identification and validation of an immune-related gene signature predictive of overall survival in colon cancer. Aging (Albany NY) 2020; 12:26095-26120. [PMID: 33401247 PMCID: PMC7803520 DOI: 10.18632/aging.202317] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023]
Abstract
The heterogeneity and complexity of tumor-immune microenvironments lead to diverse immunotherapy effects among colon cancer patients. It is crucial to identify immune microenvironment-related biomarkers and construct prognostic risk models. In this study, the immune and stromal scores of 415 cases from TCGA were calculated using the ESTIMATE algorithm. AXIN2, CCL22, CLEC10A, CRIP2, RUNX3, and TRPM5 were screened and established a prognostic immune-related gene (IRG) signature using by univariate, LASSO, and multivariate Cox regression models. The predicted performance of IRG signature was external validated by GSE39582 (n=519). Stratified survival analysis showed IRG signature was an effective predictor of survival in patients with different clinical characteristics. The protein expression level of six genes was validated by immunohistochemistry analysis. Difference analysis indicated the mutation rate, immune cell of resting NK cells and regulatory T cells infiltration and four immune checkpoints of PD-1, PD-L1, LAG3 and VSIR expression levels in the high-risk group were significantly higher than those in the low-risk group. A nomogram incorporating the gene signatures and clinical factors was demonstrated had a good accuracy (1-, 3-, and 5-year AUC= 0.799, 0.791, 0.738). Our study identified a novel IRG signature, which may provide some references for the clinical precision immunotherapy of patients.
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Affiliation(s)
- Xuening Zhang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Hao Zhao
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Xuezhong Shi
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Xiaocan Jia
- Zhengzhou University Library, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Yongli Yang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
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11
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Qu Z, Wong KY, Moniruzzaman M, Begun J, Santos HA, Hasnain SZ, Kumeria T, McGuckin MA, Popat A. One‐Pot Synthesis of pH‐Responsive Eudragit‐Mesoporous Silica Nanocomposites Enable Colonic Delivery of Glucocorticoids for the Treatment of Inflammatory Bowel Disease. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000165] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Zhi Qu
- School of Pharmacy The University of Queensland Brisbane QLD 4102 Australia
- Immunopathology Group Mater Research Institute –The University of Queensland Translational Research Institute Brisbane QLD 4102 Australia
| | - Kuan Yau Wong
- Immunopathology Group Mater Research Institute –The University of Queensland Translational Research Institute Brisbane QLD 4102 Australia
| | - Md. Moniruzzaman
- School of Pharmacy The University of Queensland Brisbane QLD 4102 Australia
- Inflammatory Bowel Disease Group, Mater Research Institute–The University of Queensland Translational Research Institute Brisbane QLD 4102 Australia
| | - Jakob Begun
- Inflammatory Bowel Disease Group, Mater Research Institute–The University of Queensland Translational Research Institute Brisbane QLD 4102 Australia
- Mater Hospital Brisbane Mater Health Services South Brisbane QLD 4102 Australia
| | - Hélder A Santos
- Drug Research Program Division of Pharmaceutical Chemistry and Technology Faculty of Pharmacy University of Helsinki Helsinki FI‐00014 Finland
- Helsinki Institute of Life Science (HiLIFE) University of Helsinki Helsinki FI‐00014 Finland
| | - Sumaira Z. Hasnain
- School of Pharmacy The University of Queensland Brisbane QLD 4102 Australia
- Immunopathology Group Mater Research Institute –The University of Queensland Translational Research Institute Brisbane QLD 4102 Australia
| | - Tushar Kumeria
- School of Pharmacy The University of Queensland Brisbane QLD 4102 Australia
- Immunopathology Group Mater Research Institute –The University of Queensland Translational Research Institute Brisbane QLD 4102 Australia
| | - Michael A. McGuckin
- Faculty of Medicine Dentistry and Health Sciences the University of Melbourne Melbourne VIC 3010 Australia
| | - Amirali Popat
- School of Pharmacy The University of Queensland Brisbane QLD 4102 Australia
- Immunopathology Group Mater Research Institute –The University of Queensland Translational Research Institute Brisbane QLD 4102 Australia
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12
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Wrotek S, Sobocińska J, Kozłowski HM, Pawlikowska M, Jędrzejewski T, Dzialuk A. New Insights into the Role of Glutathione in the Mechanism of Fever. Int J Mol Sci 2020; 21:ijms21041393. [PMID: 32092904 PMCID: PMC7073131 DOI: 10.3390/ijms21041393] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 12/17/2022] Open
Abstract
Glutathione is one of the most important and potent antioxidants. The development of pharmacological compounds that can either increase or decrease glutathione concentrations has allowed investigation into the role of glutathione in various biological processes, including immune responses. Recent findings have shown that glutathione not only affects certain factors involved in immunological processes but also modifies complex immune reactions such as fever. Until recently, it was not known why some patients do not develop fever during infection. Data suggest that fever induction is associated with oxidative stress; therefore, antioxidants such as glutathione can reduce pyrexia. Surprisingly, new studies have shown that low glutathione levels can also inhibit fever. In this review, we focus on recent advances in this area, with an emphasis on the role of glutathione in immune responses accompanied by fever. We describe evidence showing that disturbed glutathione homeostasis may be responsible for the lack of fever during infections. We also discuss the biological significance of the antipyretic effects produced by pharmacological glutathione modulators.
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Affiliation(s)
- Sylwia Wrotek
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 1 Lwowska Str., 87-100 Torun, Poland; (J.S.); (H.M.K.); (M.P.); (T.J.)
- Correspondence: (S.W.); (A.D.)
| | - Justyna Sobocińska
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 1 Lwowska Str., 87-100 Torun, Poland; (J.S.); (H.M.K.); (M.P.); (T.J.)
| | - Henryk M. Kozłowski
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 1 Lwowska Str., 87-100 Torun, Poland; (J.S.); (H.M.K.); (M.P.); (T.J.)
| | - Małgorzata Pawlikowska
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 1 Lwowska Str., 87-100 Torun, Poland; (J.S.); (H.M.K.); (M.P.); (T.J.)
| | - Tomasz Jędrzejewski
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 1 Lwowska Str., 87-100 Torun, Poland; (J.S.); (H.M.K.); (M.P.); (T.J.)
| | - Artur Dzialuk
- Department of Genetics, Faculty of Biological Sciences, Kazimierz Wielki University, 10 Powstańców Wielkopolskich Ave., 85-090 Bydgoszcz, Poland
- Correspondence: (S.W.); (A.D.)
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13
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Lee KH, Ahn BS, Cha D, Jang WW, Choi E, Park S, Park JH, Oh J, Jung DE, Park H, Park JH, Suh Y, Jin D, Lee S, Jang YH, Yoon T, Park MK, Seong Y, Pyo J, Yang S, Kwon Y, Jung H, Lim CK, Hong JB, Park Y, Choi E, Shin JI, Kronbichler A. Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene modulation: A comprehensive review. Autoimmun Rev 2020; 19:102469. [PMID: 31918027 DOI: 10.1016/j.autrev.2020.102469] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 09/20/2019] [Indexed: 12/21/2022]
Abstract
Autoimmune diseases are clinical syndromes that result from pathogenic inflammatory responses driven by inadequate immune activation by T- and B-cells. Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Recently, with the advancement of understanding of the immunological and molecular basis of autoimmune diseases, gene modulation has become a potential approach for the tailored treatment of autoimmune disorders. Gene modulation can be applied to regulate the levels of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines by inhibiting these cytokine expressions using short interfering ribonucleic acid (siRNA) or by inhibiting cytokine signaling using small molecules. In addition, gene modulation delivering anti-inflammatory cytokines or cytokine antagonists showed effectiveness in regulating autoimmunity. In this review, we summarize the potential target genes for gene or immunomodulation in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human. Emerging approaches to investigate cytokine regulation through gene modulation may be a potential approach for the tailored immunomodulation of some autoimmune diseases near in the future.
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Affiliation(s)
- Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung Soo Ahn
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dohyeon Cha
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Woo Jang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eugene Choi
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soohyun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Hyeong Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Junseok Oh
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Da Eun Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Heeryun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ju Ha Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Youngsong Suh
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dongwan Jin
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Siyeon Lee
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Hwan Jang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tehwook Yoon
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Min-Kyu Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoonje Seong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jihoon Pyo
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sunmo Yang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Youngin Kwon
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunjean Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chae Kwang Lim
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Beom Hong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yeoeun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eunjin Choi
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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14
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Shahriyari E, Vahedi L, Roshanipour N, Jafarabadi MA, Khamaneh A, Laleh MG. Exploring the association of IL-10 polymorphisms in Behcet's disease: a systematic review and meta-analysis. JOURNAL OF INFLAMMATION-LONDON 2019; 16:26. [PMID: 31889911 PMCID: PMC6929502 DOI: 10.1186/s12950-019-0230-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 12/05/2019] [Indexed: 12/21/2022]
Abstract
Background Polymorphisms in the interleukin-10 (IL-10) gene have been studied in various ethnic groups for possible association with Behçet’s disease (BD). This study aimed to perform a meta-analysis of eligible studies to calculate the association of IL-10 polymorphisms with BD. A systematic literature search was carried out in PubMed, Embase, Web of Science, and Scopus databases to identify relevant publications, and extracted the respective results. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the power of association with a random-effects model. Results A total of 19 articles, consisting of 10,626 patients and 13,592 controls were included in the meta-analysis. The meta-analysis revealed significant associations in allelic and genotypic test models of − 819 (C vs. T: OR = 0.691, P < 0.001; CC vs. TT: OR = 0.466, P < 0.001; CC + CT vs. TT: OR = 0.692, P < 0.001; and CC vs. CT + TT: OR = 0.557, P < 0.001), − 592 (C vs. A: OR = 0.779, P = 0.002; CC + AA vs. AA: OR = 0.713, P = 0.021; and CA vs. AA: OR = 0.716, P = 0.016), rs1518111 (G vs. A: OR = 0.738, P < 0.001; GG vs. AA: OR = 0.570, P < 0.001; GG + AG vs. AA: OR = 0.697, P < 0.001; GG vs. GA + AA: OR = 0.701, P < 0.001; and AG vs. GG: OR = 0.786, P = 0.004) and rs1554286 (C vs. T: OR = 0.582, P < 0.001; CC vs. TT: OR = 0.508, P < 0.001; CC + CT vs. TT: OR = 0.605, P < 0.001; CC vs. CT + TT: OR = 0.665, P = 0.012; and CT vs. TT: OR = 0.646, P = 0.001). However, we failed to find any association between − 1082 polymorphism and susceptibility of BD. Conclusion This meta-analysis demonstrated that the interleukin-10 -819, − 596, rs1518111 and rs1554286 polymorphisms could be responsible against BD susceptibility, and should probably be regarded as a protective factor for Behçet’s disease.
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Affiliation(s)
- Elham Shahriyari
- 1Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.,2Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Vahedi
- 2Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasrin Roshanipour
- 3Department of Biology, School of Genetic, Azad University of Tabriz, Tabriz, Iran
| | - Mohammad Asghari Jafarabadi
- 4Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Khamaneh
- 5Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Ghaffari Laleh
- 1Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.,4Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
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15
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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: 377] [Impact Index Per Article: 62.8] [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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16
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Hopkin SJ, Lewis JW, Krautter F, Chimen M, McGettrick HM. Triggering the Resolution of Immune Mediated Inflammatory Diseases: Can Targeting Leukocyte Migration Be the Answer? Front Pharmacol 2019; 10:184. [PMID: 30881306 PMCID: PMC6407428 DOI: 10.3389/fphar.2019.00184] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 02/14/2019] [Indexed: 12/16/2022] Open
Abstract
Leukocyte recruitment is a pivotal process in the regulation and resolution of an inflammatory episode. It is vital for the protective responses to microbial infection and tissue damage, but is the unwanted reaction contributing to pathology in many immune mediated inflammatory diseases (IMIDs). Indeed, it is now recognized that patients with IMIDs have defects in at least one, if not multiple, check-points regulating the entry and exit of leukocytes from the inflamed site. In this review, we will explore our understanding of the imbalance in recruitment that permits the accumulation and persistence of leukocytes in IMIDs. We will highlight old and novel pharmacological tools targeting these processes in an attempt to trigger resolution of the inflammatory response. In this context, we will focus on cytokines, chemokines, known pro-resolving lipid mediators and potential novel lipids (e.g., sphingosine-1-phosphate), along with the actions of glucocorticoids mediated by 11-beta hydroxysteroid dehydrogenase 1 and 2.
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Affiliation(s)
- Sophie J. Hopkin
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Jonathan W. Lewis
- Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Franziska Krautter
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Myriam Chimen
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Helen M. McGettrick
- Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
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17
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Wen S, Wu Y, Pan Y, Cao M, Zhao D, Wang C, Wang C, Kong F, Li J, Niu J, Jiang J. Association of IL-10 and IL-10RA single nucleotide polymorphisms with the responsiveness to HBV vaccination in Chinese infants of HBsAg(+)/HBeAg(-) mothers: a nested case-control study. BMJ Open 2018; 8:e022334. [PMID: 30498038 PMCID: PMC6278805 DOI: 10.1136/bmjopen-2018-022334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 07/02/2018] [Accepted: 09/27/2018] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES To investigate the association of interleukin (IL)-10 and IL-10 receptor A (IL-10RA) single nucleotide polymorphisms with the responsiveness to hepatitis B virus (HBV) vaccination in newborns whose mothers were hepatitis B surface antigen (HBsAg)(+)/hepatitis B e antigen (HBeAg)(-). DESIGN Nested case-control study. SETTING Changchun, China. PARTICIPANTS 713 infants from a Han Chinese population whose mothers were HBsAg(+)/HBeAg(-) and participated in the prevention of mother-to-child transmission of HBV at the First Hospital of Jilin University from July 2012 to July 2015 were included. Infants were excluded for HBsAg-positive; unstandardised vaccination process; inadequate blood samples; not Han Chinese and failed genotyping. RESULTS Infants with artificial feeding pattern were correlated with low responsiveness to HBV vaccination (p=0.009). The GG genotype of IL-10 rs3021094 was correlated with a higher risk of low responsiveness to HBV vaccination (OR 2.80, 95% CI 1.35 to 5.83). No haplotype was found to be correlated with responsiveness to HBV vaccination. No gene-gene interaction was found between IL-10 and IL-10RA. CONCLUSIONS Our study found that IL-10 gene variants were significantly associated with the immune response to the HBV vaccine. Identifying these high-risk infants who born to HBsAg(+)/HBeAg(-) mothers and low responses to hepatitis B vaccination will provide evidence for individualised prevention strategies.
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Affiliation(s)
- Simin Wen
- Department of Clinical Research, First Hospital of Jilin University, Changchun, China
| | - Yanhua Wu
- Department of Clinical Research, First Hospital of Jilin University, Changchun, China
| | - Yuchen Pan
- Department of Clinical Research, First Hospital of Jilin University, Changchun, China
| | - Mengzhuo Cao
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Division of Education, Beijing Jishuitan Hospital, Beijing, China
| | - Dan Zhao
- Department of Clinical Research, First Hospital of Jilin University, Changchun, China
| | - Chong Wang
- Department of Hepatology, First Hospital of Jilin University, Changchun, China
| | - Chuan Wang
- Department of Child Healthcare, Maternal and Child Health Care and Family Planning Service Center of Chaoyang District, Beijing, China
| | - Fei Kong
- Department of Hepatology, First Hospital of Jilin University, Changchun, China
| | - Jie Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Changchun, China
| | - Jing Jiang
- Department of Clinical Research, First Hospital of Jilin University, Changchun, China
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18
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Lin HP, Zheng YQ, Zhou ZP, Wang GX, Guo PF. Ryanodine receptor antagonism alleviates skeletal muscle ischemia reperfusion injury by modulating TNF-α and IL-10. Clin Hemorheol Microcirc 2018; 70:51-58. [PMID: 29660904 DOI: 10.3233/ch-170276] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Intracellular calcium overload has been implicated in various pathological conditions including ischemia reperfusion injury. This study aims to explore the effect and probable mechanism of dantrolene, a ryanodine receptor and intracellular calcium antagonist, on the skeletal muscle ischemia reperfusion injury. MATERIALS AND METHODS SD rats were randomly divided into three groups: sham group which underwent anaesthesia and exposure of femoral vein, reperfusion group that received 2 h ischemia and the amount of diluent via femoral vein before 4 h reperfusion, dantrolene group that underwent 2 h ischemia and was given 2 mg/kg dantrolene via femoral vein before 4 h reperfusion. The parameters measured at the end of reperfusion included serum maleic dialdehyde (MDA), tissue myeloperoxidase (MPO) and muscle histology, as well as serum TNF-α and IL-10. RESULTS Levels of MDA, MPO and TNF-α increased in the reperfusion group, whereas the relevant expressions in the dantrolene group decreased significantly. Histological examination demonstrated significant improvements between the same both groups. IL-10 reflected the protection observed above with a significant up-regulation of expression after dantrolene administration. CONCLUSION Ryanodine receptor antagonist dantrolene exerted a significant protective effect against the inflammatory injury of skeletal muscle ischemia reperfusion. The underlying molecular mechanism is probably related to the suppression of TNF-α levels and the increment of IL-10 expression.
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Affiliation(s)
- Hai-Peng Lin
- Department of General Surgery, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yan-Qing Zheng
- Department of E.N.T, Quanzhou Women's and Children's Hospital, Quanzhou, China
| | - Zhi-Ping Zhou
- Department of General Surgery, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Gao-Xiong Wang
- Department of General Surgery, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Ping-Fan Guo
- Department of Vascular Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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19
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Cardiotrophin-1 attenuates experimental colitis in mice. Clin Sci (Lond) 2018; 132:985-1001. [PMID: 29572384 DOI: 10.1042/cs20171513] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 03/09/2018] [Accepted: 03/12/2018] [Indexed: 12/19/2022]
Abstract
Cardiotrophin-1 (CT-1) holds potent anti-inflammatory, cytoprotective, and anti-apoptotic effects in the liver, kidneys, and heart. In the present study, the role of endogenous CT-1 and the effect of exogenous CT-1 were evaluated in experimental ulcerative colitis. Colitis was induced in CT-1 knockout and wild-type (WT) mice by administration of dextran sulphate sodium (DSS) in the drinking water during 7 days. CT-1 knockout mice showed higher colon damage and disease severity than WT mice. In addition, CT-1 (200 µg/kg/day, iv) or vehicle (as control) was administered during 3 days to WT, colitic mice, starting on day 4 after initiation of DSS. Disease activity index (DAI), inflammatory markers (tumor necrosis factor α (TNF-α), INFγ, IL-17, IL-10, inducible nitric oxide synthase (iNOS)), colon damage, apoptosis (cleaved caspase 3), nuclear factor κB (NFκB) and STAT-3 activation, and bacterial translocation were measured. Compared with mice treated with DSS, mice also treated with exogenous CT-1 showed lower colon damage, DAI, plasma levels of TNFα, colon expression of TNF-α, INFγ, IL-17, iNOS and cleaved caspase 3, higher NFκB and signal transducer and activator of transcription 3 (STAT3) pathways activation, and absence of bacterial translocation. We conclude that endogenous CT-1 plays a role in the defense and repair response of the colon against ulcerative lesions through an anti-inflammatory and anti-apoptotic effect. Supplementation with exogenous CT-1 ameliorates disease symptoms, which opens a potentially new therapeutic strategy for ulcerative colitis.
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Afkari B, Babaloo Z, Dolati S, Khabazi A, Jadidi-Niaragh F, Talei M, Shanehbandi D, Mahmoudi S, Hazhirkarzar B, Sakhinia E. Molecular analysis of interleukin-10 gene polymorphisms in patients with Behçet's disease. Immunol Lett 2017; 194:56-61. [PMID: 29294320 DOI: 10.1016/j.imlet.2017.12.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 12/02/2017] [Accepted: 12/20/2017] [Indexed: 01/20/2023]
Abstract
BACKGROUND Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that play a fundamental role in restrictive host immune response to pathogens, by means of that is a crucial importance for chronic inflammatory disease studies. Therefore, the goal of this study was to measure the correlation of the IL-10 gene polymorphisms with the susceptibility to Behçet's disease compared with the control group in the Azeri population and to determine the expression of this gene in the two groups. Also, real-time PCR was performed for evaluate the IL-10 mRNA expression of the associated polymorphisms. METHODS In this study, blood samples from 47 (1 missed) patients and 58 (3 missed) healthy control were taken, and then mononuclear cells isolated with ficoll protocol. The DNA and RNA were subsequently extracted. They were examined for -592A/C (rs1800872) of IL-10 gene single nucleotide polymorphism (SNP) using RFLP-PCR. Allele and genotype distributions were evaluated among groups using chi-square or Fisher's test. Following this, the extracted RNA was converted to cDNA using the RT-PCR method, after that expression of IL-10 evaluated by Real-time PCR. Serum levels of IL-10 were measured using Enzyme-linked immunosorbent assay (ELISA). RESULTS Rates of the rs1800872 A allele was statistically lower in the control group compared with BD patients (p = 0.0315 and OR = 1.90 (1.05-3.42)). Also, as we expected, the expression level of the IL-10 gene was seen to significantly decrease in the patient group compared to the control. CONCLUSIONS Our study showed that the rs1800872 A allele of the IL-10 gene may contribute to the genetic susceptibility of BD by regulating the expression of IL-10. Also as we expected, the expression level of this gene was seen to significantly decrease in the patient group compared to the control.
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Affiliation(s)
- Babak Afkari
- Connective Tissue Research Center, Tabriz University of Medical Science, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Iran; Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Babaloo
- Connective Tissue Research Center, Tabriz University of Medical Science, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran.
| | - Sanam Dolati
- Connective Tissue Research Center, Tabriz University of Medical Science, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
| | - Alireza Khabazi
- Connective Tissue Research Center, Tabriz University of Medical Science, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
| | - Mahsa Talei
- Immunology Research Center, Tabriz University of Medical Sciences, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
| | | | - Shiva Mahmoudi
- Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | - Bita Hazhirkarzar
- Research Center for Evidence Based Medicine, Tabriz University of Medical Science, Iran
| | - Ebrahim Sakhinia
- Connective Tissue Research Center, Tabriz University of Medical Science, Iran; Department of Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Attarwala H, Han M, Kim J, Amiji M. Oral nucleic acid therapy using multicompartmental delivery systems. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2017; 10. [PMID: 28544521 DOI: 10.1002/wnan.1478] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 11/12/2016] [Accepted: 03/31/2017] [Indexed: 12/18/2022]
Abstract
Nucleic acid-based therapeutics has the potential for treating numerous diseases by correcting abnormal expression of specific genes. Lack of safe and efficacious delivery strategies poses a major obstacle limiting clinical advancement of nucleic acid therapeutics. Oral route of drug administration has greater delivery challenges, because the administered genes or oligonucleotides have to bypass degrading environment of the gastrointestinal (GI) tract in addition to overcoming other cellular barriers preventing nucleic acid delivery. For efficient oral nucleic acid delivery, vector should be such that it can protect encapsulated material during transit through the GI tract, facilitate efficient uptake and intracellular trafficking at desired target sites, along with being safe and well tolerated. In this review, we have discussed multicompartmental systems for overcoming extracellular and intracellular barriers to oral delivery of nucleic acids. A nanoparticles-in-microsphere oral system-based multicompartmental system was developed and tested for in vivo gene and small interfering RNA delivery for treating colitis in mice. This system has shown efficient transgene expression or gene silencing when delivered orally along with favorable downstream anti-inflammatory effects, when tested in a mouse model of intestinal bowel disease. WIREs Nanomed Nanobiotechnol 2018, 10:e1478. doi: 10.1002/wnan.1478 This article is categorized under: Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Husain Attarwala
- Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA
| | - Murui Han
- Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA
| | - Jonghan Kim
- Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA
| | - Mansoor Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA
- Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
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Vasovic M, Gajovic N, Brajkovic D, Jovanovic M, Zdravkovaic N, Kanjevac T. The relationship between the immune system and oral manifestations of inflammatory bowel disease: a review. Cent Eur J Immunol 2016; 41:302-310. [PMID: 27833449 PMCID: PMC5099388 DOI: 10.5114/ceji.2016.63131] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 07/28/2015] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic, relapsing inflammatory diseases characterized by exacerbations and remissions of the gastrointestinal tract, clinically manifested as Crohn's disease and ulcerative colitis. The etiology of IBDs is considered to be multi factorial, comprising environmental, immune, microbial and genetic factors. Clinical signs may include abdominal pain, frequent bloody diarrheas, mucorrhea, vomiting, fever, fatigue or weight loss. Changes in the oral cavity often precede intestinal symptoms. Inflammatory bowel disease leads to a significant deterioration of oral health, which indicates that cooperation between the dentist and the gastroenterologist is necessary when considering patients' welfare. Patients with IBD have an altered immune response, but microorganisms of the oral cavity may also be responsible for its modification. This review paper discusses the correlation between the immune system and inflammatory bowel disease manifestations in the oral cavity.
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Affiliation(s)
- Miroslav Vasovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Nevena Gajovic
- Center for Molecular Medicine and Stem Cells Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Denis Brajkovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Marina Jovanovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Natasa Zdravkovaic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Tatjana Kanjevac
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Serbia
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23
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Buckinx R, Timmermans JP. Targeting the gastrointestinal tract with viral vectors: state of the art and possible applications in research and therapy. Histochem Cell Biol 2016; 146:709-720. [PMID: 27665281 DOI: 10.1007/s00418-016-1496-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2016] [Indexed: 12/11/2022]
Abstract
While there is a large body of preclinical data on the use of viral vectors in gene transfer, relatively little is known about viral gene transfer in the gastrointestinal tract. Viral vector technology is especially underused in the field of neurogastroenterology when compared to brain research. This review provides an overview of the studies employing viral vectors-in particular retroviruses, adenoviruses and adeno-associated viruses-to transduce different cell types in the intestine. Early work mainly focused on mucosal transduction, but had limited success due to the harsh luminal conditions in the gastrointestinal tract and the high turnover rate of enterocytes. More recently, several studies have successfully employed viral gene transfer to target the enteric nervous system and its progenitors. Although several hurdles still need to be overcome, in particular on how to augment transduction efficiency and specific cell targeting, viral vector technology holds strong potential not only as a valid research tool in fundamental gastroenterological research but also as a therapeutic agent in translational (bio)medical research.
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Affiliation(s)
- Roeland Buckinx
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Jean-Pierre Timmermans
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
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Wrotek S, Jędrzejewski T, Piotrowski J, Kozak W. N-Acetyl-l-cysteine exacerbates generation of IL-10 in cells stimulated with endotoxin in vitro and produces antipyresis via IL-10 dependent pathway in vivo. Immunol Lett 2016; 177:1-5. [PMID: 27363620 DOI: 10.1016/j.imlet.2016.06.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 06/20/2016] [Accepted: 06/26/2016] [Indexed: 01/08/2023]
Abstract
N-Acetyl-l-cysteine (NAC) is a well-known medication, primarily used as a mucolytic agent in pulmonary disease. Recently, we have found that NAC possesses antipyretic properties. The aim of the present study was to investigate the mechanism by which NAC attenuates fever. The concentration of interleukin (IL)-10 and prostaglandin (PG) E2 were measured using ELISA kit in the supernatants aspirated after stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS, 1μg/mL) and NAC (10mM). The body temperature of the Wistar rats was measured using biotelemetry system. To inhibit endotoxic fever, NAC (200mg/kg; i.p.) was injected into the rats one hour prior to the LPS administration (50μg/kg; i.p.). The pre-treatment of LPS-stimulated PBMCs with NAC resulted in a significant decrease in PGE2 concentration in comparison to the cells treated with LPS alone (PGE2 level was 386.1±61.9pg/mL vs. 2078.9±157.9pg/mL, respectively, p<0.001). Furthermore, in these cells we observed a significant increase in IL-10 level (142.1±2.62pg/mL in NAC+LPS stimulated cells vs. 54.4±0.6pg/mL in LPS stimulated cells, p<0.001). The injection of anti-IL-10 antibody into the rats abolished antipyretic properties of NAC. Body temperature in animals treated with anti-IL-10+NAC/LPS was 38.28±0.12°C vs. 37.73±0.06°C in IgG+NAC/LPS rats (p<0.001) and 38.31±0.20°C in NaCl/LPS-treated animals (n.s.). Based on these data, we conclude that NAC acts as an antipyretic via IL-10 stimulation. This finding provides a new insight into the immunopharmacology of NAC, and we believe that in a future it will contribute to the new and/or more accurate application of NAC in medicine.
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Affiliation(s)
- Sylwia Wrotek
- Department of Immunology, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100, Torun, Poland.
| | - Tomasz Jędrzejewski
- Department of Immunology, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100, Torun, Poland.
| | - Jakub Piotrowski
- Department of Immunology, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100, Torun, Poland; Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Wilenska 4, 87-100, Torun, Poland.
| | - Wiesław Kozak
- Department of Immunology, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100, Torun, Poland.
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Miyoshi E, Shinzaki S, Fujii H, Iijima H, Kamada Y, Takehara T. Role of aberrant IgG glycosylation in the pathogenesis of inflammatory bowel disease. Proteomics Clin Appl 2016; 10:384-390. [PMID: 26427763 DOI: 10.1002/prca.201500089] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Revised: 08/31/2015] [Accepted: 09/24/2015] [Indexed: 01/02/2023]
Abstract
The intestine is one of the most important organs associated with the immune system. It is thought that disruption of intestinal immunity causes inflammatory bowel disease (IBD). Recent advances in immune glycobiology have provided novel insights into many human diseases. For example, studies of glycosylation remodeling in mice have underscored the importance of oligosaccharides in the pathogenesis of IBD. Furthermore, aberrant glycosylation of IgG is a good serum marker of IBD activity. In this review, we examine current understanding of the role of aberrant glycosylation in the pathogenesis of IBD in terms of our original data and recent reports.
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Affiliation(s)
- Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shinichiro Shinzaki
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hironobu Fujii
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hideki Iijima
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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Valatas V, Bamias G, Kolios G. Experimental colitis models: Insights into the pathogenesis of inflammatory bowel disease and translational issues. Eur J Pharmacol 2015; 759:253-264. [PMID: 25814256 DOI: 10.1016/j.ejphar.2015.03.017] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Revised: 02/03/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel diseases, ulcerative colitis and Crohn׳s disease are characterized by chronic relapsing inflammation of the gastrointestinal tract of unknown etiology that seems to be the consequence of a genetically driven dysregulated immune response against various local and environmental triggers through a defective epithelial barrier. During the last decades, a large number of animal experimental models of intestinal inflammation have been generated and provided valuable insights into the mechanisms that either maintain mucosal homeostasis or drive intestinal inflammation. Their study enabled the identification of various treatment targets and the development a large pipeline of new drugs, mostly biologics. Safety and therapeutic efficacy of these agents have been evaluated in a large number of clinical trials but only a minority has reached the clinic so far. Translational successes but mostly translational failures have prompted to re-evaluate results of efficacy and safety generated by pre-clinical testing and to re-examine the way to interpret experimental in vivo data. This review examines the contribution of the most popular experimental colitis models to our understanding of the pathogenesis of human inflammatory bowel diseases and their translational input in drug development and discusses ways to improve translational outcome.
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Affiliation(s)
- Vassilis Valatas
- Laboratory of Gastroenterology, Faculty of Medicine, University of Crete, Greece.
| | - Giorgos Bamias
- Academic Department of Gastroenterology, Laikon Hospital, Kapodistriakon University of Athens, Athens, Greece.
| | - George Kolios
- Laboratory of Pharmacology, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
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27
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Abstract
Importance of chronic fibroproliferative diseases (FDs) including pulmonary fibrosis, chronic kidney diseases, inflammatory bowel disease, and cardiovascular or liver fibrosis is rapidly increasing and they have become a major public health problem. According to some estimates about 45% of all deaths are attributed to FDs in the developed world. Independently of their etiology the common hallmark of FDs is chronic inflammation. Infiltrating immune cells, endothelial, epithelial, and other resident cells of the injured organ release an orchestra of inflammatory mediators, which stimulate the proliferation and excessive extracellular matrix (ECM) production of myofibroblasts, the effector cells of organ fibrosis. Abnormal amount of ECM disturbs the original organ architecture leading to the decline of function. Although our knowledge is rapidly expanding, we still have neither a diagnostic tool to detect nor a drug to specifically target fibrosis. Therefore, there is an urgent need for the more comprehensive understanding of the pathomechanism of fibrosis and development of novel diagnostic and therapeutic strategies. In the present review we provide an overview of the common key mediators of organ fibrosis highlighting the role of interleukin-10 (IL-10) cytokine family members (IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26), which recently came into focus as tissue remodeling-related inflammatory cytokines.
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Hu J, Hou S, Zhu X, Fang J, Zhou Y, Liu Y, Bai L, Kijlstra A, Yang P. Interleukin-10 gene polymorphisms are associated with Behcet's disease but not with Vogt-Koyanagi-Harada syndrome in the Chinese Han population. Mol Vis 2015; 21:589-603. [PMID: 26015771 PMCID: PMC4443582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 05/20/2015] [Indexed: 11/06/2022] Open
Abstract
PURPOSE This study aimed to investigate the association of interleukin (IL)-10 gene polymorphisms with Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in the Chinese Han population. METHODS A two-stage association study was performed on 718 BD patients, 300 VKH patients, and 1,753 controls. Genotyping of the IL-10 gene was performed for six single nucleotide polymorphisms (SNPs), including rs1800871, rs1800872, rs1800896, rs3021094, rs3790622, and rs1554286 using PCR-restricted fragment length polymorphism or TaqMan SNP assays. Real-time PCR was performed to test the IL-10 mRNA expression of the associated polymorphisms. RESULTS The first-stage result showed significantly increased frequencies of the rs1800871 T allele, rs1800872 A allele, and rs1554286 T allele in BD patients compared with controls (Pcorrected (Pcorr)=1.82×10(-5), OR=1.837; Pcorr=6.1×10(-5), OR=1.780; Pcorr=3.15×10(-5), OR=1.794, respectively). There was no association of the tested six SNPs with VKH syndrome. A second-stage study was therefore performed in BD patients to validate the result of the first stage, showing a significantly increased frequency of the rs1800871 T allele (Second stage, Pcorr=5.59×10(-5), OR=1.493; Combined data, Pcorr=3.65×10(-11), OR=1.632). Compared to the controls, an increased frequency of the rs1800871 T allele was observed in BD patients with extraocular findings, including genital ulcers, skin lesions, and a positive pathergy test. No difference was found among the mRNA expressions of IL-10 in the peripheral blood mononuclear cells (PBMCs) of controls with different genotypes of rs1800871 after stimulation of lipopolysaccharide (LPS) or anti-CD3/CD28 antibodies. CONCLUSIONS The findings showed that IL-10 is a risk gene for BD but not for VKH syndrome.
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Affiliation(s)
- Jianmin Hu
- Department of Ophthalmology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shengping Hou
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Eye Institute, Chongqing Key Laboratory of Ophthalmology, Chongqing, China
| | - Xueping Zhu
- Department of Ophthalmology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Jing Fang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Eye Institute, Chongqing Key Laboratory of Ophthalmology, Chongqing, China
| | - Yan Zhou
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Eye Institute, Chongqing Key Laboratory of Ophthalmology, Chongqing, China
| | - Yunjia Liu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Eye Institute, Chongqing Key Laboratory of Ophthalmology, Chongqing, China
| | - Lin Bai
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Eye Institute, Chongqing Key Laboratory of Ophthalmology, Chongqing, China
| | - Aize Kijlstra
- University Eye Clinic Maastricht, Maastricht, The Netherlands
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Eye Institute, Chongqing Key Laboratory of Ophthalmology, Chongqing, China
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Kumar A, Gautam S, Rawat JK, Singh M, Saraf SA, Kaithwas G. Effect of palonosetron (5HT-3 antagonist) and pantoprazole (proton pump inhibitor) against surgical esophagitis induced by forestomach and pylorus ligation in albino rats. Hum Exp Toxicol 2015; 35:41-50. [DOI: 10.1177/0960327115575759] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This study was embarked upon to evaluate the effects of pantoprazole and palonosetron on experimental esophagitis in albino wistar rats. Groups of rats, fasted for 36 h, were subjected to pylorus and forestomach ligation, supervened by treatment with normal saline (3 ml/kg, po, sham control), esophagitis control (3 ml/kg, po), pantoprazole (30 mg/kg, po), palonosetron (0.5 mg/kg, po), and their combination. Animals were sacrificed after 12 h and appraised for the volume of gastric juices, total acidity, free acidity, and esophagitis index. Esophageal tissues were further figured out biochemically for markers of oxidative stress and inflammatory mediators. The combination therapy comparably inhibited the esophagitis index (52.86%), gastric volume (66.04%), free acidity (43.76%), and total acidity (42.60%) in comparison with toxic control. The combination therapy also subsidized the biochemical and inflammatory markers to the purview less than toxic control. The morphological changes were scrutinized by scanning electron microscopy and were observed to demonstrate momentous protection by the amalgamation therapy. Combination therapy with pantoprazole and palonosetron flaunted sententious protection against experimental esophagitis.
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Affiliation(s)
- A Kumar
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
| | - S Gautam
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
| | - JK Rawat
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
| | - M Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
| | - SA Saraf
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
| | - G Kaithwas
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
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Bermúdez-Humarán LG, Motta JP, Aubry C, Kharrat P, Rous-Martin L, Sallenave JM, Deraison C, Vergnolle N, Langella P. Serine protease inhibitors protect better than IL-10 and TGF-β anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci. Microb Cell Fact 2015; 14:26. [PMID: 25889561 PMCID: PMC4371826 DOI: 10.1186/s12934-015-0198-4] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 01/23/2015] [Indexed: 12/18/2022] Open
Abstract
Background Different studies have described the successful use of recombinant lactic acid bacteria (recLAB) to deliver anti-inflammatory molecules at the mucosal level to treat Inflammatory Bowel Disease (IBD). Methods In order to identify the best strategy to treat IBD using recLAB, we compared the efficacy of different recombinant strains of Lactococcus lactis (the model LAB) secreting two types of anti-inflammatory molecules: cytokines (IL-10 and TGF-β1) and serine protease inhibitors (Elafin and Secretory Leukocyte Protease Inhibitor: SLPI), using a dextran sulfate sodium (DSS)-induced mouse model of colitis. Results Our results show that oral administration of recombinant L. lactis strains expressing either IL-10 or TGF-β1 display moderate anti-inflammatory effects in inflamed mice and only for some clinical parameters. In contrast, delivery of either serine protease inhibitors Elafin or SLPI by recLAB led to a significant reduction of intestinal inflammation for all clinical parameters tested. Since the best results were obtained with Elafin-producing L. lactis strain, we then tried to enhance Elafin expression and hence its delivery rate by producing it in a L. lactis mutant strain inactivated in its major housekeeping protease, HtrA. Strikingly, a higher reduction of intestinal inflammation in DSS-treated mice was observed with the Elafin-overproducing htrA strain suggesting a dose-dependent Elafin effect. Conclusions Altogether, these results strongly suggest that serine protease inhibitors are the most efficient anti-inflammatory molecules to be delivered by recLAB at the mucosal level for IBD treatment.
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Affiliation(s)
- Luis G Bermúdez-Humarán
- INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. .,AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France.
| | - Jean-Paul Motta
- Inserm, U1043, Toulouse, F-31300, France. .,CNRS, U5282, Toulouse, F-31300, France. .,Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France. .,Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
| | - Camille Aubry
- INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. .,AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France.
| | - Pascale Kharrat
- INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. .,AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France.
| | - Laurence Rous-Martin
- Inserm, U1043, Toulouse, F-31300, France. .,CNRS, U5282, Toulouse, F-31300, France. .,Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
| | - Jean-Michel Sallenave
- INSERM U874, Institut Pasteur, 25 rue du Dr Roux, 75015, Paris, France. .,INSERM U1152, Faculté de Médecine site Bichat, Université Paris Diderot, 16, rue Henri Huchard, 75018, Paris, France. .,Université Sorbonne Paris Cité, Université Paris Diderot, rue du Dr Roux, 75015, Paris, France.
| | - Céline Deraison
- Inserm, U1043, Toulouse, F-31300, France. .,CNRS, U5282, Toulouse, F-31300, France. .,Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
| | - Nathalie Vergnolle
- Inserm, U1043, Toulouse, F-31300, France. .,CNRS, U5282, Toulouse, F-31300, France. .,Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France. .,Université Sorbonne Paris Cité, Université Paris Diderot, rue du Dr Roux, 75015, Paris, France.
| | - Philippe Langella
- INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. .,AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France.
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Mu J, Zhuang X, Wang Q, Jiang H, Deng ZB, Wang B, Zhang L, Kakar S, Jun Y, Miller D, Zhang HG. Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol Nutr Food Res 2014; 58:1561-73. [PMID: 24842810 PMCID: PMC4851829 DOI: 10.1002/mnfr.201300729] [Citation(s) in RCA: 444] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 03/31/2014] [Accepted: 03/31/2014] [Indexed: 12/14/2022]
Abstract
SCOPE Exosomes, small vesicles participating in intercellular communication, have been extensively studied recently; however, the role of edible plant derived exosomes in interspecies communication has not been investigated. Here, we investigate the biological effects of edible plant derived exosome-like nanoparticles (EPDENs) on mammalian cells. METHODS AND RESULTS In this study, exosome-like nanoparticles from four edible plants were isolated and characterized. We show that these EPDENs contain proteins, lipids, and microRNA. EPDENs are taken up by intestinal macrophages and stem cells. The results generated from EPDEN-transfected macrophages indicate that ginger EPDENs preferentially induce the expression of the antioxidation gene, heme oxygenase-1 and the anti-inflammatory cytokine, IL-10; whereas grapefruit, ginger, and carrot EPDENs promote activation of nuclear factor like (erythroid-derived 2). Furthermore, analysis of the intestines of canonical Wnt-reporter mice, i.e. B6.Cg-Tg(BAT-lacZ)3Picc/J mice, revealed that the numbers of β-galactosidase(+) (β-Gal) intestinal crypts are increased, suggesting that EPDEN treatment of mice leads to Wnt-mediated activation of the TCF4 transcription machinery in the crypts. CONCLUSION The data suggest a role for EPDEN-mediated interspecies communication by inducing expression of genes for anti-inflammation cytokines, antioxidation, and activation of Wnt signaling, which are crucial for maintaining intestinal homeostasis.
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Affiliation(s)
- Jingyao Mu
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Xiaoying Zhuang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Qilong Wang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Hong Jiang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Zhong-Bin Deng
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Baomei Wang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Lifeng Zhang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Sham Kakar
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Yan Jun
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Donald Miller
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Huang-Ge Zhang
- Louisville Veterans Administration Medical Center, Louisville, KY 40206
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
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Matsumoto H, Haga K, Ohno I, Hiraoka K, Kimura T, Hermann K, Kasahara N, Anton P, McGowan I. Mucosal gene therapy using a pseudotyped lentivirus vector encoding murine interleukin-10 (mIL-10) suppresses the development and relapse of experimental murine colitis. BMC Gastroenterol 2014; 14:68. [PMID: 24712338 PMCID: PMC3991919 DOI: 10.1186/1471-230x-14-68] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Accepted: 04/02/2014] [Indexed: 12/23/2022] Open
Abstract
Background Therapeutic gene transfer is currently being evaluated as a potential therapy for inflammatory bowel disease. This study investigates the safety and therapeutic benefit of a locally administered lentiviral vector encoding murine interleukin-10 in altering the onset and relapse of dextran sodium sulfate induced murine colitis. Methods Lentiviral vectors encoding the reporter genes firefly-luciferase and murine interleukin-10 were administered by intrarectal instillation, either once or twice following an ethanol enema to facilitate mucosal uptake, on Days 3 and 20 in Balb/c mice with acute and relapsing colitis induced with dextran sulfate sodium (DSS). DSS colitis was characterized using clinical disease activity, macroscopic, and microscopic scores. Bioluminescence optical imaging analysis was employed to examine mucosal lentiviral vector uptake and transgene expression. Levels of tumor necrosis factor-α and interleukin-6 in homogenates of rectal tissue were measured by ELISA. Biodistribution of the lentiviral vector to other organs was evaluated by real time quantitative PCR. Results Mucosal delivery of lentiviral vector resulted in significant transduction of colorectal mucosa, as shown by bioluminescence imaging analysis. Lentiviral vector-mediated local expression of interleukin-10 resulted in significantly increased levels of this cytokine, as well as reduced levels of tumor necrosis factor-α and interleukin-6, and significantly reduced the clinical disease activity, macroscopic, and microscopic scores of DSS colitis. Systemic biodistribution of locally instilled lentiviral vector to other organs was not detected. Conclusions Topically-delivered lentiviral vectors encoding interleukin-10 safely penetrated local mucosal tissue and had therapeutic benefit in this DSS model of murine colitis.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Ian McGowan
- Magee-Womens Research Institute, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Lv H, Jiang Y, Li J, Zhang M, Shang Z, Zheng J, Wu X, Liu P, Zhang R, Yu H. Association between polymorphisms in the promoter region of interleukin-10 and susceptibility to inflammatory bowel disease. Mol Biol Rep 2014; 41:1299-310. [PMID: 24407599 DOI: 10.1007/s11033-013-2975-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 12/24/2013] [Indexed: 12/19/2022]
Abstract
The aim of this study was to assess the association of polymorphisms in the promoter region of the IL-10 gene with the risk of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Fifteen studies (3,693 cases and 4,574 controls) were included in a meta-analysis of association between IL-10 -1082G/A, -819C/T and -592C/A polymorphisms, and IBD, CD and UC using allele contrast and the recessive, dominant, and additive models. Hardy-Weinberg equilibrium was confirmed for each study. Heterogeneity and study quality were investigated using stratification analyses and sensitivity analyses. Polymorphism -1082G/A showed significant association with CD, with odds ratios (ORs) for the GG + GA genotype and GG versus AA genotype of 1.278 (1.004-1.627) and 1.238 (1.027-1.492) in all subjects. Significant associations were found in the Caucasian subgroup using the allele contrast, dominant, and additive models. C-allele carriers of the -819C/T polymorphism were at increased risk of IBD (OR 1.093, 95% CI 1.004-1.190). Association with the -819C/T polymorphism was also found in Caucasians with CD (C vs. T: OR 1.104, 95% CI 1.010-1.206; CC + CT vs. TT: OR 1.328, 95% CI 1.006-1.754; CC vs. TT: OR 1.339, 95% CI 1.008-1.778), and with UC (CC vs. CT + TT: OR 1.188, 95% CI 1.019-1.385). No significant association was found between the -592C/A polymorphism and IBD, CD or UC. In conclusion, the meta-analysis demonstrated clear association between the IL-10 polymorphisms -1082G/A and -819C/T and the risk of IBD.
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Affiliation(s)
- Hongchao Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, People's Republic of China
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Xiong J, Lin YH, Bi LH, Wang JD, Bai Y, Liu SD. Effects of interleukin-4 or interleukin-10 gene therapy on trinitrobenzenesulfonic acid-induced murine colitis. BMC Gastroenterol 2013; 13:165. [PMID: 24314293 PMCID: PMC3897998 DOI: 10.1186/1471-230x-13-165] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 11/14/2013] [Indexed: 02/08/2023] Open
Abstract
Background Inflammatory bowel disease (IBD) is characterized by disturbance of pro-inflammatory cytokines and anti-inflammatory cytokines. Previous studies have demonstrated the effect of anti-inflammatory cytokines, such as interleukin-10 (IL-10) or IL-4 on IBD, but their data were controversial. This study further investigated the effect of IL-4 (IL-4), IL-10 and their combination on treatment of trinitrobenzenesulfonic acid (TNBS)-induced murine colitis. Methods pcDNA3.0 carrying murine IL-4 or IL-10 cDNA was encapsulated with LipofectAMINE 2000 and intraperitoneally injected into mice with TNBS-induced colitis. The levels of intestinal IL-4 and IL-10 mRNA were confirmed by quantitative-RT-PCR. Inflamed tissues were assessed by histology and expression of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-6. Results The data confirmed that IL-4 or IL-10 over-expression was successfully induced in murine colon tissues after intraperitoneal injection. Injections of IL-4 or IL-10 significantly inhibited TNBS-induced colon tissue damage, disease activity index (DAI) and body weight loss compared to the control mice. Furthermore, expression of IFN-γ, TNF-α and IL-6 was markedly blocked by injections of IL-4 or IL-10 plasmid. However, there was less therapeutic effect in mice injected with the combination of IL-4 and IL-10. Conclusions These data suggest that intraperitoneal injection of IL-4 or IL-10 plasmid was a potential strategy in control of TNBS-induced murine colitis, but their combination had less effect.
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Affiliation(s)
| | | | | | | | - Yang Bai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Tuna H, Avdiushko RG, Sindhava VJ, Wedlund L, Kaetzel CS, Kaplan AM, Bondada S, Cohen DA. Regulation of the mucosal phenotype in dendritic cells by PPARγ: role of tissue microenvironment. J Leukoc Biol 2013; 95:471-85. [PMID: 24295831 DOI: 10.1189/jlb.0713408] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Mucosal DCs play a critical role in tissue homeostasis. Several stimuli can induce a mucosal phenotype; however, molecular pathways that regulate development of mucosal DC function are relatively unknown. This study sought to determine whether PPARγ contributes to the development of the "mucosal" phenotype in mouse DCs. Experiments demonstrated that PPARγ activation in BMDCs induced an immunosuppressive phenotype in which BMDCs had reduced expression of MHC class II and costimulatory molecules, increased IL-10 secretion, and reduced the ability to induce CD4 T cell proliferation. Activation of PPARγ enhanced the ability of BMDC to polarize CD4 T cells toward iTregs and to induce T cell expression of the mucosal homing receptor, CCR9. Activation of PPARγ increased the ability of BMDCs to induce T cell-independent IgA production in B cells. BMDCs from PPARγ(ΔDC) mice displayed enhanced expression of costimulatory molecules, enhanced proinflammatory cytokine production, and decreased IL-10 synthesis. Contrary to the inflammatory BMDC phenotype in vitro, PPARγ(ΔDC) mice showed no change in the frequency or phenotype of mDC in the colon. In contrast, mDCs in the lungs were increased significantly in PPARγ(ΔDC) mice. A modest increase in colitis severity was observed in DSS-treated PPARγ(ΔDC) mice compared with control. These results indicate that PPARγ activation induces a mucosal phenotype in mDCs and that loss of PPARγ promotes an inflammatory phenotype. However, the intestinal microenvironment in vivo can maintain the mucosal DC phenotype of via PPARγ-independent mechanisms.
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Affiliation(s)
- Halide Tuna
- 1.Immunology and Molecular Genetics, University of Kentucky, 800 Rose St., Room MS419, Lexington, KY 40536-0298, USA.
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Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochem Pharmacol 2013; 85:1306-16. [PMID: 23415610 DOI: 10.1016/j.bcp.2013.01.017] [Citation(s) in RCA: 202] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Revised: 01/22/2013] [Accepted: 01/22/2013] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) is an incurable disease which affects millions of people in industrialized countries. Anecdotal and scientific evidence suggests that Cannabis use may have a positive impact in IBD patients. Here, we investigated the effect of cannabigerol (CBG), a non-psychotropic Cannabis-derived cannabinoid, in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulphonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters (colon weight/colon length ratio and myeloperoxidase activity), by histological analysis and immunohistochemistry; interleukin-1β, interleukin-10 and interferon-γ levels by ELISA, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by western blot and RT-PCR; CuZn-superoxide dismutase (SOD) activity by a colorimetric assay. Murine macrophages and intestinal epithelial cells were used to evaluate the effect of CBG on nitric oxide production and oxidative stress, respectively. CBG reduced colon weight/colon length ratio, myeloperoxidase activity, and iNOS expression, increased SOD activity and normalized interleukin-1β, interleukin-10 and interferon-γ changes associated to DNBS administration. In macrophages, CBG reduced nitric oxide production and iNOS protein (but not mRNA) expression. Rimonabant (a CB1 receptor antagonist) did not change the effect of CBG on nitric oxide production, while SR144528 (a CB2 receptor antagonist) further increased the inhibitory effect of CBG on nitric oxide production. In conclusion, CBG attenuated murine colitis, reduced nitric oxide production in macrophages (effect being modulated by the CB2 receptor) and reduced ROS formation in intestinal epithelial cells. CBG could be considered for clinical experimentation in IBD patients.
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Shah N, Kammermeier J, Elawad M, Glocker EO. Interleukin-10 and interleukin-10-receptor defects in inflammatory bowel disease. Curr Allergy Asthma Rep 2012; 12:373-9. [PMID: 22890722 DOI: 10.1007/s11882-012-0286-z] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by abdominal pain, bloody diarrhoea, and malabsorption leading to weight loss. It is considered the result of inadequate control of an excessive reaction of the immune system to the resident flora of the gut. Like other primary immunodeficiencies, IL-10 and IL-10 receptor (IL10R) deficiency present with IBD and demonstrate the sensitivity of the intestine to any changes of the immune system. Both IL-10 and IL10R deficiency cause severe early-onset enterocolitis and can be successfully treated by hematopoietic stem cell transplantation (HSCT).
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Affiliation(s)
- Neil Shah
- Department of Paediatric Gastroenterology, Great Ormond Street Hospital, University College London, London, UK
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Marel SVD, Majowicz A, Deventer SV, Petry H, Hommes DW, Ferreira V. Gene and cell therapy based treatment strategies for inflammatory bowel diseases. World J Gastrointest Pathophysiol 2011; 2:114-22. [PMID: 22180846 PMCID: PMC3240904 DOI: 10.4291/wjgp.v2.i6.114] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2011] [Revised: 08/12/2011] [Accepted: 08/19/2011] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders most commonly affecting young adults. Currently available therapies can result in induction and maintenance of remission, but are not curative and have sometimes important side effects. Advances in basic research in IBD have provided new therapeutic opportunities to target the inflammatory process involved. Gene and cell therapy approaches are suitable to prevent inflammation in the gastrointestinal tract and show therefore potential in the treatment of IBD. In this review, we present the current progress in the field of both gene and cell therapy and future prospects in the context of IBD. Regarding gene therapy, we focus on viral vectors and their applications in preclinical models. The focus for cell therapy is on regulatory T lymphocytes and mesenchymal stromal cells, their potential for the treatment of IBD and the progress made in both preclinical models and clinical trials.
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Abstract
IL-37, a newly described member of the IL-1 family, functions as a fundamental inhibitor of innate inflammation and immunity. In the present study, we examined a role for IL-37 during experimental colitis. A transgenic mouse strain was generated to express human IL-37 (hIL-37tg), and these mice were subjected to dextran sulfate sodium (DSS)-induced colitis. Despite the presence of a CMV promoter to drive expression of IL-37, mRNA transcripts were not present in colons at the resting state. Expression was observed only upon disruption of the epithelial barrier, with a six- to sevenfold increase (P = 0.02) on days 3 and 5 after continuous exposure to DSS. During the development of colitis, clinical disease scores were reduced by 50% (P < 0.001), and histological indices of colitis were one-third less in hIL-37tg mice compared with WT counterparts (P < 0.001). Reduced inflammation was associated with decreased leukocyte recruitment into the colonic lamina propria. In addition, release of IL-1β and TNFα from ex vivo colonic explant tissue was decreased 5- and 13-fold, respectively, compared with WT (P ≤ 0.005), whereas IL-10 was increased sixfold (P < 0.001). However, IL-10 was not required for the anti-inflammatory effects of IL-37 because IL-10-receptor antibody blockade did not reverse IL-37-mediated protection. Mechanistically, IL-37 originating from hematopoietic cells was sufficient to exert anti-inflammatory effects because WT mice reconstituted with hIL-37tg bone marrow were protected from colitis. Thus, IL-37 emerges as key modulator of intestinal inflammation.
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Xu J, Yang Y, Qiu G, Lal G, Yin N, Wu Z, Bromberg JS, Ding Y. Stat4 is critical for the balance between Th17 cells and regulatory T cells in colitis. THE JOURNAL OF IMMUNOLOGY 2011; 186:6597-606. [PMID: 21525389 DOI: 10.4049/jimmunol.1004074] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Th17 play a central role in autoimmune inflammatory responses. Th1 are also necessary for autoimmune disease development. The interplay of Th1 signals and how they coordinate with Th17 during inflammatory disease pathogenesis are incompletely understood. In this study, by adding Stat4 deficiency to Stat6/T-bet double knockout, we further dissected the role of Stat4 in Th1 development and colitis induction. We showed that in the absence of the strong Th2 mediator Stat6, neither Stat4 nor T-bet is required for IFN-γ production and Th1 development. However, addition of Stat4 deficiency abolished colitis induced by Stat6/T-bet double-knockout cells, despite Th1 and Th17 responses. The failure of colitis induction by Stat4/Stat6/T-bet triple-knockout cells is largely due to elevated Foxp3(+) regulatory T cell (Treg) development. These results highlight the critical role of Stat4 Th1 signals in autoimmune responses in suppressing Foxp3(+) Treg responses and altering the balance between Th17 and Tregs to favor autoimmune disease.
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Affiliation(s)
- Jiangnan Xu
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Dual TNF-α/Cyclin D1 Gene Silencing With an Oral Polymeric Microparticle System as a Novel Strategy for the Treatment of Inflammatory Bowel Disease. Clin Transl Gastroenterol 2011; 2:e2. [PMID: 23237848 PMCID: PMC3365667 DOI: 10.1038/ctg.2011.1] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVES: RNA silencing utilizing short interfering RNA (siRNA) offers a new and exciting means to overcome the limitations of current treatment options of many diseases. However, delivery of these molecules still poses a great challenge to date. METHODS: In the present study, a multicompartmental biodegradable polymer-based nanoparticles-in-microsphere oral system (NiMOS) using gelatin nanoparticles encapsulating a combination of siRNA duplexes specifically targeted against tumor necrosis factor-α (TNF-α) and cyclin D1 (Ccnd1) was employed to study its effects on a dextran sulfate sodium (DSS)-induced acute colitis mouse model mimicking inflammatory bowel disease (IBD). DSS colitis-bearing animals were divided into several control and treatment groups and received either no treatment, blank NiMOS, NiMOS-encapsulating inactive (scrambled), active TNF-α silencing, CyD1 silencing siRNA, or a combination of both active siRNAs by repeated oral administration of three NiMOS doses. RESULTS: Successful gene silencing with the aid of dual siRNA treatment led to decreased colonic levels of TNF-α or CyD1, suppressed expression of certain pro-inflammatory cytokines (interleukin-1α and -β, interferon-γ), an increase in body weight, and reduced tissue myeloperoxidase activity, while the silencing effect of CyD1 siRNA or the dual treatment was more potent than that of TNF-α siRNA alone. CONCLUSION: Results of this study demonstrate the therapeutic potential of a NiMOS-based oral combined TNF-α and CyD1 gene silencing system for the treatment of IBD as shown in an acute colitis model.
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Strisciuglio C, van Deventer S. Regulatory T cells as potential targets for immunotherapy in inflammatory bowel disease. Immunotherapy 2011; 2:749-52. [PMID: 21091105 DOI: 10.2217/imt.10.63] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Kriegel C, Amiji M. Oral TNF-α gene silencing using a polymeric microsphere-based delivery system for the treatment of inflammatory bowel disease. J Control Release 2011; 150:77-86. [PMID: 20959130 PMCID: PMC3033993 DOI: 10.1016/j.jconrel.2010.10.002] [Citation(s) in RCA: 130] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2010] [Revised: 08/31/2010] [Accepted: 10/04/2010] [Indexed: 02/08/2023]
Abstract
The purpose of this study was to evaluate down-regulation of tumor necrosis factor (TNF)-α by oral RNA interference therapy. Control (scrambled sequence) or TNF-α specific small interfering RNA (siRNA) was encapsulated in type B gelatin nanoparticles and further entrapped in poly(epsilon-caprolactone) (PCL) microspheres to form a nanoparticles-in-microsphere oral system (NiMOS). Upon confirmation of the dextran sulfate sodium (DSS)-induced acute colitis model, mice were divided into several treatment groups receiving no treatment, blank NiMOS, NiMOS with scramble siRNA, or NiMOS with TNF-α silencing siRNA by oral administration. Successful gene silencing led to decreased colonic levels of TNF-α, suppressed expression of other pro-inflammatory cytokines (e.g., interleukin (IL)-1β, interferon (IFN)-γ) and chemokines (MCP-1), an increase in body weight, and reduced tissue myeloperoxidase activity. Results of this study established the clinical potential of a NiMOS-based oral TNF-α gene silencing system for the treatment of inflammatory bowel disease as demonstrated in an acute colitis model.
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Affiliation(s)
- Christina Kriegel
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 110 Mugar Life Sciences Building, Boston MA 02115 (Tel. 617-373-3137)
| | - Mansoor Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 110 Mugar Life Sciences Building, Boston MA 02115 (Tel. 617-373-3137)
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Kim KO, Jang BI. Emerging Drugs in the Treatment of Inflammatory Bowel Disease: Beyond Anti-TNF-α. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2011; 58:235-44. [DOI: 10.4166/kjg.2011.58.5.235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Byung Ik Jang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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Kosaka S, Tamauchi H, Terashima M, Maruyama H, Habu S, Kitasato H. IL-10 controls Th2-type cytokine production and eosinophil infiltration in a mouse model of allergic airway inflammation. Immunobiology 2010; 216:811-20. [PMID: 21257225 DOI: 10.1016/j.imbio.2010.12.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Revised: 12/11/2010] [Accepted: 12/14/2010] [Indexed: 12/31/2022]
Abstract
Interleukin-10 was originally described as a factor that inhibits cytokine production by murine Th1 clones. Recent studies have since shown that IL-10 can also downregulate Th2 clones and their production of IL-4 and IL-5. Because of its immuno-suppressive properties, IL-10 has been suggested as a potential therapy for allergic inflammation and asthma. However, the pathophysiological role of IL-10 in vivo has not been clearly elucidated. We investigated the effects of IL-10 administration on the production of IgE, cytokine and allergen-induced Th2 cytokine production as well as its effects on eosinophilic inflammation. We established GATA-3/TCR double transgenic (GATA-3/TCR-Tg) mice by crossing GATA-3 transgenic mice with ovalbumin (OVA)-specific TCR transgenic mice; these mice were then sensitized using an intraperitoneal injection of OVA adsorbed to alum and challenged with the intratracheal instillation of an allergen. When GATA-3/TCR-Tg mice sensitized with OVA and alum were injected with C57-IL-10 cells before OVA inhalation, the levels of IL-5, IL-13, and IL-4 decreased by 40-85% and number of eosinophils decreased by 70% (P<0.03) in the murine bronchoalveolar lavage fluid (BALF). These results suggest that IL-10 plays an important role downstream of the inflammatory cascade in the Th2 response to antigens and in the development of BALF eosinophilia and cytokine production in a murine model of asthma. These immunosuppressive properties in animal models indicate that IL-10 could be a potential clinical therapy for the treatment of allergic inflammation.
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Affiliation(s)
- Shinichiro Kosaka
- Department of Microbiology, Kitasato University Allied Health Science, Sagamihara, Kanagawa, Japan
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Dahan A, Amidon GL, Zimmermann EM. Drug targeting strategies for the treatment of inflammatory bowel disease: a mechanistic update. Expert Rev Clin Immunol 2010; 6:543-50. [PMID: 20594127 DOI: 10.1586/eci.10.30] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The therapeutic management of inflammatory bowel disease (IBD) represents the perfect scenario for drug targeting to the site(s) of action. While existing formulation-based targeting strategies include rectal dosage forms and oral systems that target the colon by pH-, time-, microflora- and pressure-triggered drug release, novel approaches for site-specific delivery in IBD therapy will target the inflamed intestine per se rather than intestinal region. The purpose of this article is to present a mechanistic update on the strategies employed to achieve minimal systemic exposure accompanied by maximal drug levels in the inflamed intestinal tissue. The introduction of biological agents, micro/nanoparticulate carriers including liposomes, transgenic bacteria, and gene therapy opportunities are discussed, as well as the challenges remaining to be achieved in the targeted treatment of IBD.
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Affiliation(s)
- Arik Dahan
- Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
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Khokhlova EV, Efimov BA, Kafarskaia LI, Shkoporov AN. Heterologous expression of secreted biologically active human interleukin-10 in Bifidobacterium breve. Arch Microbiol 2010; 192:769-74. [PMID: 20631991 DOI: 10.1007/s00203-010-0606-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Revised: 07/03/2010] [Accepted: 07/05/2010] [Indexed: 10/19/2022]
Abstract
Construction of Bifidobacterium breve capable of production of secreted biologically active human interleukin-10 (hIL-10) is described. ORF coding for full-length mature human interleukin-10 was cloned into a series of expression vectors. This resulted in generation of translational fusions between hIL-10 and signal peptides sequences derived from Bifidobacterium breve genes sec2, apuB and B. adolescentis gene amyB under the control of constitutively active bifidobacterial promoter. We have shown that fusion to amyB signal peptide resulted in highest expression level of hIL-10 at the mRNA and protein level. Secreted hIL-10 was highly unstable in bifidobacterial culture supernatants in standard growth conditions. However, incubation of stationary cultures in buffered tissue culture medium resulted in production of stable biologically active hIL-10, albeit in low amounts (1.9 ng/ml).
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Affiliation(s)
- E V Khokhlova
- Department of Microbiology and Virology, Russian State Medical University, Moscow, Russian Federation
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New pathophysiological insights and modern treatment of IBD. J Gastroenterol 2010; 45:571-83. [PMID: 20213337 DOI: 10.1007/s00535-010-0219-3] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Accepted: 02/03/2010] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), which comprises two main types, namely, Crohn's disease and ulcerative colitis, affects approximately 3.6 million people in the USA and Europe, and an alarming rise in low-incidence areas, such as Asia, is currently being observed. In the last decade, spontaneous mutations in a diversity of genes have been identified, and these have helped to elucidate pathways that can lead to IBD. Animal studies have also increased our knowledge of the pathological dialogue between the intestinal microbiota and components of the innate and adaptive immune systems misdirecting the immune system to attack the colon. Present-day medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use may result in severe side effects and complications, such as an increased rate of malignancies or infectious diseases. In clinical practice, there is still a high frequency of incomplete or absent response to medical therapy, indicating a compelling need for new therapeutic strategies. This review summarizes current epidemiology, pathogenesis and diagnostic strategies in IBD. It also provides insight in today's differentiated clinical therapy and describes mechanisms of promising future medicinal approaches.
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Serum concentration of interleukin 10, anti-mannan Candida antibodies and the fungal colonization of the gastrointestinal tract in patients with ulcerative colitis. Adv Med Sci 2010; 54:170-6. [PMID: 19758974 DOI: 10.2478/v10039-009-0023-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE There is evidence for the immunomodulation disorders in the response to intestinal flora in inflammatory bowel disease, however, the role of yeasts in the aetiopathogenesis of ulcerative colitis has not been fully clarified. The aim of this study was to assess the serum concentration of interleukin 10 (IL-10), serum levels of anti-mannan Candida antibodies and fungal colonization of the lower part of the gastrointestinal tract in accordance with the clinical course of ulcerative colitis. MATERIAL/METHODS In 42 consecutive patients with ulcerative colitis serum concentration of IL-10 and anti-mannan Candida antibodies serum levels were measured with ELISA and the quantitative and qualitative fungal cultures of stool samples were performed. RESULTS In 20 patients IL-10 serum concentration was below the test sensitivity and in 11 patients it ranged between 0.78 and 9.43 (mean 3.38 +/- 2.8) pg/mL. Anti-mannan Candida antibodies were detected in 8 subjects (19.04%). Stool cultures revealed significant fungal colonization in 3 (8.33%) patients with the predominance of Candida albicans. In comparison with mild/moderate UC, IL-10 serum concentration was not higher in patients with severe course of the disease. CONCLUSIONS The results of our study show that IL-10 serum concentration correlates neither with the disease activity nor with the levels of anti-mannan Candida antibodies and the fungal colonization of the gastrointestinal tract in ulcerative colitis. It seems that IL-10 serum concentration cannot be a universal marker for the assessment of ulcerative colitis activity. Moreover, anti-mannan Candida antibodies and significant fungal colonization are present in the minority of patients with ulcerative colitis suggesting that yeasts have minor, if any, influence on the clinical course of the disease.
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Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. J Mol Med (Berl) 2009; 87:1111-21. [PMID: 19690824 DOI: 10.1007/s00109-009-0512-x] [Citation(s) in RCA: 155] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Revised: 07/20/2009] [Accepted: 07/22/2009] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel disease affects millions of individuals; nevertheless, pharmacological treatment is disappointingly unsatisfactory. Cannabidiol, a safe and non-psychotropic ingredient of marijuana, exerts pharmacological effects (e.g., antioxidant) and mechanisms (e.g., inhibition of endocannabinoids enzymatic degradation) potentially beneficial for the inflamed gut. Thus, we investigated the effect of cannabidiol in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulfonic acid. Inflammation was assessed both macroscopically and histologically. In the inflamed colon, cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) were evaluated by Western blot, interleukin-1beta and interleukin-10 by ELISA, and endocannabinoids by isotope dilution liquid chromatography-mass spectrometry. Human colon adenocarcinoma (Caco-2) cells were used to evaluate the effect of cannabidiol on oxidative stress. Cannabidiol reduced colon injury, inducible iNOS (but not cyclooxygenase-2) expression, and interleukin-1beta, interleukin-10, and endocannabinoid changes associated with 2,4,6-dinitrobenzene sulfonic acid administration. In Caco-2 cells, cannabidiol reduced reactive oxygen species production and lipid peroxidation. In conclusion, cannabidiol, a likely safe compound, prevents experimental colitis in mice.
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